Improved Monitoring and Prediction of Clinical Response and Disease Course During Golimumab Therapy of Patients With Axial Spondyloarthritis
Conditions: Axial Spondyloarthritis
Sponsor: Professor Mikkel Østergaard

Protocol version 4.1, 3 November 2016 
1
Protocol: 
 
Improved monitoring and prediction of clinical response and disease 
course during Golimumab therapy of patients with axial spondyloarthritis: 
The clinical utility of whole-body MRI, diffusion-weighted MRI, 
conventional MRI of sacroiliac joints and spine, and high-sensitive CRP 
and other soluble biomarkers of joint inflammation and damage. 
Short English title: Novel MRI ANd biomarkers in GOlimumab-treated patients with axial 
spondyloarthritis (MANGO). 
Danish titel: Videnskabeligt studie af nye MR- og biokemiske metoder til af følge og forudsige 
klinisk respons og sygdomsforløb hos patienter med rygsøjlegigt der påbegynder behandling 
med Golimumab  
Name of protocol: MANGO 
J. no. Scientific Committee: H1-2013-118 
J.no. Danish Heath and Medicines Agency: Not considered a “Lægemiddelforsøg” (see section 30) 
Region Hovedstaden: GLO-2013-33, GLO-2013-34 
ClinicalTrials.gov no.: NCT02011386 
Protocol version 4.1: 3 November 2016 
An investigator initiated study 
Study coordinator  
MD PhD Susanne Juhl Pedersen 
 
Videncenter for Reumatologi og Rygsygdomme VRR, Glostrup Hospital 
 
Phone +4541431326 or +4538633014, fax: +4538634192, e-mail sjp@dadlnet.dk  
Sponsor: 
Professor PhD M.Sc. Mikkel Østergaard 
 
Videncenter for Reumatologi og Rygsygdomme VRR, Glostrup Hospital 
 
Phone +4538633014 or +4521603865, fax +4538634192, e-mail: mo@dadlnet.dk 
Steering-group member:  Consultant PhD Inge Juul Sørensen 
Videncenter for Reumatologi og Rygsygdomme VRR, Glostrup Hospital  
Phone +4538633014, fax: +4538634192, e-mail ijs@dadlnet.dk 
Mailing address for all: Glostrup Hospital, Ndr. Ringvej 57, 2600 Glostrup 
The study coordinator is authorized to sign the protocol and protocol amendments on behalf of the sponsor. 
The responsible investigators from the other participating Departments of Rheumatology  
Consultant, Msc, PhD Ole Rintek Madsen, Gentofte Hospital, Niels Andersens Vej 65, 2900 Hellerup, 
phone +4539773977, e-mail Ole.Rintek.Madsen@regionh.dk 
Consultant PhD Bente Jensen, Frederiksberg Hospital, Ndr. Fasanvej 57, 2000 Frederiksberg, phone 
+4538163816, e-mail Bente.Jensen.06@regionh.dk 
Consultant, PhD, Michael Stoltenberg, Køge Sygehus, Lykkebækvej 1, 4600 Køge, phone: +4556631500, 
e-mail: mbst@regionsjaelland.dk  
Consultant, PhD, Jesper Nørregaard, Nordsjællands Hospital Hillerød, Dyrehavevej 29, 3400 Hillerød, 
phone +4548294829, e-mail: Jesper.Noerregaard.02@regionh.dk 
 
From the participating Department of Radiology 
Senior radiographer, Jakob Møller and consultant Lone Balding, Herlev Hospital, Herlev Ringvej 75, 
2730 Herlev, phone +4544884488, e-mail: Jakob.Moeller@regionh.dk and lone.balding@regionh.dk 
 
Other participants in the study 
Research laboratory technician Teresa Rozenfeld, Bindevævslaboratoriet, Videncenter for Reumatologi og 
Rygsygdomme VRR, Glostrup Hospital, Ndr. Ringvej 57, 2600 Glostrup, phone +4538632856 or 
+4520830731, fax +4538634192, e-mail teresa.rozenfeld.01@regionh.dk 

Protocol version 4.1, 3 November 2016 
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1 
CONTENT 
1 
Content ......................................................................................................................................... 2 
2 
Approval of clinical study protocol ............................................................................................. 5 
3 
Time line ...................................................................................................................................... 5 
4 
Abbreviations ............................................................................................................................... 6 
5 
Aim............................................................................................................................................... 7 
5.1 
Overall aim ........................................................................................................................... 7 
6 
Hypothesis .................................................................................................................................... 8 
6.1 
Hypotheses in relation to co-primary specific objectives .................................................... 8 
6.2 
Hypotheses in relation to secondary specific objectives ...................................................... 8 
6.3 
Hypotheses in relation to tertiary specific objectives .......................................................... 8 
7 
Background .................................................................................................................................. 8 
7.2 
New MRI methods ............................................................................................................... 9 
7.3 
Novel biomarkers ............................................................................................................... 10 
7.4 
ASAS Health Index ............................................................................................................ 11 
7.5 
The investigational medicinal product ............................................................................... 11 
8 
Literature search ......................................................................................................................... 11 
9 
Study plan .................................................................................................................................. 11 
9.1 
Endpoints for the MRI and biomarker study ..................................................................... 11 
9.2 
Endpoints for the ASAS HI sub-study ............................................................................... 12 
9.3 
Study design ....................................................................................................................... 13 
9.4 
Study periods...................................................................................................................... 13 
9.5 
Methods to reduce/eliminate bias ...................................................................................... 13 
9.6 
Study treatment .................................................................................................................. 13 
9.7 
Package .............................................................................................................................. 14 
9.8 
Label................................................................................................................................... 14 
9.9 
Patient Card ........................................................................................................................ 14 
9.10 
Storage of IMP ................................................................................................................... 14 
9.11 
Drug and label accountability ............................................................................................ 15 
9.12 
Safety procedures in relation to IMP ................................................................................. 15 
9.13 
Randomization code and procedures for breaking the code .............................................. 16 
9.14 
Source data ......................................................................................................................... 16 
9.15 
Source data in this study .................................................................................................... 16 
10 Study participants ....................................................................................................................... 16 
11 Recruitement of patients ............................................................................................................ 16 
12 Inclusion and exclusion criteria ................................................................................................. 17 
12.1 
Inclusion criteria ................................................................................................................ 17 
12.2 
Exclusion criteria ............................................................................................................... 17 
12.3 
Withdrawal criteria for an individual patient ..................................................................... 18 
12.4 
Reasons for stopping the trial............................................................................................. 19 
12.5 
Treatment ........................................................................................................................... 19 
12.6 
Treatment response ............................................................................................................ 19 
12.7 
Concomitant treatment ....................................................................................................... 19 
12.8 
Treatment after end of the study ........................................................................................ 20 
12.9 
Surveillance of compliance to treatment ............................................................................ 20 
13 Assessment of efficacy............................................................................................................... 20 
13.1 
Specification and justification of efficacy parameters ....................................................... 20 
13.2 
Methods and time points for assessment and recording of efficacy parameters ................ 20 
14 Assessment of safety .................................................................................................................. 20 
14.1 
Specification and justification of safety parameters .......................................................... 20 

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14.2 
Methods and time points for assessment, registration and analyses of safety parameters . 22 
14.3 
Procedures to avoid and treat complications ...................................................................... 22 
14.4 
Follow-up time in relation to complications ...................................................................... 22 
14.5 
Adverse events (AE) and adverse reactions (AR) ............................................................. 23 
14.6 
Pre-malignant conditions ................................................................................................... 23 
14.7 
Serious adverse event (SAE), serious adverse reaction (SAR) and suspected unexpected 
serious adverse reaction (SUSAR) ................................................................................................. 23 
14.8 
Time frames for reporting SUSARs and Suspected Unexpected Adverse Reaction ......... 24 
14.9 
How to report SUSARs and Suspected Unaxpected Adverse Reactions........................... 24 
14.10 
Additional information on malignancy to MSD ............................................................ 25 
14.11 
Annual report on SAE, SUSARs and Suspected Unexpected Adverse Reactions ........ 25 
14.12 
Practical procedures for reporting of AEs, ARs, SAEs, SARs, SUSARs ...................... 25 
15 Variables included in the study .................................................................................................. 26 
15.1 
Screening ............................................................................................................................ 26 
15.2 
Inclusion ............................................................................................................................. 27 
15.3 
Screening and inclusion (when performed together) ......................................................... 28 
15.4 
Specific for week 4 ............................................................................................................ 29 
15.5 
Specific for week 16 .......................................................................................................... 29 
15.6 
Specific for week 52 and exclusion visit ........................................................................... 30 
15.7 
All other study visits .......................................................................................................... 30 
15.8 
Patient questionnaires used in the study ............................................................................ 30 
15.9 
Physical examinations ........................................................................................................ 32 
15.10 
Imaging .......................................................................................................................... 33 
15.11 
Biochemical analyses ..................................................................................................... 34 
15.12 
Oprettelse af forskningsbiobank (section in Danish) ..................................................... 35 
16 Statistics ..................................................................................................................................... 35 
16.2 
Sample size calculation ...................................................................................................... 37 
16.3 
Criteria for ending the trial ................................................................................................. 37 
16.4 
Procedures for missing data and data not used etc. ............................................................ 37 
16.5 
Access to source data and other documents ....................................................................... 37 
16.6 
Handling, processing and storage of data .......................................................................... 38 
17 Etiske forhold (section in Danish) ............................................................................................. 38 
17.1 
Generelle etiske forhold ..................................................................................................... 38 
17.2 
Etiske forhold vedr. denne undersøgelse ........................................................................... 39 
18 Risici, bivirkninger og ulemper (section in Danish) .................................................................. 41 
19 Respekten for forsøgspersonerners fysiske og mentale integritet samt privatlivets fred (section 
in Danish) ........................................................................................................................................... 42 
20 Tilgængeligheden af oplysninger for forsøgspersonen (section in Danish) .............................. 42 
21 Information af patienterne (section in Danish) .......................................................................... 42 
21.1 
Særlige forhold vedr. afgivelse af deltagerinformation i indeværende studie ................... 42 
21.2 
Generelle forhold vedr. informtion til patienten før, under og efter forsøget .................... 43 
22 Økonomi (section in Danish) ..................................................................................................... 44 
23 Vederlag eller andre ydelser til forsøgspersoner (section in Danish) ........................................ 45 
24 Publikationsplan (section in Danish) ......................................................................................... 45 
25 Retningslinjer for medforfatterskab (section in Danish) ............................................................ 45 
26 Appendices ................................................................................................................................. 46 
27 Relevante klausuler i kontrakten mellem sponsor og forsøgsstedet (section in Danish) ........... 46 
28 Flowchart ................................................................................................................................... 47 
29 Appendices ................................................................................................................................. 49 
30 Lægemiddelstyrelsen vurdering af forsøget ............................................................................... 49 
31 Search strategy PUBMED ......................................................................................................... 50 
32 Copy of package leaflet .............................................................................................................. 52 

Protocol version 4.1, 3 November 2016 
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33 Copy of IMP package ................................................................................................................ 69 
34 Label on package ....................................................................................................................... 70 
35 Patient card ................................................................................................................................. 70 
36 Contraindications MRI ............................................................................................................... 71 
37 ASAS kriterierne for aksial spondylartritis ................................................................................ 72 
38 Laboratoriemanual for MANGO studiet .................................................................................... 73 
39 References .................................................................................................................................. 78 
 

Protocol version 4.1, 3 November 2016 
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2 
APPROVAL OF CLINICAL STUDY PROTOCOL 
 
Sponsor  
 
 
Date and signature of approval: 
 
 
Professor Mikkel Østergaard 
_______________________________________________ 
3 
TIME LINE 
The study is planned to start 1 December 2013 or as soon as possible thereafter, but not before it 
has been approved by the Scientific Committee and Authorities for Data Protection. The inclusion 
is planned to end July 2015. The last included patient is planned to have the last study visit 
performed July 2016. Evaluation of images, analyses of biomarkers and questionnaires including 
writing up manuscripts are expected to take up to a total of 5 years. A final report to the Ethical 
Committee and study participants will be send before July 2021. 
 

Protocol version 4.1, 3 November 2016 
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4 
ABBREVIATIONS 
ADC 
Apparent diffusion coefficient 
AE 
Adverse event 
AHI 
ASAS Health Index 
AS  
Ankylosing Spondylitis  
ASDAS 
Ankylosing Spondylitis Disease Activity Score  
ASAS 
Assessment of SpondyloArthritis International Society 
ASAS20 
Assessment of SpondyloArthritis International Society 20% response criteria  
ASAS40 
Assessment of SpondyloArthritis International Society 40% response criteria 
ASAS5/6 
Assessment of SpondyloArthritis International Society “5 out of 6” response criteria 
BASDAI  
Bath Ankylosing Spondylitis Disease Activity Index  
BASDAI20 Change in BASDAI of ≥ 20% 
BASDAI50 Change in BASDAI of ≥ 50% 
BASDAI70 Change in BASDAI of ≥ 70% 
BASFI 
Bath Ankylosing Spondylitis Functional Index 
BASMI 
Bath Ankylosing Spondylitis Metrology Index 
BMP 
Bone morphogenetic protein 
CTX-I 
C-terminal cross-linking telopeptide of type I collagen 
CTX-II 
C-terminal crosslinking telopeptide of type II collagen 
CRF 
Case report form 
CRP 
C Reactive Protein 
DeoxyPYD Deoxypyridinoline 
DANBIO 
The Danish Rheumatological Database 
DMARD 
Disease-Modifying-Anti-Rheumatic-Drug 
ELISA  
Enzyme-linked immune-sorbent assays 
FDA 
US Food and Drug Administration 
HLA-B27 
Human Leukocyte Antigen B27  
IL 
Interleukin 
IL-6 
Interleukin-6 
IL-22 
Interleukin-22 
IL-23 
Interleukin-23 
IgA 
Immunoglobulin A 
IgG 
Immunoglobulin G 
IgM 
Immunoglobulin M 
IMP 
Investigational Medicinal Product 
MMP-3 
Matrix Metalloproeinase 3 
MRI 
Magnetic Resonance Imaging 
mSASSS 
Modified Stoke Ankylosis Spondylitis Spine Score 
MTX 
Methotrexate;  
NSAID  
Non-Steroid Anti-Inflammatory Drug 
P1NP 
N-terminal propeptide of type 1 collagen 
PACS 
Picture archiving and communication system 
Sc.  
Subcutaneously 
SI-joints 
Sacroiliac joints 
SJC 
Swollen joint count 
SpA 
Spondyloarthritis 
SAE 
Severe Adverse Event 
SUSARs 
Suspected Unexpected Serious Adverse Reactions 
TJC 
Tender joint count 
TMF 
Trial master file 
TNF 
Tumor-Necrosis-Factor 
TNFα 
Tumor-Necrosis-Factor-alpha 
VAS 
Visual analogue scale  
VEGF 
Vascular Endothelial Growth Factor 

Protocol version 4.1, 3 November 2016 
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5 
AIM 
5.1 
Overall aim 
To compare the ability of the following methods to monitor and predict response to Golimumab 
therapy in patients with axial spondyloarthritis (SpA): 
 Whole-body MRI, diffusion-weighted MRI and conventional MRI of sacroiliac (SI) joints and 
spine. 
 High-sensitive CRP and conventional CRP. 
 Other soluble biomarkers of joint inflammation and damage.  
5.1.1 Co-primary specific objectives 
1. To investigate if whole-body MRI (respectively diffusion-weighted MRI) detect more patients 
with disease activity after 16 and 52 weeks of tumor-necrosis-factor-alpha (TNFα) inhibitor 
therapy than conventional MRI. 
2. To investigate if patients with minimal signs of inflammation on baseline MRI are less likely 
to achieve a clinical response and are less likely to reach clinical remission than patients with 
high baseline MRI inflammation (conventional, diffusion-weighted and whole-body MRI will 
be applied). 
3. To investigate if findings and changes in MRI and/or biomarkers early (at weeks 4 and 16) 
during TNFα inhibitor therapy will predict clinical response and clinical remission at 52 
weeks. 
4. To explore the relative predictive value of the matrix model1 and whole-body MRI, diffusion-
weighted MRI and conventional MRI (at weeks 0, 4 and 16) for clinical response and clinical 
remission at 52 weeks. 
5.1.2 Secondary objectives 
1. To investigate if circulating biomarkers of inflammation, cartilage and bone turnover detect 
more patients with disease activity after 16 and 52 weeks of TNFα inhibitor therapy than 
conventional MRI. 
2. To investigate if patients with minimal baseline signs of inflammation as assessed by 
conventional CRP, high-sensitivity CRP and other experimental biomarkers of inflammation 
are less likely to achieve a clinical response and are less likely to reach clinical remission than 
patients with high baseline CRP, inflammation on whole-body MRI, diffusion weighted MRI 
and conventional MRI. 
3. To investigate if changes in biomarkers early (at weeks 4 and 16) during TNFα inhibitor 
therapy will predict clinical response and clinical remission at 52 weeks. 
4. To explore the relative predictive value of the matrix model1 and circulting biomarkers of 
inflammation, cartilage and bone turnover (at weeks 0, 4 and 16) for clinical response and 
clinical remission at 52 weeks. 
5.1.3 Tertiary objectives 
1. To described baseline findings and changes in a novel questionnaire, the ASAS Health Index 
(AHI, in Danish ASAS Sundhedsindex), before and during TNFα inhibitor therapy. 
2. To investigate the association between AHI and inflammation and structural findings on 
conventional and novel MRI sequences at baseline and during TNFα inhibitor therapy. 
3. To investigate the association between AHI and conventional and experimental measures of 
disease activity (including CRP), function, quality of life, and association with sleep, fatigue 
and depression at baseline and during TNFα inhibitor therapy. 
4. To investigate the responsiveness of AHI as compared to the variables mentioned above (2. 
and 3.). 

Protocol version 4.1, 3 November 2016 
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6 
HYPOTHESIS 
6.1 
Hypotheses in relation to co-primary specific objectives 
1. Whole-body MRI (respectively diffusion-weighted MRI is more sensitive for detection of 
inflammation than conventional MRI in patients receiving TNFα inhibitor therapy. 
2. Minimal inflammation on baseline whole body MRI (respectively baseline diffusion-weighted 
MRI and baseline conventional MRI) reduces the chance of clinical response and of clinical 
remission after 1 year of TNFα inhibitor therapy. 
3. MRI findings and biomarkers early (4 weeks and/or 16 weeks) during TNFα inhibitor therapy 
can predict long-term (52 weeks) clinical response and clinical remission. 
4. The matrix model (at weeks 0, 4 and 16) is equally predictive of clinical response and clinical 
remission at 52 weeks as whole-body MRI, diffusion-weighted MRI and conventional MRI. 
6.2 
Hypotheses in relation to secondary specific objectives 
1. One or more selected biomarkers are more sensitive for detection of inflammation than 
conventional MRI in patients receiving TNFα inhibitor therapy. 
2. Minimal inflammation as assessed by circulating biomarkers at baseline reduces the chance of 
clinical response and of clinical remission after 1 year of TNFα inhibitor therapy. 
3. The concentration of circulating biomarkers early (4 weeks and/or 16 weeks) during TNFα 
inhibitor therapy can predict long-term (52 weeks) clinical response and clinical remission. 
4. The matrix model (at weeks 0, 4 and 16) is equally predictive of clinical response and clinical 
remission at 52 weeks as by inflammatory biomarkers as by whole-body MRI, diffusion-
weighted MRI and conventional MRI. 
6.3 
Hypotheses in relation to tertiary specific objectives 
1. AHI is associated with conventional measures of disease activity, function, quality of life, 
sleep, fatigue and depression at baseline, and changes in AHI is associated with changes in 
these variables during TNFα inhibitor therapy. 
2. AHI provides information on aspects of physical function, activity and participaton that is not 
entirely covered by the domains mentioned above. 
3. AHI is associated both with inflammatory and structural findings on conventional MRI, and 
with inflammatory findings on novel MRI at baseline, and changes in relation to changes in 
inflammation during TNFα inhibitor therapy.  
4. Although AHI is responsive, it is less responsive than conventional measures of disease 
activity including novel and conventional MRI and biochemical measures of inflammation 
during TNFα inhibitor therapy. This is based on that structural damage of the spine 
(ankylosis) will have negative impact on function, activity and participation, and therefore 
limit the responsiveness of the AHI as compared to other more direct measures of 
inflammation. 
7 
BACKGROUND 
Axial sponyloarthritis (SpA) comprises a group of interrelated rheumatic diseases including 
ankylosing spondylitis (AS). The disease is characterized by inflammation in the sacroiliac (SI) 
joints and spine. Many of the patients also have peripheral arthritis and pain at enthesial sites. Axial 
spondyloarthritis is estimated to affect 1-2% of the Danish population, and has high costs for the 
society due to high frequency of sick leave and expensive treatment in form of tumor-necrosis-
factor-alpha (TNFα) inhibitor therapy. 

Protocol version 4.1, 3 November 2016 
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7.1.1 Prediction of treatment response  
Currently, the response to TNFα inhibitor therapy in individual patients with ankylosing spondylitis 
(AS) and axial spondyloarthritis (SpA) cannot be reliably predicted. Serum concentration of C-
reactive protein (CRP) and inflammation present on magnetic resonance imaging (MRI) have in a 
few studies been associated with the clinical response to a TNFα inhibitor2-6. Furthermore, CRP and 
findings by MRI of the spine and sacroiliac (SI) joints2-6 have together with a matrix model1, so far 
been the most promising parameters for this purpose. However, a clinical response can still occur 
despite normal CRP (as measured by the conventional method) and no MRI inflammation in the 
spine (on conventional MRI)3;5.This may be caused by the fact that the current conventional 
methods are not sufficiently sensitive (CRP and MRI) or do not cover all inflamed areas (MRI)7-11. 
7.1.2 Remission in patients with axial SpA 
Remission is increasingly becoming the goal of modern therapy in AS, but there is no consensus on 
how it should be defined12;13. The importance of obtaining remission in patients with axial SpA 
have recently been emphasized by an international group of experts in the Treat to Target (T2T) 
initiative14. However, the literature search of the group revealed that there are no clinical studies 
addressing the question. Currently, the criteria for disease activity and treatment response have been 
defined according to expert opinion. It is likly that remission criteria would benefit from including 
MRI measures and/or novel biomarkers. Exploration of the MRI/biomarker findings in patients in 
clinical remission, and in various definitions of MRI remissions, and their relation to concurrent and 
subsequent clinical outcomes, would be very relevant12. 
7.2 
New MRI methods 
Better methods than conventional CRP and MRI are now available. High-sensitive CRP assays, that 
measures CRP levels below the lower threshold of conventional CRP assays15. Novel experimental 
MRI-techniques include “head-to-toe” whole-body MRI7;11;16;17 and an even more experimental 
method, such as diffusion-weighted MRI18-20. 
7.2.1 5.1.1 Whole-body MRI 
Patients with axial SpA often have widespread disease activity outside the SI-joints and spine, and 
more comprehensive and objective methods for examination the disease burden are needed in the 
clinic. “Head-to-toe” whole-body MRI allows examination of peripheral and axial joints and 
entheses in one scan. This includes imaging of hip and shoulder joints and entheses or other more 
peripheral joints such as knee, ankles, feet, elbows wrists and hands. Furthermore, joints of the 
anterior chest wall and costo-transversal joints, which are not assessable by conventional SI 
joint/spine MRI is also assessed by whole-body MRI. To date, only one clinical trial has been 
published with ‘head-to-toe’ whole-body in patients with axial SpA treated with TNFα inhibitor21. 
This study showed that patients have more inflammation than expected and they have inflammation 
in areas that cannot assessed by clinical examination22. Department of Radiology, Herlev Hospital, 
earlier this year had a new MR-scanner that has a very high performance in making “head-to-toe” 
whole-body MRI i.e. with better image quality and shorter scan time. Thus scanner will be used in 
the study. 
7.2.2 5.1.2 Diffusion-weighted MRI 
Diffusion-weighted MRI depicts the free movements of water molecules (Brownian movements) in 
the interstitial space between the cells and outside the vessels23. The diffusion of water molecules is 
reduced if there is more cells or more proteins in the interstitial space, e.g. as if in inflammed, 
infected or infiltrated with cancer cells. Diffusion-weighted MRI is a new imaging modality in 
assessment of arthritis, which reveals other aspects of inflammation than conventional MRI18-20, and 
it may be more sensitive for detection of inflammation in SI-joints and spine. Only few studies have 

Protocol version 4.1, 3 November 2016 
10
investigated diffusion-weighted imaging in patients with axial SpA. Patients with axial SpA have 
higher ADCs values in the SI-joints as compared to patients with back pain of other reasons and 
healthy subjects24. A very small study has shown that patients with axial SpA treated with TNFα 
inhibitor decreased significantly in ADC over 1 year as compared to patients treated with non-
steroid-anti-inflammatory drugs or glucocorticoids25. We have performed a reliability study of 
diffusion-weighted MRI of the SI-joint and spine in patients with axial SpA (H-3-2012-085). The 
preliminary results show, that ADC is reproducible. It is possible that diffusion-weighted MRI can 
give a more sensitive measure of inflammation, and therefore have a future in the assessment of 
patients with axial SpA. 
7.3 
Novel biomarkers 
7.3.1 New biomarkers for inflammation, cartilage and bone turnover 
A range of novel circulating biomarkers for inflammation, cartilage and bone turnover may be of 
potential use for monitoring and predicting the response to TNFα inhibitor therapy and the disease 
course.  
The biomarkers interlekin (IL)-6, IL-22 and IL-23 and vascular endothelial growth factor (VEGF) 
reflect inflammation26;27 and the latter also neovascularization28;29. The C-terminal crosslinking 
telopeptide of type II collagen (CTX-II) is a biomarker of degradation of type II collagen, which is 
present in joint cartilage, and matrix metalloproteinase 3 (MMP-3) is a biomarker of extracellular 
matrix degradation in connective tissue30;31. Deoxypyridinoline (DeoxyPYD) and the C-terminal 
crosslinking telopeptide of type I collagen (CTX-I) are both biomarkers of bone degradation, 
whereas osteocalcin (OC) and N-terminale propeptide of of type I collagene (P1NP) are markers of 
bone formation32;33. Citrullinated vimentin has been proposed to be the degradation fragment of 
vimentin, which is a type III intermediate filament protein, which are important for the 
cytoskeleton34. Sclerostin is an inhibitor of the Wnt and bone morphogenetic protein (BMP) 
signaling pathway, and down-regulates new bone formation 35. Periostin is predominantly expressed 
in collagen-rich fibrous connective tissues under constant mechanical stress such as bone and 
tendons, and it increases bone formation by inhibiting sclerostin36. 
Among the most promising biomarkers for monitoring and prediction of response treatment 
response are IL-615;37-39, VEGF37;38;40;41, CTX-II37;41-43, MMP-337;38;41;42;44, deoxypyridinoline45, 
CTX-I 15;37;40;43;44, OC15;37;40;46, PINP46;47. Furthermore, studies have shown that novels biomarkers 
as sclerostin35;48-50  and citrullinated vimentin34;51 may be of value to assess disease activity and 
treatment response in patients with ankylosing spondylitis. However, novel biomarkers of 
inflammation such as IL-2252;53 and IL-2326;54-58 and of regulation of bone formation such as 
periostin36  may also be valuable for this purpose, but have not been investigated.  
N-terminal peptide of procollagen type II (PIINP) reflects formation of type II collagen [Munk HL, 
Gudmann NS, Christensen AF, Ejstrup L, Sorensen GL, Loft AG, et al. Cartilage collagen type II 
seromarker patterns in axial spondyloarthritis and psoriatic arthritis: associations with disease 
activity, smoking and HLA-B27. Rheumatol Int. 2016;36(4):541-9]. MMP-derived type II collagen 
neoepitope (C2M) and MMP-derived type III collagen neoepitope (C3M) are degradation products 
of collagen type II and III [Bay-Jensen AC, Wichuk S, Byrjalsen I, Leeming DJ, Morency N, 
Christiansen C, et al. Circulating protein fragments of cartilage and connective tissue degradation 
are diagnostic and prognostic markers of rheumatoid arthritis and ankylosing spondylitis. PLoS 
One. 2013;8(1):e54504]. 
All the above-mentioned biomarkers except for IL-22, IL-23 and periostin, which not have been 
investigated, have been shown either to change during treatment with TNFα inhibitor or to be 
possible independent predictors of structural damage progression. Nevertheless, they have been 
investigated in none respectively very few studies including imaging, and further investigations are 
needed. One or a panel of the mentioned bio- and MRI-markers could be useful for monitoring, and 
perhaps predicting, outcome.  

