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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT03815448
Recruitment Status : Not yet recruiting
First Posted : January 24, 2019
Last Update Posted : March 13, 2019
Peking Union Medical College Hospital
Third Affiliated Hospital, Sun Yat-Sen University
Beijing Hospital
Xuanwu Hospital, Beijing
First Affiliated Hospital of Harbin Medical University
The First Affiliated Hospital of Anhui Medical University
The Second People's Hospital of GuangDong Province
Peking University People's Hospital
Information provided by (Responsible Party):
Ding Changhai, Zhujiang Hospital

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 Not Applicable

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.

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Study Type : Interventional  (Clinical Trial)
Estimated 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
Estimated Study Start Date : March 2019
Estimated Primary Completion Date : December 2020
Estimated Study Completion Date : December 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Osteoarthritis

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 Name: 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.

Primary Outcome Measures :
  1. Effusion-synovitis [ Time Frame: 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.

  2. VAS knee pain [ Time Frame: 12 months ]
    Knee pain will be assessed by a 100mm VAS with terminal descriptors of "no pain" and "worst pain possible".

Secondary Outcome Measures :
  1. Infrapatellar fat pad (IPFP) signal intensity alteration [ Time Frame: 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.

  2. Western Ontario and McMaster Universities Index (WOMAC) total score [ Time Frame: 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.

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

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   45 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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 and arthroscopic examinations were performed or planned within one year, malalignment or previous traumatic history
  • MRI contraindications
  • Intra-articular injection, intramuscular injection and 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, 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), diseases of gastrointestinal, endocrine, heart, nerve or brain
  • Infectious history such as herpes zoster and HIV infection
  • Hypersensitivity to methotrexate
  • Pregnant and Lactating women

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT03815448

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Contact: Zhaohua Zhu, MD +8615626060171
Contact: Youling Xu, RN +8618210623686

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China, Guangdong
Zhujiang Hospital Not yet recruiting
Guangzhou, Guangdong, China, 510280
Contact: Zhaohua Zhu, PhD    +8615626060171   
Sponsors and Collaborators
Zhujiang Hospital
Peking Union Medical College Hospital
Third Affiliated Hospital, Sun Yat-Sen University
Beijing Hospital
Xuanwu Hospital, Beijing
First Affiliated Hospital of Harbin Medical University
The First Affiliated Hospital of Anhui Medical University
The Second People's Hospital of GuangDong Province
Peking University People's Hospital
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Principal Investigator: Changhai Ding, MD Clinical Research Center of Zhujiang Hospital

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Responsible Party: Ding Changhai, Director,Clinical Research Center, Zhujiang Hospital Identifier: NCT03815448     History of Changes
Other Study ID Numbers: 2018-FSMYK-001
First Posted: January 24, 2019    Key Record Dates
Last Update Posted: March 13, 2019
Last Verified: March 2019

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Ding Changhai, Zhujiang Hospital:
knee osteoarthritis
Magnetic Resonance imaging
Additional relevant MeSH terms:
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Osteoarthritis, Knee
Joint Diseases
Musculoskeletal Diseases
Rheumatic Diseases
Abortifacient Agents, Nonsteroidal
Abortifacient Agents
Reproductive Control Agents
Physiological Effects of Drugs
Antimetabolites, Antineoplastic
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Dermatologic Agents
Enzyme Inhibitors
Folic Acid Antagonists
Immunosuppressive Agents
Immunologic Factors
Antirheumatic Agents
Nucleic Acid Synthesis Inhibitors