Methotrexate in Erosive Inflammatory Hand Osteoarthritis

Study Overview
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Brief Summary
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A placebo-controlled randomized controlled trial exploring the effect of methotrexate on pain, function and structural outcomes in erosive inflammatory hand osteoarthritis.

Detailed Description
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The trial will include Norwegian adult males and females with symptomatic erosive inflammatory hand osteoarthritis. Participants will be randomized 1:1 to either: Methotrexate oral x 1/week; weekly starting dose 15 mg for two weeks, followed by 20 mg the remaining weeks (intervention group). Dosage can be reduced to as low as 10 mg if higher doses are not tolerated. Placebo (control group). Both arms will receive folic acid 1mg daily. The treatment duration for both groups is 52 weeks.

Official Title
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The Methotrexate in ERosive INflammatory Osteoarthritis (MERINO) Trial: A Randomized Placebo-controlled Trial to Investigate Clinical Efficacy and Safety of Methotrexate in Erosive Inflammatory Hand Osteoarthritis.

Conditions
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Hand Osteoarthritis, Erosive Osteoarthritis

Intervention / Treatment
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* Drug: Methotrexate Tablets
* Drug: Placebo
* Drug: Folic Acid 1 MG


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Finger joint pain 40-80 on 0-100 visual analog scale (VAS) with insufficient pain relief from, inability to tolerate or contra-indications to oral paracetamol and/or NSAIDs, and hand symptoms (pain, aching, or stiffness) on most days the previous 6 weeks before randomization. Hand OA according to the American College of Rheumatology (ACR) criteria, at least 1 distal (DIP) or proximal interphalangeal (PIP) joint of the 2nd-5th finger with radiographic pre-erosive (J-phase) or erosive disease (E-phase) according to the Verbruggen-Veys anatomical phase system, and at least two DIP/PIP joints with power Doppler signal of at least grade 1 or grey-scale synovitis of at least grade 2 on ultrasound. Exclusion Criteria: A full list of the exclusion criteria for this study comprised the following: Contraindications to methotrexate: Abnormal renal function, defined as serum creatinine >142 µmol/L in women and >168 µmol/L in men, or a glomeruli filtration rate (GFR) <40 mL/min/1.73 m2. Abnormal liver function, defined as transaminases above the upper normal limit, active or previous hepatitis B or C infection, or known cirrhosis Lung fibrosis (maximum 6 months old x-ray), active infection, or reduced hematopoiesis (i.e. anemia, leukopenia and/or thrombocytopenia). Planned pregnancy within 18 months after screening (men/women), and pregnancy, breastfeeding, or insufficient anti-conception therapy for female fertile participants. Contraception should be maintained during treatment and until the end of systemic exposure, i.e. 3 months after methotrexate discontinuation. Sufficient anti-conception therapy consists of intra-uterine device (coil) or hormonal anti-conception (birth control pills, implant, intra-uterine system, dermal patch, vaginal ring, or injections). Alcohol or other drug abuse in the last year. Intolerance to lactose. Chronic inflammatory rheumatic diseases (such as rheumatoid arthritis and psoriatic arthritis or gout), active inflammatory bowel disease, or positive rheumatoid factor or anti-CCP antibodies. Other severe co-morbidities such as hemochromatosis, fibromyalgia, psoriasis, blood dyscrasias, and coagulation disorders, history of malignancy (except successfully treated squamous or basal cell skin carcinoma), uncontrolled diabetes mellitus, severe hypertension, unstable ischemic heart disease, severe heart failure, severe pulmonary disease, severe and/or opportunistic infections and/or chronic infections, active tuberculosis, positive human immunodeficiency virus (HIV) status, recent stroke, bone marrow hypoplasia, or demyelinating diseases of the central nervous system. Other likely causes of hand symptoms: thoracic outlet syndrome, carpal tunnel disease, diabetic cheiropathy, injury in finger joints previous 6 months, or palmar tenosynovitis/trigger finger. Oral or intra-muscular steroids in the previous month Intra-articular treatments or aspirations of any kind of any joint in the hands 3 months before inclusion Analgesics or NSAIDs, unless stable dosage for ≥1 month. Symptomatic slow-acting drugs for OA (SYSADOA), unless stable dose for ≥3 months and require stable dose throughout the study. Disease-modifying osteoarthritis drugs (DMOADs) previous three months. Scheduled hand surgery during study participation. Planning to start other treatments for hand OA in the study participation period. Not able to adhere to the study visit schedule and protocol requirements.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: An investigator-initiated, randomized, double-blinded, placebo-controlled, parallel-group, single-center, phase IV, superiority study, exploring the effect of methotrexate on pain, function and structural outcomes in erosive inflammatory hand osteoarthritis.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Methotrexate<br>Methotrexate oral x 1/week; weekly starting dose 15 mg for two weeks, followed by 20 mg the remaining weeks. Additional Folic acid 1mg prescribed daily. | Drug: Methotrexate Tablets<br>* Methotrexate 2.5mg oral tablet.<br>Drug: Folic Acid 1 MG<br>* Folic acid<br>|
| Placebo Comparator: Placebo<br>3 capsules per week for two weeks, followed by 4 capsules the remaining weeks. Additional Folic acid 1mg prescribed daily. | Drug: Placebo<br>* Placebo capsule<br>Drug: Folic Acid 1 MG<br>* Folic acid<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Finger pain on a visual analogue scale | Difference in self-reported finger joint pain previous 48 hours on a 0-100 mm scale at 6 months of treatment; higher value indicate worse outcome. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| OMERACT-OARSI responder criteria | Fulfillment of Outcome Measures in Rheumatology Osteoarthritis Research Society International (OMERACT-OARSI) responder criteria. | Month 1, 3, 6, 9 and 12. | 
| Finger pain on a visual analogue scale | Self-reported finger pain previous 48 hours on a 0-100 mm scale; higher value indicate worse outcome. | Month 1, 3, 6, 9 and 12. | 
| Thumb pain on a visual analogue scale | Self-reported thumb pain previous 48 hours on a 0-100 mm scale; higher value indicate worse outcome. | Month 1, 3, 6, 9 and 12. | 
| Pain most painful finger joint on a visual analogue scale | Pain most painful finger joint last 48 hours on a 0-100 mm scale; higher value indicate worse outcome. | Month 1, 3, 6, 9 and 12. | 
| Patient-reported disease activity on a visual analogue scale | Patient-reported disease activity last 48 hours on a 0-100 mm scale; higher value indicate worse outcome. | Month 1, 3, 6, 9 and 12. | 
| AUSCAN | Australian/Canadian hand index (AUSCAN), sum score 0-60, higher value indicate worse outcome. | Month 1, 3, 6, 9 and 12. | 
| EQ-5D | Quality-adjusted life years (QALYs) based on the health-related utility scores measured by the generic instrument EuroQol 5 dimensions (EQ-5D), sum score 5-35, higher value indicate worse outcome, in addition to a 0-100 visual analogue scale where higher value indicate better outcome. | Month 1, 3, 6, 9 and 12. | 
| Concomitant medication | Concomitant medication | Month 1, 3, 6, 9 and 12. | 
| Tender and swollen joints | Number of tender and swollen joints (range 0-30), higher values indicate more affected joints. | Month 1, 3, 6, 9 and 12. | 
| Grip strength | Grip strength (in kg; using a hand dynamometer) | Month 1, 3, 6, 9 and 12. | 
| Pain sensitization | Pain sensitization: Pressure Pain Thresholds (PPT) by digital algometer; temporal summation by punctate probes; Conditioned Pain Modulation (CPM) by blood pressure ischemic test. | Month 1, 3, 6, 9 and 12. | 
| Ultrasound | Ultrasound: number of finger joints with synovial thickening and power Doppler signals. | Month 1, 3, 6, 9 and 12. | 
| Hand diagram pain | Finger pain and thumb base pain (yes/no) on hand diagram | Month 6. | 
| MHOQ | Michigan Hand Outcomes Questionnaire (MHOQ) pain and physical function subscales; function subscale range 10-50, higher value indicate worse outcome; task subscale range 17-85, higher value indicate worse outcome; work subscale range 5-25, higher value indicate worse outcome; pain subscale range 10-48, higher value indicate better outcome. | Month 6. | 
| Morning stiffness fingers | Duration of morning stiffness in finger joints in minutes, higher value indicate worse outcome. | Month 6. | 
| Morning stiffness thumbs | Duration of morning stiffness in thumb base joints in minutes, higher value indicate worse outcome. | Month 6. | 
| HADS | Hospital Anxiety and Depression Scales (HADS), range 0-42, higher value indicate worse outcome. | Month 6. | 
| PCS | Pain Catastrophizing Scale (PCS), range 0-12, higher value indicate worse outcome. | Month 6. | 
| PSQ | Pain Sensitivity Questionnaire (PSQ), range 0-170, higher value indicate worse outcome. | Month 6. | 
| KOOS-12 | Knee injury and Osteoarthritis Outcome Score (KOOS)-12, range 12-60, higher value indicate worse outcome. | Month 6. | 
| HOOS-12 | Hip disability and Osteoarthritis Outcome Score (HOOS)-12, range 12-60, higher value indicate worse outcome. | Month 6. | 
| Radiographs: Kellgren Lawrence | Conventional radiographs: change in radiographic severity according to Kellgren-Lawrence scale, range 0-4 in each finger joints, in total 30 joints; higher value indicate worse outcome. | Month 6 and 12 | 
| Radiographs: Verbruggen-Veys anatomical phase scoring system | Conventional radiographs: change in radiographic severity in finger joints according to Verbruggen-Veys anatomical phase scoring system, range 1-5 in each finger joint, in total 30 finger joints; higher value indicate worse outcome. | Month 6 and 12 | 
| Radiographs: OARSI atlas | Conventional radiographs: change in radiographic severity according to the Osteoarthritis Research Society International (OARSI) atlas for the presence/severity of osteophytes, joint space narrowing and erosions. | Month 6 and 12 | 
| Soluble biomarkers of extracellular matrix turnover | Markers of collagen degradation (s-COMP, s-C1M, s-C2M, s-C3M, s-CTX1, sHA), collagen synthesis (s-proC2), aggrecan degradation (s-huARGS) and inflammation (s-calprotectin, s- vimentin, s-hsCRP and s-CRPM); Inflammatory cytokines (IL-1β, IL-1ra, IL-4, IL-6, IL-10, IL-12, IL-17, IL-18, IL-21, IFN-γ, TNF-α, VEGF, GM-CSF, CCL2, CCL3, CCL4, CXCL10) and hormones (leptin and resistin). | Month 6 and 12 | 
| Adverse events | Number of adverse events, serious adverse events, and withdrawals because of adverse events. | Through study completion, maximum 12 months, in addition to 3 months after end of treatment. |