Protocol version 4.1, 3 November 2016 
11
7.4 
ASAS Health Index 
ASAS, an organisation of international SpA researchers, have recently developed a questionnaire 
called ASAS Health Index (AHI, ASAS Sundhedsindex), based on the core domains in the ICF i.e. 
the International Classification of Functioning, Disability and Health from the World Health 
Organisation (http://www.who.int/classifications/icf/en/). AHI is anticipated to reflect the patients’ 
perception of their physical function, activity and participation, which is not covered by the 
currently used questionnaires that primarily covers disease activity and selected aspects of function. 
Currently, AHI is translated from English into different languages including Danish. Before the 
Danish version of AHI can be implemented in daily clinical practice, it is important to investigate 
its face and construct validity, and its responsiveness in relation to conventional measures of disease 
activity (including clinical examinations), function and quality of life, and more experimental 
measures of sleep and fatigue, and inflammatory and structural findings on MRI. Sleep disturbance 
and fatigue are often very prominent symptoms in patients with axial SpA, but not thoroughly 
assessed by use of the conventional questionnaires, and only very few studies have been performed 
including these measures. 
7.5 
The investigational medicinal product 
The investigational medicinal product (IMP) in the study is Golimumab (Simponi®), which is a 
human monoclonal antibody directed against TNFα. In the study, the drug is applied as approved by 
the European and Danish authorities for patients with ankylosing spondylitis i.e. sc. 50 mg once 
every month (at the same date). 
Currently, Golimumab is the first choice of treatment in Denmark for patients with axial 
spondyloarthritis with moderate to high disease activity, where other treatments have failed to show 
sufficient effect. This decision was made in 2012 by “Rådet for Anvendelse af Dyr Sygehusmedicin 
(RADS) for reumatologi, Danske Regioner”, which included experts in rheumatology, 
pharmacology and health economics (http://www.regioner.dk/soeg?q=RADS). Golimumab was 
chosen as the first drug of choice for the years 2013 to 2015. Which TNFα inhibitor that will be the 
drug of choice from year 2016 is currently not known.  
The study population is patients with axial spondyloarthritis including ankylosing spondylitis with 
moderate to severe disease activity, where other treatments have failed to show sufficient effect. 
The clinical indication for treatment with TNFα inhibitor in the study is the same as in the ‘real’ 
world, and follow the treatment recommendations from RADS and Dansk Reumatologisk Selskab. 
For information on known and potential risks and benefits for the patients, see the copy of the 
package leaflet, in Appendices, section 31. 
8 
LITERATURE SEARCH 
Information on the literature search performed in relation to this protocol is provided in section 31. 
9 
STUDY PLAN 
9.1 
Endpoints for the MRI and biomarker study 
Below are mentioned the primary, secondary and tertiary endpoints for the statistical analyses. 
9.1.1 Primary endpoint 
1. Fulfillment of BASDAI50 (i.e. reduction of 50%) at week 52. 

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12
9.1.2 Secondary endpoints 
1. Clinical assessments at week 16 and 52:  
a. BASDAI response defined as reduction in BASDAI of ≥20 mm or ≥50% (yes/no). 
b. ASDAS response defined as reduction in ASDAS>1.1 (yes/no). 
2. MRI assessment at week 16:  
a. MRI remission defined as minimal (≤1 DVU affected) versus above-minimal (MRI 
activity in >1 DVU) MRI activity in the spine. 
b. MRI response defined as ≥ 50% reduction in conventional MRI spine score. 
9.1.3 Tertiary endpoints 
1. Clinical assessments at week 16 and 52. 
a. Clinical remission defined as 
i. Patient being in acceptable symptom state (PASS) (yes/no). 
ii. Reaching an ASAS20 response. 
iii. ASDAS <1.3. 
b. Clinical response defined as 
i. Patient reaching an acceptable symptom state (PASS). 
ii. BASDAI20, BASDAI50 and BASDAI70 
iii. Reduction in ASDAS ≥1.1. 
iv. ASAS20, ASAS40 and ASAS5/6. 
2. MRI assessments at week 16 and 52: 
a. MRI remission defined as 
i. Inflammation in ≤2 consecutive SI-joint quadrants or ≤2 quadrants on the same 
image slice (i.e. the definition of a positive MRI for axial SpA by ASAS). 
ii. Minimal MRI inflammation in the spine (≤1 DVU affected) AND minimal MRI 
inflammation in the SI-joints (≤1 (eller 2) SI-joint quadrants involved in ≤ 1 
slice) 
b. MRI response defined as 
i. ≥50% reduction in conventional SI-joint MRI score. 
ii. ≥50% reduction in conventional total spine MRI score. 
iii. ≥50% reduction in conventional combined spine and SI-joint MRI score. 
iv. ≥50% reduction in number of peripheral joints with inflammation on whole-
body MRI. 
v. ≥50% reduction in number of axial joins with inflammation on whole-body 
MRI. 
vi. ≥50% reduction in number of entheses with inflammation on whole-body MRI. 
vii. ≥50% reduction in number of peripheral and axial joints and entheses with 
inflammation on whole-body MRI (i.e. total inflammatory load). 
viii. ≥50% reduction in SI-joint MRI score when assessed on diffusion weighted 
images. 
ix. ≥50% reduction in spine MRI score when assessed on diffusion weighted 
images. 
x. ≥50% reduction in combined SI-joints and spine MRI score when assessed on 
diffusion weighted images. 
9.2 
Endpoints for the ASAS HI sub-study 
There are no specific endpoints for the ASAS HI study. ASAS HI is new questionnaire and no 
formal definitions high and low scores or for changes in scores are available. At the time for the 
statistical analyses the definitions that are available will be used.  

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13
9.3 
Study design 
The study is an open, longitudinal, 52-week observational cohort study of 50 patients with axial 
SpA, who starts treatment with Golimumab and are followed during treatment.  
9.4 
Study periods 
The study is performed in three parts: 
9.4.1 Part 1, week -2 to 0 (duration 0 to 2 weeks) 
MRI and X-rays are performed as close as possible to the week 0 visit at not earlier than 2 weeks 
before. The medical and biochemal screening procedures before initiation of TNFα inhibitor 
therapy may be performed in this period, but they may also be performed before this period if they 
are not older than accepted by the local recommendations (typically 3 months). This will depend on, 
what is most practical for the participaring departments.  
9.4.2 Part 2, week 0 to 16 (16 weeks) 
All patients are treated with sc. Golimumab 50 mg every month (on the same date). Four injections 
are given in this period. 
9.4.3 Part 3, week 16 to 52 (36 weeks) 
Clinical responders (for definition, see section 9.1) continue sc. Golimumab 50 mg every month 
(on the same date). Eight injections are given in this period. At week 16, clinical non-responders 
change treatment at discretion of the treating rheumatologist, and they continue to be followed in 
the study if they are treated with TNFα inhibitor.  
9.5 
Methods to reduce/eliminate bias 
There is no randomization, blinding or placebo in the study in relation to the IMP.  
The study participants and the treating rheumatologists are blinded to all MRI information during 
the study besides to a brief description of the images performed before inclusion. The description of 
the screening MRI and X-ray is specifically made to support the decision of inclusion/not inclusion 
into the study i.e. guiding the diagnosis of axial SpA. The rheumatologists and radiologists can 
usually see the MRI scans that are stored in the PACS system. Scans performed in this study will be 
locked in PACS, and thus cannot be opened without a special request, which has to be made by the 
study coordinator. 
9.6 
Study treatment 
 The patients are treated with sc. Golimumab 50 mg every month (on the same date).  
 The study medication is provided as prefilled pens with Golimumab 50 mg dispensed in 0.5 
ml. sterile water containing sorbitol (E420), L-histidin, L-histidin monohydrochlorid-
monohydrat, polysorbat 80.  
 The protection on the needle is made of latex. 
 One package contains one injection pen. 
 MSD will provide Golimumab pens for the first 7 injections (7 pens) and the participating 
departments will provide Golimumab pens for the last 5 injections (5 pens). 
 The IMP from MSD is taken from the same supplies as the medicine sold to Danske 
Regioner.  

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14
9.7 
Package 
9.7.1 Information about the package 
For copy of the print on the IMP package, see section 33. 
 The IMP is delivered in packages, which have information and print identical to the 
packages sold to Danske Regioner. 
 The IMP is in the study applied used as described on the package and package leaflet. 
9.7.2 Information on the package 
 Name, pharmaceutical dosage form, route of administration, quantity of dosage units, 
strength/potency. 
 The batch and/or code number to identify the contents and packaging operation. 
 Directions for use. 
 Storage conditions. 
 Period of use. 
 “Keep out of reach of children”. 
9.8 
Label 
9.8.1 Information about the label 
The label is shown in section 34. 
 The label will measure 38 mm x 99 mm. 
 The label will be applied on the blank/empty side of the package. 
 All labels used in the study will be manufactured at “Videncenter for Reumatologi og 
Rygsydomme” and will be distributed to the participating departments. 
 The packages provided by MSD will be labelled by the investigator before being distributed 
to the patient.  
 Both sponsor and investigator will keep an accountability log for labels, see section 9.11.  
9.8.2 Information on the label 
The label is shown in section 34 
 The information that is provided on the package is not mentioned on the label. 
 Name, address and telephone number of the sponsor.  
 Name, address and telephone number of the investigator is not provided on the package, but 
is provided on the patient card (see section 35). 
 Name of trial and trial reference code. 
 The trial subject identification number is provided.  
 The visit number is not provided since it is not relevant.  
9.9 
Patient Card 
The patient card is provided in section 35. The patient will be asked to carry the card at all times 
from week 0 (first injection of Golimumab) to week 52 (last study visit). 
9.10 Storage of IMP 
Special requirements in relation to the IMP (copy from Danish package leaflet) 
 Opbevares utilgængeligt for børn. 

Protocol version 4.1, 3 November 2016 
15
 Brug ikke dette lægemiddel efter den udløbsdato, der står på etiketten og pakningen efter 
”EXP”. Udløbsdatoen er den sidste dag i den nævnte måned. 
 Opbevares i køleskab (2°C - 8°C). Må ikke nedfryses. 
 Opbevar den fyldte pen i den ydre karton for at beskytte mod lys. 
 Brug ikke dette lægemiddel, hvis De kan se, at væsken ikke er en klar til lys gullig farve, 
eller hvis den er grumset eller indeholder fremmede partikler. 
9.11 Drug and label accountability 
9.11.1 Sponsor 
“Videncenter for Reumatologi og Rygsygdomme” (sponsor) will maintain an accountability log for 
the IMP received from MSD, which also will include the shipping receipts. They will also maintain 
an accountability log for the IMP and the labels they send to the participating centers. Sponsor has 
made standardized forms that fulfill the requirement of GCP. 
Before study start, labels for all packages are printed i.e. 12 labels per patient plus one additional in 
case of injection failure etc. The packages with IMP provided by MSD will be send to the 
investigator with all lables, and investigator will lable the IMP before giving it to the patient. 
Furthermore, they will keep an accoutability log for the labels. Dedicated nurses who have 
experience with GCP will maintain both accountability logs. 
9.11.2  Investigator 
The investigators will maintain an accountability log for the IMP and labels they receive from 
sponsor and for the individual patient. Labels that are not used in the study are stored together with 
the accountability log for the IMP. The accountability log for the individual patient will include a 
detailed recording of injections performed at the center, no. of packages with IMP given to the 
patient for injection at home, and number of empty devices returned from the patient. Empty 
devices are stored until the patient has finalized the study. Before the empty devices are destroyed 
the information in the accountability log of the patient should be checked, and signed by the study 
nurse.  
9.12 Safety procedures in relation to IMP 
9.12.1 Receival of IMP and labelling procedure 
At “Videncenter for Reumatology and Rygsygdomme”, the staff that receives the IMP will include 
two persons of whom at least one will be a study nurse. Both persons are used to receive IMPs and 
comply with GCP and the required documentation. It is the same persons, who maintain the 
accountability log. 
Shipment of IMP from “Videncenter for Reumatologi og Rygsygdomme” to the investigators will 
be planned in advance. At the investigators site, study nurses will maintain the accountability logs, 
and they will also label the IMP. The investigators study nurses are used to comply with GCP in 
pharmaceutical studies. The procedure for recieval of IMP, labelling and maintenance of 
accountability logs this study will be discussed at local meetings before at the centers before the 
study is initiated. 
9.12.2 Storage of IMP 
At sponsors site and the participating centers, the IMP is stored in refrigerators that are under 
continuous temperature surveillance connected to a central alarm in the hospital. In case, there is no 
electronic temperature surveillance, a thermometer showing the min/max. temperature will be place 
in the refrigerator. Sponsor and the centers keep a temperature log according to the 

Protocol version 4.1, 3 November 2016 
16
recommendations at the individual hospital, which fulfils the requirements of GCP. This may be 
either a manual log or an electronic readout. 
At home, the patient store the IMP in his/her refrigerator. The study nurse routinely inform the 
patient about the importance of storage conditions at home and under transportation including at 
vacation. The patient also informed about the importance of having a thermometer in the 
refrigerator and check it regularly. The IMP is stored in a cooling bag under transportation from the 
hospital. This is all routine procedures in clinical practise.  
9.12.3 Injection of IMP 
The study nurses that participate in the study routinely inform and teach patients about how to inject 
the IMP. Furthermore, they are aware of patients that may need help or may benefit from having the 
injections performed at the hospital or by a nurse at home. 
The first injection will be given at the centre once all study-related procedures have been performed 
and under the direct supervision of a study nurse. This supervision enables the study nurse to check 
that the correct technique for subcutaneous injection is used. If needed, the second injection can be 
given at the center. The injection technique is described on the package leaflet. 
Each time the patients get new packages of IMP (every second month) they are routinely screened 
by the study nurses for problems with injection tecknique, adverse reactions in relation to the 
injection and for storage problems. 
9.13 Randomization code and procedures for breaking the code 
Not relevant for this study.  
9.14 Source data 
9.14.1 Definition of source data 
Source documents are original records in which raw data are first recorded. These may include 
hospital records, X-rays, MRI scans, laboratory results, ECG or other printouts. If patient 
questionnaires are fill-in on paper and later entered into the e-CRF the paper based questionnaires 
are the source document.  
9.15 Source data in this study 
Source data will be defined before initiation of the study. A list will be available in the TMFs. 
For information on variables and items included in the study, see section 15. 
10 STUDY PARTICIPANTS 
The study includes 50 patients with axial SpA or AS. The patients are recruited from the 
participating centers among the patients that are offered treatment with TNFα inhibitor due to 
moderate to high disease activity despite other treatment. Patients will not be recruited by use of 
advertisements. 
11 RECRUITEMENT OF PATIENTS 
The patients are recruited from the participting rheumatologic departments among their own 
patients. This is done without any use of advertisements etc. See section about information of the 
patients for further details (section 21 

Protocol version 4.1, 3 November 2016 
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12 INCLUSION AND EXCLUSION CRITERIA 
12.1 Inclusion criteria 
1. Age >18 years and <85 years. 
2. Spondyloarthritis according to the ASAS classification criteria for axial SpA (see section 
37). 
3. Sacroiliitis on conventional X-rays or MRI. 
4. Disease activity assessed by BASDAI >40 mm despite treatment with NSAID. 
5. Clinical indication for TNFα inhibitor treatment by the treating physician. 
6. No contraindications for TNFα inhibitor treatment (see section 12.2.1). 
7. No contraindications for MRI (see section 36). 
8. Sufficient contraception for women (see section 12.2.2). 
9. Capable of giving informed consent. 
10. Capable of complying with the examination programme of the protocol. 
12.2 Exclusion criteria 
1. Pregnancy wish, pregnancy or breast-feeding. 
2. Oral, intra-articular or intramuscular glucocorticoid within 4 weeks prior to inclusion. 
3. DMARDs are allowed during the study, but the dose cannot be changed from 4 weeks 
before the first MRI scan and until week 16. 
4. The use of other study drugs within 4 weeks prior to inclusion or less than 5 half-lives of the 
study drug before inclusion if this is more than 4 weeks. 
5. The use of suspected disease-modifying or immunosuppressive drugs within 4 weeks before 
to inclusion. 
6. Previous treatment TNFα inhibitor.  
7. Contraindications for TNFα inhibitor treatment (see section 7). 
8. Contraindications for MRI (see section 36). 
9. Known recent drug or alcohol abuse. 
10. Failure to provide written consent. 
11. Incapable of complying with the examination programme for physical or mental reasons. 
12.2.1 Contraindications to TNFα inhibitor treatment 
The patients are asked about previous and current diseases, with focus on the following conditions 
and circumstances that may influence the decicion of starting TNFα inhibitor treatment:  
1. Active infections or persistent chronic infections that have required treatment with 
intravenous drugs within 30 days, or oral drugs within 14 days, before the start of TNFα 
inhibitor. 
2. Immunosuppressive conditions or new HIV infection. 
3. Active or chronic Hepatitis B and/or C virus infection. 
4. Persons with latent tuberculosis (TB) (Quantiferon test and/or chest X-ray indicating TB) or 
other risk factors for activation of latent TB must undergo TB prophylaxis starting 4 weeks 
before the first administration of golimumab. The prophylactic treatment follows the 
guidelines of the treating department. 
5. Severe, uncontrolled medical disease, such as uncontrolled diabetes with documented 
previous repeat infections, unstable heart disease, heart failure or recent cerebrovascular 
event.  
6. Neurological symptoms indicative of demyelinating disease of the central nervous system, 
e.g. multiple sclerosis. 
7. Heart failure (NYHA group 3 and 4). 

Protocol version 4.1, 3 November 2016 
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8. Malignant diseases except well-treated non-metastatic squamous or basal cell skin 
carcinoma and/or carcinoma in situ cervix uteri. 
9. New SLE or SLE-like disease. 
10. Current and/or imminent wish to become pregnant.  
11. Postive serum HCG. 
In case of contraindications to the treatment with TNFα inhibitor the patient cannot be included in 
the study. 
12.2.2 Sufficient contraception for women  
Copy of text from http://laegemiddelstyrelsen.dk. 
 
Det skal I indeværende forsøg sikres, at fertile kvinder ikke er gravide inden indtræden i forsøget 
(negativ graviditetstest forud for indgåelse i forsøget), samt at der benyttes sikker antikonception. 
 
Sundhedsstyrelsen anser følgende svangerskabsforebyggende midler som sikker antikonception i 
forbindelse med lægemiddelforsøg: Spiral eller hormonel antikonception (p-piller, implantat, 
transdermal depotplastre, vaginalring eller depotinjektion). I visse tilfælde kan steril fast partner 
eller brug af dobbeltbarriere findes acceptabelt. Dette forudsætter en gyldig begrundelse i særlige 
forhold omkring forsøgsdesign, præparatkarakteristika og/eller patientpopulationen. Ved 
dobbeltbarriere forstås kondom kombineret med pessar. 
 
Fertile kvinder, som inkluderes i forsøg, skal således anvende svangerskabsforebyggende midler i 
overensstemmelse med ovenstående i hele forsøgsperioden og efter forsøgsophør i en periode på 6 
måneder (information fra MSD). 
 
Sterile eller infertile forsøgsdeltagere er fritaget for kravet om brug af antikonception. For at 
betragtes som steril eller infertil må man almindeligvis være kirurgisk steriliseret 
(vasektomi/bilateral tubektomi, hysterektomi og bilateral ovarektomi) eller være postmenopausal, 
defineret som udebleven menstruation i mindst 12 måneder før studie indrullering. 
 
Der kan for enkelte individer eller særlige populationer være forhold, som taler imod brug af 
ovenstående metoder. Eksempler kan være alvorligt svækkede hospitaliserede patienter eller ikke 
seksuelt aktive fertile børn. En sådan vurdering tages af investigator og er dennes ansvar. 
Begrundelsen for afvigelsen skal nedskrives (f.eks. i CRF), og skal ikke indsendes til 
Sundhedsstyrelsen, men kunne dokumenteres ved en eventuel fremtidig inspektion. 
12.3 Withdrawal criteria for an individual patient  
Investigators should contact study coordinator whenever possible to discuss the withdrawal of a 
subject in advance. 
 
Reasons for withdrawal: 
1. Development of an illness that interferes with continued treatment with TNFα inhibitor (i.e. 
TNFα inhibitor stopped permanently and no new TNFα inhibitor initiated). 
2. Withdrawal of Golimumab treatment before week 16. 
3. Non-compliance with study procedures including the treatment in the opinion of the 
investigator. 
4. Withdrawal of informed consent for any reason and at any time. 
5. Confirmation of a pregnancy during the study, as evidenced by a positive pregnancy test. 
6. If sponsor or a regulatory agency requests withdrawal of the patient. 
In case of withdrawal from the study, the subject should have the Withdrawal Visit 
(Eksklusionsbeøg) performed.   

