Long-term Effects of Methotrexate in Adults With Erosive Hand Osteoarthritis: A 30-month Follow-up of Former MERINO Participants (MERINO:2).
Conditions: Hand Osteoarthritis, Erosive Osteoarthritis
Sponsor: Diakonhjemmet Hospital

 
Protocol 1.1 
 
© 2015-2021 TransCelerate BioPharma 
1 
 
 
Protocol Title: 
Long-term effects of Methotrexate in adults with erosive hand 
osteoarthritis: A 30-month follow-up of former MERINO 
participants (MERINO:2). 
Protocol Number:   
1.1 
Date:  
 
 
29.07.2024 
Amendment Number:  
1 
Country:  
 
 
NOR 
Compound:   
 
Methotrexate vs. treatment as usual  
Brief Title:  
A 30-month follow-up of MERINO participants to evaluate long-
term effects of Methotrexate in erosive hand OA. 
Study Phase:   
 
Phase 4 
Acronym:  
 
 
MERINO:2 
Sponsor Name:  
 
Diakonhjemmet Hospital AS 
Legal Registered Address:  Box 23 Vinderen, 0319 Oslo 
 
Regulatory Agency Identifier Number(s): 
Regional committee for medical and health research ethics (REK): 715758 
ClinicalTrials.gov: NCT06281184 
Internal identification number: DIA2024.1 
 
Approval Date:  
 
10.04.2024 
 
 
 

 
Protocol 1.1 
 
© 2015-2021 TransCelerate BioPharma 
2 
Sponsor Signatory: 
 
 
 
 
          12.02.2024 
Espen Haavardsholm 
Head of Research and Innovation & Professor & Center 
Director REMEDY 
 
Date 
 
 
Medical Monitor Name and Contact Information: 
Alexander Mathiessen 
MD, PhD 
alexander.mathiessen@diakonsyk.no 
+47-97501889 
 
 
 

 
Protocol 1.1 
 
© 2015-2021 TransCelerate BioPharma 
3 
Protocol Amendment Summary of Changes Table 
 
Document 
Date 
Version 
Original protocol 
12.01.2024 
Version 1.0 
Amendment 1 
25.07.2024 
Version 1.1 
 
AMENDMENT 1, 25.07.2024 
Overall rationale for the amendment: Complying with conditional approval from REK 
 
Section # 
Description of Change 
Brief Rationale 
Protocol title 
“Long-term effects of Methotrexate in 
adults with erosive hand osteoarthritis: 
A 30-month follow-up of former 
MERINO participants (MERINO:2)”. 
A more precise phrase to harmonize with the 
following two changes below. 
4.1 Overall design 
Changed observational time from 12 
months to 18 months after the 
completion of the MERINO trial. The 
follow-up in MERINO:2 will thus be 
scheduled 30 months after entering the 
MERINO trial, or 18 months after 
completing the MERINO trial. 
To ensure higher recruitment rates, we have 
extended the follow-up period. The new 
follow-up will be scheduled 30 months after 
entering the MERINO trial, or 18 months after 
its completion. Additionally, we have clarified 
that follow-ups can deviate by up to 10 weeks 
from this time point, addressing a 
specification that was missing in the original 
protocol. 
4.1 Overall design 
Changed potential participants from 
those completing the MERINO trial to 
all recruited MERINO participants.  
As this is a new study with a separate consent 
form, we propose offering the current study to 
all participants originally recruited for the 
MERINO trial. We recognize the importance 
of including those who did not complete the 
MERINO trial, including those who withdrew 
shortly after enrolling. These participants will 
have experienced an extended period of 
'treatment as usual,' which will enhance the 
robustness of our results. 
4.1 Overall design 
Changed the description of participants 
who finished the MERINO trial and 
who did not request further MTX 
treatment from “no treatment” to 
“treatment as usual”. 
This is a more precise description of the 
period after completing the original MERINO 
trial. 
Consent form 
Minor word improvement of the 
consent form. 
Comply with the conditional approval from 
REK as well as harmonization with the 
changes described above. 
 
 

 
Protocol 1.1 
 
© 2015-2021 TransCelerate BioPharma 
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Table of Contents 
 
1. 
PROTOCOL SUMMARY ................................................................................................................................. 7 
1.1. 
SYNOPSIS .................................................................................................................................................... 7 
1.2. 
SCHEMA ...................................................................................................................................................... 9 
1.3. 
SCHEDULE OF ACTIVITIES (SOA) .............................................................................................................. 10 
2. 
INTRODUCTION ............................................................................................................................................ 12 
2.1. 
STUDY RATIONALE ................................................................................................................................... 12 
2.2. 
BACKGROUND ........................................................................................................................................... 13 
2.3. 
BENEFIT/RISK ASSESSMENT ...................................................................................................................... 13 
2.3.1. 
Adverse and toxic effects of MTX ......................................................................................................... 13 
2.3.2. 
Risk of study-related procedures ......................................................................................................... 15 
2.3.3. 
Benefit Assessment ............................................................................................................................... 15 
2.3.4. 
Overall Benefit Risk Conclusion .......................................................................................................... 15 
3. 
OBJECTIVES AND ENDPOINTS ................................................................................................................. 16 
4. 
STUDY DESIGN .............................................................................................................................................. 17 
4.1. 
OVERALL DESIGN...................................................................................................................................... 17 
4.2. 
SCIENTIFIC RATIONALE FOR STUDY DESIGN ............................................................................................. 17 
4.2.1. 
Patient Input into Design ..................................................................................................................... 17 
4.3. 
JUSTIFICATION FOR DOSE .......................................................................................................................... 17 
4.4. 
END-OF-STUDY DEFINITION ...................................................................................................................... 18 
5. 
STUDY POPULATION................................................................................................................................... 19 
6. 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY ........................................................... 20 
6.1. 
STUDY INTERVENTION ADMINISTERED ..................................................................................................... 20 
6.1.1. 
Investigational medicinal product (IMP) ............................................................................................. 20 
6.2. 
PREPARATION, HANDLING, STORAGE, AND ACCOUNTABILITY.................................................................. 21 
6.3. 
ASSIGNMENT TO STUDY INTERVENTION.................................................................................................... 21 
6.4. 
BLINDING .................................................................................................................................................. 21 
6.5. 
STUDY INTERVENTION COMPLIANCE ........................................................................................................ 21 
6.6. 
DOSE MODIFICATION ................................................................................................................................ 21 
6.7. 
CONTINUED ACCESS TO STUDY INTERVENTION AFTER THE END OF THE STUDY ....................................... 21 
6.8. 
TREATMENT OF OVERDOSE ....................................................................................................................... 21 
6.9. 
PRIOR AND CONCOMITANT THERAPY ........................................................................................................ 22 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ................................................................................................................ 23 
7.1. 
DISCONTINUATION OF STUDY INTERVENTION ........................................................................................... 23 
7.2. 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY.......................................................... 23 
7.3. 
LOST TO FOLLOW-UP ................................................................................................................................. 23 
8. 
STUDY ASSESSMENTS AND PROCEDURES ........................................................................................... 24 
8.1. 
PATIENT-REPORTED OUTCOME MEASURES ................................................................................................ 24 
8.1.1. 
VAS pain .............................................................................................................................................. 24 
8.1.2. 
OMERACT-OARSI responder criteria................................................................................................. 24 
8.1.3. 
Australian/Canadian Hand Index (AUSCAN) ..................................................................................... 25 
8.1.4. 
The EuroQol 5 dimensions 5 levels (EQ-5D-5L) ................................................................................. 25 
8.2. 
CONVENTIONAL HAND RADIOGRAPHS ....................................................................................................... 26 
8.3. 
SAFETY ASSESSMENTS .............................................................................................................................. 26 
8.3.1. 
Side effects and abnormal laboratory results ...................................................................................... 27 

 
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8.4. 
ADVERSE EVENTS (AES) SERIOUS ADVERSE EVENTS (SAES), AND OTHER SAFETY REPORTING ............. 28 
8.4.1. 
Time Period and Frequency for Collecting AE and SAE Information ................................................. 28 
8.4.2. 
Method of Detecting AEs and SAEs ..................................................................................................... 29 
8.4.3. 
Follow-up of AEs and SAEs ................................................................................................................. 29 
8.4.4. 
Regulatory Reporting Requirements for SAEs ..................................................................................... 29 
8.4.5. 
Pregnancy ............................................................................................................................................ 29 
8.4.6. 
Adverse Events of Special Interest ....................................................................................................... 30 
8.5. 
PHARMACOKINETICS ................................................................................................................................. 30 
8.6. 
PHARMACODYNAMICS............................................................................................................................... 30 
8.7. 
GENETICS .................................................................................................................................................. 30 
8.8. 
BIOMARKERS ............................................................................................................................................. 30 
8.9. 
IMMUNOGENICITY ASSESSMENTS .............................................................................................................. 30 
8.10. 
MEDICAL RESOURCE UTILIZATION AND HEALTH ECONOMICS .................................................................. 30 
9. 
STATISTICAL CONSIDERATIONS ............................................................................................................ 31 
9.1. 
STATISTICAL HYPOTHESES ........................................................................................................................ 31 
9.2. 
ANALYSIS SETS ......................................................................................................................................... 32 
9.3. 
STATISTICAL ANALYSES ........................................................................................................................... 32 
9.4. 
INTERIM ANALYSIS ................................................................................................................................... 32 
9.5. 
SAMPLE SIZE DETERMINATION ................................................................................................................. 32 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS............................... 33 
10.1. 
APPENDIX 1: REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS .................................. 33 
10.1.1. 
Regulatory and Ethical Considerations .......................................................................................... 33 
10.1.2. 
Financial Disclosure ....................................................................................................................... 33 
10.1.3. 
Informed Consent Process .............................................................................................................. 34 
10.1.4. 
Recruitment strategy ....................................................................................................................... 34 
10.1.5. 
Data Protection ............................................................................................................................... 34 
10.1.6. 
Committees Structure ...................................................................................................................... 35 
10.1.7. 
Dissemination of Clinical Study Data ............................................................................................. 35 
10.1.8. 
Data Quality Assurance .................................................................................................................. 35 
10.1.9. 
Source Documents........................................................................................................................... 36 
10.1.10. 
Study and Site Start and Closure .................................................................................................... 36 
10.1.11. 
Publication Policy ........................................................................................................................... 37 
10.2. 
APPENDIX 2: PATIENT REPORTED OUTCOME MEASURES ............................................................................ 38 
10.2.1. 
VAS pain.......................................................................................................................................... 38 
10.2.2. 
Australian/Canadian Hand Index (AUSCAN) ................................................................................. 39 
10.2.3. 
The EuroQol 5 dimensions 5 levels (EQ-5D-5L) ............................................................................ 42 
10.2.4. 
Medisiner ........................................................................................................................................ 43 
10.3. 
APPENDIX 3: AES AND SAES: DEFINITIONS AND PROCEDURES FOR RECORDING, EVALUATING, FOLLOW-
UP, AND REPORTING ................................................................................................................................................ 45 
10.3.1. 
Definition of AE .............................................................................................................................. 45 
10.3.2. 
Definition of SAE ............................................................................................................................ 46 
10.3.3. 
Recording and Follow-Up of AE and/or SAE ................................................................................. 47 
10.3.4. 
Reporting of SAEs ........................................................................................................................... 48 
10.4. 
APPENDIX 4: CONTRACEPTIVE GUIDANCE AND COLLECTION OF PREGNANCY INFORMATION ................... 49 
11. 
REFERENCES ................................................................................................................................................. 51 
 
