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Knee OsteoarthritisNCT03815448

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

A study testing Methotrexate in people with Knee Osteoarthritis and Effusion Synovial, run by Zhujiang Hospital at 11 sites in China.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 45 to 70 years
Conditions the study is for
Knee Osteoarthritis, Effusion Synovial, Knee Pain
What is being tested?
Methotrexate
Type of treatment
Pill or oral medicine
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
215 participants
Where
11 sitesChina
Study dates
18 Jul 2019to 1 Dec 2023
Phase
Interventional
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 45 to 70 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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

Who cannot join

  • 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
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  • Infectious history such as HIV infection
  • Hypersensitivity to methotrexate
  • Pregnant and Lactating women

Trial locations and contacts

11 sites in 1 country.

11 sites in 1 country

China11 sites

  • Beijing Hospital

    Beijing, Guangdong

  • Peking University People's Hospital

    Beijing, 100044

  • Xuanwu Hospital Capital Medical University

    Beijing, 100053

  • Peking Union Medical College University

    Beijing, 10032

  • Zhujiang Hospital

    Guangzhou, Guangdong, 510280

  • The Third Affiliated Hospital of Sun Yat-sen University

    Guangzhou, Guangdong

  • Second People's Hospital of Guangdong Province

    Guanzhou, Guangdong

  • The 1st Affiliated Hospital of Anhui Medical University

    Hefei, Anhui, 230000

  • Qingyuan People's Hospital

    Qingyuan, Guangdong

  • The Third Hospital of Shenzhen

    Shenzhen, Guangdong

  • Central People's Hospital of Zhanjiang

    Zhanjiang, Guangdong

Other trials in China

About this study

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

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).

Read the 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.

Being tested
Methotrexate, Placebo
Keywords
Methotrexate, knee osteoarthritis, Magnetic Resonance imaging, pain, synovitis
Medical subject headings
Osteoarthritis, Knee, Hydrarthrosis, Pain, Synovitis

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • MethotrexateDrug

    Also called MTX

    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.

  • PlaceboOther

    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.

Study groups in NCT03815448
Study groupRoleWhat they receive
MethotrexateExperimentalMethotrexate 2.5mg/ tablet, oral, once a week, 2-6 tablets each time
Receives: Drug: Methotrexate
PlaceboPlacebo comparatorPlacebo 2.5mg/ tablet,oral,once a week,2-6 tablets each time
Receives: Other: Placebo

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Effusion-synovitis

    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.

    Measured: 12 months

  2. VAS knee pain

    Knee pain will be assessed by a 100mm VAS with terminal descriptors of "no pain" and "worst pain possible".

    Measured: 12 months

Secondary outcomes (3)

  1. Infrapatellar fat pad (IPFP) signal intensity alteration

    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.

    Measured: 12 months

  2. Western Ontario and McMaster Universities Index (WOMAC) total score

    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.

    Measured: 12 months

  3. Outcome Measures in Rheumatology Arthritis Clinical Trials-Osteoarthritis Research Society International (OMERACT-OARSI) responders

    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.

    Measured: 12 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted24 Jan 2019
  2. Study start18 Jul 2019
  3. Primary completion1 Nov 2023
  4. Study completion1 Dec 2023

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase N/A
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Triple blind
Who is masked
Participant, Investigator, Outcomes assessor
Enrolment
215 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03815448
Sponsor's protocol ID
2018-FSMYK-001
Status last verified
Feb 2024
First submitted
21 Jan 2019
Last updated
28 Feb 2024
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No

Publications

  • 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.

    PubMed 40455462

  • 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.

    PubMed 39757775

  • 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.

    PubMed 32938470

Questions about this trial

What is this clinical trial studying?

A study testing Methotrexate in people with Knee Osteoarthritis and Effusion Synovial, run by Zhujiang Hospital at 11 sites in China.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 6 inclusion and 9 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 28 Feb 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 11 sites in China. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Effusion-synovitis (time frame: 12 months). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03815448, which also lists 3 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 28 Feb 2024.

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