Protocol version 4.1, 3 November 2016 
19
 
Withdrawn subjects will not be replaced with new patients in the study.  
12.4 Reasons for stopping the trial 
 Golimumab has been used since 2009 in US and Europe for treating patients with 
rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis. It belongs to a group of 
drugs, the TNFα inhibitors, which has been used since year 2000 all over the world. 
Although there are differences in the biochemistry, farmacokineics etc. the clinical response, 
frequence of adverse events etc. appear similar. Therefore, we do not expect the study to 
stopped before time due to unexpected drug reaction etc. 
 Should the MRI scanner used in the study go down it is usually repaired within a few days. 
However, in case of a longer break down, there are other MRI scanners at the Department of 
Radiology at Herlev Hospital, which can make the same type of sequences. 
 If requested by a regulatory agency. 
12.5 Treatment  
Week 0 to 16: Patients are treated with sc. Golimumab 50 mg every month (on the same date) 
Week 16 to 52: Clinical responders continue sc. Golimumab 50 mg every month (on the same date). 
Clinical non-responders change treatment according to the treating rheumatologist.  At week 16, 
clinical non-responders change treatment at discretion of the treating rheumatologist, and they 
continue to be followed in the study if they are treated with TNFα inhibitor.  
12.6 Treatment response 
Treatment response is evaluated at week 16 and 52. A clinical response is defined as a reduction in 
BASDAI of ≥ 20 mm or ≥ 50%.  
12.7 Concomitant treatment 
12.7.1 Prohibited concomitant treatments during the study 
The following treatments are not allowed during the study.  
 Other drugs with a potential disease-modifying effect (except DMARDs). 
 Other study drugs. 
12.7.2 Permitted under special circumstances and in certain time intervals only 
 Glucocorticoids. At specific time points during the study, intraarticular or intramuscular 
injection with glucocorticoid are allowed.  
o Before week -4 before the MRI scans 
o From week 4 after all study procedures have been performed and until week 8 
o From week 16 after all study procedures have been performed and until week 20 
o From week 28 after all study procedures have been performed and until week 32 
o From week 40 after all study procedures have been performed and until week 44 
 Oral and intravenous glucocorticoids are not allowed at any time point. 
12.7.3 Permitted concomitant treatment during the study 
The following treatments are allowed during the study, and the use should be recorded in the CRF 
at each visit. 

Protocol version 4.1, 3 November 2016 
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 Paracetamol. 
 NSAIDs (if taken, dose must be fixed from 2 weeks before the first MRI scans through 
week 4 after completion of examination programme). 
 Tramadol. 
 DMARDs (dose must be fixed from 4 weeks before the first MRI scan to week 16). 
In case of lack of improvement in disease activity during the study despite paracetamol, NSAID 
and/or tramadol treatment the patient must not be excluded before contact with the study 
coordinator, so that another effective treatment may be initiated. 
Collectively, paracetamol and tramadol are also referred to as rescue medication. 
12.8 Treatment after end of the study 
Clinical responders at week 52 continue with sc. Golimumab 50 mg once every month (at the same 
date). In case of insufficient treatment effect, treatment will be changed in accordance with the 
guidelines of the department concerned and at discreation of the treating rheumatologist. 
12.9 Surveillance of compliance to treatment 
The first and eventually the second injection of Golimumab will be given at the participating center 
under supervision of a study nurse. All other doses can be given outside the center. To document 
compliance, all pens (pre-filled pens given to the patient, empty pens returned used or unused from 
the patient) have to be counted and documented in the accountability log for the individual patient. 
13 ASSESSMENT OF EFFICACY 
13.1 Specification and justification of efficacy parameters 
The criteria for inclusion in this study regarding diagnosis and clinical disease activity (point 2. and 
4.) and all contraindications to TNFα inhibitor are the same as is used in clinical practice.  
The primary treatment response used in the study (BASDAI response) is the treatment response that 
also is used in clinical practice as the primary treatment response. Of the other criteria used in the 
study, ASAS and ASDAS response criteria are primarily used in studies.  
PASS is an overall subjective measure of disease activity that has only been investigated in few 
studies of patients with axial SpA. MRI is used in clinical practice for diagnosing axial SpA, but is 
at the moment not routinely recommended for assessment of treatment response, due to the lack of 
definitions of response and remission criteria. 
13.2 Methods and time points for assessment and recording of efficacy parameters 
For information on analyses of the efficacy parameters, see section 13. 
For an overview over time points for assessment of the efficacy parameters, see flowchart section 
28.  
For an overview of the acceptable time window for all the study visits, see flowcart section 28. 
14 ASSESSMENT OF SAFETY 
14.1 Specification and justification of safety parameters 
The safety assessments performed before treatment initiation in the study are the same as used in 
daily clinical practise. The participating departments of rheumatology have different levels of safety 

Protocol version 4.1, 3 November 2016 
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assessment during treatment with TNFα inhibitor. During the study, the centers will follow their 
own recommendations in supplement to those described below. 
14.1.1 Methods and time points for assessment of safety parameters before week 0 
Safety assessments before initiation of the IMP include a screening for previous and current 
diseases (see section 14.1). This is done by review of the patient’s medical record, interview with 
the patient, and clinical, biochemical and imaging assessments. The biochemical screening can be 
performed within 3 months before initiation of the IMP - the same period as is used in clinical 
practice, except for infections, and liver and kidney dysfunctions, which should be re-assessed at 
the week 0 visit together with the urine test, and the blood tests, which not should be more than 1-2 
weeks old. 
The screening visit in the study can be performed within 4 weeks before the inclusion visit (week 0) 
or it can be performed together with the inclusion visit, if all screenings procedures have been 
performed within the acceptable time frames (see above and below) and all tests all are normal.  
 
History of TB exposure 
The rheumatologist asks the patients to previous exposure for TB, which includes an anamnesis of 
previous travels and living in other countries than Denmark, TB among family, friends and 
collegues etc. Calmette vacination status.  
 
Chest X-ray 
To screen for tuberculosis a radiological chest examination is performed before inclusion. A 
previous examination can be used provided it has been performed within 3 months before treatment 
initiation. 
 
Quantiferon tests 
Quantiferon test is carried out with-in 3 months before treatment initiation. The Quantiferon test 
(QFT-G) detects the release of interferon-gamma (IFN-γ) in fresh heparinised whole blood from 
sensitised patients when incubated with mixtures of synthetic peptides representing 2 proteins (early 
secretory antigenic target-6 (ESAT-6) and culture filtrate protein-10 (CFP-10)), which are present 
in M Tuberculosis. Direct comparisons have shown that the sensitivity of QFT-G was not 
statistically different from Tuberculin Skin Test (TST) in terms of detecting an infection in persons 
with untreated culture-positive tuberculosis. According to the US Centres for Disease Control and 
Prevention, QFT-G can be used for the same groups of persons as TST, including screening for TB. 
(http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5415a4.htm). 
 
Electrocardiogram (ECG) 
A 12-lead electrocardiogram has to be performed within 3 months before treatment initiation.  
 
Hepatitis and HIV 
All patients are screened for hepatitis B and C (HBsAg, anti-HBs, anti-HCV) and HIV within 3 
months before treatment initiation. 
 
Pregnancy test 
Women of childbearing potential will be tested for pregnancy (sHCG) before inclusion into the 
study. The samples are analysed at the biochemical department where they are collected. 
 
Physical examination 
Before the start TNFα inhibitor treatment the patient undergoes a physical examination. The general 
physical examination includes an assessment of the general condition, oral cavity, lymph node 
status, auscultation of heart and lungs, abdominal examination, musculoskeletal conditions, skin 
and neurology.  

Protocol version 4.1, 3 November 2016 
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Vital signs 
Pulse and blood pressure are measured at week 0 and 52 and at exclusion, and besides that only if 
necessary.  
 
Safety blood and urine samples 
Before the start of the TNFα inhibitor treatment the following blood and urine, samples are 
collected: 
Haemoglobin, CRP, leukocytes, differentials, platelets, albumin, ALAT or ASAT, LDH, alkaline 
phosphatase, creatinine at every study visit. ANA screening is performed at week 0 and 52.  
The urine is analysed for haemoglobin, albumin, glucose, leukocytes and nitrite and is performed at 
week 0 and 4 and whenever clinically indicated, or recommended locally at the centre. 
14.2 Methods and time points for assessment, registration and analyses of safety parameters  
For methods and time points for assessment of safety parameters, see flowchart section 28. 
The values of the safety parameters are not recorded in the CRF, but only indirectly in a checklist to 
assure that the treating rheumatologist have seen the results and the patients can continue treatment 
with the IMP (or after week 16 with the other TNFα inhibitor) in the study. Only if the safety 
parameter is considered an adverse event, it should be recorded exactly as a part of the report to the 
Danish Health and Medicines Authorities.  
None of the safety parameters is included in the source data if not reported as an adverse event.  
14.3 Procedures to avoid and treat complications 
The participating centers are all used to treat patients with axial SpA with the IMP used in the study 
and with other TNFα inhibitors, and they have implemented care programs to avoid complications. 
These care programs are based on international and national recommendations for screening for 
contraindications before initiation of TNFα inhibitor, and for screening for complications during 
this treatment. The rheumatologists that treat patients in the study are either rheumatologic 
specialists, and if not, they treat the patients in the study under close supervision of rheumatologic 
specialists. 
14.4 Follow-up time in relation to complications 
SAE and SUSARs are followed until the first coming annual rapport the Ethical Committee and for 
the last included patient until the closure of study letter to the Ethical Committee. Assessemt and 
reporting of adverse events 

Protocol version 4.1, 3 November 2016 
23
14.5 Depression screening 
14.6 The results of the depression screening (CES-D) will be provided to the treating physician 
in the eCRF. The results will be provided in five categories as defined by CES-D i.e. “no 
clinical significance”, “subthreshold depression symptoms”, “possible major depressive 
episode”, “probable major depressive episode”, or “meets criteria for major depressive 
episode”. The treating rheumatologist is responsible making a clinical judgement of the 
patient as it is performed in daily clinical practise, and to document it in the patient record 
if there is any suspicion of depression. Furthermore, the treating rheumatologist is 
responsible for taking action according to his/her individual clinical judgment of the 
patient, and refer the patient to his/her general practisioner or a psychiatrist.Adverse 
events (AE) and adverse reactions (AR) 
14.6.1 Definition Adverse Event (AE) 
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily have to 
have a causal relationship with this treatment. An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding, for example), symptom, or disease 
temporally associated with the use of a medicinal product, whether or not considered related to this 
medicinal product. 
14.6.2 Definition Adverse Reaction (AR) 
All noxious and unintended responses to a medicinal product related to any dose should be 
considered adverse drug reactions. The phrase "responses to a medicinal product" means that a 
causal relationship between a medicinal product and an adverse event is at least a possibility (refer 
to ICH E2A). A reaction, in contrast to an event, is characterized by the fact that a causal 
relationship between the drug and the occurrence is suspected. If an event is spontaneously 
reported, even if the relationship is unknown or unstated, it meets the definition of an adverse drug 
reaction. 
14.6.3 Recording of Adverse Events (AE) and Adverse Reacstions (AR) 
AE and AR are not recorded in the study.  
14.7 Pre-malignant conditions 
 MSD has special focus on pre-malignant conditions, which should be reported as such under 
Adverse Events in the CRF. 
 At the end of the study, the investigator will submit a complete line listing of all Adverse 
Events that have been captured throughout the study to MSD. MSD will review this for 
possible premalignant conditions. If any are reported, MSD will contact the Investigator 
with a dedicated follow-up request to be completed. In case a pre-malignant condition has 
progressed to a malignancy, the Investigator will need to complete the Malignancy Follow-
Up Questionnaire, according to the above procedure. 
14.8 Serious adverse event (SAE), serious adverse reaction (SAR) and suspected unexpected 
serious adverse reaction (SUSAR) 
14.8.1 Definition of Serious Adverse Event (SAE) 
Any untoward medical occurrence or effect that at any dose. 

Protocol version 4.1, 3 November 2016 
24
 Results in death. 
 Is life threatning. 
 Requires hospitalisation or prolongation of existing inpatients’ hospitalisation. 
 Results in persistent or significant disability or incapacity. 
 Is a congenital anomaly or birth defect. 
 Cancer. 
 Overdose. 
Other important medical events that may jeopardize the patient or may require intervention to prevent 
one of the outcomes listed previously should also be considered “serious”. 
14.8.2 Reporting of Suspected Unexpected Serious Adverse Reaction (SUSAR) and Suspected 
Unexpected Adverse Reaction 
All suspected adverse reactions related to an IMP and comparators that are both unexpected and 
serious or non-serious are subject to expedited reporting. 
14.8.3 Definition of Unexpected Event – and specification of the reference document used in the 
study 
Any event that is not included in the appropriate Reference Safety Information (Investigator’s 
Brochure) or one that is more severe or more specific, than what is included in the Reference Safety 
Information. 
In this study, the reference document used for defining an unexpected event is the Investigator’s 
Brochure. There will be copy of the Investigator’s Brochure in the TMF. 
14.9 Time frames for reporting SUSARs and Suspected Unexpected Adverse Reaction 
Investigator must report all SUSARs and Suspected Unexpected Adverse Reactions within 24 hours 
to sponsor, who will take care of the reporting to the authorities and MSD. The sponsor must ensure 
that all relevant information about  
 SUSARs that are fatal or life threatening should be reported to the health authorities as 
soon as possible and in no case later than 7 days after such a case has come to the sponsor’s 
knowledge. Relevant follow-up information is subsequently communicated within 
additional 8 days. MSD has to be informed within 48 hours. 
 All other SUSARs must be reported to the Danish Health and Medicines Agency as soon as 
possible, no later than 15 days from the sponsor’s first knowledge of such reactions. The 
Etical Committee has to be informed within 7 days. MSD has to be informed within 48 
hours. 
 Suspected Unexpected Adverse Reaction must be reported to the health authorities as 
soon as possible, no later than 15 days from the sponsor’s first knowledge of such reactions. 
MSD will be informed within 48 hours. 
SAE, SUSAR and Suspected Unexpected Adverse Reactions are reported to the Danish Health and 
Medicines Authorities, the Ethics Committee and MSD within the time periods mentioned above 
(see also table below). 
14.10 How to report SUSARs and Suspected Unaxpected Adverse Reactions 
Each report should be submitted on a CIOMS-form (the form used in DANBIO). Each report 
should also include the study number and accompanied by comments on any possible consequences 
for the trial. The investigator must complete all fields in the CIOMS form. CIOMS-forms filled in 
in the eCRF, and paper-based back-ups are present in the paper CRF.  
All patients with SAEs, SUSARs and Unexpected Adverse Reactions must be followed up for 
outcome, and this will be done by sponsor in relation to the annual report to the Ethics Committee 
and MSD. 

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14.11 Additional information on malignancy to MSD 
As part of a US Food and Drug Administration (FDA) requirement for all TNFα inhibitor agents, 
all malignancies occurring in patients 30 years of age or younger who received golimumab 
(Simponi) must be reported to MSD within 48 hours using the same method described above for 
SAE reporting. MSD will follow-up with the Investigator by sending a dedicated Malignancy 
Follow-up Questionnaire that has to be completed by the Investigator(s) and submitted to MSD 
within 2 weeks of receipt, using the same method described above for SAE reporting. The 
Investigator must make at least two attempts to contact the patient or guardian to complete the 
Malignancy Follow -up Questionnaire. If the attempts are not successful, the reason 
for each unsuccessful attempt must be documented (e.g., patient lost-to-follow-up, patient refuses to 
supply the additional information, etc.). 
14.12 Annual report on SAE, SUSARs and Suspected Unexpected Adverse Reactions 
The investigator must once yearly throughout the entire trial period submit an annual report to and 
the Independent Ethics Committee.  
 
The investigator agrees to submit to the Danish Health and Medicines Authority and MSD all 
information concerning participants’ safety; SAE/SUSAR/pregnancy reports & annual report to:  
 Att. Pharmacovigilance by fax +45 4439 5004 
14.13 Practical procedures for reporting of AEs, ARs, SAEs, SARs, SUSARs 
The following table provides an overview of responses/reactions that must be reported. 
 

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15 VARIABLES INCLUDED IN THE STUDY 
Different variabels are included in the study. These are either directly related to the aims of the 
study or indirectly by providing other types of information, which are important for the study e.g. 
fulfillment of inclusion and not exclusion criteria, contraindications for TNFα inhibitor, time frames 
for study visits etc. 
Below as listed the variables that are considered the core variables in the study, which are collected 
by the investigator. For patient questionnaires, see separate file with these. 
15.1 Screening  
When the visit is not performed together with the inclusion visit. 
 Informed consent. 
 Patient ID.  
 Date. 
 Name of rheumatologist. 
 Gender. 
 Height and weight. 
 HLA-B27. 
 Symptom duration. 
 Disease duration. 
 
 REQUIRED REPORTING OF AE 
PRACTICAL 
PROCEDURES 
FOR 
REPORTING 
ADVERSE 
EVENT 
FOR 
 
Type 
of 
adverse event 
 
MSD 
SST Afdeling 
for  
Lægemiddel-
overvågning 
og Medicinsk 
Udstyr 
Independent 
Ethics 
Committee 
(IEC) 
 
INVESTIGATOR 
 
SPONSOR 
Expected 
AR 
and AE 
No 
No 
No 
No 
No 
Unexpected 
Non-serious 
AR 
Yes 
Yes 
No 
Report immediately  
to SST via 
DANBIO, and e-
mail letter to 
sponsor 
 Fax to MSD 
within 48 hours 
 
Serious 
AE 
(SAE) 
Yes 
 
Yes 
Yes 
Report immediately  
to SST via 
DANBIO, and e-
mail letter to 
sponsor 
 Fax to MSD 
within 48 
 Letter to IEC 
within 7 days  
Suspected 
Unexpected 
Serious 
Adverse 
Reactions 
(SUSAR) 
Yes 
Yes  
 
Yes  
Report immediately  
to SST via 
DANBIO, and e-
mail letter to 
sponsor 
 Fax to MSD 
 Letter to IEC 
within 7 days 
Sponsor 
to 
submit 
an 
annual report 
Yes 
No 
Yes 
NA 
 Letter to IEC on 
SAE and SUSAR 

Protocol version 4.1, 3 November 2016 
27
 Tobacco and alcohol consumption. 
 Clincal history incl. past medical history (medical and surgical diseases). 
 Presence of benign diseases/conditions that is associated with increased development of 
cells in the bone marrow (i.e. being blood donor, anemia, infections etc.).  
 ASAS classification criteria (see section 37). 
 Contraindications for TNFα inhibitor (see section 12.2.1). 
 Inclusion criteria (see section 12.2.1). 
 Exclusion criteria (see section 12.2). 
 BAS questionnaire: Pain, patient global assessment, BASDAI and BASFI.  
 HAQ questionnaire 
 BASMI. 
 Physician global assessment. 
 Blood pressure and pulse. 
 General clinical assessment. 
 Clinical assessments in relation to eligibility for TNFα inhibitor. 
 MRI scans and conventional radiography 
 Radiological assessments in relation to eligibility for TNFα inhibitor. 
 Biochemical assessments in relation to eligibility for TNFα inhibitor. 
 ANA test. 
 Conventional blood tests (see section 14.1). 
 Conventional urine tests (see section 14.1). 
15.2 Inclusion 
When the visit is not performed together with the screening visit. 
 Patient ID. 
 Date. 
 Name of rheumatologist. 
 Clincal history incl. past medical history (medical and surgical diseases). 
 Presence of benign diseases/conditions that is associated with increased development of 
cells in the bone marrow (i.e. being blood donor, anemia, infections etc.).  
 Contraindications for TNFα inhibitor (see section 12.2.1). 
 Inclusion criteria (see section 12.2.1). 
 Exclusion criteria (see section 12.2). 
 Target joints (axial and peripheral) and entheses. 
 BAS questionnaire: Pain, patient global assessment, BASDAI and BASFI.  
 HAQ questionnaire 
 Other patient questionnaires (see separate file). 
 BASMI. 
 Examination of 66/68 periperal joint (tender/swollen). 
 Examination of 35 entheses (tender). 
 BASMI. 
 Physician global assessment.  
 Blood pressure and pulse. 
 General clinical assessment. 
 Treatment after the study visit. 
 Concomitant medication (also in relation to all other diseases). 
 Accountability log for the IMP. 
 Check that MRI scans and radiography of the SIJs and spine have been perfomed. 
 

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 Check that radiological assessments in relation to eligibility for TNFα inhibitor have been 
performed. 
 Check that biochemical assessments in relation to eligibility for TNFα inhibitor have been 
performed. 
 Conventional blood tests (see section 14.1). 
 Conventional urine tests (see section 14.1). 
 Experimental biomarkers. 
15.3 Screening and inclusion (when performed together) 
When the visits are performed together. 
 Informed consent. 
 Patient ID.  
 Date. 
 Name of rheumatologist. 
 Gender. 
 Height and weight. 
 HLA-B27. 
 Symptom duration. 
 Disease duration. 
 Tobacco and alcohol consumption. 
 Clincal history incl. past medical history (medical and surgical diseases). 
 Presence of benign diseases/conditions that is associated with increased development of 
cells in the bone marrow (i.e. being blood donor, anemia, infections etc.).  
 ASAS classification criteria (see section 37). 
 Contraindications for TNFα inhibitor (see section 12.2.1). 
 Inclusion criteria (see section 12.2.1). 
 Exclusion criteria (see section 12.2). 
 Target joints (axial and peripheral) and entheses. 
 BAS questionnaire: Pain, patient global assessment, BASDAI and BASFI. 
 HAQ questionnaire 
 Other patient questionnaires (see separate file). 
 Examination of 66/68 periperal joint (tender/swollen). 
 Examination of 35 entheses (tender). 
 BASMI 
 Physician global assessment 
 Blood pressure and pulse. 
 General clinical assessment including assessment in relation to eligibility for TNFα 
inhibitor. 
 Treatment after the study visit. 
 Concomitant medication (also in relation to all other diseases). 
 Accountability log for the IMP. 
 Check that MRI scans and radiography of the SIJs and spine have been perfomed. 
 Check that radiological assessments in relation to eligibility for TNFα inhibitor have been 
performed. 
 Check that biochemical assessments in relation to eligibility for TNFα inhibitor have been 
performed. 
 Conventional blood tests (see section 14.1). 
 Conventional urine tests (see section 14.1). 
 Experimental biomarkers. 

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15.4 Specific for week 4 
 Patient ID. 
 Date. 
 Name of rheumatologist. 
 Presence of benign diseases/conditions that is associated with increased development of 
cells in the bone marrow (i.e. being blood donor, anemia, infections etc.).  
 Target joints (axial and peripheral and including entheses). 
 BAS questionnaire: Pain, patient global assessment, BASDAI and BASFI. 
 HAQ questionnaire 
 Other patient questionnaires (see separate file). 
 Examination of 66/68 periperal joint (tender/swollen). 
 Examination of 35 entheses (tender). 
 Physician global assessment 
 Treatment after the study visit. 
 Concomitant medication (also in relation to all other diseases). 
 Accountability log for the IMP. 
 Registration SAE, SUSARs and Suspected Unexpected Adverse Reactions. 
 Pregnancy obtained in the study after initation of TNFα inhibitor. 
 MRI scans and conventional radiography. 
 Conventional blood tests (see section 14.1). 
 Conventional urine tests (see section 14.1). 
 Conclusion conventional blood tests (see section 14.1). 
 Experimental biomarkers. 
15.5 Specific for week 16 
 Patient ID. 
 Date. 
 Name of rheumatologist. 
 Presence of benign diseases/conditions that is associated with increased development of 
cells in the bone marrow (i.e. being blood donor, anemia, infections etc.).  
 Target joints (axial and peripheral and including entheses). 
 BAS questionnaire: Pain, patient global assessment, BASDAI and BASFI. 
 HAQ questionnaire 
 Other patient questionnaires (see separate file). 
 Examination of 66/68 periperal joint (tender/swollen). 
 Examination of 35 entheses (tender). 
 Physician global assessment. 
 Treatment response i.e. reduktion i BASDAI ≤20 mm or ≤50%). 
 Treatment after the study visit. 
 Concomitant medication (also in relation to all other diseases). 
 Accountability log for the IMP. 
 Registration SAE, SUSARs and Suspected Unexpected Adverse Reactions. 
 Pregnancy obtained in the study after initation of TNFα inhibitor. 
 MRI scans. 
 Conventional blood tests (see section 14.1). 
 Conventional urine tests (see section 14.1). 
 Conclusion conventional blood and urine tests (see section 14.1). 
 Experimental biomarkers. 

