Clinical trial NCT03815448: Methotrexate in the Treatment of Advanced Knee Osteoarthritis With Effusion-synovitis
Official title: A Randomized, Double-blind, Placebo-controlled Clinical Trial of Methotrexate (MTX) in the Treatment of Advanced Knee Osteoarthritis With Effusion-synovitis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Knee Osteoarthritis
Effusion Synovial
Knee Pain
Keywords: Methotrexate
knee osteoarthritis
Magnetic Resonance imaging
pain
synovitis
Lead sponsor: Zhujiang Hospital
Sponsor class: OTHER
Collaborators: name: Peking Union Medical College Hospital
name: Third Affiliated Hospital, Sun Yat-Sen University
name: Beijing Hospital
name: Xuanwu Hospital, Beijing
name: The First Affiliated Hospital of Anhui Medical University
name: The Second People's Hospital of GuangDong Province
name: Peking University People's Hospital
name: Shenzhen Third People's Hospital
name: Central People's Hospital of Zhanjiang
name: Qingyuan People's Hospital
First posted: 2019-01-24
Enrollment: 215
Sex: ALL
Minimum age (years): 45
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This multicentre randomized placebo-controlled clinical trial aims to evaluate whether methotrexate (MTX) has effects of relieving symptoms and reducing inflammation on advanced knee osteoarthritis (OA) with inflammatory phenotype. Participants will be randomly allocated to either MTX group or placebo group receiving MTX or placebo once a week. The primary outcomes are effusion-synovitis volume measured by magnetic resonance imaging (MRI) and knee pain assessed by visual analogue scale (VAS).

Detailed description: OA is a common chronic musculoskeletal disease in middle-aged and elderly people, which is characterized by loss of articular cartilage and other structural damage of joints. Currently, there is no effective treatment to reduce disease severity and progression of knee OA, particularly in mid to late-stages. Analgesics and anti-inflammatory drugs can only have effects in a short time, with obvious side effects, and are not effective for all patients. In the late stage, most patients are performed with arthroplasty. However, arthroplasty is expensive and has high technical requirements for surgeons. Therefore, it is urgent to find effective drugs or means to control the symptoms and disease progression of knee OA.

Due to different etiologies, OA may have different clinical phenotypes, one of which is mainly manifested by synovitis and is common in patients with advanced OA. Pathological studies have shown that OA synovitis is significantly related to adjacent cartilage lesions, and its pathological changes were similar to rheumatoid arthritis (RA), but the degree of the latter is relatively mild. MTX can alleviate joint inflammation and delay joint structural damage. In patients with rheumatoid arthritis, MTX can reduce suprapatellar bursa synovitis by 35%, inhibit the inflammatory response of synovial tissue, including reducing the number of macrophage, inhibiting the expression of intercellular adhesion molecule -1, interleukin (IL)-1, tumour necrosis factor (TNF)-α and C-reactive protein (CRP), and even reduce bone marrow lesions (BMLs) and synovitis in very early stages. In patients with early-stage undifferentiated arthritis, MTX treatment for two months can significantly reduce synovitis and exudation, alleviate BMLs and reduce serum CRP level. Chronic calcium pyrophosphate deposition disease is a non-autoimmunity inflammatory arthritis which can be followed by more severe OA. After 6-81 months of treatment with MTX (5-20 mg/week), the pain intensity, swelling and the number of involved joints were significantly decreased. Based on all the evidence as discussed above, MTX may have beneficial effects on OA via a variety of mechanisms, including reduction of synovitis and effusion, and decreases in inflammatory cytokines.

The investigators design a multicentre randomized placebo-controlled clinical trial over 12 months. The aim is to determine if MTX can relieve symptom and reduce effusion-synovitis in patients with advanced knee OA. The investigators will recruit 200 participants who are in the advanced stage of symptomatic knee OA with effusion-synovitis grade of ≥ 2 (assessed by MRI). Participants will be randomly allocated to MTX group (start from 5 mg per week for the first two weeks and increase to 10 mg per week for the second two weeks and 15 mg per week for the remaining period if tolerated) or placebo group. Intention to treat and per protocol analyses of primary and secondary outcomes will be performed.