 

 
Protocol 1.1 
 
© 2015-2021 TransCelerate BioPharma 
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List of Abbreviations  
 
OA 
Osteoarthritis 
MTX 
Methotrexate 
RCT 
Randomized controlled trial 
DMARDs 
Disease-Modifying Antirheumatic Drugs 
NSAIDs 
Nonsteroidal anti-inflammatory drugs 
VAS 
Visual analogue scale 

 
Protocol 1.1 
 
© 2015-2021 TransCelerate BioPharma 
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1. 
Protocol Summary 
1.1. 
Synopsis 
Protocol Title:  
Long-term effects of Methotrexate in adults with erosive hand osteoarthritis: A 30-month follow-
up of former MERINO participants (MERINO:2). 
Brief Title: 
A 30-month follow-up of MERINO participants to evaluate long-term effects of Methotrexate in 
erosive hand OA. 
Regulatory Agency Identifier Number(s): 
REK 
715758 
Rationale: 
In response to the high prevalence of synovitis in hand osteoarthritis (OA) and its association 
with pain, there's a compelling rationale for investigating the efficacy of MTX in managing 
inflammatory erosive hand OA. Recent guidelines highlight the need for large, well-designed 
trials to assess the effectiveness of MTX. A recent trial (METHODS study) showed promising 
pain reduction with MTX, but due to pandemic-related protocol changes, the duration of the 
study was limited to six months. The ongoing MERINO trial randomizes participants to MTX or 
placebo for one year. After completing the MERINO trial, several participants asked for MTX 
open label. In the subsequent MERINO:2 study, participants from the MERINO trial will be 
invited to a structured follow-up 30 months after MERINO recruitment, including electronic 
questionnaires and hand radiographs, providing valuable long-term data on the effects of MTX in 
hand OA. Together, these trials aim to fill gaps in understanding the long-term impact of MTX in 
hand OA, particularly on structural progression. 
Objectives and Endpoints: 
In the MERINO:2 study, our main objectives are to explore the long-term effects of MTX in 
hand OA on structural progression, pain, and function. We will obtain hand radiographs and 
acquire patient-reported outcome measures through questionnaires: 
Objectives 
Endpoints 
Primary  
• 
Effect of MTX on radiographic 
progression of erosive hand OA. 
• 
Progression in Verbruggen-Veys anatomical atlas score at 18 months 
Secondary 
• 
Effect of MTX on pain, function and life 
quality 
• 
Finger joint pain previous 48 hours (VAS) at 18 months 
• 
Thumb base joint pain previous 48 hours (VAS) at 18 months 
• 
Pain most painful finger joint previous 48 hours (VAS) at 18 months 
• 
AUSCAN pain and function subscales at 18 months  

 
Protocol 1.1 
 
© 2015-2021 TransCelerate BioPharma 
8 
• 
OMERACT-OARSI responder criteria at 18 months  
• 
Patient-reported disease activity previous 48 hours (VAS) at 18 months 
• 
EQ-5D at 18 months  
• 
Effect of MTX on radiographic 
progression of hand OA. 
• 
KL grades 
• 
OARSI atlas (osteophytes, joint space narrowing, erosions) 
 
Overall Design: 
The MERINO:2 is an extension of the MERINO trial (EudraCT number 2019-004641-33, 
Clincaltrials.gov number NCT04579848, REK ID 2020/187524, CTIS number 2023-510523-30-
00), with an expanded observational period of 18 months after ending the MERINO trial (i.e. 30 
months after staring MERINO). MERINO:2 is an investigator-initiated and open-label 
observational study. Participants are male and female adults with erosive hand osteoarthritis. 
Following the completion of the MERINO trial, participants either ended their treatment or were 
prescribed MTX open-label (oral or s.c. 5-25mg per week as well as folic acid 1mg daily). 
Brief Summary: 
The primary aim is to demonstrate the superiority of Methotrexate (MTX) over treatment as 
usual in slowing radiographic progression over 30 months in individuals with erosive hand 
osteoarthritis (OA).  
OA is a leading cause of disability and affecting millions worldwide, with a significant impact on 
knee, hip, and hand joints. Despite its high prevalence and symptomatic burden, effective 
disease-modifying treatments remain elusive, with current options limited to pain management 
and joint replacement.  
MTX, recognized for its disease-modifying effects in systemic inflammatory joint diseases, 
offers promising potential in OA treatment, with previous trials indicating its anti-inflammatory 
properties and potential for joint damage reduction. In the ongoing MERINO trial, 153 
participants are randomly assigned to either MTX or a placebo. Following completion of the 
trial, several participants have expressed interest in MTX treatment, which is sometimes used 
off-label for erosive hand OA patients experiencing unmanageable pain and inflammation. As a 
result, some MERINO trial participants will receive MTX treatment.  
In the MERINO:2 study, we will conduct a structured follow-up 18 months post-MERINO trial 
completion, incorporating hand radiographs and pain questionnaires. This endeavor will furnish 
invaluable insights into the long-term effects of MTX treatment in erosive hand OA, a gap in 
current knowledge, particularly regarding structural progression. This will provide valuable data 
on long-term effects of MTX treatment in erosive hand OA, which is not currently described in 
the literature, especially on structural progression. 
Number of Participants: 
We estimate 153 recruited participants from the MERINO trial as potential candidates for the 
MERINO:2 trial.  
Study Arms and Duration: 

 
Protocol 1.1 
 
© 2015-2021 TransCelerate BioPharma 
9 
All participants recruited to the MERINO trial will be asked to provide conventional radiographs 
and electronic questionnaires 30 months after starting the MERINO trial. This results in four 
potential arms of the MERINO:2 trial, depending on the two former arms of the MERINO trial, 
each with a duration of 12+18=30 months: 
• MTX → MTX 
• MTX → Treatment as usual 
• Placebo → MTX 
• Placebo → Treatment as usual 
 
Data Monitoring/Other Committee: No 
 
 
1.2. 
Schema 
Figure 1. Overview of study design 
 
 
 
 

 
Protocol 1.1 
 
© 2015-2021 TransCelerate BioPharma 
10 
1.3. 
Schedule of Activities (SoA) 
 
 
MERINO 
MERINO:2 
Overview of the data collection 
Screen 
M00 
M01 
M02 
M03 
M06 
M09 
M12 
M12-
M30 
M30 
Weeks 
(-4)–0 
1 
5 
+/- 1 
9 
+/- 1 
13  
+/- 2 
26  
+/- 2 
39  
+/- 2 
52  
+/- 2 
52-
130 9) 
130 
+/- 10 
Study information, eligibility1), and informed consent 
X 
 
 
 
 
 
 
 
X 
 
Regular visit 
 
X 
X 
 
X 
X 
X 
X 
 
 
Safety monitoring 
 
 
X 
X 
X 
X 
X 
X 
X 
 
First dose 
 
X 
 
 
 
 
 
 
 
 
Medical drug extradition to patient 
 
X 
 
 
 
X 
 
 
X 
 
Medical drug counting 
 
 
 
 
 
X 
 
X 
 
X 
Person characteristics 
 
 
 
 
 
 
 
 
 
 
Demographic and medical history 1) 
 
X 
 
 
 
 
 
 
 
 
Concomitant medication 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
Safety and laboratory assessments 
 
 
 
 
 
 
 
 
 
 
Laboratory sample for screening 2) 
X 
 
 
 
 
 
 
 
 
 
Laboratory safety monitoring 
 
 
X 
X 
X 
X 
X 
X 
X 10) 
 
Biobank samples  
 
X 3) 
 
 
 
X 4) 
 
X 4) 
 
 
Adverse events 
 
 
X 
 
X 
X 
X 
X 
X 
 
Serum hCG in fertile women 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Patient-reported outcome measures 
 
 
 
 
 
 
 
 
 
 
Hand pain on most days (yes/no) 
X 
 
 
 
 
 
 
 
 
 
Hand pain previous 48 hours (VAS) 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
Pain in most painful joint previous 48 hours (VAS) 
 
X 
X 
 
X 
X 
X 
X 
 
X 
Hand diagram 
 
X 
 
 
 
X 
 
 
 
 
OMERACT-OARSI responder criteria 
 
X 
X 
 
X 
X 
X 
X 
 
X 
Australian/Canadian hand index (AUSCAN) 
 
X 
X 
 
X 
X 
X 
X 
 
X 
Heath-related quality of life (EQ-5D) 
 
X 
X 
 
X 
X 
X 
X 
 
X 
Michigan Hand Outcomes questionnaire (MHOQ) 
 
X 
 
 
 
X 
 
 
 
 
Hospital Anxiety and Depression scale (HADS) 
 
X 
 
 
 
X 
 
 
 
 
Pain Catastrophizing Scale (PCS) 
 
X 
 
 
 
X 
 
 
 
 
Pain Sensitivity Questionnaire (PSQ) 
 
X 
 
 
 
X 
 
 
 
 
Knee injury and Osteoarthritis Outcome Score (KOOS)-12 
 
X 
 
 
 
X 
 
 
 
 
Hip disability and Osteoarthritis Outcome Score (HOOS)-12 
 
X 
 
 
 
X 
 
 
 
 
Physical examination 
 
 
 
 
 
 
 
 
 
 

 
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ACR criteria for hand, hip and knee OA 
X 
 
 
 
 
 
 
 
 
 
Tender and swollen joint count 
 
X 
X 
 
X 
X 
X 
X 
 
 
Anthropometric and cardiovascular assessment 5) 
 
X 
X 
 
X 
X 
X 
X 
 
 
Grip strength  
 
X 
 
 
 
X 
 
X 
 
 
Pain sensitization 6) 
 
X 
 
 
 
X 
 
 
 
 
Imaging outcome measures 
 
 
 
 
 
 
 
 
 
 
Chest radiograph 
X 
 
 
 
 
 
 
 
 
 
Conventional hand radiographs 
X 
 
 
 
 
X 
 
X 
 
X 
Ultrasound of fingers 
X 7) 
X 
X 
 
X 
X 
X 
X 
 
 
Ultrasound of hips and knees 
X 
 
 
 
 
X 
 
 
 
 
MRI 
 
X 
 
 
 
X 
 
 
 
 
Knee OA sub-study 8) 
 
 
 
 
 
 
 
 
 
 
Synovial needle biopsy of one knee 
 
X 
 
 
 
X 
 
 
 
 
Knee pain previous 48 hours (VAS) 
 
X 
 
 
 
X 
 
 
 
 
 
VAS = visual analogue scale; OMERACT-OARSI = Outcome Measures in Rheumatology Osteoarthritis Research 
Society International; EQ-5D = EuroQol 5 dimensions; MRI = Magnetic Resonance Imaging. 
1. 
Birth date, sex, ethnic origin, marital and work status, exercise, smoking, alcohol, hormonal factors (women), 
previous joint-related therapies, and comorbidities.  
2. 
Hemoglobin, white blood cells with differentials, platelet counts, ASAT, ALAT, albumin, creatinine, GFR, 
CRP, ESR, IGRA, HIV, Hepatitis B and C. 
3. 
Plasma, serum and full blood. 
4. 
Plasma and serum. 
5. 
Including pulse rate, systolic and diastolic blood pressure and body weight will be assessed at all visits. Height 
will be measured at baseline only. 
6. 
Includes Pressure Pain Thresholds (PPT), CPM = Conditioned Pain Modulation and temporal summation. 
7. 
Confirm two interphalangeal joints with a positive power Doppler signal of at least grade 1 or B mode grey 
scale synovitis of at least grade 2 on ultrasound. 
8. 
Sixteen volunteers with concomitant knee OA. 
9. 
Follow-up in the outpatient clinic as agreed between participant and treating physician.  
10. Safety monitoring according to National recommendations in Norway for DMARD treatment. 
 

