NCT03815448

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).

Trial Health

87
On Track

Trial Health Score

Automated assessment based on enrollment pace, timeline, and geographic reach

Enrollment
215

participants targeted

Target at P75+ for not_applicable knee-osteoarthritis

Timeline
Completed

Started Jul 2019

Longer than P75 for not_applicable knee-osteoarthritis

Geographic Reach
1 country

11 active sites

Status
completed

Health score is calculated from publicly available data and should be used for screening purposes only.

Trial Relationships

Click on a node to explore related trials.

Study Timeline

Key milestones and dates

First Submitted

Initial submission to the registry

January 21, 2019

Completed
3 days until next milestone

First Posted

Study publicly available on registry

January 24, 2019

Completed
6 months until next milestone

Study Start

First participant enrolled

July 18, 2019

Completed
4.3 years until next milestone

Primary Completion

Last participant's last visit for primary outcome

November 1, 2023

Completed
1 month until next milestone

Study Completion

Last participant's last visit for all outcomes

December 1, 2023

Completed
Last Updated

February 28, 2024

Status Verified

February 1, 2024

Enrollment Period

4.3 years

First QC Date

January 21, 2019

Last Update Submit

February 25, 2024

Conditions

Knee OsteoarthritisEffusion SynovialKnee Pain

Keywords

Methotrexateknee osteoarthritisMagnetic Resonance imagingpainsynovitis

Outcome Measures

Primary Outcomes (2)

  • 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.

    12 months

  • VAS knee pain

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

    12 months

Secondary Outcomes (3)

  • Infrapatellar fat pad (IPFP) signal intensity alteration

    12 months

  • Western Ontario and McMaster Universities Index (WOMAC) total score

    12 months

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

    12 months

Study Arms (2)

Methotrexate

EXPERIMENTAL

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

Drug: Methotrexate

Placebo

PLACEBO COMPARATOR

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

Other: Placebo

Interventions

MethotrexateDRUG

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.

Also known as: MTX
Methotrexate
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.

Placebo

Eligibility Criteria

Age45 Years - 70 Years
Sexall
Healthy VolunteersNo
Age GroupsAdult (18-64), Older Adult (65+)

You may qualify if:

  • 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

You may not qualify if:

  • 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

Contact the study team to confirm eligibility.

Sponsors & Collaborators

Study Sites (11)

The 1st Affiliated Hospital of Anhui Medical University

Hefei, Anhui, 230000, China

Location

Beijing Hospital

Beijing, Guangdong, China

Location

Zhujiang Hospital

Guangzhou, Guangdong, 510280, China

Location

The Third Affiliated Hospital of Sun Yat-sen University

Guangzhou, Guangdong, China

Location

Second People's Hospital of Guangdong Province

Guanzhou, Guangdong, China

Location

Qingyuan People's Hospital

Qingyuan, Guangdong, China

Location

The Third Hospital of Shenzhen

Shenzhen, Guangdong, China

Location

Central People's Hospital of Zhanjiang

Zhanjiang, Guangdong, China

Location

Peking University People's Hospital

Beijing, 100044, China

Location

Xuanwu Hospital Capital Medical University

Beijing, 100053, China

Location

Peking Union Medical College University

Beijing, 10032, China

Location

Related Publications (3)

  • 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.

    PMID: 40455462DERIVED

  • 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.

    PMID: 39757775DERIVED

  • 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.

    PMID: 32938470DERIVED

MeSH Terms

Conditions

Osteoarthritis, KneeHydrarthrosisPainSynovitis

Interventions

Methotrexate

Condition Hierarchy (Ancestors)

OsteoarthritisArthritisJoint DiseasesMusculoskeletal DiseasesRheumatic DiseasesNeurologic ManifestationsSigns and SymptomsPathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

AminopterinPterinsPteridinesHeterocyclic Compounds, 2-RingHeterocyclic Compounds, Fused-RingHeterocyclic Compounds

Study Officials

  • Changhai Ding, MD

    Clinical Research Center of Zhujiang Hospital

    PRINCIPAL INVESTIGATOR

Study Design

Study Type
interventional
Phase
not applicable
Allocation
RANDOMIZED
Masking
TRIPLE
Who Masked
PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
Purpose
TREATMENT
Intervention Model
PARALLEL
Sponsor Type
OTHER
Responsible Party
PRINCIPAL INVESTIGATOR
PI Title
Director,Clinical Research Center

Study Record Dates

First Submitted

January 21, 2019

First Posted

January 24, 2019

Study Start

July 18, 2019

Primary Completion

November 1, 2023

Study Completion

December 1, 2023

Last Updated

February 28, 2024

Record last verified: 2024-02

Locations

CN(11)