Methotrexate in Erosive Inflammatory Hand Osteoarthritis (MERINO)

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.

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

Study Overview

• Status: Recruiting
• Conditions: Hand Osteoarthritis; Erosive Osteoarthritis
• Intervention / Treatment: Drug: Placebo; Drug: Methotrexate Tablets; Drug: Folic Acid 1 MG

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 Type: Interventional
• Enrollment (Estimated): 153
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Ida K. Haugen, MD, PhD; Phone Number: 95859884; Email: ida.k.haugen@gmail.com
• Study Contact Backup: Name: Alexander Mathiessen, MD, PhD; Phone Number: 97501889; Email: alexander_mathiessen@hotmail.com

Study Locations

• Norway
  • Oslo, Norway
    • Recruiting
    • Diakonhjemmet Hospital
    • Contact: Ida K Haugen, MD, PhD; Phone Number: +47 95859884; Email: ida.k.haugen@gmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Methotrexate; 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; Methotrexate 2.5mg oral tablet.; Drug: Folic Acid 1 MG; Folic acid
Placebo Comparator: Placebo; 3 capsules per week for two weeks, followed by 4 capsules the remaining weeks. Additional Folic acid 1mg prescribed daily.	Drug: Placebo; Placebo capsule; Drug: Folic Acid 1 MG; Folic acid

What is the study measuring?

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.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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

Collaborators and Investigators

• Sponsor: Diakonhjemmet Hospital
• Collaborators: Oslo University Hospital
• Investigators: Study Chair: Tore K Kvien, MD, PhD, Professor Em.

Study record dates

Study Major Dates

• Study Start (Actual): August 12, 2021
• Primary Completion (Estimated): June 30, 2025
• Study Completion (Estimated): December 31, 2025

Study Registration Dates

• First Submitted: September 22, 2020
• First Submitted That Met QC Criteria: October 1, 2020
• First Posted (Actual): October 8, 2020

Study Record Updates

• Last Update Posted (Actual): November 1, 2023
• Last Update Submitted That Met QC Criteria: October 30, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Arthritis; Osteoarthritis; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Dermatologic Agents; Micronutrients; Vitamins; Reproductive Control Agents; Vitamin B Complex; Hematinics; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Folic Acid Antagonists; Methotrexate; Folic Acid
• Other Study ID Numbers: DIA2020-01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

IPD Plan Description

The trialists and other study personnel that conceive of the study, and then plan, manage, monitor, analyze and publish it, will have access to IPD. Participants' identification code numbers are de-identified by replacing the original code number with a new random code number. Only the PI and project coordinator have access to this code.

The protocol, SAP, ICF, and CSR will be shared with regulatory agents as required.

Study Data/Documents

1. Study Protocol
2. Informed Consent Form
3. Informed Consent Form

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No