 
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2. 
Introduction 
The MERINO:2 study is an extension of the ongoing MERINO trial. This trial involves 
participants with erosive hand OA receiving either MTX or placebo. The MERINO:2 plans for 
an extended observational period of the MERINO trial, 30 months after starting the original 
study. Some of these participants have expressed a desire to receive MTX open-label after the 
MERINO trial and are followed as ordinary in an outpatient clinic. The study aims to provide 
unique data on the long-term effects of sustained MTX treatment, particularly on structural joint 
damage. 
2.1. 
Study Rationale 
Based on the high frequency of synovitis in hand OA, especially in erosive disease (1), and the 
relationships to pain (2, 3), there is a significant rationale for testing MTX in the management of 
the phenotype inflammatory erosive hand OA. The updated international guidelines for 
management of hand OA recently concluded that future well-designed larger RCTs are needed to 
explore the efficacy of MTX (4), and more knowledge is needed regarding how to optimize 
personalized treatment in OA. A recent double-blind, randomized, placebo-controlled trial (the 
METHODS study) involving participants with hand OA and synovitis treated with 20 mg MTX 
weekly for 6 months resulted in a significant reduction in pain compared to placebo (mean 
between-group difference of -9.9 mm on a 100 mm visual analogue scale, 95% CI -19.3 to -0.6, 
p=0.037) (5). However, although the study was designed to find out whether MTX reduced pain 
and radiographic progression in 2 years, the COVID-19 pandemic and subsequent lockdowns in 
Australia altered the trial protocol, focusing on pain reduction at 6 months as the primary 
endpoint, and no imaging results have been published. 
Participants in the ongoing MERINO trial are randomized to placebo or MTX for one year. The 
study encompasses extensive data collection including radiographs, ultrasound, MRI, clinical 
examination, laboratory tests, and a large range of patient-reported outcomes. Several 
participants in the MERINO trial ask if they can receive MTX after MERINO. Although 
not evidence-based, MTX is occasionally used off-label in erosive hand OA patients with 
unmanageable pain and inflammation and is considered on an individual level in 
conjunction with the physician and participant.  
In this proposed open-label observational study, the MERINO:2 study, we will do a structured 
follow-up of all participants after the MERINO trial, some of whom will be prescribed MTX 
after the MERINO trial. In addition to ordinary follow-up consultations in the outpatient clinic, 
we will organize electronic questionnaires and hand radiographs 30 months after entering 
the MERINO trial. We see this as an opportunity to re-use existing electronic data collection 
schemes and ongoing collaborations with our service departments to provide a structured and 
long-term follow-up of participants who seek to receive MTX treatment after the MERINO RCT 
trial.  
The MERINO and MERINO:2 trials will provide additional data to the current literature 
on long-term effects of MTX treatment in hand OA patients, especially on structural 
progression which has not yet been studied by any other group. 

 
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2.2. 
Background 
OA is the most common joint disease and the fastest-growing cause of disability. Current 
estimates suggest that 250 million people worldwide are affected by knee OA (6), and similar 
numbers are affected by hip or hand OA. The lifetime risk of symptomatic hand OA is 40% and 
of symptomatic knee OA 45% (7). Main symptoms are pain, swelling, stiffness, and 
malformation of joints. However, no effective disease-modifying treatment exists for OA, and 
current treatment options are limited to pain reduction and joint replacement. Hence, OA is a 
prevalent disease with high unmet needs. 
MTX is classified as a disease-modifying drug for systemic inflammatory joint diseases with 
acceptable tolerability and good effects on symptoms, inflammation, and disease progression. 
Previous OA trials have shown anti-inflammatory treatment’s possible effect on reducing joint 
damage and facilitating bone remodelling (8, 9), but with conflicting effects on symptoms (9, 
10).  Therefore, we now run the MERINO trial to explore whether MTX for one year has a 
symptomatic, anti-inflammatory, and disease-modifying effect in erosive hand OA with an 
acceptable safety profile.  
2.3. 
Benefit/Risk Assessment 
Benefits: 
- 
Understanding Long-term Effects: The study aims to provide valuable insights into the 
long-term effects of MTX on erosive hand OA, which could significantly contribute to 
the management of this condition. 
- 
Improved Treatment Strategies: Data from this study could help in refining treatment 
strategies for erosive hand OA, potentially leading to better patient outcomes. 
- 
Patient Well-being: Continuous observation and treatment could benefit the participants' 
health and quality of life. 
Risks: 
- 
Side Effects of the treatment: MTX is known to have side effects, which could include 
liver damage, lung disease, and others. Monitoring these side effects is crucial. See 
section 7.2. 
- 
Ethical Considerations: The ethical implications of long-term drug administration need 
careful consideration, especially regarding consent and the management of any adverse 
effects. 
- 
Data Management Risks: As with any clinical study, there are risks related to data 
privacy and the management of sensitive patient information. 
2.3.1. 
Adverse and toxic effects of MTX 
The long-term clinical efficacy and relative safety of MTX in inflammatory joint disease remain 
impressive. Yet, adverse effects of MTX can occur at therapeutic levels and include headache, 
malaise, mouth ulcers and hair-fall. In overdose, vomiting, diarrhea and gastrointestinal bleeding 
may occur, as well as severe bone marrow suppression and disturbance of liver function. Long-

 
Protocol 1.1 
 
© 2015-2021 TransCelerate BioPharma 
14 
term liver injury, normally accompanied by elevations of liver transaminases, can result in 
hepatic fibrosis. Liver toxicity is more likely in patients with pre-existing risk factors for liver 
disease, and in patients taking MTX for the treatment of psoriasis than those taking it for the 
treatment of RA. 
MTX can induce acute pneumonitis, which can be fatal. Patients may present with acute 
shortness of breath and a dry, persistent cough, possibly with fever. A chest x-ray prior to 
initiating MTX is obtained to facilitate the diagnosis of potential lung disease at a later date. 
Co-administration of folic acid 1 mg daily has been shown to reduce the risk of adverse effects 
such as abdominal pain and nausea, abnormal serum transaminase levels, and increases 
adherence with a MTX regimen. 
Managing the risks of MTX in the MERINO:2 study 
Given the number of documented fatalities which have arisen from simple errors in medicine 
dosing frequency, the most important lesson is to emphasize that MTX should be taken as a 
weekly dose only and to put in place procedures, safeguards and reminders to ensure this dosage 
is followed by the participants.  
According to current clinical practice at Diakonhjemmet Hospital, every participant has 
consulted a nurse before receiving any study medication. Patients is advised on key symptoms of 
MTX toxicity such as a sore throat, mouth ulcers, fever, dry persistent cough, vomiting or 
diarrhea, and to report if any of these occur. We will also emphasize to the patient the differences 
between MTX and folic acid – cases have occurred where the two dosing regimens were 
inadvertently swapped by the patient.  
To avoid reactivation or worsening of infectious diseases, we have screened for hepatitis B/C 
and tuberculosis in the original MERINO trial. Due to risk of MTX-induced lung disease, chest 
radiographs is obtained at screening and repeated if lung symptoms. Alcohol increases the risk 
for liver damage while taking MTX, and should be used with care. MTX must be discontinued 
three months before planned fertilization for women (due to risk of serious birth defects) and 
men (due to oligo- or teratozoo-spermia). Persons with planned pregnancy during the study 
period are thus excluded. Furthermore, MTX is excreted in breast milk in low concentrations and 
can accumulate in neonatal tissues; thus, it is contraindicated during breastfeeding. 
A full blood count, liver and renal function tests will be carried out before starting MTX, and 
repeated every four weeks initially, then every three months if results have been normal and the 
dose is stable, according to national guidelines. 
Conclusion 
In systemic inflammatory joint diseases, MTX is administered at low doses (usually 10-25 mg x 
1/week) and is relatively well-tolerated, provided that there is careful participant selection and 
regular monitoring for adverse effects and drug interactions during MTX therapy is carried out. 
Taking into account the measures taken to minimize risk to participants participating in this 
study, the potential risks identified in association with MTX are justified by the anticipated 
benefits that may be afforded to participants with inflammatory erosive hand OA. 

 
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2.3.2. 
Risk of study-related procedures 
Conventional radiography 
We are exposed to natural sources of radiation all the time. The average person in the U.S. 
receives an effective dose of about 3 mSv per year from natural radiation, which includes cosmic 
radiation from outer space. The amount of radiation from one adult extremity (hand, knee, etc.) 
x-ray equals 0.001 mSv or 3 hours of natural background radiation.  
2.3.3. 
Benefit Assessment 
Personalized medicine in OA is emerging, as it is unlikely that one single treatment will have an 
effect in all patients due to the heterogeneity of the disease. Previous trials have shown possible 
effects of biological anti-inflammatory drugs on reducing joint damage in hand OA (8), but 
disappointing effect on symptoms (10). To avoid failures of future OA trials, the heterogeneity of 
the disease must be acknowledged. The involvement of various tissues will differ across patients 
and at different disease stages. Further, pain is strongly influenced by genetic predisposition, 
psychological and social factors and differences in the pain processing system, which may affect 
the treatment responses. There are reasons to believe that some phenotypes may benefit from 
anti-inflammatory treatments, whereas others may benefit from therapies directed at bone or 
cartilage, central sensitization or cognitive aspects.  
In clinical practice, MTX is occasionally used off-label in OA patients with unmanageable pain 
and inflammation, but the practice is currently not evidence-based. Previous studies (mainly 
open-label) have indicated a symptomatic effect in patients with knee and hand OA (11-13), but 
high-quality RCTs are needed to provide clear evidence in support of or against current practice. 
A small (n=30) open-label trial found ≥30% reduction in VAS pain in 43% of the knee OA 
participants given MTX, suggesting an analgesic efficacy (11). A recent small RCT of persons 
with erosive hand OA (n=64) showed a positive trend with larger pain relief in patients treated 
with MTX vs. placebo after 3 months (decrease of mean (standard deviation; SD) visual 
analogue scale (VAS) pain: 17.5 (28.4) vs. 8.4 (25.3); p=0.18) (14). However, the lack of 
inflammation in the majority of patients and the low dose of MTX (10 mg/week) make us unable 
to draw firm conclusions about its efficacy. Interestingly, fewer patients developed new erosions 
in the MTX vs. placebo arm (8% vs. 29%; p=0.09), suggesting a disease-modifying effect.  
2.3.4. 
Overall Benefit Risk Conclusion 
In summary, the potential benefits of the MERINO:2 study include a deeper understanding of 
MTX's long-term effects and improved patient care. Given the nature of this observational study, 
we are providing a structured follow-up regardless of which treatment the participants ends up 
receiving. Decisions on treatment are discussed between participants and the treating physician. 
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events (AEs) of MTX may be found in the summary of product characteristics 
(SmPC).  

 
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3. 
Objectives and Endpoints  
In the MERINO:2 study, our main objectives are to explore the long-term effects of MTX in 
hand OA on structural progression, pain, and function. We will obtain hand radiographs and 
acquire patient-reported outcome measures through questionnaires (Table 1). 
 
Table 1. Objectives and endpoints 
Objectives 
Endpoints 
Primary  
• 
Effect of MTX on radiographic 
progression of erosive hand OA. 
• 
Progression in Verbruggen-Veys anatomical atlas score at 18 months 
Secondary 
• 
Effect of MTX on pain, function and life 
quality 
• 
Finger joint pain previous 48 hours (VAS) at 18 months 
• 
Thumb base joint pain previous 48 hours (VAS) at 18 months 
• 
Pain most painful finger joint previous 48 hours (VAS) at 18 months 
• 
AUSCAN pain and function subscales at 18 months  
• 
OMERACT-OARSI responder criteria at 18 months  
• 
Patient-reported disease activity previous 48 hours (VAS) at 18 months 
• 
EQ-5D at 18 months  
• 
Effect of MTX on radiographic 
progression of hand OA. 
• 
KL grades 
• 
OARSI atlas (osteophytes, joint space narrowing, erosions) 
AUSCAN = Australian/Canadian hand index; EQ-5D = EuroQol 5 dimensions; KL = Kellgren and Lawrence; 
MHOQ = Michigan Hand Outcomes questionnaire pain and function subscales; OARSI = Osteoarthritis Research 
Society International; OMERACT-OARSI = Outcome Measures in Rheumatology Osteoarthritis Research Society 
International; VAS = visual analogue scale. 
 

 
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4. 
Study Design 
4.1. 
Overall Design 
The MERINO:2 is an investigator-initiated and open label observational study with one-year 
parallel group treatment with MTX in male and female adults with erosive hand osteoarthritis.  
Eligible participants are those recruited to the MERINO-trial (EudraCT number 2019-004641-33, 
Clincaltrials.gov number NCT04579848, REK ID 2020/187524, CTIS number 2023-510523-30-
00).  
After the MERINO trial, participants may either continue treatment as usual or be prescribed 
MTX open-label (oral or s.c. 5-25mg per week as well as folic acid 1mg daily).  
Especially of interest is to compare those who first receive placebo and then treatment as usual 
throughout the MERINO and MERINO:2 trials with those receiving MTX throughout the whole 
period, as this comparison will reflect the effect of long-term treatment with MTX over 2,5 
consecutive years. Further, the Placebo→MTX crossover group will complement the data from 
the MERINO trial on shorter MTX treatment. 
4.2. 
Scientific Rationale for Study Design 
This study stands to fill a significant gap in OA research and could potentially guide future 
treatment protocols. OA is a slowly progressive disease but there are no studies examining the 
long-term (2 year) effect on structural progression of MTX treatment in erosive hand OA. The 
requests to explore MTX treatment after the MERINO trial prompted us to organize the follow-
up within our outpatient clinic. This arrangement enables us to efficiently collect supplementary 
data. This approach also capitalizes on existing collaborations with our service departments, 
maximizing resource utilization and ensuring comprehensive patient care.  
4.2.1. 
Patient Input into Design 
The communication with users has over the years evolved into a strong partnership at 
Diakonhjemmet Hospital, where patient representatives, clinicians and researchers work together 
to improve the quality of care for people with rheumatic diseases. The collaboration continues in 
this project, where two patient representatives have been involved in the protocol development, 
and will also be consulted during the ongoing trial and before dissemination and publication of 
the results. Additionally, the project leader is also co-leader of the representative organization 
“REMEDY pasientråd”. 
4.3. 
Justification for Dose 
Being an open-label observational study, the doses and treatment length of MTX will vary 
depending on the physicians and participants preferences. At the one-year control, we will use 
self-reported doses and The Norwegian Prescription Database (Reseptregisteret) to calculate the 
doses during the follow-up year. 

 
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4.4. 
End-of-Study Definition 
The end of the study is defined as the date of the last scheduled procedure shown in the schedule 
of activities for the last participant in the study.  
A participant is considered to have completed the study if the participant has completed one-time 
follow-up procedure shown in the SoA 30 months after entering the original MERINO trial. 

 
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5. 
Study Population 
All participants entering the MERINO trial (see section 4.1) will be asked if they can voluntarily 
can provide a 30-month conventional radiographs and an electronic questionnaire. This results in 
four potential arms of the MERINO:2 trial, depending on the two former arms of the MERINO 
trial (Table 2). 
The participants must be capable of giving signed informed consent as described in Appendix 1 
which includes compliance with the requirements and restrictions listed in the informed consent 
form (ICF) and in this protocol. 
We otherwise refer to the MERINO-protocol for study population description. 
 
Table 2.  Study Arms 
MERINO 
MERINO:2 
12 months 
18 months 
MTX 10-20mg weekly 
→ Treatment as usual 
MTX 10-20mg weekly 
→ MTX 7,5-20mg weekly 
Placebo 
→ Treatment as usual 
Placebo 
→ MTX 7,5-20mg weekly 
 

 
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6. 
Study Intervention(s) and Concomitant Therapy 
Study interventions are all pre-specified, investigational, and non-investigational medicinal 
products intended to be administered to the study participants during the study conduct. 
6.1. 
Study Intervention Administered 
Study intervention is defined as any investigational intervention(s), marketed product(s), or 
placebo intended to be administered to a study participant according to the study protocol (Table 
3). 
Table 3. Study interventions 
ARM Name 
Intervention 
Co-medication 
Intervention Name 
MTX  
Folic acid  
Producer 
Pfizer  
Orifarm Generics (Orifarm Healthcare AS) 
ATC 
L04A X03 
B03B B01  
Type  
Drug 
Drug 
Dose Formulation 
Tablet 
Tablet 
Box size 
206 (x2) 
100 
Unit Dose Strength(s) 
Methotrexate 2.5mg 
1mg 
Frequency 
Weekly 
Daily 
Dosage Level(s) 
Decided by the treating physician, usually 10-
20mg weekly, with a down-scaled dose the first 
2-3 weeks.  
1mg x 1  
Route of Administration 
Oral 
Oral 
Use 
Intervention 
Minimize expected adverse reactions to 
methotrexate  
IMP and NIMP 
IMP 
NIMP 
Sourcing 
Provided by local pharmacy 
Provided by local pharmacy 
Packaging and Labeling 
Provided by local pharmacy according to 
national routines. 
Provided by local pharmacy according to 
national routines. 
6.1.1. 
Investigational medicinal product (IMP)  
MTX 2.5 mg oral tablet; standard treatment is 15 mg x 1 per week the first two weeks, and then 
20 mg x 1 per week to end of study. Physician may deviate from standard treatment dose, 
example in the case of adverse events, preferences by the participants or similar. Subcutaneous 
MTX can be provided and will be treated equally to oral tablets.  

 
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6.2. 
Preparation, Handling, Storage, and Accountability 
Only participants enrolled in the study may receive study intervention, and only authorized 
pharmacy staff may supply, prepare, or administer study intervention.  
6.3. 
Assignment to Study Intervention 
The treating physician will decide, based on best clinical practice, if the patient should try MTX 
after the MERINO-trial. Central to this approach is the collaborative effort between the physician 
and participant, fostering an environment where patient perspectives are integral to treatment 
decisions. It will be emphasized by the physician prescribing MTX open-label that this is not 
evidence-based treatment until results of the MERINO-trial are published. We do, however, 
justify the continuation of MTX based on recent results from the METHODS trial (5). In the 
cases where the physician finds an indication for trying MTX after the MERINO trial, usual 
practice would be to try MTX for three months and then evaluate whether the patient should 
continue the treatment or not, based on synovitis scores and self-reported effects.  
As described in section 5, this result in four groups in the MERINO:2 study, but since MTX 
treatment length and MTX doses could vary substantial in the observational time of the 
MERINO:2 study, we will adjust for this in the analyses. 
6.4. 
Blinding 
This is an open-label study; potential bias will be reduced by blinding the researcher who will 
interpret and score the radiographs.  
6.5. 
Study Intervention Compliance 
Treatment length and doses will be assessed by questionnaires at 18 months as well as data from 
the The Norwegian Prescription Database (Reseptregisteret). 
6.6. 
Dose Modification 
The treating physician may decide on other doses of MTX than 20mg per week according to 
standard clinical practice.  
6.7. 
Continued Access to Study Intervention after the End of the Study 
There are currently no planned extension studies, but the participants have the possibility for 
continued access to the study intervention beyond completion of the study at the patient level. 
6.8. 
Treatment of Overdose 
There have been documented cases of death attributable to MTX. These have often involved 
patients taking MTX as a daily, rather than weekly dose due to patient, clinician and/or 
pharmacy error. In the United Kingdom, the National Patient Safety Authority released a report 
in 2004 on MTX prescribing after 25 deaths and 26 incidents of serious harm in the preceding 

 
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decade. In some of these cases, even once the error was identified, patients died due to ongoing 
deterioration after MTX withdrawal. 
For this study, any dose of MTX greater than 30mg/week will be considered an overdose, but 
there is no clear dose cut-of as for when overdose symptoms can occur, especially since this is 
regarded a low dose treatment of MTX. No specific treatment for an overdose is recommended.  
In the event of an overdose, the investigator or treating physician should: 
1. Contact the Medical Monitor immediately. 
2. Closely monitor the participant for any AE/SAE and laboratory abnormalities. 
3. Document the quantity of the excess dose as well as the duration of the overdose in the 
electronic patient journal. 
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the Medical Monitor based on the clinical evaluation of the participant. 
6.9. 
Prior and Concomitant Therapy 
• Prior therapy is recorded in the MERINO trial eCRF. 
• All concomitant medication at 18 months in the MERINO:2 study should be recorded in the 
eCRF.  
• Intra-articular corticosteroids during the MERINO:2 study will be registrered from the 
outpatient clinic notes.  

 
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7. 
Discontinuation of Study Intervention and 
Participant Discontinuation/Withdrawal 
Discontinuation of the study as a whole is detailed in Appendix 1. 
7.1. 
Discontinuation of Study Intervention 
In some instances, it may be necessary for a participant to permanently discontinue study 
intervention. See Section 8.3 for safety assessments.  
7.2. 
Participant Discontinuation/Withdrawal from the Study 
If study intervention is permanently discontinued, the participant will still be invited to the 12-
month visit.  
If the participant withdraws consent for disclosure of future information, the sponsor may retain 
and continue to use any data collected before such a withdrawal of consent.  
The participant may request destruction of any samples taken and not tested, and the investigator 
must document this in the site study records. 
7.3. 
Lost to Follow-up 
Not applicable. Examination at 18 months is voluntary. Missing data due to lost to follow-up 
will not be subject for data imputation.  

