Methotrexate in Erosive Inflammatory Hand Osteoarthritis

Phase 4

Recruiting

• Conditions: Hand Osteoarthritis; Erosive Osteoarthritis
• Interventions: Drug: Methotrexate Tablets; Drug: Placebo; Drug: Folic Acid 1 MG

• Registration Number: NCT04579848
• Lead Sponsor: Diakonhjemmet Hospital

Brief Summary

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

Detailed Description

The trial will include Norwegian adult males and females with symptomatic erosive inflammatory hand osteoarthritis.

Participants will be randomized 1:1 to either:

1. 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.

2. Placebo (control group).

Both arms will receive folic acid 1mg daily.

The treatment duration for both groups is 52 weeks.

Study Timeline

• Study First Submitted: 2020-09-22
• Study First Submitted QC: 2020-10-01
• Study First Posted: 2020-10-08
• Study Start: 2021-08-12
• Status Verified: 2025-05
• Last Update Submitted: 2025-05-22
• Last Update Posted: 2025-05-29
• Primary Completion: 2026-06-30
• Study Completion: 2026-12-31

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 163

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Methotrexate	Methotrexate Tablets	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.
Methotrexate	Folic Acid 1 MG	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.
Placebo	Placebo	3 capsules per week for two weeks, followed by 4 capsules the remaining weeks. Additional Folic acid 1mg prescribed daily.
Placebo	Folic Acid 1 MG	3 capsules per week for two weeks, followed by 4 capsules the remaining weeks. Additional Folic acid 1mg prescribed daily.

Primary Outcome Measures

Name	Time	Method
Finger pain on a visual analogue scale	6 months	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.

Secondary Outcome Measures

Name	Time	Method
AUSCAN	Month 1, 3, 6, 9 and 12.	Australian/Canadian hand index (AUSCAN), sum score 0-60, higher value indicate worse outcome.
Finger pain on a visual analogue scale	Month 1, 3, 9 and 12.	Self-reported finger pain previous 48 hours on a 0-100 mm scale; higher value indicate worse outcome.
Thumb pain on a visual analogue scale	Month 1, 3, 6, 9 and 12.	Self-reported thumb pain previous 48 hours on a 0-100 mm scale; higher value indicate worse outcome.
Pain most painful finger joint on a visual analogue scale	Month 1, 3, 6, 9 and 12.	Pain most painful finger joint last 48 hours on a 0-100 mm scale; higher value indicate worse outcome.
Patient-reported disease activity on a visual analogue scale	Month 1, 3, 6, 9 and 12.	Patient-reported disease activity last 48 hours on a 0-100 mm scale; higher value indicate worse outcome.
Pain all joints on a visual analogue scale	Month 1, 3, 6, 9 and 12.	Pain all joints last 48 hours on a 0-100 mm scale; higher value indicate worse outcome.
Hand diagram pain	Month 6.	Finger pain and thumb base pain (yes/no) on hand diagram
Body diagram pain	Month 6.	Pain in other joints (yes/no) on body diagram
OMERACT-OARSI responder criteria	Month 1, 3, 6, 9 and 12.	Fulfillment of Outcome Measures in Rheumatology Osteoarthritis Research Society International (OMERACT-OARSI) responder criteria.
EQ-5D	Month 1, 3, 6, 9 and 12.	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.
MHOQ	Month 6.	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.
Grip strength	Month 1, 3, 6, 9 and 12.	Grip strength (in kg; using a hand dynamometer)
HOOS-12	Month 6.	Hip disability and Osteoarthritis Outcome Score (HOOS)-12, range 12-60, higher value indicate worse outcome.
KOOS-12	Month 6.	Knee injury and Osteoarthritis Outcome Score (KOOS)-12, range 12-60, higher value indicate worse outcome.
Concomitant medication	Month 1, 3, 6, 9 and 12.	Concomitant medication
Tender and swollen joints	Month 1, 3, 6, 9 and 12.	Number of tender and swollen joints (range 0-30), higher values indicate more affected joints.
Physician-reported disease activity on a visual analogue scale	Month 1, 3, 6, 9 and 12.	Patient-reported disease activity on a 0-100 mm scale; higher value indicate worse outcome.
Hand radiographs: Kellgren Lawrence	Month 6 and 12	Conventional radiographs: change in radiographic severity according to Kellgren-Lawrence scale, range 0-4 in each joint higher value indicate worse outcome.
Hand radiographs: Verbruggen-Veys anatomical phase scoring system	Month 6 and 12	Conventional radiographs: radiographic severity in finger joints according to Verbruggen-Veys anatomical phase scoring system, range 1-5; higher value indicate worse outcome.
Hand radiographs: OARSI atlas	Month 6 and 12	Conventional radiographs: rdiographic severity according to the Osteoarthritis Research Society International (OARSI) atlas for the presence/severity of osteophytes, joint space narrowing and erosions.
Hand MRI	Month 6	MRI of dominant hand: number of joints with synovitis and BMLs
Hand ultrasound	Month 1, 3, 6, 9 and 12.	Ultrasound: number of finger joints with synovial thickening and power Doppler signals.
Knee ultrasound	Month 6	Ultrasound: degree of synovitis in knee joints
Hip ultrasound	Month 6	Ultrasound: degree of synovitis in hip joints
Adverse events	Through study completion, maximum 12 months, in addition to 3 months after end of treatment.	Number of adverse events, serious adverse events, and withdrawals because of adverse events.

Trial Locations

Locations (1)

Diakonhjemmet Hospital; 🇳🇴 Oslo, Norway