Clinical trial NCT04579848: Methotrexate in Erosive Inflammatory Hand Osteoarthritis
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.
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Hand Osteoarthritis
Erosive Osteoarthritis
Lead sponsor: Diakonhjemmet Hospital
Sponsor class: OTHER
Collaborators: name: Oslo University Hospital
First posted: 2020-10-08
Enrollment: 163
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention 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.
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Finger pain on a visual analogue scale
timeFrame: 6 months
Secondary outcomes:
measure: Finger pain on a visual analogue scale
timeFrame: Month 1, 3, 9 and 12.
measure: Thumb pain on a visual analogue scale
timeFrame: Month 1, 3, 6, 9 and 12.
measure: Pain most painful finger joint on a visual analogue scale
timeFrame: Month 1, 3, 6, 9 and 12.
measure: Patient-reported disease activity on a visual analogue scale
timeFrame: Month 1, 3, 6, 9 and 12.
measure: Pain all joints on a visual analogue scale
timeFrame: Month 1, 3, 6, 9 and 12.
measure: Hand diagram pain
timeFrame: Month 6.
measure: Body diagram pain
timeFrame: Month 6.
measure: AUSCAN
timeFrame: Month 1, 3, 6, 9 and 12.
measure: OMERACT-OARSI responder criteria
timeFrame: Month 1, 3, 6, 9 and 12.
measure: EQ-5D
timeFrame: Month 1, 3, 6, 9 and 12.
measure: MHOQ
timeFrame: Month 6.
measure: Grip strength
timeFrame: Month 1, 3, 6, 9 and 12.
measure: HOOS-12
timeFrame: Month 6.
measure: KOOS-12
timeFrame: Month 6.
measure: Concomitant medication
timeFrame: Month 1, 3, 6, 9 and 12.
measure: Tender and swollen joints
timeFrame: Month 1, 3, 6, 9 and 12.
measure: Physician-reported disease activity on a visual analogue scale
timeFrame: Month 1, 3, 6, 9 and 12.
measure: Hand radiographs: Kellgren Lawrence
timeFrame: Month 6 and 12
measure: Hand radiographs: Verbruggen-Veys anatomical phase scoring system
timeFrame: Month 6 and 12
measure: Hand radiographs: OARSI atlas
timeFrame: Month 6 and 12
measure: Hand MRI
timeFrame: Month 6
measure: Hand ultrasound
timeFrame: Month 1, 3, 6, 9 and 12.
measure: Knee ultrasound
timeFrame: Month 6
measure: Hip ultrasound
timeFrame: Month 6
measure: Adverse events
timeFrame: Through study completion, maximum 12 months, in addition to 3 months after end of treatment.
Other outcomes:
measure: Sub-study: biopsy of knee OA
timeFrame: Month 6
measure: Sub-study: knee pain on a visual analogue scale
timeFrame: Month 6
measure: Question about blinding
timeFrame: Month 12
measure: HADS
timeFrame: Month 6
measure: PCS
timeFrame: Month 6
measure: PSQ
timeFrame: Month 6
measure: Anchor questions for MCII and PASS
timeFrame: Month 6
measure: ASES
timeFrame: Month 6
measure: Pain sensitization
timeFrame: Month 6
measure: Soluble biomarkers of extracellular matrix turnover
timeFrame: Month 6 and 12
measure: Omics
timeFrame: Month 6 and 12
Locations:
city: Oslo
country: Norway
facility: Diakonhjemmet Hospital
Study officials:
affiliation: Professor Em.
name: Tore K Kvien, MD, PhD
role: STUDY_CHAIR
References: