Methotrexate in the Treatment of Advanced Knee Osteoarthritis With Effusion-synovitis

NCT ID: NCT03815448

Last Updated: 2024-02-28

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 215 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-07-18
• Study Completion Date: 2023-12-01

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.

Conditions

Knee Osteoarthritis; Effusion Synovial; Knee Pain

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

Methotrexate

Methotrexate 2.5mg/ tablet, oral, once a week, 2-6 tablets each time

Group Type: EXPERIMENTAL

Methotrexate

Intervention Type: DRUG

Participants randomized to methotrexate group will receive active drug, methotrexate. Starting from 5 mg/week, the dosage will be adjusted to 10 mg/week if the participants can tolerate for 2 weeks. After 2 weeks, the dosage will be adjusted to 15 mg/week until the end of the study if the participants can tolerate.

Placebo

Placebo 2.5mg/ tablet,oral,once a week,2-6 tablets each time

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: OTHER

Participants randomized to placebo group will receive placebo tablets. Starting from 5 mg/week for 2 weeks, the dosage will be adjusted to 10 mg/week; after 2 weeks, the dosage will be adjusted to 15 mg/week until the end of the study.

Interventions

Methotrexate

Participants randomized to methotrexate group will receive active drug, methotrexate. Starting from 5 mg/week, the dosage will be adjusted to 10 mg/week if the participants can tolerate for 2 weeks. After 2 weeks, the dosage will be adjusted to 15 mg/week until the end of the study if the participants can tolerate.

Intervention Type: DRUG

Placebo

Participants randomized to placebo group will receive placebo tablets. Starting from 5 mg/week for 2 weeks, the dosage will be adjusted to 10 mg/week; after 2 weeks, the dosage will be adjusted to 15 mg/week until the end of the study.

Intervention Type: OTHER

Other Intervention Names

MTX

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

• Minimum Eligible Age: 45 Years
• Maximum Eligible Age: 70 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Peking Union Medical College Hospital

OTHER

Sponsor Role: collaborator

Third Affiliated Hospital, Sun Yat-Sen University

OTHER

Sponsor Role: collaborator

Beijing Hospital

OTHER_GOV

Sponsor Role: collaborator

Xuanwu Hospital, Beijing

OTHER

Sponsor Role: collaborator

The First Affiliated Hospital of Anhui Medical University

OTHER

Sponsor Role: collaborator

The Second People's Hospital of GuangDong Province

OTHER

Sponsor Role: collaborator

Peking University People's Hospital

OTHER

Sponsor Role: collaborator

Shenzhen Third People's Hospital

OTHER

Sponsor Role: collaborator

Central People's Hospital of Zhanjiang

OTHER

Sponsor Role: collaborator

Qingyuan People's Hospital

OTHER

Sponsor Role: collaborator

Zhujiang Hospital

OTHER

Sponsor Role: lead

Responsible Party

Ding Changhai

Director,Clinical Research Center

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Changhai Ding, MD

Role: PRINCIPAL_INVESTIGATOR

Clinical Research Center of Zhujiang Hospital

Locations

The 1st Affiliated Hospital of Anhui Medical University

Hefei, Anhui, China

Beijing Hospital

Beijing, Guangdong, China

Zhujiang Hospital

Guangzhou, Guangdong, China

The Third Affiliated Hospital of Sun Yat-sen University

Guangzhou, Guangdong, China

Second People's Hospital of Guangdong Province

Guanzhou, Guangdong, China

Qingyuan People's Hospital

Qingyuan, Guangdong, China

The Third Hospital of Shenzhen

Shenzhen, Guangdong, China

Central People's Hospital of Zhanjiang

Zhanjiang, Guangdong, China

Peking University People's Hospital

Beijing, , China

Xuanwu Hospital Capital Medical University

Beijing, , China

Peking Union Medical College University

Beijing, , China

Countries

China

References

Zhu Z, Yu Q, Leng X, Xu J, Ren L, Wang K, Huang C, Pan Y, Zhao Y, Li T, Mei Y, Guan M, Li X, Zhang Z, Wu J, Chen Y, Qu Y, Zhu X, Liao Q, Wang Z, Liao Z, Xi Y, Deng W, Wang K, Zhu T, Zhang Y, Gao L, Zhou X, Han W, Ruan G, Zhang Y, Cao P, Gao P, Chen H, Dang Q, Cicuttini FM, Hunter DJ, Li Z, Zeng X, Ding C. Low-Dose Methotrexate for the Treatment of Inflammatory Knee Osteoarthritis: A Randomized Clinical Trial. JAMA Intern Med. 2025 Jul 1;185(7):808-816. doi: 10.1001/jamainternmed.2025.1359.

Reference Type: DERIVED

PMID: 40455462 (View on PubMed)

Liu Q, Ren J, Zhang W, Liang T, Wang Z, Xie S, Li Y, Hou J, Wang K, He R. Measured Resection as Gap Balance Method in Mobile-Bearing Medial Unicompartmental Knee Arthroplasty: A Randomized Controlled Trial. Orthop Surg. 2025 Feb;17(2):603-613. doi: 10.1111/os.14346. Epub 2025 Jan 5.

Reference Type: DERIVED

PMID: 39757775 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 32938470 (View on PubMed)

Other Identifiers

2018-FSMYK-001

Identifier Type: -

Identifier Source: org_study_id