Protocol version 4.1, 3 November 2016 
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15.6 Specific for week 52 and exclusion visit 
 Patient ID. 
 Date. 
 Name of rheumatologist. 
 ”End of study” i.e. reasons for if the patient has not followed the study protocol). 
 Presence of benign diseases/conditions that is associated with increased development of 
cells in the bone marrow (i.e. being blood donor, anemia, infections etc.).  
 Target joints (axial and peripheral and including entheses). 
 BAS questionnaire: Pain, patient global assessment, BASDAI and BASFI. 
 HAQ questionnaire 
 Other patient questionnaires (see separate file). 
 Treatment response i.e. reduktion i BASDAI ≤20 mm or ≤50%). 
 Examination of 66/68 periperal joint (tender/swollen). 
 Examination of 35 entheses (tender). 
 Physician global assessment. 
 Blood pressure and pulse. 
 General clinical assessment. 
 Treatment after the study visit. 
 Concomitant medication (also in relation to all other diseases). 
 Accountability log for the IMP. 
 Registration SAE, SUSARs and Suspected Unexpected Adverse Reactions. 
 Pregnancy obtained in the study after initation of TNFα inhibitor. 
 MRI scans and conventional radiography. 
 Conventional blood tests (see section 14.1). 
 Conventional urine tests (see section 14.1). 
 Experimental biomarkers. 
15.7 All other study visits  
 Patient ID. 
 Date. 
 Name of rheumatologist. 
 Presence of benign diseases/conditions that is associated with increased development of 
cells in the bone marrow (i.e. being blood donor, anemia, infections etc.).  
 BAS questionnaire: Pain, patient global assessment, BASDAI and BASFI. 
 HAQ questionnaire 
 Examination of 66/68 periperal joint (tender/swollen). 
 Treatment after the study visit. 
 Concomitant medication (also in relation to all other diseases). 
 Accountability log for the IMP. 
 Registration SAE, SUSARs and Suspected Unexpected Adverse Reactions. 
 Pregnancy obtained in the study after initation of TNFα inhibitor. 
 Conventional blood tests (see section 14.1). 
15.8 Patient questionnaires used in the study 
The patient completes different questionnaires covering disease activity, functional ability, pain and 
the overall effect of the arthritis in everyday life. The individual components of the questionnaires 
are described below. 
 Patient Acceptable Symptom State (PASS) (see separate file). 

Protocol version 4.1, 3 November 2016 
31
 The BAS (Bath Ankylosing Spondylitis) questionnaire, which includes pain, patient global 
assessment, BASDAI and BASFI (see separate file). 
 The HAQ (Health Assessment Questionnaire) including 5 additional questions (2 
catagories) with relation to axial SpA (see separate file) 
 The ASAS Health Index (ASAS HI) including contextual factors (see separate file). 
 Quality of life: Short-Form-36 (SF-36), EuroQol and 15D 
 Fatigue: Multidimensinal Fatigue Inventory (MFI) (see separate file) and the Bristol 
Rheumatoid Arthritis Fatigue MultiDimentionelt Queationnaire, (BRAF-MDQ and BRAF-
NRS) (see separate file). 
 Sleep: Pittsburgh Sleep Quality Index (PSQI) (see separate file).  
 Depression: Center for Epidemiologic Studies Depression Scale (CES-D) (see separate file). 
 
Pain 
On a horizontal visual analogue scale (VAS scale), the patient indicates the degree of pain. The 
scale is divided into an area from "no" to "intolerable” pain. The scale is a horizontal 100 mm line 
and the distance (in mm) from "no" is recorded.  
 
Patient global 
The patient's general assessment of the influence of the disease on life is indicated on a VAS scale 
(0-100 mm) as descriebed above (see separate file). 
 
BASDAI (Bath Ankylosing Spondylitis Disease Activity Index) 
On VAS scales (0 to 100 mm) the patient indicates the severity of six types of discomfort related to 
disease activity59. A BASDAI index is calculated based on the patient's replies to the six questions 
(see separate file). 
 
BASFI (The Bath Ankylosing Spondylitis Functional Index) 
The patient indicates on VAS scales (0 to 100 mm) the ability to perform 10 actions or 
movements60. The questions are primarily related to axial arthritis. A BASFI index is calculated 
(see separate file). 
 
HAQ (Health Assessment Questionnaire) 
The patient's functional status is assessed using a questionnaire with 20 questions that assesses how 
difficult it is for the patient to perform eight functions. The questions are primarily related to 
arthritis in peripheral joints. A score (HAQ score) is calculated (see separate file). The 
questionnaire is extended so it includes 5 additional questions (2 catagories) with relation to axial 
SpA. 
 
ASDAS (Ankylosing Spondylitis Disease Activity Score) 
A new compositive measure of disease activity based on four answers from BASDAI in the BAS 
questionnaire and CRP 61.  
 
Patient Acceptable Symptom State (PASS) 
Includes essentially a single question about the patient find the current state of disease acceptable 
(yes/no) 62. However, methodologic researchers has developed several different versions of the 
question, which may lead to different answers. Three of the questions will be used in the study (see 
separate file). 
 
ASAS Health Index 
Furthermore, a Danish translation of the ASAS Health Index will be applied in the study. ASAS 
Health Index is a new 17 item questionnaire that covers patients’ perception of their physical 
function, activity and participation63. The questionnaire includes 9 additional questions, which are 

Protocol version 4.1, 3 November 2016 
32
believed to constitute important contextual factors, which also should be assessed (see separate 
file). 
 
The patient's assessment of health related quality of life 
The patients complete three different questionnaires to assess their own health related quality of 
life: SF3664, EuroQol 65 and 15D66. These questionnaires assess different aspects of health related 
quality of life (see separate file).  
 
The Multidimensional Fatigue Inventory (MFI) 
The Multidimensional Fatigue Inventory (MFI)67 includes 20 questions. It was primarily invented 
for cancer patients, but today it is regarded a generic instrument for assessment of fatigue. MFI is 
included to have a conventional measure of fatigue (see separate file).. 
 
The Bristol Rheumatoid Arthritis Fatigue Scale (BRAF) 
The Bristol Rheumatoid Arthritis Fatigue Scale (BRAF)68 is a new questionnaire, that includes 23 
questions related to fatigue in patients with rheumatoid arthritis. Only few studies have used the 
BRAF questionnaire, and none of these have included patients with axial SpA, who often complain 
of fatigue (see separate file). 
 
The Pittsburgh Sleep Quality Index (PSQI) 
Sleep quality is assessed by the Pittsburgh Sleep Quality Index (PSQI)69. This questionnaire 
includes 9 questions, and is one of the most used sleep quality questionnaires (see separate file).  
 
The Center for Epidemiologic Studies Depression Scale (CES-D) 
The Center for Epidemiologic Studies Depression Scale (CES-D)70 is a screening instrument for 
depression in epidemiologic studies. In this study it is included because depression is a well-known 
confounder for fatigue and sleep disturbances, and it may also affect physical function, activity and 
participation, which is assessed by ASAS HI (see separate file).  
15.9 Physical examinations 
The physical examination includes both a general physical examination and an assessment of the 
presence of spondyloarthritis-related diseases and co-morbidities. If possible, the same 
rheumatologist perform all the examinations of an individual patient.  
 
General physical examination 
Performed at weeks 0, and 52, and when necessary. The general physical examination includes an 
assessment of the general condition, fidings in oral cavity, lymph node status, auscultation of heart 
and lungs, abdominal examination, musculoskeletal conditions, skin and neurology.  
 
The Bath Ankylosing Spondylitis Metrology Index (BASMI) 
The treating rheumatologist performs five measurements, where the results for each conventionally 
is transformed to a scale from 0 to 2 and the BASMI 0-2 score is subsequently calculated. In this 
study the exact result of the 5 measurements are recorded so different version of BASMI can be 
calculated i.e. the conventional BASMI 0-2 and the linear BASMI 0-10. Performed at all study 
visits (see separate file). 
 
Thorax expansion 
Thorax expansion is measured at maximum inspiration following a maximum expiration 
corresponding to the fourth intercostal space in men and just below the breast in women. Performed 
at weeks 0, 4, 16, 28, 40 and 52.  
 
Assessment of joints 

Protocol version 4.1, 3 November 2016 
33
In total 66 joints are examined for swelling and 68 joints for tenderness. The following joints are 
examined: Right and left temperomandibular joint, sternoclavicular joint, acromioclavicular joint, 
humeral articulation, elbow joint, wrist, midtarsal joint, ankle joint, knee joint, hip joint (for 
tenderness only) as well as carpometacarpal joint, 10 MCP-joints, 10 PIP-joints, 10 DIP-joints in 
the hands and 10 MTP-joints, great toe joints, PIP-toe joints. The result of the joint examination 
should be stated on a separate joint examination sheet. All patients are examined whether or not 
they have symptoms in the joints. Performed at all study visits. 
 
Assessment of entheses 
The following entheses will be assessed clinically: Medial and lateral epicondyle of humerus, 
supraspinatus tendon insertion into the greater tuberosity of humerus, 1st and 7th costochondral 
joint, iliac crest, anterior superior iliac spine, posterior superior iliac spine, spinous process of L5, 
tuber ishiadici, greater trochanter of femur, medial and lateral femur condyle, quadriceps tendon at 
the insertion into patella, the patella ligaments insertion into patella and tibia, Achilles tendon and 
fascia plantaris at the insertion into calcaneus. From these different enthesis indices will be 
calculated: Berlin 71, San Francisco72, Leeds 73, SPARCC 74, and MASES75. Performed at weeks 0, 
4, 16 and 52. The assessment of enthesitis on whole-body MRI will include the above mentioned 
entheses and other entheses e.g. at pelvis, which cannot be examined clinically due to their location 
in the body. 
 
Assessment of other co-morbidities (uveitis and psoriasis) 
The patient is asked about signs of uveitis and if necessary the patient is referred to an 
ophthalmologist. The patient is also asked about signs of psoriasis, and if present, the patient is 
examined. Performed at all study visitis. 
 
The physician's assessment of disease activity 
Should be stated on both BAS and HAQ. This is a subjective assessment on a 100 mm VAS scale. 
Performed at all study visits. 
15.10 Imaging 
MRI 
Whole-body MRI, diffusion weighted MRI and conventional MRI of the sacroiliac joints and spine 
will be performed on all patients before inclusion as well as at weeks 4, 16 and 52. The MRI in 
connection with screening should be performed as close to week 0 as possible, and in any case not 
earlier than 4 weeks before. The MRIs are performed on the same 3T MRI maschine.  
 
The duration of the MRI scans will be less than 60 minutes. A final scan protocol will be available 
before study start. All MRIs are performed on the same scanner. 
 
The MRI protocol is under development and will be available before the first patient is included in 
the study. There will not be used any intravenous MRI contrast in the study.  
 
Conventional radiography  
X-rays of the SI-joints and the total spine (lumbar, thoracic and cervical spine) will be will 
performed on all patients prior to inclusion as well as at week 52.  
 
15.10.1 Evaluation of X-ray and MR images 
A trained SpA expert assesses X-rays and conventional MRI of SI-joints and spine obtained before 
inclusion. The results regarding presence of sacroilitis and radiological SpA diagnosis are send to 
the department. The first whole-body MRI is reviewed by a radiologist for unexpected changes (e.g. 
in the organs) that should prompt further investigation. The scans are only reviewed and no detailed 
description is given. The remaining MRI scans including whole-body MRI are not described while 

Protocol version 4.1, 3 November 2016 
34
the project is going on, and will only in special circumstances be descriebed. The scans are not 
evaluated for clinical practise after the study, but if there are a special clinical indication it may be 
possible to have a description of the conventional MRI performed at week 52.  
After the end of the study the X-rays and MRI scans will be anonymised and evaluated in 
accordance with international guidelines at the time of evaluation and by use of validated MR-
scores. The readers are experienced with MRI and conventional radiography in SpA. Those who 
evaluate the MRI images will be blinded for clinical, biochemical and other imaging data as well as 
in relation to the chronology of the images. 
15.11 Biochemical analyses 
Conventional biochemical and urinary analyses 
At the screening visit and at all other scheduled study visits the following blood samples will be 
performed: Haemoglobin, CRP, leukocytes, differentials, platelets, albumin, ALAT, LDH, alkaline 
phosphatase, creatinine. The urine is analysed for haemoglobin, albumin, glucose, leukocytes and 
nitrite. All above-mentioned samples are analysed at the local biochemical department. ANA 
screening is performed at screening and week 52. The volume comprise 11 ml. at the inclusion and 
week 52 study visit and 7 ml. at all other visits.  
The urine is analysed for haemoglobin, albumin, glucose, leukocytes and nitrite at screening, 
inclusion and at week 4, and therafter only when considered clinically necessary. 
 
Experimental biochemical analyses 
The following experimental biomarkers will be measured by central research laboratories 
experienced in these types of analysis. Commercial methods for analyses will be used such as 
ELISA technique, gene and microRNA arrays and PCR. Since the methods improves all the time, 
the methods used for the analyses of the experimental biomarkers in this study will not be decided 
before the analyses are performed. 
 
Blood and urine samples for analyses of experimental biomarkers are obtained at weeks 0, 4, 16 and 
52, and stored at -80C˚ and -2C˚, respectively. A detailed description of the acquisition, handling 
and storage of these samples are provided in the laboratory manual, see Appendices section 38. The 
blood and urine volumn for analyses of experimental biomarkers comprise 254 ml and 40 ml, 
respectively, for all 4 study visits. 
 
The following biomarkers are measures 
 Conventional CRP and high sensitivity (hs-) CRP 
 Biomarkers of inflammation: IL-6, IL-22, IL-23 and VEGF 
 Biomarkers of cartilage and extracellular matrix formation and degradation: CTX-II, MMP-
3, N-terminal peptide of procollagen type II (PIINP), MMP-derived type II collagen 
neoepitope (C2M), and MMP-derived type III collagen neoepitope (C3M) 
 Biomarkers of bone turnover: DeoxyPYD, CTX-I, OC, PINP, sclerostin and periostin 
 Citrullinated vimentin 
 HLA-B27 
 
It is to be expected that new potential biomarkers (proteins, genes, mRNA, mikroRNA, 
metabolittes) including genetic markers for assessment of disease activity, treatment response and 
prognosis in patients with axial SpA will be discovered within the next 5-10 years. Therefore blood 
and urine samples will be stored in a research biobank until December 2019, and thereafter the 
samples will be moved to a biobank dedicated for future research. For further information on the 
biobank, see section below. Before biochemical analyses not included in this protocol are 
performed, the steering committee has to apply the Ethical Committee for permission. The gene 
analyses that may be performed later on, will NOT include a substantial analyses of the genome (in 

Protocol version 4.1, 3 November 2016 
35
Danish: omfattende kortlægning af individets arvemasse), but will be performed only to identify the 
presence of pre-specified genes, that may contribute to an improved assessment of clinical disease 
activity, treatment response or prognostication for patients with axial SpA including AS. 
15.12 Oprettelse af forskningsbiobank (section in Danish) 
Blodprøverne vil blive taget ved inklusion, 4, 16, og 52 uger og ved evt. eksklusion. Projekt- og 
rutineblodprøver tages samtidigt. Projektblodprøverne udgør 77 ml ved det første besøg og derefter 
59 ml ved de øvrige 3 besøg svarende til i alt 254 ml. over 52 uger. Blodprøver mærkes i 
”anonymiseret” form (patientnummer, initialer og dato).  
Blodprøverne opbevares i en minus 80 
oC fryser i ”Videncenter for Reumatologi og 
Rygsygdomme”, i det forskningslaboratorium, der hører under professor Mikkel Østergaard. 
Urinprøverne opbevares ved minus 20 oC. Såvel blod- og urinprøver opbevares i en aflåst fryser i et 
aflåst lokale geografisk adskilt fra Reumatologisk Ambulatorium. Fryseren er under kontinuerlig 
central elektroniske overvågning døgnet rundt i forhold til temperaturændringer. Separat herfor 
opbevares en liste med den ”nøgle”, som kobler patientnummer til CPR-nummer. Denne liste 
bruges alene i forbindelse med, at prøvesvar kobles til kliniske oplysninger og MR-fund, som led i 
dataanalyse i projektet. Kun Susanne Juhl Pedersen og bioanalytiker Teresa Rozenfeld og evt. andre 
personer, som har fået tilladelse hertil af Region Hovedstaden/Glostrup Hospital, vil have adgang til 
disse lister. Listerne opbevares på separat netværks drev, iht. databehandlingsaftalen med Region 
Hovedstaden og Glostrup Hospital. 
Biobankens styregruppe udgøres af læge, ph.d. Susanne Juhl Pedersen, professor Mikkel 
Østergaard, overlæge ph.d. Inge Juul Sørensen. Blodprøverne samt de tilhørende kliniske data vil 
blive gjort tilgængelige for andre forskere med interesse for patienter med aksial SpA efter skriftlig 
aftale med styregruppen.  
Eksterne samarbejdspartnere i ind- og udland, der måler på blodprøverne, vil få disse tilsendt i 
anonymiseret form og i afmålte voluminer, og evt. overskydende materiale returneres til 
forskningsbiobanken. De fleste af blod- og urinprøverne analyseres af bioanalytiker ansat på 
Glostrup Hospital. Der foreligger aktuelt ingen aftaler med eksterne samarbejdspartnere herunder 
udenlandske samarbejdspartnere, og det kan derfor ikke på nuværende tidspunkt oplyses, hvem der 
evt. vil blive samarbejdet med. Den gældende lovgivning for udlevering af biologisk materiale og 
data følges. 
Bestemmelse af andre biomarkører end dem, der er beskrevet i denne protokol, skal godkendes 
styregruppe og derefter separat af Videnskabsetisk Komité. Forud for blodprøvetagningen giver 
patienten informeret samtykke til afgivelse af blod, der indsamles og opbevares i en 
forskningsbiobank til analyse af forudbestemte prøver, der er nævnt i indeværende protokol og til 
senere analyse af nye biomarkører som omfatter proteiner, gener, mRNA, mikroRNA og 
metabolitter med relation til sygdomsaktivitet, behandlingsrespons og prognose hos patienter med 
axial SpA inkl. AS.  
Prøverne vil befinde sig i forskningsbiobanken indtil og med december 2019. Herefter overgår 
blod- og urinprøverne til en biobank mhp. fremtidig forskning. Blodprøverne opbevares ialt i 25 år 
fra studiets afslutning dvs. frem til december 2041, hvorefter materialet destrueres. Lov om 
behandling af personoplysninger vil blive overholdt. 
16 STATISTICS 
16.1.1 Statistical plan for primary objective 
The plan for the statistical analyses for the primary objective is provided below.  
 
The primary analysis set will be the intention-to-treat (ITT) population, which comprises all 
included patients. An additional Per Protocol (PP) analysis will be done as a robustness analysis. 

Protocol version 4.1, 3 November 2016 
36
Included patients will be divided into: 
1. Clinical non-responders versus clinical responders at week 16 and 52 (based on BASDAI 
response respectively on ASDAS response (delta-ASDAS>1.1). Fulfilment (yes/no) of 
BASDAI50 improvement (=reduction in BASDAI of >50% or 20 mm) at week 52 is the 
primary clinical endpoint.  
2. MRI remission versus MRI non-remission: Minimal (≤1 DVU affected; equalling MRI-
remission) versus above-minimal (MRI activity in >1 DVU) MRI activity at week 16 
3. MRI-responders (50% reduction in conventional MRI spine score at week 16.  
 
The statistical analyses will include: 
Descriptive statistics for all patients, responders and non-responders (number, median/mean/range 
of conventional and experimental data). 
 
Comparison between groups mentioned above (responders vs. non-responders, MRI-
remission vs. MRI non-remission) 
o 
Changes in biomarkers, imaging and clinical parameters 
 Changes within the groups: Paired T-test (in case of normal distribution), 
Wilcoxon-Pratt test (in case of non-normal distribution) 
 
Comparison between the groups – unpaired T-test (normal distribution) or 
Mann Whitney test (non-normal distribution).  
o 
Week 0 (baseline), week 4, week 16, week 52 and AUC (area under the curve) 
values for biomarkers as well as imaging and clinical parameters 
 
Unpaired T-test or Mann-Whitney test (see above) 
 
Correlation analysis 
o 
Test for correlation (Pearson's test if normal distribution, Spearman's if non-normal 
distribution) between: 
 
Changes in biomarkers, clinical and imaging parameters between baseline 
and week 4, 16 and 52  
 
Absolute values for biomarkers, clinical and imaging parameters both at 
baseline and week 4, 16 and 52 
 
Furthermore, clinical and MRI outcomes at week 52 will be compared between patients with and 
without clinical and MRI response at weeks 4 and 16 and between patients with and without MRI-
remission at week 4 and 16, and the correlation between the image parameters internally and with 
clinical parameters will be assessed by unpaired T-tests/Mann-Whitney tests, correlation analysis 
and logistic regression (to assess predictive value).  
 
Finally, as a secondary analysis, the predictive value of the MRI parameters will be compared to the 
predictive value of the matrix model developed by Vastesaeger et al1 
Finally, the variation between the evaluators will be assessed upon repeated blind evaluation of 
imaging data, and the smallest demonstrable difference (SDD) calculated. Based on SDD, the 
number of definitive cases of improvement/worsening for the individual measures will be 
calculated. 
 
For secondary and tertiary outcome measures, an analysis plan will be developed before start of the 
analyses. This is reasonable since there within the the next few years will be publications with 
relation to ASAS HI and maybe also some of the experimental biomarkers, which are important for 
the planning of the analyses. 

Protocol version 4.1, 3 November 2016 
37
16.2 Sample size calculation 
16.2.1 Sample size calculation for the primary objective 
The calculation of power in this study is based on the following:  
a. Concerning the sensitivity of conventional versus whole-body MRI to detect inflammation 
in patients treated with TNFα inhibitor therapy: the expected proportion of patients who has 
a “conventional MRI minimal disease activity” at week 16 is assumed to be 0.5 (based on 
Braun et al, Ann Rheum Dis, 201276), whereas the assumed proportion of patients with “a 
minimal WBMRI MRI disease activity” is 0.25. With a risk of type 1 error of 5% (=0.05) 
and a power of 70% (ß=0.30), 37 patients will be needed to test a difference between the 
sensitivities of the 2 methods.  
b. Concerning MRI response at week 16 predicting clinical response at week 52: 60% of 
patients are expected to have an “MRI response” (defined as 50% reduction in conventional 
MRI activity) at week 16. Among MRI responders at week 16, the expected proportion of 
patients who have a clinical response at week 52 is 80%, whereas 40% among MRI-non-
responders at week 16. With a risk of type 1 error of 5% (=0.05) and a power of 70% 
(ß=0.30), 38 patients will be needed to test the predictive value of early MRI response for 
clinical response at week 52. 
c. Concerning “MRI remission” at week 16 predicting clinical response at week 52: 50% of 
patients are expected to be in “conventional MRI remission” (defined as ≤ 1 DVU with MRI 
inflammation) at week 16. The expected proportion of patients who have a clinical response 
at month 52 is 80% among patients with “conventional MRI remission” at week 16 and 40% 
among those without “conventional MRI remission” at week 16. With a risk of type 1 error 
of 5% (=0.05) and a power of 70% (ß=0.30), 46 patients will be needed to test the 
predictive value of early MRI remission for clinical response at week 52. 
 
Experience shows that a dropout of at least 4 patients (app. 10%) can be expected. On this basis a 
sample size of 50 patients has been decided. 
It is not possible to calculate the exact number of patients, who have to complete the study to ensure 
a high power in the statistical analysis of biomarkers, since the variation of the biomarkers is 
unknown. 
16.2.2 Sample size calculation for secondary and tertiary obejectives  
Since there is no studies published on ASAS HI and only few studies published for many of the 
biomarkers, little is known about the variation in these and therefore it is not possible to calculate 
the sample size. Thus, this part of the study can be considered a ‘pilot’ study. It is anticipated, that 
the study population has a sufficient size to perform a later assessment of the variation. 
16.3 Criteria for ending the trial 
There are no statistical criteria for ending the trial.  
16.4 Procedures for missing data and data not used etc.  
Details of imputation for missing data due to protocol deviation or premature withdrawal will be 
pre-specified a detailed plan of the statistical analyses before these are performed.  
16.5 Access to source data and other documents 
The Investigator will permit study-related audits by the study coordinator and inspections by the 
Scientific Commetee after reasonable notice. The main purposes of an audit or inspection are to 
confirm that the rights and well-being of the subjects enrolled have been protected, that enrolled 

Protocol version 4.1, 3 November 2016 
38
subjects (i.e. signing consent and undergoing study procedures) are appropriate for the study, and 
that all data relevant for the evaluation of the investigational medicinal product have been processed 
and reported in compliance with the planned arrangements, the protocol, investigational site, Ethical 
Committee and rules for GCP. The Investigator will provide direct access to all study documents, 
source records, and source data. If an inspection by a regulatory authority is announced, the 
Investigator will immediately inform Mikkel Østergaard. 
16.6 Handling, processing and storage of data 
16.6.1 Practical handling of source documents 
All source documents (paperbased or electronic) must be accurate, clear, unambiguous, permanent, 
and capable of being audited. The primary CRF in this study will be an electronic CRF, with a 
paper based back-up. 
The paper CRF should be filled-in with some permanent form of recording. Corrections are made 
according to the GCP. Changes should not be obscured by correction fluid or have temporary 
attachments such as removable self-stick notes. Photocopies of CRFs are not considered acceptable 
source documents. Any change or correction to the paper CRF should be dated, initialed, and 
explained (if necessary) and should not obscure the original entry. Use of correction fluid is not 
permitted. For the e-CRF, for all data entry and changes it should be possible to track who 
entered/changed data, time points, and the original data if changed. Detailed instructions will be 
provided in the CRF Completion Guidelines. 
The investigator will maintain a list of personnel authorized to enter data into the paper and e-CRF. 
16.6.2 Storage of source documents 
Source documents on paper should be kept in a secure, limited access area at the centers according 
to the Danish Legislation. Sponsor store the orginal paper CRF, whereas investigator store a copy of 
the paper CRF. The e-CRF is located in the DANBIO database (https://danbio-online.dk/Danbio-
yearly-report-2007-eng.pdf/view), where data are stored also according to Danish Legislation i.e. 10 
years. If data is entered directly into the e-CRF at the visit, the e-CRF is the sorce document.  
17 ETISKE FORHOLD (SECTION IN DANISH) 
17.1 Generelle etiske forhold 
Forsøget vil blive gennemført i overensstemmelse med anbefalinger vedrørende biomedicinsk 
forskning med mennesket som forsøgsperson, som vedtaget af den 18. World Medical Assembly, 
Helsinki, Finland, juni 1964 og senere revisioner. 
God klinisk praksis kræver, at den kliniske protokol, alle protokolændringer, informeret 
samtykkeerklæring, og alle andre former for deltagerinformation (f.eks. annoncer til rekruttering af 
deltagere) samt alle andre nødvendige dokumenter skal vurderes af den Videnskabssetiske Komité. 
Der vil blive indhentet godkendelse af protokollen, den informerede samtykkeerklæring, al 
information 
til 
deltagerne 
og/eller 
eventuelle 
annoncer 
fra 
Lægemiddelstyrelsen 
og 
Videnskabssetiske Komité før påbegyndelse af forsøget. 
I løbet af forsøget skal sponsor straks udlevere skriftlige rapporter til Lægemiddelstyrelsen og 
Videnskabsetiske Komité vedrørende enhver ændring, som har betydning for udførelsen af forsøget 
og/eller øger risikoen for deltagerne. Det er ligeledes sponsors ansvar at holde Lægemiddelstyrelsen 
informeret om enhver alvorlig utilsigtet hændelse i henhold til lovgivningen. 