 
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8. 
Study Assessments and Procedures 
• Study procedures and their timing are summarized in the SoA. Protocol waivers or 
exemptions are not allowed. 
• To minimize questionnaires and procedures for the participants and the study team, we 
will use 12-month data from the MERINO trial as baseline data in the MERINO:2 study, 
including person characteristics, patient-reported outcome measures, clinical examination 
and imaging. 
• Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct. 
• Procedures conducted as part of the participant’s routine clinical management and 
obtained before signing of the ICF may be utilized for research purposes. 
• In the event of a significant study-continuity issue (eg, caused by a pandemic), alternate 
strategies for participant visits, assessments, medication distribution and monitoring may 
be implemented by the sponsor or the investigator, as per local health authority/ethics 
requirements.   
8.1. 
Patient-reported outcome measures 
The following patient-reported questionnaires are to be answered at 18 months using ViedocMe. 
See Appendix 2 for language and wording of the questionnaires. 
8.1.1. 
VAS pain 
The time interval in which pain should be assessed varies across studies. A long interval may 
lead to recall bias, whereas a too short interval may possibly not adequately cover the whole pain 
spectrum. In the current study, we ask the participants about their symptoms the last 48 hours: 
• Overall finger joint pain, VAS 0-100 
• Overall thumb base joint pain, VAS 0-100  
• Pain in most painful finger joint (“index joint”) VAS 0-100; in case of two or more 
equally painful joints, a joint is selected randomly 
• Overall disease activity in hands, VAS 0-100 
• Overall pain in all body joints, VAS 0-100 
8.1.2. 
OMERACT-OARSI responder criteria 
The OMERACT-OARSI responder criteria are validated criteria to assess response to treatment 
in OA clinical trials (15, 16). The OMERACT–OARSI criteria for response are (1) a relative 
improvement in AUSCAN pain or physical function ≥50% and an absolute change ≥20 mm; or 
(2) a relative improvement of ≥20% with an absolute change ≥10 mm in at least two of the 
following three categories: AUSCAN pain, AUSCAN physical function, and patient's global 
assessment. 
 

 
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In the OMERACT-OARSI criteria, the AUSCAN pain and function subscale scores are used on 
a 0-100 scale. Since we used the Likert version of the AUSCAN questionnaire in this trial, the 
AUSCAN pain and function subscale scores were rescaled from 0-20 and 0-36, respectively, to 
0-100. Absolute change was calculated as baseline minus follow-up score, and relative change as 
absolute change divided by baseline score.  
8.1.3. 
Australian/Canadian Hand Index (AUSCAN) 
The AUSCAN pain subscale 
The hand OA-specific questionnaire AUSCAN includes five items about pain at rest and during 
activities (gripping, lifting, turning and squeezing objects) during the last 48 hours (17). In the 
MERINO trial we are using the Likert version, but AUSCAN also exists as numeric rating scales 
(NRS) and VAS. The response categories for all items are ranging from 0 (“None”) to 4 
(“Extreme”). A sum score (0-20 scale) can be calculated. There are no instructions on how to 
handle missing values, and the “half-rule” are applied in the MERINO trial, which means that 
missing items should be replaced with the mean of the answered items if 50% or more of the 
items in the respective subscale have been answered. The scale has been translated to Norwegian 
and validated (18).  
The AUSCAN physical function subscale 
The hand OA-specific questionnaire AUSCAN includes nine questions concerning tasks 
requiring grip strength and precision tasks (17). The response categories for all items are ranging 
from 0 (“None”) to 4 (“Extreme”). A sum score (0-36 scale) can be calculated. There are no 
instructions on how to handle missing values, and the “half-rule” are applied in the MERINO 
trial. The scale has been translated to Norwegian and validated (18). 
The AUSCAN stiffness subscale 
The hand OA-specific questionnaire AUSCAN includes one question concerning stiffness in the 
hands in the morning with response options ranging from 0=none to 4=extreme (17). The scale 
has been translated to Norwegian and validated (18). 
8.1.4. 
The EuroQol 5 dimensions 5 levels (EQ-5D-5L)  
The generic instrument EQ-5D-5L captures five health dimensions (mobility, self-care, usual 
activity, pain/discomfort and anxiety/depression) (19). The EQ-5D-5L encompasses 243 
different health states and is one of the most widely used utility instruments in the field of 
medicine (20). The questionnaire has been translated to Norwegian, and has been used in several 
Norwegian studies (21). We used the five-level version (EQ-5D-5L). On the EQ-VAS the 
participant was instructed to self-rate their health on a 0-100 VAS, where 0=worst health and 
100=best health. The EQ-5D-5L can be converted to a single summary index by using a formula 
with different weights to each level in the dimension. European value sets have been defined 
(22). Based on participant responses, an index score will be calculated to reflect the participant’s 
HRQoL, using the preference scores published from a UK population (23). 
 
 

 
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8.2. 
Conventional hand radiographs 
The participants are invited for bilateral hand radiographs at 18 months. 
The participant is sitting with the hand on the detector (posteroanterior view), and front images 
are obtained (source to image-receptor distance (SID): 115 cm; exposure: 46 kVp and 2 mAs).  
OA in the DIP, PIP, MCP, first carpometacarpal (CMC-1) and scapho-trapezio-trapzoidal (STT) 
joint will be assessed according to validated scoring systems: 
• The Kellgren-Lawrence (KL) scale from 1957 is a global index that grades OA on a semi-
quantitative five-point scale based on the presence/severity of osteophytes/ossicles, 
narrowing of the joint space, sclerosis of the subchondral bone, pseudocystic areas, and 
altered shape of bone ends (24, 25). We will use a modified version, as previously used in 
the Framingham study (26). The original publication includes DIP, PIP, thumb IP, MCP 
and CMC-1, and the STT joint will be added in the MERINO trial.  
• The Verbruggen-Veys scoring system has been proposed for the evaluation of the 
anatomical phases in patients with erosive disease (N=normal, S=stationary, J=joint 
space narrowing, E=erosive, R=remodelled) (27). In the original publication, DIP, PIP, 
thumb IP and MCP (2-5) joints were included. In the MERINO trial, only the 2nd-5th DIP 
and PIP joints will be assessed. Joints with remodelling in more than 70% of the joint 
will be scored as E/R, whereas completely remodelled joints will be scored as R.  
• Using the OARSI atlas from 1995 (revision from 2007) (28, 29) as a reference, the 
presence/severity of individual features such as osteophytes (grade 0-3) and joint space 
narrowing (grade 0-3), will be assessed on semi-quantitative scales. In the OARSI atlas 
only DIP, PIP, thumb IP and CMC-1 are included. In the MERINO trial, also the MCP 
and STT joints will be scored.  
8.3. 
Safety Assessments 
All participants will be monitored according to the National procedure for diagnosis, treatment 
and follow-up of rheumatoid arthritis in Norway (30), chapter 10.1. Blood tests recommended 
for monitoring: Hemoglobin, red blood cells, white blood cells with diff. Counts, platelets, ALT, 
creatinine, (SR and CRP). Patients with comorbidity, abnormal blood tests, and / or 
polypharmacy treated with DMARD may require more frequent laboratory tests than the general 
recommendations in the table. 
Table: Monitoring interval for blood testing in patients using DMARDs  
Drug 
Monitoring interval based on duration of treatment 
<3 months 
3-6 months 
>6 months 
Metotreksat 
2–4 weeks 
8–12 weeks 
12 weeks 

 
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8.3.1. 
Side effects and abnormal laboratory results 
Discontinuation of study intervention is required by the investigator when a participant meets 
one of the conditions outlined in the algorithm below or if the investigator believes that it is in 
best interest of the participant. 
The algorithm below provides recommended actions in case of side effects and abnormal 
laboratory results according to the shared care protocol by Oxford University Hospital, NHS 
(https://www.ouh.nhs.uk/oxparc/professionals/documents/methotrexate-scp-july-2015.pdf). In 
the event of a medically significant unexplained abnormal laboratory test value the test should be 
followed up until they have returned to the normal range and/or an adequate explanation of the 
abnormality is found. 
Side effects 
Action 
WBC < 4 x 109/l  
WBC < 3.5 x 109/l  
Adults: Perform a differential and increase frequency of monitoring.  
Withhold and discuss with specialist. Bone marrow suppression can occur abruptly. 
Neutrophils < 2 x 109/l 
Withhold and discuss with specialist. Bone marrow suppression can occur abruptly. 
Platelets < 150 x 109/l 
Withhold and discuss with specialist. Bone marrow suppression can occur abruptly. 
MCV >110 fl  
MCV >105 - 110 fl  
 
Stop methotrexate and seek advice. 
Check folate, B12 and thyroid function tests and treat if appropriate. If WBC normal 
repeat in 4 weeks.  
Liver function 2 - 3 fold rise in ALT  
>3 fold rise in ALT 
Reduce the dose and repeat in 1 - 2 weeks.  
Withhold until discussed with specialist. 
Renal impairment 
 
Patients who develop dehydration, pre-renal or acute renal failure while on 
methotrexate should have methotrexate withheld and FBC monitored closely. 
Review any changes in medication particularly ACEI and ARB.  
Unexplained fall in albumin 
Withhold and speak to specialist. 
Nausea and/or vomiting 
Usually improves over time.  
If troublesome for adults consider:  
• Increasing the dose of folic acid to 5 mg daily up to 6 days a week - omitting on 
the day methotrexate is taken.  
• Splitting methotrexate dose over one evening and next morning.  
• A short-term anti-emetic.  
If unable to tolerate refer back to specialist for review. 
Hair loss 
Usually mild, rarely significant. Reversible on stopping drug. 
Rash 
Withhold treatment and discuss with specialist.  

 
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Mouth ulcers, mucositis 
Mouth ulcers may respond to increasing folic acid as above. If severe despite extra 
folic acid stop methotrexate and refer to a specialist for advice.  
Menstrual dysfunction/amenorrhoea 
May occur during treatment and for a short while after cessation.  
Otherwise unexplained dyspnoea or 
cough (especially if accompanied by 
fever/sweats) 
Methotrexate pneumonitis may occur. Withhold treatment, arrange chest X-ray and 
discuss urgently with consultant. 
Abnormal bruising  
Withhold until FBC result available. 
Sore throat or other unusual infection 
Urgent FBC and withhold until FBC result available. Susceptible to opportunistic 
infections such as viral wart, tuberculosis and pneumocystitis. 
Cervical dysplasia  
Contact gynecologist. 
Diarrhea 
Consider reducing dose. 
Fever, chills 
Withhold until FBC result available 
 FBC=full blood count, MCV=mean corpuscular volume, WBC=white blood cells, ALT= alanine aminotransferase  
8.4. 
Adverse Events (AEs) Serious Adverse Events (SAEs), and Other 
Safety Reporting 
The definitions of adverse events (AEs) and serious adverse events (SAEs) can be found in 
Appendix 3. 
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up AEs that are serious, considered related to the study intervention or study procedures, or that 
caused the participant to discontinue the study intervention. This includes events reported by the 
participant (or, when appropriate, by a caregiver, surrogate, or the participant’s legally 
authorized representative). 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 3. 
8.4.1. 
Time Period and Frequency for Collecting AE and SAE Information 
All SAEs will be collected from the signing of the informed consent form until the scheduled 30-
month visit (after entering the MERINO trial). Medical occurrences that begin before the start of 
study intervention but after obtaining informed consent will be recorded as medical 
history/current medical conditions, not as AEs. 
All SAEs will be recorded and reported to the sponsor or designee immediately and under no 
circumstance should this exceed 24 hours, as indicated in Appendix 3. The investigator will 
submit any updated SAE data to the sponsor within 24 hours of it being available. 