Eligibility criteria: Inclusion Criteria:

* Meet the America College of Rheumatology (ACR) criteria for clinical knee OA assessed by a rheumatologist
* Knee pain, visual analogue scale (VAS) pain at least 40mm
* Kellgren-Lawrence(K-L) grade of 2-4
* Physical examination showed signs of inflammation (at least 2 of the following 4 clinical signs of inflammation: warmth around the joint; tenderness around joint margin; articular cavity effusion; swelling of soft tissue around the knee joint)
* MRI evaluated effusion synovitis grade of ≥ 2
* Capable of understanding the study requirements and willing to cooperate with study instructions, and voluntarily sign informed consent

Exclusion Criteria:

* Inflammatory arthritis (such as gout, reactive arthritis, rheumatoid arthritis, psoriatic arthritis, seronegative spondyloarthropathy), systemic lupus erythematosus
* Knee surgery or arthroscopic examinations were performed or planned within one year, Severe valgus knee deformity (angle of genu valgum \> 30°) or previous traumatic history
* MRI contraindications
* Intra-articular injection, intramuscular injection or oral glucocorticoid were used within the last 4 weeks
* Other anti-synovitis agents (such as hydroxychloroquine and sulfasalazine) were applied in the past 3 months
* Clinical significant conditions, such as (but not limited to) active malignant tumor, abnormal renal function (assessed by GFR), hepatic abnormalities \[active hepatitis B, hepatitis C, abnormal liver function (ALT is more than twice the upper limit)\], respiratory diseases (lung infection, pulmonary fibrosis), hematological changes (e.g white blood cell (WBC) count \< 4 x 10\^9 /L, platelet \< 100 x 10\^9 /L or hemoglobin \< 100 g/L), serious diseases of gastrointestinal, endocrine, heart, nerve or brain assessed by clinical physicians
* Infectious history such as HIV infection
* Hypersensitivity to methotrexate
* Pregnant and Lactating women

Primary outcomes:
measure: Effusion-synovitis
timeFrame: 12 months
measure: VAS knee pain
timeFrame: 12 months
Secondary outcomes:
measure: Infrapatellar fat pad (IPFP) signal intensity alteration
timeFrame: 12 months
measure: Western Ontario and McMaster Universities Index (WOMAC) total score
timeFrame: 12 months
measure: Outcome Measures in Rheumatology Arthritis Clinical Trials-Osteoarthritis Research Society International (OMERACT-OARSI) responders
timeFrame: 12 months
Other outcomes:
Locations:
city: Hefei
country: China
facility: The 1st Affiliated Hospital of Anhui Medical University
state: Anhui
city: Beijing
country: China
facility: Beijing Hospital
state: Guangdong
city: Guangzhou
country: China
facility: Zhujiang Hospital
state: Guangdong
city: Guangzhou
country: China
facility: The Third Affiliated Hospital of Sun Yat-sen University
state: Guangdong
city: Guanzhou
country: China
facility: Second People's Hospital of Guangdong Province
state: Guangdong
city: Qingyuan
country: China
facility: Qingyuan People's Hospital
state: Guangdong
city: Shenzhen
country: China
facility: The Third Hospital of Shenzhen
state: Guangdong
city: Zhanjiang
country: China
facility: Central People's Hospital of Zhanjiang
state: Guangdong
city: Beijing
country: China
facility: Peking University People's Hospital
city: Beijing
country: China
facility: Xuanwu Hospital Capital Medical University
city: Beijing
country: China
facility: Peking Union Medical College University
Study officials:
affiliation: Clinical Research Center of Zhujiang Hospital
name: Changhai Ding, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Zhu Z, Yu Q, Leng X, Han W, Li Z, Huang C, Gu J, Zhao Y, Wang K, Li T, Mei Y, Xu J, Zhang Z, Hunter D, Cicuttini F, Zeng X, Ding C. Can low-dose methotrexate reduce effusion-synovitis and symptoms in patients with mid- to late-stage knee osteoarthritis? Study protocol for a randomised, double-blind, and placebo-controlled trial. Trials. 2020 Sep 16;21(1):795. doi: 10.1186/s13063-020-04687-3.