Protocol version 4.1, 3 November 2016 
39
17.2 Etiske forhold vedr. denne undersøgelse 
17.2.1 Etiske forhold til behandling 
De patienter, der tilbydes inklusion i forsøget, er alle patienter med vedvarende moderat til høj 
sygdomsaktivitet, der i daglig klinisk praksis er kandidater til behandling med TNFα inhibitor. Der 
inkluderes ikke patienter, der under normale forhold ikke ville blive tilbudt denne behandling. 
Golimumab blev sammen med tre andre TNFα inhibitorer sidste år vurderet af et ekspertpanel 
under Rådet for Anvendelse af Dyr Sygehusmedicin (RADS), der fandt, at de alle var ligeværdige i 
forhold til effekt og bivirkninger til behandling af axial SpA. Efter en udbudsrunde blev 
Golimumab valgt som førstevalgspræparat til denne patientgruppe til og med år 2015. Da der derfor 
ingen etiske overvejelser ved valget af behandlingen i forsøget, da patienterne uden for forsøget vil 
blive tilbudt den samme behandling. Golimumab gives i forsøget i den rekommanderede dosis. 
Hvilken TNFα inhibitor behanding, der bliver første valgsbehanding i næste udbudsrunde vides 
aktuelt ikke. 
Såfremt patienterne forud for inklusion dagligt behandles med NSAID (non-steroide-anti-
inflammatoriske stoffer, gigtmedicin), skal denne behandling så vidt muligt fastholdes i de første 4 
uger af forsøget. En del patienter er dog ophørt med NSAID grundet manglende behandlingseffekt, 
eller fordi de ikke tåler NSAID, og de skal ikke tage NSAID i forsøget. Ligeledes skal patienter, der 
er i behandling med DMARDs (f.eks. methotrexate eller salazopyrin) grundet perifer ledinvolvering 
forblive i denne behandling til og med uge 16. Dosis fastholdes fra 4 uger inden inklusion til uge 4 
eller så længe der er behov herfor. I daglig klinisk praksis vil man normalt før vælge at trappe ud af 
DMARD behandling efter at man har sikret sig, at der er et tilstrækkeligt behandlingsrespons på 
Golimumab. Efter uge 4 må patienterne tage NSAID ved behov og efter eget ønske, og patienter i 
behandling med DMARDs kan evt. reducere eller ophøre med behandlingen efter aftale med den 
behandlende læge. 
17.2.2 Etiske forhold til MR-skanning og røntgenundersøgelse 
Udsættelse for MR-skannerens radiobølger og magnetfelt er uden bivirkninger, og giver ikke nogle 
skadelige følger på kortere eller længere sigt. MR-skanningerne udføres uden anvendelse af 
intravenøst kontrastmiddel. En MR-skanning indebærer ingen røntgenbestråling. 
Da tidligere studier omfattende patienter med SpA og reumatoid arthritis har vist, at signifikante 
ændringer i MR-inflammations score kan observeres efter 4 til 6 ugers behandling med TNFα 
inhibitor, er det i forsøget valgt at gennemføre den første opfølgningsskanning efter 4 uger, da 
behandling med Golimumab gives hver måned (på den samme dato). 
Ved helkrops MR-skanningen fokuseres der på såvel perifere led som rygsøjlens led. Det betyder, 
at de indre organer kun fremstilles som mørke skygger. Undersøgelsen kan derfor ikke anvendes 
som screening for sygdomme i de indre organer, og resultaterne vedr. leddene må betragtes som 
eksperimentelle, da helkrops MR-skanning ved gigtsygdomme er et helt nyt videnskabeligt 
forskningsområde. Der foreligger en lille risiko for, at helkrops MR-skanningen afslører ikke 
forventede forandringer i de indre organer. Dette vil medføre yderligere billeddiagnostiske og evt. 
biokemiske undersøgelser, der kan opleves som en psykisk belastning. Omvendt kan deltagelse i 
studiet også potentielt medføre, at nogle få patienter får diagnosticeret en behandlingskrævende 
sygdom tidligere end ellers med forbedret prognose til følge. Den første helkrops MR-skanning vil 
blive set igennem af en erfaren radiolog mhp. dette.  
Diffusionsvægtet MR-skanning er en ny skanningsmetode, der kun er blevet udersøgt i få studier. 
Det vides endnu ikke om skanningen kan finde klinisk anvendelse og der gives derfor ikke svar på 
denne skanning, der heller ikke vurderes i forbindelse med patientens inklusion i studiet.  
I dag kendes værdien af MR-skanning til vurdering af behandingseffekt og prognose hos patienter 
med aksial SpA ikke, og den anvendes derfor ikke rutinemæssigt i den kliniske dagligdag. For at 
kunne vurdere betydningen af fund på MR-skanning mest optimalt, vil alle fraset studiekoordinator 
være blindet for MR-skanningerne udført under studiet. Der vil blive udsendt et skriftligt svar på 

Protocol version 4.1, 3 November 2016 
40
skanningen udført forud for inklusion, men ikke på de øvrige skanninger. MR-skanningen vil ellers 
kunne blive anvendt til vurdering af behandlingseffekt på et ikke evidensbaseret grundlag, hvilket 
vil kunne medføre en skævvridning af studiets resultater (bias) i studiet, der dermed ikke vil kunne 
genere valide resultater.  
Ved røntgenundersøgelserne af sacroiliacaled og rygsøjle udsættes patienten for røntgenstråling 
svarende til den naturlige baggrundsstråling over 1 år. Røntgenundersøgelse af rygsøjle og 
sacroiliacaled i daglig klinisk praksis er standardundersøgelser i forhold til klassifikation af 
sygdommen og for vurdering af sygdomsprogression, og de billeder der tages i forsøget erstatter de 
undersøgelser, der ellers ville blive taget i daglig klinisk praksis. Efter studiets afslutning vil 
billederne blive tilgængelige for klinisk brug. 
17.2.3 Etiske forhold til blodprøvetagning 
Det forudgående screeningsprogram, og de gentagne rutineblod- og urinprøver, der tages af 
sikkerhedsmæssige årsager svarer i indhold og hyppighed til daglig klinisk praksis. 
Projektblodprøverne vil blive taget ved inklusion, 4, 16, og 52 uger og ved evt. eksklusion. Projekt- 
og rutineblodprøver tages samtidigt. Projektblodprøverne udgør 76 ml ved det første besøg og 
derefter 58 ml ved de øvrige 3 besøg svarende til i alt 254 ml. over 52 uger, hvilket ikke påvirker 
patientens blodprocent eller helbred i øvrigt. Klinisk vil patienterne traditionelt blive vurderet ved 
læge mindst 6-7 gange i det første år. Det betyder i praksis, at deltagelse i studiet ikke medfører 
ekstra konsultationer på reumatologisk afdeling end som i den kliniske dagligdag. 
Undersøgelsen forventes at kunne bidrage med ny væsentlig viden om anvendelsen af MR-skanning 
til monitorering og forudsigelse af behandlingsrespons. De potentielle patientfordele skønnes derfor 
etisk at retfærdiggøre de ulemper, som undersøgelsen medfører for patienterne i form af gener i 
forbindelse med gentagne kliniske, biokemiske og billeddiagnostiske undersøgelser, samt for de 
deltagende afdelinger i form af øget ressourceforbrug. 
17.2.4 Etiske forhold til spørgeskemaer 
Patienterne besvarer en lang række spørgeskemaer i studiet vedr. sygdomsaktivitet og livskvalitet, 
hvilket de også rutinemæssigt gør i daglig klinisk praksis via den landsdækkende reumatologiske 
database, DANBIO (www.danbio-online.dk). Derud får de studiet et nyt spørgeskema omhandlende 
fysisk funktion, aktivitet og deltagelse, som er udarbejdet særligt til denne patientgruppe (ASAS 
Sundhedsindex). Spørgsmålene vedr. fysisk aktivitetsniveu og spørgeskemaerne vedr. udmattethed 
(fatigue), søvn og depression er medtaget for at kunne analysere besvarelserne af ASAS HI mest 
optimalt. Flere af disse spørgeskemaer er eksperimentelle, da de ikke tidligere har været anvendt på 
denne patientgruppe. Den behandlende læge vil have adgang til oplysninger om, hvorvidt alle de 
ikke traditionelt anvendte spørgeskemaer er blevet besvaret, men ikke til selve besvarelsen af disse 
ud over for depressionsscreeningen (CES-D).  
For depressionsscreeningen vil den behandlende læge kunne se hvilken svargruppe, som patienten 
tilhører jfr. definitionerne i spørgeskemaet. For patienter, der har iht. spørgeskemaet har en 
“possible major depressive episode”, “probable major depressive episode”, eller “meets criteria for 
major depressive episode”, vil den behandlende reumatolog vurdere om patienten har en 
depression. Dette gøres på samme måde ved en almindelig konsultation i reumatologisk 
ambulatorium, og det dokumenteres på tilsvarende vis i patientjournalen. Det er kendt at 
screeningsspørgeskemaer ikke altid diagnosticerer patienterne korrekt, herunder vil nogle fejlagtigt 
blive screenet positivt for depression uden at have det og vice versa. Da flere af symptomerne, der 
ses ved axial SpA også ses ved depression (f.eks. natlig opvågning), så er dette af og til en 
differentialdiagnostisk overvejelse i klinisk praksis, og indgår i vurderingen af patienten. Patienter, 
der i hht. spørgeskemaet viser tegn på depression, vil blive vurderet af den behandlende reumatolog 
og ved behov henvist til videre udregning og behandling hos egen læge eller psykiater. Det skønnes 
derfor ikke at udgøre et etisk problemstilling at anvende spørgeskemaet for depression i forsøget.  
 
 

Protocol version 4.1, 3 November 2016 
41
Det skønnes, at de resultater som forsøget vil kunne generere, langt overstiger ulemperne ved det 
forøgede tidsmæssige forbrug for de deltagende patienter og personale, samt de ricisi og 
belastninger, der i øvrigt er forbundet med deltagelse i forsøget. 
18 RISICI, BIVIRKNINGER OG ULEMPER (SECTION IN DANISH) 
18.1.1 Risici, bivirkninger og ulemper til behandling 
Patienten vil i forsøget modtage samme behandling som uden for forsøget, da den anvendte 
behandling er den samme, som den anbefalede behandling iht. retningslinjerne fra Rådet for 
Anvendelse af Dyr Sygehusmedicin (RADS) til og med år 2015. Fra år 2016 og fremefter vides det 
ikke, hvilken TNFα hæmmer som vil blive førstevalgsbehandling. I forsøget gives Golimumab i 
samme dosis og med samme tidsinterval, som det er recommenderet. Forsøget inklusionskriterier 
for opstart af behandling er de samme, som dem der anvendes i den kliniske dagligdag. Da forsøget 
kun omfatter patienter, der under alle omstændigheder ville blive tilbudt behandlingen, så udsættes 
ingen patienter for en risiko for bivirkninger, som de ikke ville bllive udsat for. 
Kontrolforanstaltningerne i forsøget de samme, som i den kliniske dagligdag. 
18.1.1 Risici, bivirkninger og ulemper til MR-skanning og røntgenundersøgelse 
Der er ingen kendte bivirkninger på kortere eller længere sigt ved gennemførelse af MR-skanning, 
når blot eksklusionskriterierne overholdes. Der skal ikke tages andre forholdsregler ved MRI i 3.0 T 
magnetfelt end i et 1.5 T magnetfelt, hvorfor der anvendes de samme eksklusionskriterier, og 
hvorfor f.eks. brugen af spiral (intrauterin device) ikke har nogen betydning for deltagelse. Den 
anvendte 3.0 T MR-skanner anvendes i daglig klinisk praksis på Herlev Hospital. Forud for 
inklusion i forsøget sikres det, at der ikke er kontraindikationer for MR-skanning. Dette gøres 
rutinemæssigt ved der udfyldes et skema vedr. disse når skanning bestilles. Disse retningslinjer er 
fælles for Region Hovedstadens. Desuden gennemgår radiograferne skemaet med forsøgsdeltageren 
lige før skanningen.  Der anvendes ikke intra-venøst kontraststof ved forsøget. MR-skanningerne i 
alt maksimalt tage 60 min., hvilket patienterne erfaringsmæssigt finder acceptabelt. Det er muligt at 
indlægge en pause midtvejs i skanningen. 
Der gennemføres en traditionel røntgenundersøgelse af columna totalis og sacroiliacaled 2 gange i 
løbet af studiet. Ved denne undersøgelse udsættes patienten for røntgenstråling svarende til 1 og 2.5 
mSv, hvilket svarer til den naturlige baggrundsstråling over ca. 1 år (www.sundhed.dk). Der er en 
ganske lille stråledosis, der skønnes at udgøre en meget lille risko. Det skønnes at denne dosis kan 
øge livstidsrisikoen for cancer med 1 ud at 100.000 til 1 ud af 10.000. Dette skal ses i lyset af at 
livstidsricikoen for at få cancer er ca. 25%.  
18.1.1 Risici, bivirkninger og ulemper til blodprøvetagning 
Under projektet vil der blive udtaget 318 ml. fuldblod (heraf anvendes de 254 ml. til analyse af 
projektblodprøver og 64 ml til analyse af rutineblodprøver), hvilket ikke vil indebære nogen risiko 
for blodmangel. Der er en ubetydelig risiko for infektion og hæmatom (lille blodansamling uden for 
venen), hvilket skønnes til mindre en 1 ud af 10.000. Begge er forbigående og giver kun anledning 
til minimale gener. 
De potentielle patientfordele på længere sigt i form af mere følsomme metoder til opfølgning og 
forudsigelse af sygdomsforløbet ved SpA skønnes klart etisk at retfærdiggøre de risici, bivirkninger 
og ulemper som deltagelse i studiet kan medføre. 
18.1.2 Ricisi, bivirkninger og ulemper til spørgeskemaerne 
En ulempe for patienterne er, at det tager tid at udfylde spørgeskemaerne, men vi skønner at den 
ekstra tid det tager, er rimelig i forhold til gevinsten af de resultater, der opnås, da aktuelt ikke 

Protocol version 4.1, 3 November 2016 
42
foreligger nogen viden om ASAS HI. Der foreligger i øvrigt heller ikke megen viden om 
udmattethed, søvn mv. hos denne patientgruppe, der har store problemer med forstyrret nattesøvn 
gr. sygdomsaktivitet. Det kan ikke udelukkes, at der er enkelte spørgsmål i ASAS HI og de øvrige 
spørgskemaer, som nogle patienter vil synes er for personlige til at de vil besvare, men vi skønner 
dog, at de vil udgøre en fåtal og derfor ikke udgøre et problem for undersøgelsen.  
Det er kendt at screeningsspørgeskemaer ikke altid får diagnosticeret patienterne korrekt, herunder 
vil nogle fejlagtigt blive screenet positive for depression uden at have det og vice versa. Derfor er 
selve besvarelsen af spørgeskemaet ikke det samme som en diagnose, der skal behandles. Den 
behandlende reumatolog vil for alle patienter, lige som de gør i daglig klinisk praksis vurdere om 
patienten har symptomer på depression, og såfremt der er mistanke herom henvise vedkommende til 
egen læge eller psykiater mhp. yderligere vurdering og behandling. Reumatologens vurdering 
baseres på et lægeligt skøn ud fra kendskabet til patienten og faglig vurdering på samme måde som 
i daglig klinisk praksis. Patienter, der har tegn på depression jfr. svarkategorierne (” possible 
major depressive episode”, ”probable major depressive episode” og ”meets criteria for major 
depressive episode”) iht. besvarelse af spørgeskemaet, vil blive vurderet for depression af den 
behandlende reumatolog på samme måde som i daglig klinisk praksis, og henvist til videre 
vurdering og behandling hos egen læge eller psykiater efter behov og efter aftale med patienten. 
For patienter, der har en depression, kan det såvel på kortere som på længere sigt kun være en 
fordel at få stillet diagnosen depression.  
Det skønnes, at de resultater som forsøget vil kunne generere, lagt overstiger ulemperne ved det 
tidsmæssige forbrug for de deltagende patienter og personale, samt de ricisi og belastninger, der i 
øvrigt er forbundet med deltagelse i forsøget. 
19 RESPEKTEN 
FOR 
FORSØGSPERSONERNERS 
FYSISKE 
OG 
MENTALE 
INTEGRITET SAMT PRIVATLIVETS FRED (SECTION IN DANISH) 
Oplysningerne om forsøgspersonen beskyttes efter lov om behandling af personoplysninger og 
sundhedsloven. Projektet anmeldes til Region Hovedstaden IMT og Glostrup Hospital, der 
varetager ”paraply”-anmeldelse af alle forskningsprojekter til Datatilsynet. Lov om behandling af 
personoplysninger vil blive overholdt. 
20 TILGÆNGELIGHEDEN AF OPLYSNINGER FOR FORSØGSPERSONEN (SECTION 
IN DANISH) 
Patienten informeres mundligt og skriftligt om navn, adresse, kontakt telefonnummer til den 
reumatolog, der behandler dem under studiet. De vil af vedkommende kunne få adgang til flere 
oplysninger om projektet. Ligeledes kan studiekoordinator Susanne Juhl Pedersen kontaktes per 
telefon eller e-mail adresse. 
21 INFORMATION AF PATIENTERNE (SECTION IN DANISH) 
21.1 Særlige forhold vedr. afgivelse af deltagerinformation i indeværende studie 
 Den første kontakt til forsøgspersonen vil foregå i relation til en ambulant kontrol i det 
reumatologiske ambulatorium på en af de deltagende afdelinger. Der anvendes ikke opslag. 
 Den mundtlige information i indeværende forsøg vil blive givet af den behandlende reumatolog 
ved eller i relation til en ambulant kontrol i reumatologisk ambulatorium. 
 Den skriftlige information kan udleveres før den mundlige information gives og vice versa. Det 
vil afhænge af de lokale forhold. 

Protocol version 4.1, 3 November 2016 
43
 Det sikres at informationssamtalen foregår uforstyrret ved at forsøgsdeltageren gives 
informationen ved en konsultation i reumatologisk ambulatorium. Såfremt, der foretages 
telefonisk kontakt spørges forsøgsdeltageren, om tidspunktet for kontakten er passende, og  
tilbydes i øvrigt en tid til samtale i reumatologisk ambulatorium. 
 Det sikres at forsøgspersonen får mulighed for at få en bisidder med ved informationssamtalen 
ved at gøre opmærksom på denne mulighed såvel skriftligt som mundtligt, og ved at 
forsøgspersonen tilbydes en ekstra informationssamtale, hvor bisidderen kan være tilstede. 
 Der vil mindst være en betænkningstid på 2-3 dage mellem den mundtlige/skriftlige information 
og den senere underskrift på samtykkeerklæringen. Typisk vil der være endnu længere tid og 
oftest et par uger. 
 Samtykket søges indhentet når en patient på afdelingen bliver kandidat behandling med TNFα 
hæmmer. Inden patienten kan tilbydes behandlingen har vedkommende betænkningstid vedr. om 
de ønsker behandlingen, og det skal på fælleskonference besluttes at afdelingen vil tilbyde 
han/hende behandlingen. I forbindelse med dette forløb informeres vedkommende om 
muligheden for at deltage i forsøget. Der vil derfor være en klar sammenhæng mellem 
stillingtagen til samtykket i relation til at informationen omkring forsøget er givet.  
21.2 Generelle forhold vedr. informtion til patienten før, under og efter forsøget 
Inden informationssamtalen:  
 Skal der træffes aftale om tid og sted for samtalen.  
 Skal det oplyses, at der er tale om en forespørgsel om deltagelse i et sundhedsvidenskabeligt 
forskningsprojekt. 
 Skal der gøres opmærksom på, at det er muligt at medbringe en bisidder til samtalen. 
 Skal der oplyses, om retten til betænkningstid efter informationen. Betænkningstiden afhænger 
af forsøgets karakter. Som udgangspunkt må denne være mindst et døgn. 
 Skal forsker have overvejet retten til at frabede sig viden om nye væsentlige helbredsoplysninger 
i projektet. 
 
Informationssamtalen:  
 Skal være nøje planlagt. 
 Skal foregå i uforstyrrede rammer og uden afbrydelser. 
 Skal tilrettelægges så forsøgspersonerne har tilstrækkelig tid til at læse den skriftlige 
information, lytte til den mundtlige information og stille spørgsmål. 
 Skal indeholde en forståelig fremstilling af forskningsprojektet uden brug af tekniske eller 
værdiladede vendinger, og gives på en hensynsfuld måde tilpasset modtagerens individuelle 
forudsætninger m.h.t. alder, modenhed, erfaring m.v. 
 Skal indeholde oplysning om eventuelle forudsigelige risici, bivirkninger, komplikationer og 
ulemper, samt at der kan være uforudsigelige risici og belastninger knyttet til deltagelse i et 
sundhedsvidenskabeligt forskningsprojekt. 
 Skal indeholde oplysninger om andre behandlingsmetoder, jf. § 5, stk. 3 i bekendtgørelse om 
anmeldelse og information, såfremt forskningsprojektet også har et behandlingsmæssigt sigte, 
samt om der i forbindelse med projektet indhentes oplysninger fra forsøgspersonens 
patientjournal. 
 Skal indeholde en beskrivelse af det informerede samtykkes omfang, herunder at samtykket 
omfatter adgang til videregivelse og behandling af nødvendige oplysninger om forsøgspersonens 
helbred, øvrige rent private forhold og andre fortrolige oplysninger som led i den kvalitetskontrol 
og monitorering, som en sponsor og eventuel monitor er forpligtede til at udføre, jf. § 5, stk. 5, i 
bekendtgørelse om anmeldelse og information. 
 Skal indeholde oplysninger om forhold, som forsøgspersonen i øvrigt skønnes at være uvidende 
om, men som har betydning for forsøgspersonens stillingtagen, fx at vederlag til deltagerne er 
skattepligtige. 
 

Protocol version 4.1, 3 November 2016 
44
Efter informationssamtalen:  
 Skal forsøgspersonen informeres, såfremt der under gennemførelsen af forsøget fremkommer 
nye oplysninger om effekt, risici, bivirkninger, komplikationer eller ulemper. 
 Skal den forsøgsperson, der fortsat er aktivt med i forsøget, informeres, såfremt 
forskningsprojektets forsøgsdesign ændres væsentligt i forhold til forsøgspersonens sikkerhed. 
 Skal forsøgspersonen informeres, såfremt der under gennemførelsen af forskningsprojektet 
fremkommer væsentlige oplysninger om forsøgspersonens helbredstilstand, medmindre 
forsøgspersonen utvetydigt har givet udtryk for, at den pågældende ikke ønsker dette, jf. 
bekendtgørelse om anmeldelse og information, § 14. 
 Skal den forsøgsansvarlige, eller den informerende sundhedsperson, ved projektets 
afrapportering informere forsøgspersonen om de resultater, der er opnået samt om eventuelle 
konsekvenser for den enkelte. Dette forudsætter, at det er praktisk muligt og forsøgspersonen 
ønsker dette.Hvis forsøget afbrydes, skal forsøgspersonen informeres om årsagen hertil. 
22 ØKONOMI (SECTION IN DANISH) 
Undersøgelsen er en investigator-initieret undersøgelse i gang sat af en gruppe reumatologer 
bestående af Mikkel Østergaard og Susanne Juhl Pedersen. MSD støtter studiet med i alt 2.513.231 
kr. og leverer medicin til 7 af de 12 måneder. 
 