 
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Investigators are not obligated to actively seek information on AEs or SAEs after conclusion of 
the study participation. However, if the investigator learns of any SAE, including a death, at any 
time after a participant has been discharged from the study, and the investigator considers the 
event to be reasonably related to the study intervention or study participation, the investigator 
must promptly notify the sponsor. 
8.4.2. 
Method of Detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about AE 
occurrences. 
8.4.3. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts. All SAEs and AEs of special interest (as defined in Section 8.4.6) 
will be followed until resolution, stabilization, or the event is otherwise explained. Further 
information on follow-up procedures is provided in Appendix 3. 
8.4.4. 
Regulatory Reporting Requirements for SAEs 
• Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study intervention under clinical investigation are met. 
• The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, institutional review boards 
(IRBs)/independent ethics committees (IECs), and investigators. 
• An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs) from the sponsor will 
review and then file it along with the IB and will notify the IRB/IEC, if appropriate 
according to local requirements. 
• Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and sponsor policy and 
forwarded to investigators as necessary. 
8.4.5. 
Pregnancy 
• A female/male participant must be instructed to immediately inform the investigator if 
she/his partner becomes pregnant during the study. For details on collection of pregnancy 
information, see Appendix 4.  

 
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• While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be reported 
as an AE or SAE. 
• Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs and will be reported as 
such. 
• The participant/pregnant female partner will be followed to determine the outcome of the 
pregnancy. The investigator will collect follow-up information on the 
participant/pregnant female partner and the neonate and the information will be 
forwarded to the sponsor. 
• Any poststudy pregnancy-related SAE considered reasonably related to the study 
intervention by the investigator will be reported to the sponsor as described in 
Section 8.4.4. While the investigator is not obligated to actively seek this information in 
former study participants/pregnant female partner, he or she may learn of an SAE through 
spontaneous reporting.  
• A pregnant participant should be withdrawn from the study. 
8.4.6. 
Adverse Events of Special Interest 
A prolonged cough of more than 4 weeks duration is of special interest and should be followed 
up promptly with a CT of the lungs. 
8.5. 
Pharmacokinetics 
Pharmacokinetic parameters are not evaluated in this study. 
8.6. 
Pharmacodynamics 
Pharmacodynamic parameters are not evaluated in this study. 
8.7. 
Genetics 
Genetics are not evaluated in this study. 
8.8. 
Biomarkers 
Biomarkers are not evaluated in this study. 
8.9. 
Immunogenicity Assessments 
Antibodies are not evaluated in this study. 
8.10. 
Medical Resource Utilization and Health Economics 
Medical resource utilization and health economics parameters are not evaluated in this study. 

 
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9. 
Statistical Considerations 
The analysis and reporting will be done on all data from all participants at the time the study 
ends. The statistical analysis plan will be finalized prior to database lock, and it will include a 
more technical and detailed description of the statistical analyses described in this section. This 
section is a summary of the planned statistical analyses of the most important endpoints 
including primary and secondary endpoints. 
9.1. 
Statistical Hypotheses 
The primary objective is to demonstrate that MTX is superior to treatment as usual in achieving 
slower radiographic progression at 30 months. Thus, the null hypothesis to be tested in relation 
to the primary estimand is as follows: 
• Null hypothesis: MTX treatment for 30 months is not different from placebo (12 months) 
and subsequent treatment as usual (18 months) with respect to the progression of 
Verbruggen-Veys scoring system in participants with erosive hand OA. 
vs.  
• Alternative hypothesis: MTX treatment for 30 months is different from placebo (12 
months) and subsequent treatment as usual (18 months) with respect to the progression of 
Verbruggen-Veys scoring system in participants with erosive hand OA. 
 
Secondary outcomes (1): 
• Null hypothesis: MTX treatment for 30 months is not different from placebo (12 months) 
and subsequent treatment as usual (18 months) with respect to the progression of KL 
scale or OARSI atlas in participants with erosive hand OA. 
• Alternative hypothesis: MTX treatment for 30 months is different from placebo (12 
months) and subsequent treatment as usual (18 months) with respect to the progression of 
KL scale or OARSI atlas in participants with erosive hand OA. 
Secondary objective (2) 
• Null hypothesis: MTX is not different from placebo/treatment as usual with respect to 
change from baseline to 12/30 months in OMERACT-OARSI responder criteria, 
AUSCAN or EQ-5D-5L. 
• Alternative hypothesis: MTX is different from placebo/treatment as usual with respect to 
change from baseline to 12/30 months in OMERACT-OARSI responder criteria, 
AUSCAN or EQ-5D-5L. 
 
Multiplicity control is not relevant for the study. 

 
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9.2. 
Analysis Sets 
For the purposes of analysis, the following analysis sets are defined: 
Participant Analysis Set 
Description 
Full analysis set (FAS) 
All randomized participants.  
Safety analysis set (SAS) 
All participants who are exposed to investigational intervention. 
The full analysis set will be used to analyze endpoints related to the efficacy objectives and the 
safety analysis set will be used to analyze the endpoints and assessments related to safety.  
For the efficacy analyses, participants will be included in the analyses according to the planned 
investigational intervention; whereas for safety analyses, participants will be included in the 
analyses according to the investigational intervention they actually received. 
9.3. 
Statistical Analyses 
Continuous variables will be subject to linear mixed models. Binary response variables will be 
analyzed using logistic regression models (possibly adjusting for within-subject dependencies by 
mixed model approaches). Analyses at the joint level will apply generalized estimating equations 
(GEE) to account for dependency between joints within one person. The SAP will detail these 
procedures. 
The hypotheses will be evaluated by the p-value associated with the between group difference at 
study end. A conclusion of superiority will be made if the null hypothesis is rejected on an 
overall significance level of 5%. The SAP will detail these procedures, as well as alternative and 
further supportive evaluations, such as analyses including unbalanced baseline predictors or 
modifications of the linear regression model in case validity assumptions are not met.  
9.4. 
Interim Analysis 
Interim analysis is not performed in this study. 
9.5. 
Sample Size Determination 
The sample size is not based on statistical considerations. All participants entering the MERINO 
trial will be asked to complete a 30-month follow-up visit in the MERINO:2 study. The 
MERINO trial aims to include 153 participants. 

 
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10. 
Supporting Documentation and Operational 
Considerations 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations 
10.1.1. 
Regulatory and Ethical Considerations 
• This study will be conducted in accordance with the protocol and with the following: 
o Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) international ethical guidelines 
o Applicable ICH Good Clinical Practice (GCP) guidelines 
o Applicable laws and regulations 
• The protocol, protocol amendments, ICF, investigator’s brochure, and other relevant 
documents (eg, advertisements) must be submitted to an IRB/IEC by the investigator and 
reviewed and approved by the IRB/IEC before the study is initiated. 
• Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an 
immediate hazard to study participants.  
• Protocols and any substantial amendments to the protocol will require health authority 
approval prior to initiation except for changes necessary to eliminate an immediate 
hazard to study participants. 
• The investigator will be responsible for the following, as applicable: 
o Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC 
o Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
o Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 
536/2014 for clinical studies, European Medical Device Regulation 2017/745 for 
clinical device research, and all other applicable local regulations 
10.1.2. 
Financial Disclosure 
Investigators and subinvestigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 

 
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responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study. 
The MERINO:2 study is supported by a grant from the Diakohjemmet Hospital research fund of 
NOK 125.000,-. 
10.1.3. 
Informed Consent Process 
• The investigator or the investigator’s representative will explain the nature of the study, 
including the risks and benefits, to the potential participant and answer all questions 
regarding the study. 
• Potential participants must be informed that their participation is voluntary. They are 
required to sign a statement of informed consent that meets the requirements of 21 CFR 
50, local regulations, ICH guidelines, privacy and data protection requirements, where 
applicable, and the IRB/IEC or study center. 
• The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICF. 
• Participants must be reconsented to the most current version of the ICF(s) during their 
participation in the study. 
• A copy of the ICF(s) must be provided to the participant. 
10.1.4. 
Recruitment strategy 
Former participants of the MERINO trial will be contacted by SMS: “We invite you to 
participate in a one-year follow-up examination in the MERINO trial, including hand 
radiographs and questionnaires. Please click the link to read more.” The link will guide them to a 
one-page information pamphlet, from which they can click to a digital ICS with BankID 
identification through the University of Oslo portal “Nettskjema” and “TSD”.  
10.1.5. 
Data Protection 
• Participants will be assigned a unique identifier by the sponsor. Any participant records 
or datasets that are transferred to the sponsor will contain the identifier only; participant 
names or any information which would make the participant identifiable will not be 
transferred. 
• The participant must be informed that their personal study-related data will be used by 
the sponsor in accordance with local data protection law. The level of disclosure must 
also be explained to the participant who will be required to give consent for their data to 
be used as described in the informed consent  
• The participant must be informed that their medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
IEC members, and by inspectors from regulatory authorities. 

 
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• The contract between sponsor and study sites specifies responsibilities of the parties 
related data protection, including handling of data security breaches and respective 
communication and cooperation of the parties. 
• Information technology systems used to collect, process, and store study-related data are 
secured by technical and organizational security measures designed to protect such data 
against accidental or unlawful loss, alteration, or unauthorized disclosure or access. 
10.1.6. 
Committees Structure 
In addition to approval by the REC, the study will be reviewed and approved by the local 
hospital Data Protection Officer and the local hospital Research Council.  
10.1.7. 
Dissemination of Clinical Study Data 
• After completion of the study, a Clinical Study Report (including results on all study 
objectives) according to ICH Topic E3 will be written by the Sponsor or the designated 
CRO. 
• The Investigators will inform the Sponsor in advance of any plans to publish or present 
data from the study. Any publications and presentations of the results (abstracts in 
journals or newspapers, oral presentations etc.), either in whole or in part, by 
Investigators or their representatives will require pre-submission review by the Sponsor. 
• The Sponsor will not suppress or veto publications but maintains the right to delay 
publication to protect intellectual property rights. 
• The study will be posted on clinicaltrials.gov 
10.1.8. 
Data Quality Assurance 
• All participant data relating to the study will be recorded on printed or electronic CRFs 
unless transmitted to the sponsor or designee electronically (eg, laboratory data). A web-
based eCRF software solution will be used to collect study data (Viedoc™, Uppsala, 
Sweden). The investigator is responsible for verifying that data entries are accurate and 
correct by physically or electronically signing the CRF. 
• The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source documents. 
• Monitoring details describing strategy, including definition of study critical data items 
and processes (eg, risk-based initiatives in operations and quality such as risk 
management and mitigation strategies and analytical risk-based monitoring), methods, 
responsibilities, and requirements, including handling of noncompliance issues and 
monitoring techniques (central, remote, or on-site monitoring) are provided in the 
monitoring plan. 
• The sponsor or designee is responsible for the data management of this study, including 
quality checking of the data. 

