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

Sponsor

Zhujiang Hospital (Other)

Overall Status

Recruiting

CT.gov ID

NCT03815448

Collaborator

Peking Union Medical College Hospital (Other), Third Affiliated Hospital, Sun Yat-Sen University (Other), Beijing Hospital (Other), Xuanwu Hospital, Beijing (Other), First Affiliated Hospital of Harbin Medical University (Other), The First Affiliated Hospital of Anhui Medical University (Other), The Second People's Hospital of GuangDong Province (Other), Peking University People's Hospital (Other)

200

Enrollment

Locations

Arms

40.3

Anticipated Duration (Months)

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

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).

Condition or Disease	Intervention/Treatment	Phase
Knee Osteoarthritis Effusion Synovial Knee Pain	Drug: Methotrexate Other: Placebo	N/A

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

200 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Triple (Participant, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

A Randomized, Double-blind, Placebo-controlled Clinical Trial of Methotrexate (MTX) in the Treatment of Advanced Knee Osteoarthritis With Effusion-synovitis

Actual Study Start Date :

Jul 24, 2019

Anticipated Primary Completion Date :

Oct 1, 2022

Anticipated Study Completion Date :

Dec 1, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Methotrexate Methotrexate 2.5mg/ tablet, oral, once a week, 2-6 tablets each time	Drug: 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. Other Names: MTX
Placebo Comparator: Placebo Placebo 2.5mg/ tablet,oral,once a week,2-6 tablets each time	Other: 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.

Arm

Intervention/Treatment

Experimental: Methotrexate

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

Drug: 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.

Other Names:

MTX

Placebo Comparator: Placebo

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

Other: 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.

Outcome Measures

Primary Outcome Measures

Effusion-synovitis [12 months]
Knee effusion-synovitis volume/maximal area at suprapatellar pouch will be measured, and severity will be scored from 0-3 in terms of the estimated maximal distension of the synovial cavity by assessing the amount of intra-articular fluid-equivalent signal on T2-weighted MRI. Effusion at central portion, posterior femoral recess and subpopliteal recess will also be assessed.
VAS knee pain [12 months]
Knee pain will be assessed by a 100mm VAS with terminal descriptors of "no pain" and "worst pain possible".

Secondary Outcome Measures

Infrapatellar fat pad (IPFP) signal intensity alteration [12 months]
Signal intensity alterations with IPFP was defined as discrete areas of increased signal. Standard deviation of IPFP signal intensity and Clustering Factor was used to represent the signal intensity alteration with IPFP.
Western Ontario and McMaster Universities Index (WOMAC) total score [12 months]
WOMAC is widely used in the evaluation of Hip and Knee Osteoarthritis. It is a self-administered questionnaire consisting of 24 items divided into 3 subscales: pain (5 items), stiffness (2 items) and physical function (17 items).The score is higher, the knee function is worse.
Outcome Measures in Rheumatology Arthritis Clinical Trials-Osteoarthritis Research Society International (OMERACT-OARSI) responders [12 months]
The OMERACT-OARSI consists outcome measures in rheumatology arthritis clinical trials including pain, functional impairment and patient's global assessment. For each of these domains, a response was defined by both relative and an absolute change.

Eligibility Criteria

Criteria

Ages Eligible for Study:

45 Years to 70 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	The 1st Affiliated Hospital of Anhui Medical University	Hefei	Anhui	China	230000
2	Zhujiang Hospital	Guangzhou	Guangdong	China	510280
3	Peking University People's Hospital	Beijing		China	100044
4	Xuanwu Hospital Capital Medical University	Beijing		China	100053
5	Peking Union Medical College University	Beijing		China	10032