Følgende budgetaftale er indgået: 
 
Løn til studiekoordinator   
 
 
 
     86.250 kr.1 
Løn til central bioanalytiker  
  
 
 
     37.375 kr.2 
Minus 80 grader fryser (ca. 50% af prisen) 
 
 
     32.488 kr. 
Statistiker 
  
30.015 kr. 
Gebyr ansøgning SST 
 
 
 
 
       5.750 kr. 
Monitorering, eCRF og dataindtastning  
 
 
   115.000kr. 
Ekstra til justering for prisstigninger  
 
 
 
   113.928 kr. 
Per patient per studiebesøg 
Screeningsbesøg 
 
 
 
 
       0,00 kr.  
Inklusionsbesøg3 
 
 
 
 
2.012,00 kr. 
Besøg uge 43  
 
 
 
 
1.437,00 kr. 
Besøg uge 163 
 
 
 
 
1.437,00 kr. 
Besøg uge 28 
 
 
  
 
   862,00 kr. 
Besøg uge 40 
 
 
 
 
   862,00 kr. 
Afsluttende studiebesøg4   
 
 
 
2.012,00 kr. 
Eksklusionsbesøg 
 
 
 
 
   862,00 kr. 
 
Per patient pr udført ydelse 
Analyse af eksperimentelle biomarkører  
 
 
1.765,25 kr. 
MR-skanning (udførelse, blinding og evaluering billeder) 
 
5.750,00 kr. 
Røntgenundersøgelse (udførelse, blinding og evaluering billeder) 
 
1.150,00 kr. 
 
De enkelte afdelinger indgår selv aftaler med deres lokale laboratorier om tagning af experimentelle 
blodprøver, opbevaring og forsendelse af disse, og betaler selv for disse ydelser. Beløbet per 
studiebesøg, hvor der indgår eksperimentelle blodprøver er forøget for at kompensere herfor, om 
end det ikke nødvendigvis dækker de fulde omkostninger. Beløbet, der udbetales for de kliniske 
besøg omfatter også alle øvrige udgifter i forbindelse med forsøget herunder aflønning af personale 
for selve besøget, initeringsmøde, modtagelse og håndtering af medicin mv. 
MSD overfører alle beløb vedr. studiet til en forskningskonto på Glostrup Hospital. MSD overfører 
midlerne iht. en aftale vedr. datoer for opnåelse af ”milestones”. Mikkel Østergaard overfører 

Protocol version 4.1, 3 November 2016 
45
midler til de deltagende afdelingers forskningskontier. De deltagende afdelinger afregner selv med 
deres respektive laboratorier. De deltagende afdelinger får samlet udbetalt midler når den sidst 
inkluderede patient har gennemført sidste studiebesøg. 
 
De deltagende afdelinger bidrager med medicin til de sidste 5 måneder i studiet. 
Den forsøgsansvarlige modtager ikke vederlag for studiet. 
Evt. overskydende beløb vil blive anvendt til dækning af andre udgifter i forbindelse med studiet 
herunder forsendelse af studiemedicin fra sponsor til investigator, løn til studentermedhjælp til 
fremstilling og fotokopiering af CRFer og TMFs mv. Desuden vil der formentlig være behov for 
yderligere midler til finaciering af biomarkørdelen af studiet.  
 
1 Til skrivning af protokol, udarbejdelse af eCRF og papir CRF, TMFs, initieringsmøder og løbende 
arbejde f.eks. kontakt til afdelingerne osv., beløbet svarer til ca. 1.7 måneds overenskomstmæssig 
løn). 
2Indsamling af blodprøver, varetagelse af biobank. 
3Besøg, hvor der tages eksperimentelle blodprøver. 
 
Den forsøgsansvarlige og studiekoordinator har ingen privat eller økonomisk tilknytning til private 
virksomheder, fonde mv. som har interesser i det pågældende projekt. 
23 VEDERLAG ELLER ANDRE YDELSER TIL FORSØGSPERSONER (SECTION IN 
DANISH) 
Der ydes ikke vederlag eller andre ydelser til forsøgspersoner. Der ydes ikke transport godtgørelse 
eller tabt arbejdsfortjeneste.  
24 PUBLIKATIONSPLAN (SECTION IN DANISH) 
Det forventes muligt at indsende et abstrakt til European League Against Rheumatism (EULAR) 
kongressen i år 2018, og efterfølgende kongresser som f.eks. American College of Rheumatology 
(ACR). Hovedstudiet og delprojekter vil forsøges publiceret i velestimerede reumatologiske 
tidsskrifter som f.eks. Annals of the Rheumatic Diseases eller Arthritis and Rheumatism. Såvel 
positive, negative eller inkonklusive undersøgelsesresultater vil blive publiceret. Offentliggørelsen 
vil finde sted så hurtigt, som det er muligt, fagligt forsvarligt og i overensstemmelse med lov om 
behandling af personoplysninger. Såfremt studie ikke kan blive publiceret på anden vis, så vil det 
blive offentliggjort på anden vis enten via afdelingens hjemmeside eller www.clinicaltrials.gov.  
25 RETNINGSLINJER FOR MEDFORFATTERSKAB (SECTION IN DANISH) 
Projektets styregruppe består af studiekoordinator læge ph.d. Susanne Juhl Pedersen, professor 
Mikkel Østergaard og overlæge, ph.d. Inge Juul Sørensen, Reumatologisk Klinik, alle fra 
”Videncenter for Reumatologi og Rygsygdomme”, Glostrup Hospital. 
Manuskripter tilsigtes publiceret i engelsksprogede internationale tidsskrifter med medlemmer af 
styregruppen som første, anden og sidste forfattere, med mindre styregruppen internt har truffet 
beslutning om andet. De deltagende afdelinger opnår ét medforfatterskab for hver seks patienter, 
der gennemfører undersøgelsen, hvor medforfatteren yderligere deltager i analyser og diskussion af 
resultater samt artikelskrivning. Andre personer, som har ydet et stort bidrag, herunder mindst én 
repræsentant fra den deltagende radiologiske afdeling, kan være medforfattere. Ved uenighed 
træffes den endelige beslutning herom af styregruppen. 

Protocol version 4.1, 3 November 2016 
46
Oplæg til manuskripter vedrørende hovedstudiet udfærdiges af styregruppen i fællesskab, og de 
forelægges øvrige deltagere i projektet til kommentarer og revision.  
Delprojekter og tillægsprojekter, der ikke er omfattet af indeværende protokol kan eventuelt 
analyseres af de for disse forsøg ansvarlige forskere og publiceres med disse forskere som 
førsteforfattere. Forinden skal der foreligge en skriftlig aftale mellem disse forskere og 
styregruppen. Øvrige forfatterskaber på del- og tillægsprojekter afhænger af tillægsprojektets 
karakter, men såfremt der anvendes kliniske data indsamlet af de deltagende afdelinger, vil disse 
blive kreditteret med medforfatterskab. Forfatterlisten skal beskrives i den omtalte skriftlige aftale 
og vil generelt, udover personer substantielt involveret i tillægsprojektet, omfatte de mest 
substantielt bidragende investigatorer i grundprojektet, herunder styregruppens medlemmer. 
Økonomiske sponsorer herunder MSD har ingen indflydelse på eller involvering i dataanalysen 
eller i udarbejdelsen af manuskripter herunder abstrakts. Økonomiske sponsorer vil i alle 
publikationer blive anerkendt for at have støttet forsøget. 
26 APPENDICES  
The file ”Andre relevante bilag” contains all appendices in relation to this protocol i.e.  
27 RELEVANTE 
KLAUSULER 
I 
KONTRAKTEN 
MELLEM 
SPONSOR 
OG 
FORSØGSSTEDET (SECTION IN DANISH) 
Udvalgte passager fra kontrakten mellem professor Mikkel Østergaard, Videncenter for 
Reumatologi og Rygsygdomme, Glostrup Hospital og MSD med relevans for Videnskabsetisk 
Komite er vedlagt følgebrevet.  
 
References 
 

Protocol version 4.1, 3 November 2016 
47
28 FLOWCHART 
 
 
#Screening and week 0: The visits can be performed simultaneously if the patient has had a recent clinical 
examination and the screenings test have been checked before the MRI scans and X-rays are performed.  
 
Visit number 
S 
1 
2 
3 
4 
5 
6 
E 
Week number  
-2# 
0# 
4* 
16* 
28 
40 
52 
 
Allowed time shift (+/- days) 
14 
0 
3 
7 
10 
10 
10 
7 
 
 
 
 
 
 
 
 
 
Screening for TNFα inhibitor eligibility 
 
 
 
 
 
 
 
 
Screening for TNFα inhibitor eligibility 
X 
 
 
 
 
 
 
 
Quantiferon test for TB 
X 
 
 
 
 
 
 
 
Chest X-ray (if older than 3 months) 
X 
 
 
 
 
 
 
 
ECG 
X 
 
 
 
 
 
 
 
Hepatitis B and C screening and HIV 
X 
 
 
 
 
 
 
 
HCG (women only) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study related procedures 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
Clinical history incl. past medical and surgical history 
X 
 
 
 
 
 
 
 
Inclusion and exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical procedures 
 
 
 
 
 
 
 
 
BAS questionnaire (pain, global, BASDAI, BASFI) 
X 
X 
X 
X 
X 
X 
X 
X 
HAQ questionnaire (HAQ, pain, global) 
 
X 
X 
X 
X 
X 
X 
X 
Patient Acceptable Symptom State (PASS) 
 
X 
X 
X 
 
 
X 
X 
ASAS Health Index 
 
X 
X 
X 
 
 
X 
X 
Health-related Quality of Life (SF-36, 15D,  EuroQol) 
 
X 
X 
X 
 
 
X 
X 
Questionnaires sleep, fatigue and depression 
 
X 
X 
X 
 
 
X 
X 
Questionnaires physical activity 
 
X 
X 
X 
 
 
X 
X 
BASMI incl. thorax expansion 
 
X 
X 
X 
X 
X 
X 
X 
Swollen/tender  joint counts (66/68) 
 
X 
X 
X 
X 
X 
X 
X 
Enthesitis indices 
 
X 
X 
X 
 
 
X 
X 
Physician global 
 
X 
X 
X 
X 
X 
X 
X 
ASDAS 
 
X 
X 
X 
X 
X 
X 
X 
Detailed physical examination  
X 
 
 
 
 
 
X 
X 
Vital signs (blood pressure and hart rate) 
X 
 
 
 
 
 
X 
X 
Adverse event registration  
 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
Imaging procedures 
 
 
 
 
 
 
 
 
MRI scans of SI-joints and spine (whole-body, diffusion 
weighted, conventional) 
 
X 
X 
X 
 
 
X 
 
X-rays of SI-joints and spine 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Laboratory procedures 
 
 
 
 
 
 
 
 
HLA-B27 
X 
 
 
 
 
 
 
 
ANA 
X 
 
 
 
 
 
X 
 
Routine blood tests  
X 
X 
X 
X 
X 
X 
X 
X 
Urine 
X 
X 
X 
 
 
 
 
 
Blood and urine samples to be stored (experimental 
biomarkers) 
 
X 
X 
X 
 
 
X 
X 

Protocol version 4.1, 3 November 2016 
48
*Week 4 and 16: Injection with Golimumab not allowed before the examination program has been 
completed. 
 
Patients will be asked to complete examination program, even if Golimumab therapy is stopped.  
 
E: Exclusion visit to be performed, if possible before other therapies are initiated, in patients who are to be 
excluded of study.  

Protocol version 4.1, 3 November 2016 
49
29 APPENDICES 
30 LÆGEMIDDELSTYRELSEN VURDERING AF FORSØGET 
 
Fra: Zainab Nawar Ajina - 9154 [ZNA@DKMA.DK] 
Sendt: 29. august 2013 08:21 
Til: Susanne Juhl Pedersen 
Emne: Vedr. forespørgsel om anmeldelsespligtigt forsøg 
Kære Susanne Juhl Pedersen 
Der skal hermed kvitteres for din mail af 19-08-2013, hvori der fremsendes projektbeskrivelse med henblik 
på vurdering af anmeldelsespligten.  
Efter gennemlæsning af protokollen, "Improved monitoring and prediction of clinical response and disease 
course during Golimumab therapy of patients with axial spondyloarthritis: The clinical utility of whole-body 
MRI, diffusion-weighted MRI, conventional MRI of sacroiliac joints and spine, and high-sensitive CRP and 
other soluble biomarkers of joint inflammation and damage", kan det oplyses, at studiet ikke er vurderet til at 
være anmeldelsespligtigt efter Lægemiddelloven § 88, stk. 1 og skal derfor ikke anmeldes til 
Sundhedsstyrelsen. 
Denne vurdering er baseret på, at forsøget har til formål undersøge MR-scanningernes evne til overvågning 
og forudsigelse af respons til Golimumab, dvs. der er tale om et observationsstudie med metodeudvikling og 
ikke en undersøgelse af Golimumabs effekt.   
Den endelige afgørelse vedrørende projektet skal derfor gives af den Videnskabsetiske komité, hvilket De 
selv anmodes om at meddele komiteen. 
For så vidt angår registrering og anden behandling af personoplysninger i undersøgelsen henviser vi til 
Datatilsynet, som fører tilsyn hermed. 
Sagsnummer 2013082500 bedes meddelt ved en eventuel henvendelse. 
Venlig hilsen 
Zainab Nawar Ajina  
Cand.pharm 
M Sc. Pharm 
T (dir) +45 44 88 91 54 
zna@dkma.dk 
  
Sundhedsstyrelsen 
Lægemiddeludvikling og -evaluering 
Danish Health and Medicines Authority 
Medicines Development and Clinical Trials 
T +45 72 22 74 00 
sst@sst.dk 
  

Protocol version 4.1, 3 November 2016 
50
31 SEARCH STRATEGY PUBMED 
 
Performed July 2013 
 
#1  
SpA ord 
“Spondylarthropathy 
OR 
spondylarthropathies 
OR 
spondyloarthr* 
OR 
spondylarthr* OR spondylitides OR ankylosing spondylitis OR bechterew OR 
bechterew* OR bekhterev OR Strumpell OR spondylitis OR Struempell OR 
ankylopoetica OR ankylopoietica” 29420 references 
 
#2  
MRI ord 
“MRI OR magnetic resonance imaging” 363441 references 
#3  
Remission 
107480 references 
#4 
Low disease activity  
34264 references 
 
#1 AND #2 AND #3 
23 of which 2 are of relevance 
#1 AND #2 AND #4 
42 of which 4 are of relevance 
 
 
#5 
ASAS Health Index  
44 references, none of relevance (abstracts containing the three words) 
 
#6  
Assessment of SpondyloArthritis International Society health index 
 
 
 
8 references of which 1 is relevant 
#7  
BRAF-MDQ 
3 references of which 0 is relevant (3 RA studies) 
 
#8 
Bristol Rheumatoid Arthritis Fatigue Scales 
7 references of which 0 are relevant 
#9  
Patient Acceptable Symptom State 
 74 references of which 10 is about SpA or AS 
 
#10 
Sleep 
 
 128552 references 
#11 
infliximab OR adalimumab OR etanercept OR golimumab OR certolizumab pegol (i.e. TNFα 
inhibitors) 
 
12770 references 
#1 AND #10 AND #11 
 
5 references of which 4 is relevant 
 
#12  Pittsburgh Sleep Quality Index  
1330 references 
#1 AND #12 
 5 references of which 4 is of relevance 
 
#1 AND #11 AND #12 
 0 references 
 
#13 Fatigue “in title” 
 16383 references 
#1 AND #13 
 44 references 
#1 AND #11 AND #13 
 3 references, all relevant 
 
 
#14 
Multidimensional Fatigue Inventory  
 343 references 
#1 AND #14 
 5 reference of which all are relevant 
#1 AND #11 AND #14 
 0 references  
 
 
 
 
 
#15 
Center for Epidemiologic Studies Depression Scale 3896 references 
#1 AND #15 
3 references, none of relevance 
 
 
#16 
IL-6 OR IL6 OR interleukin 6 OR interleukin-6 
 79696 references 
#1 OR #16 
 213 references 
#1 OR #11 OR #16 
 31 references 
 
#17 
IL-22 OR IL22 OR interleukin 22 OR interleukin-22 
 
1195 references 
#1 OR #17 
 
 
17 references 
#1 OR #11 OR #17 
 
 
1 references 
 

Protocol version 4.1, 3 November 2016 
51
#18 
Interleukin 23 OR IL-23 OR IL23 
 
 
3486 references 
#1 OR #19 
 
 
129 references 
#1 OR #11 OR #19 
 
 
7 references 
 
#19 
VEGF OR vascular endothelial growth factor 
 
 
60404 references 
#1 OR #19 
 
 
43 references 
#1 OR #11 OR #19 
 
 
12 references 
 
#20 
CTX-II OR CTXII OR cross-linking telopeptide of type II collagen  
193 references 
#1 AND #20 
 
 
 
6 references 
#1 AND #11 AND #20 
 
 
 
2 references 
 
 
#21 
MMP-3 OR "MMP 3" OR Metalloproteinase 3 OR Stromelysin 1 35905 references 
#1 OR #21 
 
 
82 references 
#1 AND #11 AND #21 
 
 
25 references 
 
#22 
DeoxyPYD 
 
 
17887 references 
#1 OR #22 
 
 
19 references 
#1 AND #11 AND #22 
 
 
1 reference 
 
#23 
CTX-I OR CTXI OR telopeptide of type I collagen  
 
2621 references 
#1 OR #23 
 
 
20 references 
#1 AND #11 AND #23 
 
 
5 references 
 
#24 
Osteocalcin OR OC 
 
 
24795 references 
#1 AND #24 
 
 
55 references 
#1 AND #11 AND #24 
 
 
8 references 
 
#25 
Propeptide of type I procallagen OR PINP 
 
 
1378 references 
#1 AND #25 
 
 
6 references 
#1 AND #11 AND #25 
 
 
2 references 
 
 
#26 
Sclerostin 
 
 
489 references 
#1 AND #26 
 
 
12 references 
#1 AND #11 AND #26 
 
 
0 references 
 
#27 
Periostin 
 
 
450 references 
#1 AND #27 
 
 
0 references 
 
#28 
Citrullinated vimentin 
 
 
147 references 
#1 AND #28 
 
 
16 references 
#1 AND #11 AND #28 
 
 
1 reference 

Protocol version 4.1, 3 November 2016 
52
32 COPY OF PACKAGE LEAFLET  
 
 
Indlægsseddel: Information til brugeren 
 
Simponi® 50 mg injektionsvæske, opløsning i en fyldt pen 
Golimumab 
 
Læs denne indlægsseddel grundigt inden De begynder at tage dette lægemiddel, da den 
indeholder vigtige oplysninger. 
- Gem indlægssedlen. De kan få brug for at læse den igen. 
- Spørg lægen, apotekspersonalet eller sundhedspersonalet, hvis der er mere, De vil vide. 
- Lægen har ordineret Simponi til Dem personligt. Lad derfor være med at give det til andre. 
Det kan være skadeligt for andre, selvom de har de samme sygdomstegn, som De har. 
- Tal med lægen, apotekspersonalet eller sundhedspersonalet, hvis en bivirkning bliver værre, 
eller De får bivirkninger, som ikke er nævnt her. 
 
Deres læge har også givet Dem et patientinformationskort, der indeholder informationer om 
sikkerhed, som De skal være opmærksom på før og under behandling med Simponi. 
 
Oversigt over indlægssedlen: 
1. Virkning og anvendelse 
2. Det skal De vide, før De begynder at tage Simponi 
3. Sådan skal De tage Simponi 
4. Bivirkninger 
5. Opbevaring 
6. Pakningsstørrelser og yderligere oplysninger 
 
 
1. 
Virkning og anvendelse 
 
Simponi indeholder det aktive stof golimumab. 
 
Simponi tilhører en medicingruppe kaldet ”TNF-blokkere”, som bruges til voksne til behandling af 
følgende betændelsessygdomme: 
 Reumatoid artrit 
 Psoriasisartrit 
 Ankyloserende spondylit 
 
Simponi virker ved at blokere virkningen af et protein, der hedder ’tumornekrosefaktor alfa’ 
(TNF). Dette protein er involveret i kroppens betændelsesprocesser, og blokering af proteinet kan 
mindske betændelsen i Deres krop. 
 
Reumatoid artrit 
Reumatoid artrit (kronisk leddegigt) er en betændelsessygdom i leddene. Hvis De har aktiv 
reumatoid artrit, vil De i første omgang blive behandlet med andre lægemidler. Hvis De ikke 
reagerer godt nok på disse lægemidler, vil De få Simponi, som De skal tage sammen med et andet 
lægemiddel, der hedder methotrexat, for at: 
 Reducere sygdomstegn og symptomer på Deres sygdom. 
 Nedsætte hastigheden af beskadigelse af Deres knogler og led. 

Protocol version 4.1, 3 November 2016 
53
 Forbedre Deres fysiske funktionsevne. 
 
Psoriasisartrit 
Psoriasisartrit er en betændelsessygdom i leddene, almindeligvis ledsaget af psoriasis, som er en 
betændelsessygdom i huden. Hvis De har aktiv psoriasisartrit, vil De først få andre lægemidler. 
Hvis De ikke reagerer godt nok på disse lægemidler, vil De få Simponi for at: 
 Reducere sygdomstegn og symptomer på Deres sygdom. 
 Nedsætte hastigheden af beskadigelse af Deres knogler og led. 
 Forbedre Deres fysiske funktionsevne. 
 
Ankyloserende spondylit 
Ankyloserende spondylit er en betændelsessygdom i rygraden. Hvis De lider af ankyloserende 
spondylit, vil De først få andre lægemidler. Hvis De ikke reagerer godt nok på disse lægemidler, vil 
De få Simponi for at: 
 Reducere sygdomstegn og symptomer på Deres sygdom. 
 Forbedre Deres fysiske funktionsevne. 
 
 
2. 
Det skal De vide, før De begynder at tage Simponi 
 
De må ikke tage Simponi: 
 hvis De er overfølsom (allergisk) over for golimumab eller et af de øvrige indholdsstoffer i 
dette lægemiddel (anført under pkt. 6). 
 hvis De har tuberkulose (TB) eller en anden alvorlig infektion. 
 hvis De har hjertesvigt i moderat eller svær grad. 
 
Hvis De er i tvivl, om noget af ovenstående gælder for Dem, så tal med Deres læge, 
apoteketspersonalet eller sundhedspersonalet, før De får Simponi. 
 
Advarsler og forsigtighedsregler 
Kontakt lægen, apoteket eller sundhedspersonalet, før De tager Simponi. 
 
Infektioner 
Fortæl straks Deres læge, hvis De har en infektion eller har symptomer på infektion under og efter 
behandling med Simponi. Tegn på infektion inkluderer feber, hoste, åndenød, influenzalignende 
symptomer, diarre, sår, tandproblemer eller en brændende smerte, når De lader vandet. 
 De kan muligvis lettere få infektioner, når De er i behandling med Simponi. 
 Disse infektioner kan udvikle sig hurtigere og være mere alvorlige end ellers. Derudover kan 
tidligere infektioner dukke op igen. 
 
Tuberkulose (TB) 
Fortæl det straks til Deres læge, hvis De får tegn på TB under eller efter behandlingen. 
Symptomer inkluderer vedvarende hoste, vægttab, træthedsfølelse, feber eller nattesved. 
 Der er set tilfælde af TB hos patienter i behandling med Simponi, i sjældne tilfælde er 
TB også set hos patienter, som har været i behandling for TB. Lægen vil undersøge, om 
De har TB. Lægen vil notere disse undersøgelser på Deres patientinformationskort. 
 Det er meget vigtigt, at De fortæller det til Deres læge, hvis De nogensinde har haft TB, 
eller hvis De har været i tæt kontakt med en person, som har eller har haft TB. 
 Hvis Deres læge tror, at De har risiko for at få TB, kan De blive behandlet med 
lægemidler mod TB, inden De får Simponi. 
 
Hepatitis B-virus (HBV) 

Protocol version 4.1, 3 November 2016 
54
 Inden De får Simponi, skal De fortælle Deres læge, hvis De er bærer af, eller hvis De 
har eller har haft HBV. 
 Fortæl det til Deres læge, hvis De tror, at De har en risiko for at få HBV. 
 Deres læge skal teste Dem for HBV. 
 Behandling med TNF-blokkere, såsom Simponi, kan medføre, at HBV igen bliver aktiv 
hos patienter, som bærer denne virus. Dette kan i nogle tilfælde være livstruende. 
 
