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

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ClinicalTrials.gov Identifier: NCT03815448
Recruitment Status : Not yet recruiting
First Posted : January 24, 2019
Last Update Posted : March 13, 2019
Sponsor:
Collaborators:
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

Tracking Information
First Submitted Date  ICMJE January 21, 2019
First Posted Date  ICMJE January 24, 2019
Last Update Posted Date March 13, 2019
Estimated Study Start Date  ICMJE March 2019
Estimated Primary Completion Date December 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 21, 2019)
  • 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.
  • 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".
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03815448 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: January 23, 2019)
  • 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.
  • 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.
  • 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: January 21, 2019)
  • 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.
  • 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 funtion is worse.
  • 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.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Methotrexate in the Treatment of Advanced Knee Osteoarthritis With Effusion-synovitis
Official Title  ICMJE A Randomized, Double-blind, Placebo-controlled Clinical Trial of Methotrexate (MTX) in the Treatment of Advanced Knee Osteoarthritis With Effusion-synovitis
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE
  • Knee Osteoarthritis
  • Effusion Synovial
  • Knee Pain
Intervention  ICMJE
  • 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
  • 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.
Study Arms  ICMJE
  • Experimental: Methotrexate
    Methotrexate 2.5mg/ tablet, oral, once a week, 2-6 tablets each time
    Intervention: Drug: Methotrexate
  • Placebo Comparator: Placebo
    Placebo 2.5mg/ tablet,oral,once a week,2-6 tablets each time
    Intervention: Other: Placebo
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Not yet recruiting
Estimated Enrollment  ICMJE
 (submitted: January 21, 2019)
200
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 2020
Estimated Primary Completion Date December 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 45 Years to 70 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Zhaohua Zhu, MD +8615626060171 zhaohuaz@utas.edu.au
Contact: Youling Xu, RN +8618210623686 xuyoulinghao@163.com
Listed Location Countries  ICMJE China
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03815448
Other Study ID Numbers  ICMJE 2018-FSMYK-001
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Ding Changhai, Zhujiang Hospital
Study Sponsor  ICMJE Zhujiang Hospital
Collaborators  ICMJE
  • 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
Investigators  ICMJE
Principal Investigator: Changhai Ding, MD Clinical Research Center of Zhujiang Hospital
PRS Account Zhujiang Hospital
Verification Date March 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP