Methotrexate in Erosive Inflammatory Hand Osteoarthritis

Hand Osteoarthritis Clinical Trial

— MERINO  

Official title:

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.

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04579848
• Other study ID #: DIA2020-01
• Status: Recruiting
• Phase: Phase 4
• Start date: August 12, 2021
• Est. completion date: December 31, 2025

Study information

• Verified date: October 2023
• Source: Diakonhjemmet Hospital
• Contact: Ida K. Haugen, MD, PhD
• Phone: 95859884
• Email: ida.k.haugen[@]gmail.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 153
• Est. completion date: December 31, 2025
• Est. primary completion date: June 30, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Erosive Osteoarthritis
• Hand Osteoarthritis
• Osteoarthritis

Intervention

Drug:
• Methotrexate Tablets
Methotrexate 2.5mg oral tablet.
• Placebo
Placebo capsule
• Folic Acid 1 MG
Folic acid

Locations

Country	Name	City	State
Norway	Diakonhjemmet Hospital	Oslo

Sponsors (2)

Lead Sponsor	Collaborator
Diakonhjemmet Hospital	Oslo University Hospital

Country where clinical trial is conducted

Norway, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Sub-study: biopsy of knee OA	Change in synovial cellular composition and gene expression with single-cell RNA sequencing analyses; subgroup analyses, n=16 patients	Month 6
Other	Sub-study: knee pain on a visual analogue scale	Self-reported knee pain previous 48 hours on a 0-100 mm scale at 6 months of treatment; higher value indicate worse outcome.	Month 6
Primary	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	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	AUSCAN	Australian/Canadian hand index (AUSCAN), sum score 0-60, higher value indicate worse outcome.	Month 1, 3, 6, 9 and 12.
Secondary	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.
Secondary	Concomitant medication	Concomitant medication	Month 1, 3, 6, 9 and 12.
Secondary	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.
Secondary	Grip strength	Grip strength (in kg; using a hand dynamometer)	Month 1, 3, 6, 9 and 12.
Secondary	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.
Secondary	Ultrasound	Ultrasound: number of finger joints with synovial thickening and power Doppler signals.	Month 1, 3, 6, 9 and 12.
Secondary	Hand diagram pain	Finger pain and thumb base pain (yes/no) on hand diagram	Month 6.
Secondary	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.
Secondary	Morning stiffness fingers	Duration of morning stiffness in finger joints in minutes, higher value indicate worse outcome.	Month 6.
Secondary	Morning stiffness thumbs	Duration of morning stiffness in thumb base joints in minutes, higher value indicate worse outcome.	Month 6.
Secondary	HADS	Hospital Anxiety and Depression Scales (HADS), range 0-42, higher value indicate worse outcome.	Month 6.
Secondary	PCS	Pain Catastrophizing Scale (PCS), range 0-12, higher value indicate worse outcome.	Month 6.
Secondary	PSQ	Pain Sensitivity Questionnaire (PSQ), range 0-170, higher value indicate worse outcome.	Month 6.
Secondary	KOOS-12	Knee injury and Osteoarthritis Outcome Score (KOOS)-12, range 12-60, higher value indicate worse outcome.	Month 6.
Secondary	HOOS-12	Hip disability and Osteoarthritis Outcome Score (HOOS)-12, range 12-60, higher value indicate worse outcome.	Month 6.
Secondary	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
Secondary	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
Secondary	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
Secondary	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-1ß, IL-1ra, IL-4, IL-6, IL-10, IL-12, IL-17, IL-18, IL-21, IFN-?, TNF-a, VEGF, GM-CSF, CCL2, CCL3, CCL4, CXCL10) and hormones (leptin and resistin).	Month 6 and 12
Secondary	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.