Invasive svampeinfektioner 
Fortæl det straks til Deres læge, hvis De har boet eller rejst i et område, hvor infektioner 
forårsaget af særlige svampetyper (kaldet histoplasmose, kokcidioidomykose eller 
blastomykose), som kan påvirke lungerne eller andre dele af kroppen, er almindelige. Spørg 
Deres læge, hvis De ikke ved, om disse infektioner er almindelige i det område, De har boet 
eller rejst i. 
 
Kræft og lymfom 
Fortæl det til Deres læge, før De får Simponi, hvis De har eller nogensinde har haft lymfom (en 
type blodkræft) eller enhver anden form for kræft. 
 Behandling med Simponi eller andre TNF-blokkere kan øge Deres risiko for at udvikle 
lymfom eller anden form for kræft. 
 Patienter med alvorlig reumatoid artrit og andre betændelsessygdomme, og som har haft 
sygdommen i lang tid, kan have en større risiko end gennemsnittet for at udvikle lymfom. 
 Nogle børn og teenagere, som har fået TNF-blokkere, har udviklet kræft inklusive 
usædvanlige typer kræft, som i visse tilfælde har været dødelige. 
 Patienter med svær vedvarende astma, kronisk obstruktiv lungesygdom (KOL), eller patienter 
som er storrygere, kan have øget risiko for kræft ved behandling med Simponi. Hvis De har 
svær astma, KOL eller er storryger, bør De tale med Deres læge, om hvorvidt TNF-blokkere 
er passende for Dem. 
 Nogle patienter, der er blevet behandlet med golimumab, har udviklet visse former for 
hudkræft. Hvis der opstår forandringer i hudens udseende eller svulster på huden under eller 
efter behandlingen, skal De fortælle det til lægen. 
 
Hjertesvigt 
Fortæl det straks til Deres læge, hvis De får nye eller forværrede tegn på hjertesvigt. Symptomer på 
hjertesvigt inkluderer åndenød eller hævelse af fødderne. 
 Nyt eller forværret hjertesvigt er set hos patienter i behandling med TNF-blokkere. 
 Hvis De har mildt hjertesvigt, og De er i behandling med Simponi, skal De nøje overvåges af 
Deres læge. 
 
Sygdom i nervesystemet 
Fortæl det straks til Deres læge, hvis De nogensinde har haft eller udvikler symptomer på en 
demyeliniserende sygdom såsom multipel sklerose. Symptomer inkluderer synsændringer, 
muskelsvaghed i Deres arme eller ben eller følelsesløshed eller prikken et sted i kroppen. Deres 
læge skal vurdere, om De skal i behandling med Simponi. 
 
Operationer eller tandbehandling 
 Fortæl Deres læge, hvis De skal have foretaget en operation eller en tandbehandling. 
 Fortæl kirurgen eller tandlægen, som foretager indgrebet, at De er i behandling med Simponi 
ved at vise dem patientinformationskortet. 
 
Autoimmun sygdom 
Fortæl det til Deres læge, hvis De udvikler symptomer på en sygdom kaldet lupus. Symptomer 
inkluderer vedvarende udslæt, feber, ledsmerter og træthed. 

Protocol version 4.1, 3 November 2016 
55
 I sjældne tilfælde har patienter behandlet med TNF-blokkere udviklet lupus. 
 
Blodsygdomme 
Hos nogle patienter kan kroppen ikke producere nok blodceller, som kan hjælpe med at bekæmpe 
infektioner eller hjælpe med at stoppe blødning. Kontakt straks Deres læge, hvis De udvikler feber, 
der ikke forsvinder, nemt får blå mærker, bløder eller ser meget bleg ud. Deres læge kan beslutte at 
stoppe behandlingen. 
 
Hvis De er i tvivl, om noget af ovenstående passer på Dem, skal De tale med Deres læge eller 
apoteket, før De tager Simponi. 
 
Vaccinationer 
Tal med Deres læge, hvis De er blevet eller planlægger at blive vaccineret. 
 De må ikke få visse (levende) vacciner, mens De er i behandling med Simponi. 
 Visse vaccinationer kan forårsage infektioner. Hvis De var i behandling med Simponi, mens 
De var gravid, kan Deres barn have en øget risiko for at få en sådan infektion i op til ca. 
6 måneder efter, De fik Deres sidste dosis under graviditeten. Det er vigtigt, at De fortæller 
barnets læge og andet sundhedspersonale om Deres behandling med Simponi, så de kan 
afgøre, hvornår Deres barn kan blive vaccineret. 
 
Allergiske reaktioner 
Fortæl det omgående til Deres læge, hvis De oplever symptomer på en allergisk reaktion efter De er 
startet i behandling med Simponi. Symptomer på en allergisk reakation kan være hævet ansigt, 
læber, mund eller hals, hvilket kan gøre det svært at synke eller trække vejret, hududslæt, 
nældefeber, hævede hænder, fødder eller ankler. 
 Nogle af disse reaktioner kan være alvorlige eller i sjældne tilfælde, livstruende. 
 Nogle af disse reaktioner forekom efter den første injektion af Simponi. 
 
Børn og teenagere 
Simponi frarådes til børn og unge (under 18 år), fordi det ikke er blevet undersøgt i denne 
aldersgruppe. 
 
Brug af anden medicin sammen med Simponi 
 Fortæl altid lægen eller på apoteket, hvis De bruger anden medicin eller har gjort det for 
nylig, herunder medicin til behandling af reumatoid artrit, psoriasisartrit eller ankyloserende 
spondylit. 
 De må ikke tage Simponi sammen med lægemidler, der indeholder de aktive stoffer anakinra 
eller abatacept. Disse lægemidler anvendes til behandling af reumatoide sygdomme. 
 Fortæl Deres læge eller apoteket, hvis De bruger anden medicin, der påvirker Deres 
immunsystem. 
 De må ikke få visse (levende) vacciner, mens De tager Simponi. 
 
Hvis De er i tvivl, om noget af ovenstående passer på Dem, skal De tale med Deres læge eller 
apoteket, før De tager Simponi. 
 
Graviditet og amning 
Tal med Deres læge, før De tager Simponi, hvis: 
 De er gravid eller planlægger at blive gravid, mens De er i behandling med Simponi. 
Virkningen af dette lægemiddel er ukendt hos gravide. Simponi frarådes til gravide kvinder. 
De skal undgå at blive gravid ved at anvende sikker prævention, mens De er i behandling med 
Simponi og mindst 6 måneder efter den sidste Simponi-injektion. 

Protocol version 4.1, 3 November 2016 
56
 De har i sinde at amme Deres barn. Før De starter med at amme, skal det være mindst 
6 måneder siden, De fik Deres sidste behandling med Simponi. De skal stoppe med at amme, 
hvis De skal i behandling med Simponi. 
 De var i behandling med Simponi under Deres graviditet, da Deres barn kan have en øget 
risiko for at få en infektion. Det er vigtigt, at De fortæller barnets læge og andet 
sundhedspersonale om Deres behandling med Simponi, før barnet bliver vaccineret (se 
punktet om vaccination for mere information). 
 
Hvis De er gravid eller ammer, har mistanke om, at De er gravid, eller planlægger at blive gravid, 
skal De spørge Deres læge eller apoteket til råds, før De tager dette lægemiddel.  
 
Trafik- og arbejdssikkerhed 
Simponi kan i mindre grad påvirke Deres evne til at køre bil og betjene værktøj eller maskiner. Der 
kan opstå svimmelhed, efter De har brugt Simponi. Hvis dette sker, må De ikke køre bil eller 
betjene nogen form for maskiner. 
 
Simponi indeholder latex og sorbitol 
Overfølsomhed over for latex 
En del af den fyldte pen, beskyttelseshætten til nålen, indeholder latex. Tal med Deres læge inden 
De anvender Simponi, hvis De eller Deres hjælper/plejer er allergisk over for latex, da latex kan 
forårsage alvorlige allergiske reaktioner. 
 
Sorbitol-intolerans 
Simponi indeholder sorbitol (E420). Kontakt lægen, før De tager denne medicin, hvis lægen har 
fortalt Dem, at De ikke tåler visse sukkerarter. 
 
 
3. 
Sådan skal De tage Simponi 
 
Brug altid dette lægemiddel nøjagtigt efter lægens eller apotekspersonalets anvisning. Er De i tvivl, 
så spørg lægen eller på apoteket. 
 
Den sædvanlige dosis 
 Den anbefalede dosering er 50 mg (indholdet af 1 fyldt pen) en gang om måneden på den 
samme dag hver måned. 
 Tal med Deres læge, før De tager den 4. dosis. Deres læge vil beslutte, om De skal fortsætte 
behandlingen med Simponi. 
 Hvis De vejer mere end 100 kg, kan dosis øges til 100 mg (indholdet af 2 fyldte penne) en 
gang om måneden på den samme dag hver måned. 
 
Sådan får De Simponi 
 Simponi gives som indsprøjtning under huden (subkutant). 
 I begyndelsen vil Deres læge eller sygeplejerske indsprøjte Simponi. De og Deres læge kan 
dog beslutte, at De selv kan indsprøjte Simponi. I dette tilfælde vil De blive trænet i, hvordan 
man selv indsprøjter Simponi. 
 
Tal med Deres læge, hvis De har spørgsmål angående indsprøjtningerne. Der er en detaljeret 
”Brugsvejledning” i slutningen af denne indlægsseddel. 
 
Hvis De har brugt for meget Simponi 

Protocol version 4.1, 3 November 2016 
57
Kontakt straks Deres læge eller apoteket, hvis De har brugt eller har fået for meget Simponi (enten 
ved at indsprøjte for meget en enkelt gang eller ved at indsprøjte for ofte). Tag altid den ydre karton 
med Dem, også selvom den er tom. 
 
Hvis De har glemt at tage Simponi 
Indsprøjt den glemte dosis, så snart De husker det, hvis De har glemt at tage Simponi på den 
planlagte dato. 
 
De må ikke tage en dobbeltdosis som erstatning for den glemte dosis. 
 
Hvornår skal den næste dosis indsprøjtes: 
 Indsprøjt den glemte dosis hurtigst muligt og fortsæt Deres oprindelige plan, hvis De er 
mindre end 2 uger forsinket. 
 Indsprøjt den glemte dosis hurtigst muligt og tal med Deres læge eller apoteket om hvornår 
De skal tage den næste dosis, hvis De er mere end 2 uger forsinket. 
 
Spørg lægen eller på apoteket, hvis der er noget, De er i tvivl om. 
 
Hvis De holder op med at tage Simponi 
Tal med lægen eller apoteket hvis De overvejer at stoppe Simponi behandling. 
 
Spørg lægen, på apoteket eller sundhedspersonalet, hvis De har yderligere spørgsmål om brugen af 
dette lægemiddel. 
 
 
4. 
Bivirkninger 
 
Dette lægemiddel kan som al anden medicin give bivirkninger, men ikke alle får bivirkninger. 
Nogle patienter kan få alvorlige bivirkninger, der skal behandles. Risikoen for at få visse 
bivirkninger er større ved en dosis på 100 mg sammenlignet med en dosis på 50 mg. Bivirkninger 
kan opstå i flere måneder efter sidste indsprøjtning. 
 
Fortæl det straks til Deres læge, hvis De bemærker noget af følgende alvorlige bivirkninger med 
Simponi: 
 Allergiske reaktioner, der kan være alvorlige eller i sjældne tilfælde livstruende 
(sjælden). Symptomer på en allergisk reaktion kan være hævelse af ansigt, læber, mund eller 
svælg, som kan forårsage besvær med at synke eller trække vejret, kløende udslæt, 
nældefeber, hævede hænder, fødder eller ankler. Nogle af disse reaktioner forekom efter 
første Simponi-dosis. 
 Alvorlige 
infektioner 
(inklusive 
TB, 
bakterieinfektioner, 
herunder 
alvorlige 
blodinfektioner 
og 
lungebetændelse, 
alvorlige 
svampeinfektioner 
og 
andre 
opportunistiske infektioner (ikke almindelige). Symptomer på en infektion kan være feber, 
træthed, (vedvarende) hoste, åndenød, influenzalignende symptomer, vægttab, nattesved, 
diarré, sår, tandproblemer eller en brændende fornemmelse, når De lader vandet. 
 Tilbagevendende hepatitis B-infektion, hvis De er smittebærer af hepatitis B-virus eller 
tidligere har haft hepatitis B (sjælden). Symptomerne kan være gulfarvning af hud og øjne, 
mørkebrun urin, smerte i højre side af maven, feber, kvalme og opkastning eller udpræget 
træthed. 
 Sygdom i nervesystemet såsom multipel sklerose (ikke almindelig). Symptomer på 
sygdom i nervesystemet kan omfatte synsændringer, muskelsvaghed i arme eller ben, 
følelsesløshed eller prikken/snurren et eller andet sted på kroppen. 

Protocol version 4.1, 3 November 2016 
58
 Kræft i lymfeknuderne (lymfom) (sjælden). Symptomer på lymfom kan være hævede 
lymfeknuder, vægttab eller feber. 
 Hjertesvigt (ikke almindelig). Symptomer på hjertesvigt kan være åndenød eller hævede 
fødder. 
 Tegn på en sygdom i immunsystemet, kaldet lupus (sjælden). Symptomer kan være 
ledsmerter eller et udslæt på kinder eller arme, som er følsomt over for sol. 
 Blodsygdom. Symptomer på blodsygdom kan være vedvarende feber, blå mærker, eller at De 
bløder meget nemt eller ser meget bleg ud.  
 
Fortæl det straks til Deres læge, hvis De bemærker nogen af ovennævnte symptomer. 
 
Følgende yderligere bivirkninger er observeret med Simponi: 
 
Meget almindelige bivirkninger (kan forekomme hos flere end 1 ud af 10 patienter): 
 Øvre luftvejsinfektioner (i næse, svælg og luftrør), ondt i halsen eller hæshed, løbende næse 
 
Almindelige bivirkninger (kan forekomme hos mellem 1 og 10 ud af 100 patienter): 
 Unormale levertal (stigning i leverenzymer) ved blodprøver, som tages af Deres læge 
 Svimmelhed 
 Hovedpine 
 Overfladisk svampeinfektion 
 Bakterielle infektioner (såsom betændelse i hudens bindevæv) 
 Nedsat antal røde blodceller 
 Positiv blodprøve for lupus 
 Søvnbesvær 
 Depression 
 Forstoppelse 
 Hårtab 
 Allergiske reaktioner 
 Udslæt og kløe på huden 
 Fordøjelsesbesvær 
 Mavesmerter 
 Kvalme 
 Følelsesløshed eller en prikkende følelse 
 Influenza 
 Bronkitis 
 Bihulebetændelse 
 Forkølelsessår 
 Højt blodtryk 
 Feber 
 Reaktioner på indsprøjtningsstedet (inklusive rødme, hårdhed, smerte, blå mærker, kløe, 
prikken og irritation) 
 Svaghedsfølelse 
 Nedsat heling 
 Ubehag i brystet 
 
Ikke almindelige bivirkninger (kan forekomme hos mellem 1 og 10 ud af 1.000 patienter): 
 Infektioner i led eller omkring liggende væv 
 Nyreinfektioner 
 Byld 
 Kræft, inklusive hudkræft og ikke-kræftagtige svulster eller knuder, inklusive modermærker 
 Psoriasis (også på håndflader og/eller fodsåler og/eller i form af blærer på huden) 

Protocol version 4.1, 3 November 2016 
59
 Lavt antal blodplader 
 Lavt antal hvide blodceller 
 Kombineret nedsat antal blodplader, røde og hvide blodceller 
 Lidelser i skjoldbruskkirtlen 
 Øget blodsukker 
 Øget kolesteroltal 
 Balanceforstyrrelser 
 Smagsforstyrrelser 
 Synsforstyrrelser 
 Følelse af uregelmæssig hjerterytme 
 Forsnævring af blodkar i hjertet 
 Blodpropper 
 Smerte og misfarvning af fingre og tæer 
 Rødmen 
 Astma, kortåndethed, hvæsen 
 Mave- og tarmlidelser inkl. betændelse i mavens slimhinde og tyktarmen, som kan give feber 
 Sure opstød 
 Smerter og sår i munden 
 Galdesten 
 Leverlidelser 
 Blærelidelser 
 Brystlidelser 
 Menstruationsforstyrrelser 
 Knoglebrud 
 Betændelse i blodkarrene i huden, hvilket resulterer i udslæt 
 
Sjældne bivirkninger (kan forekomme hos mellem 1 og 10 ud af 10.000 patienter): 
 Kronisk betændelsestilstand i lungerne 
 Nyrelidelser 
 Betændelse i blodkarrene i de indre organer 
 Leukæmi 
 Melanom (en type hudkræft) 
 Grov afskalning af huden 
 Immunsygdomme der kan påvirke lunger, hud og lymfekirtler (hyppigst visende sig som 
sarkoidose) 
 
Bivirkninger med ukendt hyppighed: 
 Knoglemarv der ikke kan producere blodceller 
 Merkelcellekarcinom (en type hudkræft) 
 
Tal med lægen, apotekspersonalet eller sundhedspersonalet, hvis De får bivirkninger, herunder 
bivirkninger, der ikke fremgår af denne indlægsseddel. 
 
 
5. 
Opbevaring 
 
 Opbevares utilgængeligt for børn. 
 Brug ikke dette lægemiddel efter den udløbsdato, der står på etiketten og pakningen efter 
”EXP”. Udløbsdatoen er den sidste dag i den nævnte måned. 
 Opbevares i køleskab (2°C - 8°C). Må ikke nedfryses. 
 Opbevar den fyldte pen i den ydre karton for at beskytte mod lys. 

Protocol version 4.1, 3 November 2016 
60
 Brug ikke dette lægemiddel, hvis De kan se, at væsken ikke er en klar til lys gullig farve, eller 
hvis den er grumset eller indeholder fremmede partikler. 
 Spørg Deres læge eller på apoteket, hvordan De skal bortskaffe medicinrester. Af hensyn til 
miljøet må De ikke smide medicinrester i afløbet, toilettet eller skraldespanden. 
 
 
6. 
 Pakningsstørrelser og yderligere oplysninger 
 
Simponi indeholder 
Det aktive stof er: Golimumab. En 0,5 ml fyldt pen indeholder 50 mg golimumab. 
De øvrige indholdsstoffer er: Sorbitol (E420), L-histidin, L-histidin monohydrochloridmonohydrat, 
polysorbat 80 og vand til injektionsvæsker. 
 
Udseende og pakningsstørrelser 
Simponi leveres som injektionsvæske i en fyldt pen til engangsbrug. Simponi er tilgængelig i en 
pakke indeholdende 1 fyldt pen og en multipakning indeholdende 3 (3 pakker a 1) fyldte penne. 
 
Begge pakningsstørrelser er ikke nødvendigvis markedsført. 
 
Opløsningen er klar til let opaliserende (en perlelignende glans), farveløs til lysegul og kan 
indeholde få, små halvgennemsigtige eller hvide partikler af protein. Anvend ikke Simponi hvis 
opløsningen er misfarvet, uklar eller hvis den indeholder fremmede partikler. 
 
Indehaver af markedsføringstilladelsen og fremstiller 
Janssen Biologics B.V. 
Einsteinweg 101 
2333 CB Leiden 
Holland 
 
Hvis De vil have yderligere oplysninger om Simponi, skal De henvende Dem til den lokale 
repræsentant: 
 
België/Belgique/Belgien 
MSD Belgium BVBA/SPRL 
Clos du Lynx/Lynx Binnenhof 5 
1200 Bruxelles/Brussels 
Tél/Tel: (0) 800 38 693  
+32 (0)2 776 62 11 
 
Luxembourg/Luxemburg 
MSD Belgium BVBA/SPRL 
Clos du Lynx/Lynx Binnenhof 5 
1200 Bruxelles/Brussels 
Tél/Tel: (0) 800 38 693  
+32 (0)2 776 62 11 
 
България 
Мерк Шарп и Доум България ЕООД 
ЕКСПО 2000 
Бул. Никола Вапцаров № 55 
Източно крило, Сектори B1&B2 
София 1407  
Тел.: +359 2 819 3737 
 
Magyarország 
MSD Pharma Hungary Kft. 
Lechner Ödön fasor 8. 
H-1095 Budapest 
Tel.:+36 1 888 5300 
 

Protocol version 4.1, 3 November 2016 
61
Česká republika 
Merck Sharp & Dohme s.r.o.  
Evropská 2588/33a 
160 00 Praha 6 
Tel: +420 233 010 111  
 
Malta 
Merck Sharp & Dohme Cyprus Limited 
Chilonos Street, 2A 
CY-1101 Nicosia 
Cyprus 
Tel.: 8007 4433 (+35699917558) 
 
Danmark 
MSD Danmark ApS 
Lautrupbjerg 4  
DK-2750 Ballerup 
Tlf: + 45 4482 4000 
 
Nederland 
Merck Sharp & Dohme BV 
Waarderweg 39 
2031 BN Haarlem 
Tel: +0800 9999000 
(+31 23 5153153) 
 
Deutschland 
MSD SHARP & DOHME GMBH 
Lindenplatz 1 
85540 Haar 
Tel: 0800 673 673 673 
(+49 (0) 89 4561 2612) 
 
Norge 
MSD (Norge) AS 
P.B 458 Brakerøya,  
N-3002 Drammen 
Tlf: +47 32 20 73 00 
 
Eesti 
Merck Sharp & Dohme OÜ 
A. H. Tammsaare tee 47 
EE-11316 Tallinn 
Tel: + 372 6144 200 
 
Österreich 
Merck Sharp & Dohme Ges.m.b.H. 
Am Euro Platz 2 
A-1120 Wien 
Tel: +43 (0) 1 26 044 
 
Ελλάδα 
MSD Α. Φ.Β.Ε.Ε. 
Αγίου Δημητρίου 63 
GR-174 56 Άλιμος 
Τηλ: + 30-210 98 97 300 
 
Polska 
MSD Polska Sp. z o.o. 
ul. Chłodna 51 
00-867 Warszawa 
Tel: +48 22 549 51 00 
 
España 
Merck Sharp & Dohme de España, S.A. 
Josefa Valcárcel, 38 
E-28027 Madrid 
Tel: + 34 91 3210600 
 
Portugal 
Merck Sharp & Dohme, Lda. 
Rua Agualva dos Açores 16 
P-2735-557 Agualva-Cacém 
Tel: + 351-21 446 58 08 
 
France 
MSD France  
34 avenue Léonard de Vinci  
F-92400 Courbevoie 
Tél: + 33-(0)1 80 46 40 40 
 
România 
Merck Sharp & Dohme Romania S.R.L.  
Bucharest Business Park 
Soseaua Bucuresti-Ploiesti nr. 1A 
Cladire C1, etaj 3 
Bucuresti, sector 1, 013681-RO 
Romania  
Tel. +40 21 529 2900 
 

Protocol version 4.1, 3 November 2016 
62
Ireland 
Merck Sharp & Dohme Ireland (Human 
Health) Limited 
Pelham House,  
South County Business Park, 
Leopardstown,  
Dublin 18,  
Ireland 
Tel: +353 (0)1 2998700 
 
Slovenija 
Merck Sharp & Dohme, inovativna zdravila 
d.o.o. 
Šmartinska cesta 140 
1000 Ljubljana 
Tel. +386 1 5204 201 
 
Ísland 
Vistor hf  
Hörgatún 2 
IS-210 Garðabær 
Sími: + 354 535 70 00  
 
Slovenská republika 
Merck Sharp & Dohme, s. r. o. 
Mlynské nivy 43 
821 09 Bratislava 2 
Tel.: +421 2 58282010 
 
Italia 
MSD Italia S.r.l.  
Via Vitorchiano, 151 
I-00189 Roma 
Tel: +39 06 361911 
 
Suomi/Finland 
MSD Finland Oy  
PL 46/PB 46 
FIN-02151 Espoo/Esbo 
Puh/Tel: + 358-(0)9 804 650 
 
Κύπρος 
Merck Sharp & Dohme Cyprus Limited.  
Οδός Χείλωνος 2Α 
CY-1101Λευκωσία 
Τηλ.: 800 00 673 
  
(+357 22866700)  
 
Sverige 
Merck Sharp & Dohme (Sweden) AB 
Box 7125 
S-192 07 Sollentuna 
Tel: +46 77 5700488 
 
Latvija 
SIA Merck Sharp & Dohme Latvija 
Skanstes iela 50A 
Rīga, LV-1013  
Tel: + 371-67364224 
 
United Kingdom 
Merck Sharp & Dohme Limited 
Hertford Road, 
Hoddesdon, 
Hertfordshire, 
EN11 9BU, 
UK 
Tel: +44 (0) 1992 467272 
 
Lietuva 
UAB Merck Sharp & Dohme 
Kęstučio g. 59/27 
LT 08124 Vilnius 
Tel. + 370 5278 02 47 
 
 
 
Denne indlægsseddel blev senest ændret: Marts 2013 
 
De kan finde yderligere information om dette lægemiddel på Det Europæiske Lægemiddelagenturs 
hjemmeside http://www.ema.europa.eu/. 