 
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• The sponsor assumes accountability for actions delegated to other individuals (eg, 
contract research organizations). 
• Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the investigator for 5 years after study completion unless local 
regulations or institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of the sponsor. No 
records may be transferred to another location or party without written notification to the 
sponsor. 
10.1.9. 
Source Documents 
• Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed at the investigator’s site. 
• Data reported on the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available. 
• Definition of what constitutes source data and its origin can be found in the Monitoring 
Plan. 
• The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
• The sponsor or designee will perform monitoring to confirm that data entered into the 
CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements. 
10.1.10. 
Study and Site Start and Closure 
The study start date is the date on which the clinical study will be open for recruitment of 
participants. The first act of recruitment is when the site first actively contacts a potential 
participant and will be the study start date. 
The sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to: 
For study termination: 
• Discontinuation of further study intervention development 

 
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For site termination: 
• Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor’s procedures, or GCP guidelines 
• Inadequate or no recruitment (evaluated after a reasonable amount of time) of 
participants by the investigator 
• Total number of participants included earlier than expected 
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any contract research organization(s) 
used in the study of the reason for termination or suspension, as specified by the applicable 
regulatory requirements. The investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up. 
10.1.11. 
Publication Policy 
• The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to the sponsor 
before submission. This allows the sponsor to protect proprietary information and to 
provide comments. 
• The sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the sponsor will generally support 
publication of multicenter studies only in their entirety and not as individual site data. In 
this case, a coordinating investigator will be designated by mutual agreement. 
• Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 
 
 

 
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10.2. 
Appendix 2: Patient reported outcome measures 
 
10.2.1. 
VAS pain  
 
SYMPTOMER I LEDD (VAS)  
 
1. Hvordan vil du beskrive de leddsmertene du har hatt i fingrene (minus tommel-
basis) i løpet av de siste 48 timene?  
 
Sett en X på skalaen under, der 0 = “ingen smerter” og 100 = ”verst tenkelig smerte”. 
 
 
2. Hvordan vil du beskrive de leddsmertene du har hatt i tomlenes grunnledd i 
løpet av de siste 48 timene?  
 
Sett en X på skalaen under, der 0 = “ingen smerter” og 100 = ”verst tenkelig smerte”. 
 
 
3. Hvis du vurderer det mest smertefulle fingerleddet, hvor vondt har dette 
leddet vært i løpet av de siste 48 timene?  
 
Sett en X på skalaen under, der 0 = “ingen smerter” og 100 = ”verst tenkelig smerte”. 
 
 
4. Vi ber deg vennligst vurdere aktiviteten i håndartrosesykdommen i løpet av de 
siste 48 timene. Når du tar alle symptomer med i betraktning, hvordan syns du 
tilstanden er? 

 
Protocol 1.1 
 
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Sett en X på skalaen under, der 0 = “ingen smerter” og 100 = ”verst tenkelig smerte”. 
 
 
5. Hvordan vil du beskrive de leddsmertene du har hatt de siste 48 timene? Ta 
alle ledd i kroppen med i betraktningen.  
 
Sett en X på skalaen under, der 0 = “ingen smerter” og 100 = ”verst tenkelig smerte”. 
 
 
 
6. Har du tatt smertestillende siste 48 timer? (Paracet/Pinex, Paralgin Forte, 
Nobligan/Tramadol, opiater/morfin etc) 
0
  Nei 
1
  Ja 
 
7. Har du tatt medisin siste 48 timer? (Voltaren, Ibux, Naproxen, Arcoxia, Vimovo 
etc) 
0
  Nei  
1
  Ja 
 
10.2.2. 
Australian/Canadian Hand Index (AUSCAN) 
 
AUSTRALIAN/CANADIAN HAND INDEX (AUSCAN) 
 
Del A. Smerte 
 
De følgende spørsmål gjelder hvor mye smerte du har opplevd som skyldes artrose i 
hendene. Angi i hvert tilfelle graden av smerte i løpet av de siste 48 timer.  

 
Protocol 1.1 
 
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Hvor sterke smerter har du i hendene dine? 
 
1. I ro ( altså når du ikke bruker hendene) 
0
 Ingen       1
 Litt       2
 Moderate       3
 Sterke       4
 Ekstreme 
 
2. Når du griper gjenstander med hendene 
0
 Ingen       1
 Litt       2
 Moderate       3
 Sterke       4
 Ekstreme 
 
3. Når du løfter gjenstander med hendene 
0
 Ingen       1
 Litt       2
 Moderate       3
 Sterke       4
 Ekstreme 
 
4. Når du snur gjenstander med hendene 
0
 Ingen       1
 Litt       2
 Moderate       3
 Sterke       4
 Ekstreme 
 
5. Når du klemmer på gjenstander med hendene 
0
 Ingen       1
 Litt       2
 Moderate       3
 Sterke       4
 Ekstreme 
 
Del B. Stivhet 
 
Det følgende spørsmål gjelder hvor mye leddstivhet (ikke smerte) du har opplevd i 
hendene de siste 48 timer. Stivhet er en følelse av hindring eller hvor vanskelig du har for 
å bevege hendene.  
 
1. Hvor kraftig er stivheten i hendene når du våkner om morgenen? 
0
 Ingen       1
 Litt       2
 Moderat       3
 Kraftig       4
 Ekstrem 
 
Del C. Vanskeligheter ved utførelse av daglige aktiviteter 
 
Følgende spørsmål omfatter din fysiske funksjon.  Med dette mener vi din 
bevegelsesevne og evnen til å klare deg selv. For hver av de følgende aktiviteter ber vi 

 
Protocol 1.1 
 
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deg beskrive vanskelighetene du har opplevd i løpet av de siste 48 timer på grunn av 
artrose i hendene.  
 
Hvor store vanskeligheter har du med følgende: 
 
1. Skru opp kraner og lignende 
0
 Ingen       1
 Litt       2
 Moderate       3
 Store       4
 Ekstreme 
 
2. Vri et rundt dør- eller skaphåndtak 
0
 Ingen       1
 Litt       2
 Moderate       3
 Store       4
 Ekstreme 
 
3. Kneppe igjen knapper 
 
 
0
 Ingen       1
 Litt       2
 Moderate       3
 Store       4
 Ekstreme 
 
4. Feste smykker (klokker, øreringer, mansjettknapper, halskjeder, nåler og armbånd) 
0
 Ingen       1
 Litt       2
 Moderate       3
 Store       4
 Ekstreme 
 
5. Åpne et nytt glass med skrulokk 
0
 Ingen       1
 Litt       2
 Moderate       3
 Store       4
 Ekstreme 
 
6. Bære en full kaffe/vannkjele med en hånd 
0
 Ingen       1
 Litt       2
 Moderate       3
 Store       4
 Ekstreme 
 
7. Skrelle grønnsaker/frukt 
0
 Ingen       1
 Litt       2
 Moderate       3
 Store       4
 Ekstreme 
 
8. Løfte opp store tunge gjenstander 
0
 Ingen       1
 Litt       2
 Moderate       3
 Store       4
 Ekstreme 
 
9. Vri opp vaskekluter 
0
 Ingen       1
 Litt       2
 Moderate       3
 Store       4
 Ekstreme 

 
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10.2.3. 
The EuroQol 5 dimensions 5 levels (EQ-5D-5L) 
 
EUROQOL 5 DIMENSIONS  
Vis hvilke utsagn som passer best på din helsetilstand i dag ved å sette et kryss i en av rutene 
utenfor hver av gruppene nedenfor.  
 
Gange 
1
 Jeg har ingen problemer med å gå omkring.  
2
 Jeg har litt problemer med å gå omkring.  
3
 Jeg har middels store problemer med å gå omkring.  
4
 Jeg har store problemer med å gå omkring. 
5
 Jeg er ute av stand til å gå omkring. 
 
 
Personlig stell 
1
 Jeg har ingen problemer med personlig stell.  
2
 Jeg har litt problemer med å vaske meg eller kle meg.  
3
 Jeg har middels store problemer med å vaske meg eller kle meg.  
4
 Jeg har store problemer med å vaske meg eller kle meg.  
5
 Jeg er ute av stand til å vaske meg eller kle meg.  
 
 
Vanlige gjøremål (for eksempel arbeid, studier, husarbeid, familie- eller fritidsaktiviteter) 
1
 Jeg har ingen problemer med å utføre mine vanlige gjøremål.  
2
 Jeg har litt problemer med å utføre mine vanlige gjøremål.  
3
 Jeg har middels store problemer med å utføre mine vanlige gjøremål.  
4
 Jeg har store problemer med å utføre mine vanlige gjøremål.  
5
 Jeg er ute av stand til å utføre mine vanlige gjøremål.  
 
Smerte/ubehag 
1
 Jeg har verken smerte eller ubehag.  

 
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2
 Jeg har litt smerter eller ubehag.  
3
 Jeg har middels sterke smerter eller ubehag.  
4
 Jeg har sterke smerter eller ubehag.  
5
 Jeg har svært sterke smerter eller ubehag.  
 
Angst/depresjon 
1
 Jeg er verken engstelig eller deprimert.  
2
 Jeg er litt engstelig eller deprimert.  
3
 Jeg er middels engstelig eller deprimert.  
4
 Jeg er svært engstelig eller deprimert.  
5
 Jeg er ekstremt engstelig eller deprimert. 
 
Vi vil gjerne vite hvor god eller dårlig helsen din er i dag.  
Sett en X på skalaen under, der 0 = den dårligste helsen du kan tenke deg og 100 = den beste 
helsen du kan tenke deg. 
 
 
10.2.4. 
Medisiner 
Hvilke medisiner brukes fast (salgsnavn, dosering og administrasjonsform)?  
Eksempel:  
Albyl-E 
E 75 mg x 1  
tablett 
 
 
Salgsnavn 
Dosering  
Adm. form 
1. 
 
 
2. 
 
 
3. 
 
 
4. 
 
 
5. 
 
 
6. 
 
 
7. 
 
 
8. 
 
 
9. 
 
 
10. 
 
 

 
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11. 
 
 
12. 
 
 
 
Hvilke medisiner brukes ved behov (navn, dosering)? 
 
Salgsnavn 
Dosering  
Adm. form 
1. 
 
 
2. 
 
 
3. 
 
 
4. 
 
 
5. 
 
 
6. 
 
 
7. 
 
 
8. 
 
 
 
 

 
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10.3. 
Appendix 3: AEs and SAEs: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting 
10.3.1. 
Definition of AE 
AE Definition 
• 
An AE is any untoward medical occurrence in a patient or clinical study participant, temporally associated with 
the use of study intervention, whether or not considered related to the study intervention. 
• 
NOTE: An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease (new or exacerbated) temporally associated with the use of study intervention. 
 