Protocol version 4.1, 3 November 2016 
63
BRUGSVEJLEDNING 
 
Hvis De ønsker selv at indsprøjte Simponi, skal De først oplæres af sundhedsfagligt personale 
i, hvordan De forbereder og giver Dem selv indsprøjtningen. Kontakt Deres læge, 
sygeplejerske eller apoteket for at aftale en træningskonsultation, hvis De ikke er blevet 
oplært. 
 
I denne brugsvejledning: 
1. 
Forberedelse til anvendelse af pennen 
2. 
Valg og forberedelse af indsprøjtningssted 
3. 
Indsprøjtning af medicinen 
4. 
Efter indsprøjtningen 
 
Diagrammet nedenfor (se figur 1) viser, hvordan ”SmartJect” fyldt pen ser ud. I denne pjece 
omtales “SmartJect” fyldt pen som “pen”. 
 
 
 
Figur 1 
 
1. 
Forberedelse til anvendelse af pennen 
 
Ryst på intet tidspunkt pennen. 
 
Fjern ikke hætten fra pennen, før det er nødvendigt. 
 
Tjek udløbsdato 
 
Tjek udløbsdato (angivet som “EXP”) på pennen. 
 
De kan også tjekke udløbsdatoen på æsken. 
Anvend ikke pennen, hvis udløbsdatoen er passeret. Udløbsdatoen er den sidste dag i den nævnte 
måned. Kontakt Deres læge eller apoteket. 
 
Tjek sikkerhedsforsegling 
 
Tjek sikkerhedsforseglingen rundt om hætten på pennen. 
Anvend ikke pennen, hvis forseglingen er brudt. Kontakt Deres læge eller apoteket. 
 
Vent 30 minutter, så pennen opnår stuetemperatur 
 
Læg pennen ved stuetemperatur uden for æsken i 30 minutter utilgængeligt for børn for at 
sikre en ordentlig indsprøjtning. 
Varm ikke pennen på andre måder (for eksempel må den ikke varmes i en mikrobølgeovn eller i 
varmt vand). 
Fjern ikke pennens hætte, mens den får lov til at nå stuetemperatur. 
 
Klargøring af resten af udstyret 

Protocol version 4.1, 3 November 2016 
64
Mens De venter, kan De klargøre resten af udstyret, som inkluderer en alkoholserviet, en vatrondel 
eller gaze og en nålebeholder. 
 
Tjek væsken i pennen 
 
Se igennem vinduet for at sikre, at væsken i pennen er klar til en anelse opaliserende (en 
perlelignende glans) og farveløs til lysegul. Injektionsvæsken kan benyttes, selv om den 
indeholder nogle få små, halvgennemsigtige eller hvide partikler af protein. 
 
De vil også bemærke en luftboble, hvilket er normalt. 
Anvend ikke pennen, hvis injektionsvæsken har en forkert farve, er uklar eller indeholder fremmede 
partikler. Tal med Deres læge eller på apoteket, hvis dette sker. 
 
2. 
Valg og forberedelse af indsprøjtningssted (se figur 2) 
 
De kan som regel indsprøjte medicinen på den øvre side af lårene. 
 
De kan også foretage indsprøjtningen på maven (abdomen) under navlen, undtagen i området 
ca. 5 cm lige under navlen. 
 
De må ikke indsprøjte i områder, hvor huden er øm, rød, skællet, hård, eller hvor der er blå 
mærker, ar eller strækmærker. 
 
 
 
Figur 2 
 
 
Valg af indsprøjtningssted for hjælpere/plejere (se figur 3) 
 
Hvis plejepersonale giver Dem indsprøjtningen, kan det ydre område af overarmen også 
anvendes. 
 
Alle de nævnte områder kan anvendes uanset Deres kropstype eller størrelse. 
 
 
 
Figur 3 
 
 
Forberedelse af indsprøjtningssted 
 
Vask hænderne grundigt med sæbe og varmt vand. 
 
Tør indsprøjtningsstedet med en alkoholserviet. 
 
Lad huden tørre inden injektion. Lad vær med at vifte eller blæse på det rene område. 
Rør ikke dette område igen før indsprøjtningen gives. 
 

Protocol version 4.1, 3 November 2016 
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3. 
Indsprøjtning af medicinen 
Hætten bør ikke fjernes, før De er klar til at indsprøjte medicinen. Medicinen skal indsprøjtes inden 
for 5 minutter efter, at hætten er fjernet. 
 
Fjern hætten (figur 4) 
 
Når De er klar til at indsprøjte, skal De vride hætten en anelse, så sikkerhedsforseglingen 
brydes. 
 
Træk hætten af og smid den ud efter indsprøjtningen.  
 
Sæt ikke hætten på igen, da den kan ødelægge nålen indeni pennen. Anvend ikke pennen hvis den 
tabes uden hætten. Kontakt Deres læge eller apoteket, hvis dette sker. 
 
 
 
Figur 4 
 
Pres pennen fast mod huden (se figur 5 og 6) 
 
Hold pennen behageligt i Deres hånd. Tryk IKKE på knappen endnu. 
 
De kan vælge mellem to injektionsmetoder. Det anbefales at foretage indsprøjtningen uden at 
klemme huden sammen (figur 5a). Men hvis De foretrækker det, kan De klemme huden 
sammen for at danne en fast overflade til indsprøjtningen (figur 5b). 
 
Pres den åbne ende af pennen fast mod huden i en ret vinkel (90 grader), indtil 
sikkerhedshætten glider helt ind i Clear Cover (figur 6). 
 
 

Protocol version 4.1, 3 November 2016 
66
 
 
 
Figur 5a 
 
 
 
 
 
Figure 5b 
 
 
 
 
 
Figur 6 
 
Tryk på knappen for indsprøjtning (se figur 7) 
 
Bliv ved med at presse pennen mod Deres hud og tryk på knappen med Deres fingre 
eller tommelfinger. De vil ikke kunne trykke knappen ind, medmindre pennen er presset 
fast mod huden, og sikkerhedshætten glider ind i Clear Cover. 
 
Så snart knappen er trykket ind, vil den forblive inde, så det er ikke nødvendigt fortsat at 
trykke på den. 
 
 

Protocol version 4.1, 3 November 2016 
67
 
Figur 7 
 
 
De vil høre et ”klik” – bliv ikke urolig. Det første “klik” betyder, at nålen er ført ind, og 
indsprøjtningen er startet. De vil muligvis mærke et nålestik. 
Løft ikke pennen væk fra huden. Hvis pennen løftes fra huden, vil De muligvis ikke få fuld 
dosis. 
 
Fortsæt med at holde indtil det andet “klik” (se figur 8) 
 
Fortsæt med at holde pennen fast mod huden, indtil De hører et nyt ”klik”. Det varer 
som regel 3-6 sekunder, men det kan tage op til 15 sekunder, før De hører det andet 
”klik”. 
 
Det andet “klik” betyder, at indsprøjtningen er færdig, og at nålen igen er tilbage i pennen. 
 
Løft pennen fra indsprøjtningsområdet. 
Tæl 15 sekunder fra tidspunktet De trykker på knappen, til De løfter pennen fra 
indsprøjtningsområdet, hvis De er hørehæmmet. 
 
 
 
Figur 8 
 

Protocol version 4.1, 3 November 2016 
68
4. 
Efter indsprøjtningen 
 
Anvend vatrondel eller gaze 
 
Der kan være en smule blod eller væske ved indsprøjtningsområdet. Dette er normalt. 
 
De kan presse en vatrondel eller gaze på indsprøjtningsområdet i 10 sekunder. 
 
Hvis det er nødvendigt, kan De dække indsprøjtningsområdet med et lille stykke plaster. 
Gnid ikke på huden. 
 
Tjek vinduet - en gul indikator bekræfter rigtig håndtering (se figur 9) 
 
Tal med Deres læge eller apoteket, hvis den gule indikator ikke er synlig i vinduet, eller hvis De har 
mistanke om, at De ikke har fået den fulde dosis. Tag ikke en ny dosis uden at have spurgt Deres 
læge. 
 
 
 
Figur 9 
 
Smid pennen væk (se figur 10) 
 
Læg straks pennen i en nålebeholder. Sørg for at De skaffer Dem af med beholderen som 
instrueret af Deres læge eller sygeplejerske. 
 
Tal med Deres læge eller apoteket, hvis De føler eller er usikker på, at der er noget der er gået galt 
med indsprøjtningen. 
 
 
Figur 10 
 

Protocol version 4.1, 3 November 2016 
69
33  COPY OF IMP PACKAGE 
 
 
 
 
 
 
 
 
 

Protocol version 4.1, 3 November 2016 
70
34 LABEL ON PACKAGE 
 
 
 
 
 
 
 
 
 
 
35 PATIENT CARD 
 
 FORSØGSDELTAGER ID-KORT 
I nødstilfælde kontakt:  
Overlæge,  
Hospital  
Afdeling  
Gadenavn, nr., postnr. og by 
Tlf. (eller vagthavende) 
 
Protokol: MANGO (H-1-2013-118) 
Forsøgsdeltagernummer:_______________________ 
Sponsor: Mikkel Østergaard, Glostrup Hospital, Tlf. 3863 3863 
(dagtid) 
DE BEDES VENLIGST BÆRE DETTE 
KORT PÅ DEM DØGNET RUNDT UNDER 
DIN DELTAGELSE I MANGE STUDIET 
Forsøgsmedicinen er Golimumab (Simponi) 50 
mg/0.5 ml, der injiceres subkutant en gang 
månedlig (på den samme dato).  
 
Forsøgspersonen har rygsøjlegigt. 
I tilfælde af problemer eller forespørgsler, 
kontakt venligst lægen, angivet på forsiden af 
dette kort. 
Subject Identification Card 
In case of emergency please contact:  
Doctor, Investigator 
Hospital name 
Department name 
Address 
Telephone 
 
Protocol: MANGO (H-1-2013-118) 
Subject identification number: _______________________ 
Sponsor: Mikkel Østergaard, Glostrup Hospital, Tlf. 3863 3863 
(dagtid) 
PLEASE CARRY THIS CARD AT ALL 
TIMES DURING THE MANGO STUDY 
The 
investigational 
medicinal 
product 
is 
Golimumab (Simponi) 50 mg/0.5 ml, which is 
injected subcutanously every month (on the same 
date). 
 
The subject suffers from axial spondyloarthritis. 
Any problems or queries should be referred to the 
investigator contact name at the front page of this 
card. 
 
 
 
 
 
Sponsor Professor Mikkel Østergaard, Videncenter for Reumatologi og 
Rygsygdomme VRR, Glostrup Hospital. Tlf.: XXXXXXXX.  
Investigator initieret forsøg. 
 
Initialer:______________________ CRF nr.:______________________  
 
Dato for udlevering:__________________________________________ 
Skal ingives som anført på æsken.  
Kun til brug i klinisk forsøg MANGO (H-1-2013-118) 

Protocol version 4.1, 3 November 2016 
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36 CONTRAINDICATIONS MRI 
 
 
 

Protocol version 4.1, 3 November 2016 
72
37 ASAS KRITERIERNE FOR AKSIAL SPONDYLARTRITIS 
ASAS 2009 kriterierne for spondylartritis omfatter såvel patienter med som uden sikre radiologiske tegn på 
sacroilitis. I henhold til kriterierne vil en patient med kroniske rygsmerter (varighed >3 mdr.) og smertedebut 
<45 års alderen blive klassificeret ved tilstedeværelse af:  
1) sacroilitis (enten sikker tilstedeværelsen på konventionel røntgenoptagelse af sacroiliacaled eller ved 
aktive inflammatoriske forandringer på MRI, der er forenelig med SpA) og opfyldelse af 1 klinisk 
kriterium 
2) HLA-B27 positiv vævstype og opfyldelse af 2 kliniske kriterier 
 
Kliniske kriterier 
Definition 
Inflammatoriske 
rygsmerter 
(IBP) 
Inflammatoriske rygsmerter vurderet af en ekspert. Mindst 4 af 5 af følgende skal 
være opfyldt: Debutalder <45 år, 2. ”Snigende” debut, 3. Lindring ved fysisk 
aktivitet, 4. Ingen lindring i hvile, 5. Natlige smerter (der mindskes når patienten er 
stået op)  
Arthritis 
Tidligere eller nuværende aktiv synovitis diagnosticeret af læge 
Enthesitis (hæl) 
Hæl enthesitis: Tidligere eller nuværende spontan smerte eller ømhed hvor 
Achillessene eller fascia plantaris insererer på calcaneus 
Uveitis 
Tidligere eller nuværende uveitis anterior diagnosticeret af øjenlæge  
Dactylitis 
Tidligere eller nuværende dactylitis diagnosticeret ved læge 
Psoriasis 
Tidligere eller nuværende psoriasis diagnosticeret ved læge 
Inflammatorisk tarmsygdom 
Tidligere eller nuværende Crohn’s sygdom eller colitis ulcerative diagnosticeret ved 
læge 
God effekt af NSAID  
24-48 timer efter en fuld dosis NSAID er rygsmerterne enten forbedret eller helt 
forsvundet 
Dispositioner til SpA 
Tilstedeværelse af en af følgende:   
a) Ankyloserende spondylitis  
b) Psoriasis  
c) Akut anterior uveitis 
d) Reaktiv arthritis 
e) Inflammatorisk tarmsygdom  
hos førstegradsslægtninge (mor, far, søstre, brødre, børn) eller andengrads slægtninge 
(bedsteforældre, forældres søskende, fætter, kusine) 
Forhøjet CRP  
C-reaktiv protein koncentration over øvre normal grænse efter at andre årsager hertil 
udelukket 
HLA-B27 
Positiv test i henhold til standard laboratorie teknikker  
Sacroiliitis på konvnetionel 
røntgenundersøgelse  
Bilateral grad 2-4 eller unilateral grad 3-4 sacroiliitis på konventionel 
røntgenundersøgelse i henhold til de modificerede New York kriterier  
Sacroiliitis på MRI 
Aktive inflammatoriske forandringer i sacroiliacaled med sikker 
knoglemarvsødem/osteitis forenelig med SpA 
 

Protocol version 4.1, 3 November 2016 
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38 LABORATORIEMANUAL FOR MANGO STUDIET 
Videnskabeligt studie af nye MR- og biokemiske metoder til af følge og 
forudsige klinisk respons og sygdomsforløb hos patienter med rygsøjlegigt der 
påbegynder behandling med Golimumab 
 
Udarbejdet af: 
Læge, ph.d. Susanne Juhl Pedersen og forskningsbioanalytiker, Teresa Rozenfeld, Videncenter for 
Reumatologi og Rygsygdomme, Glostrup Hospital 
 
Formål 
Studiet har til formål at undersøge om nye typer af MR-skanning og cirkulerende biomarkører for 
inflammation, brusk-, bindevævs- og knogleomsætning kan anvendes til at forudsige klinisk 
behandlingsrespons og sygdomsforløb hos patienter med rygsøjlegigt (axial spondylartritis herunder Mb. 
Bechterew og visse former for psoriasisgigt).  
 
Hyppighed 
Patienten afgiver blod-og urinprøver til forsøget 7 gange over 52 uger, såfremt de gennemfører studiet. Ved 
alle besøg tages rutineprøver. Ved 4 af de 6 besøg (uge 0, 4, 16 og 52) tages desuden blod- og urinprøver til 
senere analyse af eksperimentelle biomarkører. 
Rutinekontrolblodprøver: Hæmoglobin, CRP, leukocytter inkl. differentialtælling, trombocytter, albumin, 
ALAT eller ASAT, LDH, alkalisk phosphatase, kreatinin. Desuden foretages der ved uge 0 og 52 analyse af 
ANA. 
    
Patienten vil blive bedt om at afgive projektblod- og urinprøver på følgende tider: 
Besøg 1 (uge 0) 
Rutineblodprøver og eksperimentelle blod- og urinprøver 
Besøg 2 (uge 4) 
Rutineblodprøver og eksperimentelle blod- og urinprøver 
Besøg 3 (uge 16) 
Rutineblodprøver og eksperimentelle blod- og urinprøver 
Besøg 4 (uge 28) 
Rutineblodprøver 
Besøg 5 (uge 40) 
Rutineblodprøver 
Besøg 6 (uge 52) 
Rutineblodprøver og eksperimentelle blod- og urinprøver 
Besøg 7 Eksklusionsbesøg 
Rutineblodprøver og eksperimentelle blod- og urinprøver 
 
De undersøgelser, der er angivet i denne laboratorievejledning for ”Eksklusionsbesøg” udføres hurtigst 
muligt efter eksklusion ("eksklusionsbesøg"). 
 
Anvendelse 
Blod- og urinprøverne mærkes og opbevares i pseudo-anonymiseret form. Anvendelse kan kun ske efter 
godkendelse fra MANGO-styregruppen. Anvendelse af prøvematerialet til undersøgelser for specifikke 
biomarkører skal godkendes af Videnskabsetiske Komité. 
 
Blod- og urinprøver 
Den afgivne mængde blod til eksperimentelle biomarkører per gang er 58 ml fraset ved besøg 1, hvor der vil 
blive udtaget 76 ml. Den afgivne mænge urin er 10 ml. Patienten er ikke fastende. 
 

Protocol version 4.1, 3 November 2016 
74
Der tages følgende projektrelaterede blodprøver (fra perifer vene) 
a) 2 x 9 ml blod i tørglas til serum  
b) 3 x 6 ml blod i EDTA glas til EDTA-plasma  
c) 1 x 9 ml blod i citrat glas til citrat-plasma  
d) 2 x 4 ml blod i heparin glas til heparin-plasma  
e) 5 ml fuldblod fordeles i to PAXgene RNA-rør 
f) kun ved ”Besøg 1” 3 x 6 ml fuldblod i EDTA glas. 
g) 10 ml urin.  
 
Der udfyldes MANGO flow-skema ved hvert besøg (se nedenfor). 
 
Mærkning 
Alle fryserør skal mærkes med MANGO, hospitalsnavn, patient nr., patient-initialer, visit nr., dato (dag-
måned-årstal) og hvad rørene indeholder (serum, EDTA-plasma, citrat-plasma, heparin-plasma, fuldblod, 
buffy coat, urin, PAXgene RNA). Det er ikke et krav, at der anvendes farvekoder på rørene. Der anvendes 
fortrykte mærkater, således, at der kun skal anføres dato (dato-måned-årstal) med hånden (brug 
vandbestandig tusch eller kuglepen). Etiketterne fremstilles på de enkelte centre efter elektronisk ”master”. 
Prøverne vil på senere aftalte tidspunkter blive transporteret til de laboratorier, der skal foretage de enkelte 
analyser.  
 
Pakning 
Cryorørenes position i fryseæskerne noteres på flowskemaet. F.eks. K1, P1-5, hvor ”K1” angiver kasse nr. 1 
og ”P1-5” beskriver position 1-5. Hver fryseæske mærkes med MANGO, hospitals navn, patient nr., patient-
initialer, kasse nr. og materiale (mærkes på låg (nederste venstre hjørne), på siden af låg (nederste venstre 
hjørne) og på kassen (nederste venstre hjørne).   
Blodprøver (dvs. serum, EDTA-, citrat- og heparin plasma samt buffy coat) fra hver patient gemmes samlet i 
en kasse (dvs. blodprøver fra kun en patient i en kasse).  
Paxgene RNA rør opbevares i separate kasser, alle patienter i en kasse.  
Urin opbevares i separate kasser, alle patienter i en kasse. Fryses ubehandlet ved –20oC.              
Fuldblod fra ”Besøg 1” opbevares ubehandlet i separate kasser ved –20oC (alle patienter i en kasse). 
 

Protocol version 4.1, 3 November 2016 
75
MANGO flow-skema: Blod- og urinprøver 
 
Hospital:_____________________; Patient nr.:____________________; Patient initialer:________________ 
 
Måned 
0 
4 
16 
52 
Eksklusion 
Visit 
1 
2 
3 
6 
7 
Dato for blodprøvetagning 
 
 
 
 
 
2 x 9 ml blod i tørglas til serum. 
Fordeles i 5 stk Cryorør rør. RØD 
 
 
 
 
 
3 x 6 ml blod i EDTA-glas til EDTA plasma. 
Fordeles i 5 stk. Cryorør. BLÅ 
 
 
 
 
 
9 ml blod i Na-Citrat-glas 3,2 % til CITRAT 
plasma. Fordeles i 3 stk. Cryorør. HVID 
 
 
 
 
 
2 x 4 ml blod i LH-Heparin-glas til HEPARIN 
plasma. Fordeles i 3 stk. Cryorør. GRØN 
 
 
 
 
 
Buffycoat fra EDTA glas. 
Fordeles i 3 stk. Cryorør rør. GUL 
 
 
 
 
 
5 ml blod fordeles i 2 Paxgene RNA-rør 
 
 
 
 
 
 
3 x 6 ml EDTA-glas til fuldblod 
 
 
 
 
 
 
Urin 10 ml 
 
 
 
 
 
Tidspunkt for urinafgivelse 
 
 
 
 
 
 
Signatur 
 
 
 
 
 
 

Protocol version 4.1, 3 November 2016 
76
MANGO Håndtering af blodprøver for projekt  
 
VIGTIGT: Prioritering af glas: LILLA EDTA glas – RØDT tørglas – PAXgene rør – BLÅT citrat glas – GRØNT Li-heparin glas  
 
OPSAMLING  
ALLE BESØG  
2 x 9 ml RØDT 
TØRGLAS  
3 x 6 ml 
LILLA EDTA 
GLAS  
(Ekstra 3 X 6 
ML ved 
BESØG 1) 
BUFFY COAT  
(Brug glassene 
fra EDTA-
plasma rørene)  
9 ml BLÅT Na-
CITRAT 3,2 % 
GLAS 
2 x 4 ml 
GRØNT 
Lithium-
HEPARIN 
GLAS  
2 X PAX-gene 
RNA RØR  
   
   
3 x 6 ml 
LILLA 
EDTA GLAS 
(KUN BESØG 
1) 
Urin 10 ml i 10 
ml rør  
PREPARERING  
   
Henstår mindst 
30 min. og max. 
2 timer 
   
Centrifugeres 
ved 2330g  
10 min  
4° C  
   
Serum, 
undtagen det 
nederste ca. 5 
mm serumlag 
over cellelag 
overføres til    
5 x cryorør med 
rødt låg  
minimum 500 
µl  
Henstår mindst 
30 min. og max. 
2 timer 
 
   
Centrifugeres 
ved 2330g  
10 min  
4° C  
   
Fjern plasma til 
ca. 5 mm over 
cellelag.  
Plasma 
overføres til 5 x 
cryorør med 
blåt låg  
minimum 500 
µl  
Gem rør til 
Buffy coat  
Tag alle de 
hvide 
blodlegemer fra 
1 glas og kom 
dem i 1 cryorør 
med gult låg  
1 glas = 1 
cryorør  
   
   
Så man i alt har 
3 cryorør.  
Henstår mindst 
30 min. og max. 
2 timer 
 
   
Centrifugeres 
ved 2330g  
10 min  
4° C  
   
Plasma 
overføres til    
3 x cryorør med 
hvidt låg  
minimum 500 
µl  
Henstår mindst 
30 min. og max. 
2 timer 
 
   
Centrifugeres 
ved 2330g  
10 min  
4° C  
   
Plasma 
overføres til    
3 x cryorør med 
grønt låg  
minimum 500 
µl  
Vendes 
STRAKS 10 
gange efter 
blodprøvetagnin
gen.  
   
Henstår i 2-24 
timer ved stue 
tempe-ratur.  
   
   
Vendes godt 
inden røret 
fryses.  
   
 
   
OPBEVARING  
 
-80°C fryser  
 
Fryses ved -
20°C i 24-72 
timer.  
Derefter flyttes 
glasset over til -
80°C fryser. 
Fryses ved  
-20°C 

Protocol version 1, 16 October 2013 
77 
 
 
 
DATO NOTERES I FLOWSKEMA + ANTAL AF RØR  
  
PLACERING AF RØR, SE NEDENSTÅENDE  
   
    
   
73  
   
74  
   
75  
   
76  
   
77  
   
78  
   
79  
   
80  
   
81  
   
64  
   
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68  
   
69  
   
70  
   
71  
   
72  
   
55  
   
56  
   
57  
   
58  
   
59  
   
60  
   
61  
   
62  
   
63  
   
46  
   
47  
   
48  
   
49  
   
50  
   
51  
   
52  
   
53  
   
54  
   
37  
   
38  
   
39  
   
40  
   
41  
   
42  
   
43  
   
44  
   
45  
   
28  
   
29  
   
30  
   
31  
   
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33  
   
34  
   
35  
   
36  
   
19  
   
20  
   
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22  
   
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27  
   
10  
   
11  
   
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13  
   
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18  
   
1  
   
2  
   
3  
   
4  
   
5  
   
6  
   
7  
   
8  
   
9  
     
 
 
 
 

Protocol version 1, 16 October 2013 
78 
 
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