Definition of Unsolicited and Solicited AE 
• 
An unsolicited AE is an AE that was not solicited using a participant diary and that is communicated by a 
participant who has signed the informed consent. Unsolicited AEs include serious and nonserious AEs. 
• 
Potential unsolicited AEs may be medically attended (ie, symptoms or illnesses requiring a hospitalization, 
emergency room visit, or visit to/by a healthcare provider). The participants will be instructed to contact the site 
as soon as possible to report medically attended event(s), as well as any events that, though not medically 
attended, are of participant concern. Detailed information about reported unsolicited AEs will be collected by 
qualified site personnel and documented in the participant’s records. 
• 
Unsolicited AEs that are not medically attended nor perceived as a concern by the participant will be collected 
during an interview with the participants and by review of available medical records at the next visit. 
• 
Solicited AEs are predefined events for which the participant is specifically questioned, and which are noted by 
the participant in their diary. 
 
Events Meeting the AE Definition 
• 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other safety assessments 
(e.g., ECG, radiological scans, vital signs measurements), including those that worsen from baseline, considered 
clinically significant in the medical and scientific judgment of the investigator (i.e., not related to progression of 
underlying disease). 
• 
Exacerbation of a chronic or intermittent pre-existing condition including either an increase in frequency and/or 
intensity of the condition. 
• 
New conditions detected or diagnosed after study intervention administration even though it may have been 
present before the start of the study. 
• 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study intervention or a concomitant 
medication. Overdose per se will not be reported as an AE/SAE unless it is an intentional overdose taken with 
possible suicidal/self-harming intent. Such overdoses should be reported regardless of sequelae.  

 
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• 
“Lack of efficacy” or “failure of expected pharmacological action” per se will not be reported as an AE or SAE. 
Such instances will be captured in the efficacy assessments. However, the signs, symptoms, and/or clinical 
sequelae resulting from lack of efficacy will be reported as AE or SAE if they fulfil the definition of an AE or SAE. 
• 
The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be reported as AE or SAE if they 
fulfill the definition of an AE or SAE. Also, “lack of efficacy” or “failure of expected pharmacological action” also 
constitutes an AE or SAE. 
 
Events NOT Meeting the AE Definition 
• 
Any clinically significant abnormal laboratory findings or other abnormal safety assessments that are associated 
with the underlying disease, unless judged by the investigator to be more severe than expected for the 
participant’s condition. 
• 
The disease/disorder being studied or expected progression, signs, or symptoms of the disease/disorder being 
studied, unless more severe than expected for the participant’s condition. 
• 
Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that leads to the procedure is the 
AE. 
• 
Situations in which an untoward medical occurrence did not occur (social and/or convenience admission to a 
hospital). 
• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or detected at the start of the 
study that do not worsen. 
10.3.2. 
Definition of SAE 
An SAE is defined as any untoward medical occurrence that, at any dose, meets one or more of the criteria listed: 
a. 
Results in death 
b. 
Is life-threatening 
• 
The term 'life-threatening' in the definition of 'serious' refers to an event in which the participant was at risk of 
death at the time of the event. It does not refer to an event, which hypothetically might have caused death, if it 
were more severe. 
c. 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• 
In general, hospitalization signifies that the participant has been detained (usually involving at least an overnight 
stay) at the hospital or emergency ward for observation and/or treatment that would not have been appropriate in 
the physician’s office or outpatient setting. Complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is serious. When in doubt as 
to whether “hospitalization” occurred or was necessary, the AE should be considered serious. 
• 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from baseline is not 
considered an AE. 
d. 
Results in persistent disability/incapacity 
• 
The term disability means a substantial disruption of a person’s ability to conduct normal life functions. 
• 
This definition is not intended to include experiences of relatively minor medical significance such as 
uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma (e.g., sprained ankle) 
which may interfere with or prevent everyday life functions but do not constitute a substantial disruption. 

 
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e. 
Is a congenital anomaly/birth defect 
f. 
Other situations: 
• 
Medical or scientific judgment should be exercised in deciding whether SAE reporting is appropriate in other 
situations such as important medical events that may not be immediately life threatening or result in death or 
hospitalization but may jeopardize the participant or may require medical or surgical intervention to prevent one 
of the other outcomes listed in the above definition. These events should usually be considered serious. 
• 
Examples of such events include invasive or malignant cancers, intensive treatment in an emergency room or at 
home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization, or 
development of drug dependency or drug abuse. 
10.3.3. 
Recording and Follow-Up of AE and/or SAE 
AE and SAE Recording 
• 
When an AE/SAE occurs, it is the responsibility of the investigator to review all documentation (e.g., hospital 
progress notes, laboratory reports, and diagnostics reports) related to the event. 
• 
The investigator will then record all relevant AE/SAE information in the CRF. 
• 
It is not acceptable for the investigator to send photocopies of the participant’s medical records to Medical 
Monitor in lieu of completion of the AE/SAE CRF page. 
• 
There may be instances when copies of medical records for certain cases are requested by the Sponsor. In this 
case, all participant identifiers, with the exception of the participant number, will be redacted on the copies of the 
medical records before submission to the Sponsor and/or Medical Monitor. 
• 
The investigator will attempt to establish a diagnosis of the event based on signs, symptoms, and/or other clinical 
information. Whenever possible, the diagnosis (not the individual signs/symptoms) will be documented as the 
AE/SAE. 
 
Assessment of Intensity 
The investigator will make an assessment of intensity for each AE and SAE reported during the study and assign it to 1 of 
the following categories:  
• 
Mild: An event that is easily tolerated by the participant, causing minimal discomfort and not interfering with 
everyday activities. 
• 
Moderate: An event that causes sufficient discomfort and interferes with normal everyday activities. 
• 
Severe: An event that prevents normal everyday activities. An AE that is assessed as severe should not be 
confused with a SAE. Severe is a category utilized for rating the intensity of an event; and both AEs and SAEs 
can be assessed as severe. 
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as described in the definition of an 
SAE, NOT when it is rated as severe.  
 
Assessment of Causality 
• 
The investigator is obligated to assess the relationship between study intervention and each occurrence of each 
AE/SAE. 

 
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• 
A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or arguments to suggest a 
causal relationship, rather than a relationship cannot be ruled out. 
• 
The investigator will use clinical judgment to determine the relationship. 
• 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk factors, as well as the 
temporal relationship of the event to study intervention administration will be considered and investigated. 
• 
The investigator will also consult the Investigator’s Brochure (IB) and/or Product Information, for marketed 
products, in his/her assessment. 
• 
For each AE/SAE, the investigator must document in the medical notes that he/she has reviewed the AE/SAE 
and has provided an assessment of causality. 
• 
There may be situations in which an SAE has occurred and the investigator has minimal information to include in 
the initial report to the Medical Monitor. However, it is very important that the investigator always make an 
assessment of causality for every event before the initial transmission of the SAE data to the Medical Monitor. 
• 
The investigator may change his/her opinion of causality in light of follow-up information and send a SAE follow-
up report with the updated causality assessment. 
• 
The causality assessment is one of the criteria used when determining regulatory reporting requirements. 
 
Follow-up of AEs and SAEs 
• 
The investigator is obligated to perform or arrange for the conduct of supplemental measurements and/or 
evaluations as medically indicated or as requested by the Medical Monitor to elucidate the nature and/or 
causality of the AE or SAE as fully as possible. This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other health care professionals. 
• 
New or updated information will be recorded in the originally completed CRF. 
• 
The investigator will submit any updated SAE data to the Medical Monitor within 24 hours of receipt of the 
information. 
10.3.4. 
Reporting of SAEs 
SAE Reporting to Sponsor via an Electronic Data Collection Tool 
• 
The primary mechanism for reporting an SAE to Sponsor’s Safety Risk Management department will be the 
electronic data collection tool. 
• 
If the electronic system is unavailable, then the site will use the paper SAE data collection tool in order to report 
the event within 24 hours. 
• 
The site will enter the SAE data into the electronic system as soon as it becomes available. 
• 
After the study is completed at a given site, the electronic data collection tool will be taken off-line to prevent the 
entry of new data or changes to existing data. 
• 
If a site receives a report of a new SAE from a study participant or receives updated data on a previously 
reported SAE after the electronic data collection tool has been taken off-line, then the site can report this 
information on a paper SAE form (see next section) or to the Medical Monitor by telephone. 
• 
Contacts for SAE reporting can be found in the Trial Master File (TMF). 
 
 

 
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10.4. 
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below). 
If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before first dose of study intervention, additional evaluation should be considered. 
Women in the following categories are not considered WOCBP 
1. Premenarchal 
2. Premenopausal female with 1 of the following: 
• Documented hysterectomy 
• Documented bilateral salpingectomy 
• Documented bilateral oophorectomy 
 
For individuals with permanent infertility due to an alternate medical cause other than the 
above, (e.g., mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry. 
Note: Documentation can come from the site personnel’s: review of the participant’s medical 
records, medical examination, or medical history interview. 
3. Postmenopausal female 
• A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
o A high follicle stimulating hormone (FSH) level in the postmenopausal range may be 
used to confirm a postmenopausal state in women not using hormonal contraception 
or hormonal replacement therapy (HRT). However, in the absence of 12 months of 
amenorrhea, confirmation with more than one FSH measurement is required.  
• Females on HRT and whose menopausal status is in doubt will be required to use one of 
the non-estrogen hormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment. 
Contraception Guidance 
Adequate contraception includes oral, injected or implanted hormonal methods of contraception, 
placement of an intrauterine device or system, vasectomized partner or sexual abstinence. 
Collection of Pregnancy Information 
Male participants with partners who become pregnant 
• The investigator will attempt to collect pregnancy information on any male participant’s 
female partner who becomes pregnant while the male participant is in this study. This 

 
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applies only to male participants who receive methotrexate, and is a reason to blind 
break. The participant will be withdrawn from the study due to blind break.  
• After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the investigator will record pregnancy information on the appropriate form and 
submit it to the Medical Monitor within 24 hours of learning of the partner’s pregnancy. 
The female partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to the Medical 
Monitor. Generally, the follow-up will be no longer than 6 to 8 weeks following the 
estimated delivery date. Any termination of the pregnancy will be reported regardless of 
fetal status (presence or absence of anomalies) or indication for the procedure.  
Female Participants who become pregnant 
• The investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study. The initial information will be 
recorded on the appropriate form and submitted to the Medical Monitor within 24 hours 
of learning of a participant's pregnancy. This applies only to female participants who 
receive MTX. The participant will be withdrawn from the study due to blind break and 
the teratogenic effect of methotrexate. 
• 
The participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow-up information on the participant and the neonate and the 
information will be forwarded to the Medical Monitor. Generally, follow-up will not be 
required for longer than 6 to 8 weeks beyond the estimated delivery date. Any 
termination of pregnancy will be reported, regardless of fetal status (presence or absence 
of anomalies) or indication for the procedure. 
• 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be reported 
as an AE or SAE.  
• 
A spontaneous abortion (occurring at <22 weeks gestational age) or still birth (occurring 
at >22 weeks gestational age) is always considered to be an SAE and will be reported as 
such.  
• 
Any post-study pregnancy related SAE considered reasonably related to the study 
intervention by the investigator will be reported to the Medical Monitor. While the 
investigator is not obligated to actively seek this information in former study participants, 
he or she may learn of an SAE through spontaneous reporting. 
• 
Any female participant who becomes pregnant while participating in the study will 
discontinue study intervention or be withdrawn from the study. 

 
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