<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03815448</url>
  </required_header>
  <id_info>
    <org_study_id>2018-FSMYK-001</org_study_id>
    <nct_id>NCT03815448</nct_id>
  </id_info>
  <brief_title>Methotrexate in the Treatment of Advanced Knee Osteoarthritis With Effusion-synovitis</brief_title>
  <official_title>A Randomized, Double-blind, Placebo-controlled Clinical Trial of Methotrexate (MTX) in the Treatment of Advanced Knee Osteoarthritis With Effusion-synovitis</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Zhujiang Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Peking Union Medical College Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Third Affiliated Hospital, Sun Yat-Sen University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Beijing Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Xuanwu Hospital, Beijing</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>The First Affiliated Hospital of Anhui Medical University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>The Second People's Hospital of GuangDong Province</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Peking University People's Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Shenzhen Third People's Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Central People's Hospital of Zhanjiang</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Zhujiang Hospital</source>
  <oversight_info>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This multicentre randomized placebo-controlled clinical trial aims to evaluate whether&#xD;
      methotrexate (MTX) has effects of relieving symptoms and reducing inflammation on advanced&#xD;
      knee osteoarthritis (OA) with inflammatory phenotype. Participants will be randomly allocated&#xD;
      to either MTX group or placebo group receiving MTX or placebo once a week. The primary&#xD;
      outcomes are effusion-synovitis volume measured by magnetic resonance imaging (MRI) and knee&#xD;
      pain assessed by visual analogue scale (VAS).&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      OA is a common chronic musculoskeletal disease in middle-aged and elderly people, which is&#xD;
      characterized by loss of articular cartilage and other structural damage of joints.&#xD;
      Currently, there is no effective treatment to reduce disease severity and progression of knee&#xD;
      OA, particularly in mid to late-stages. Analgesics and anti-inflammatory drugs can only have&#xD;
      effects in a short time, with obvious side effects, and are not effective for all patients.&#xD;
      In the late stage, most patients are performed with arthroplasty. However, arthroplasty is&#xD;
      expensive and has high technical requirements for surgeons. Therefore, it is urgent to find&#xD;
      effective drugs or means to control the symptoms and disease progression of knee OA.&#xD;
&#xD;
      Due to different etiologies, OA may have different clinical phenotypes, one of which is&#xD;
      mainly manifested by synovitis and is common in patients with advanced OA. Pathological&#xD;
      studies have shown that OA synovitis is significantly related to adjacent cartilage lesions,&#xD;
      and its pathological changes were similar to rheumatoid arthritis (RA), but the degree of the&#xD;
      latter is relatively mild. MTX can alleviate joint inflammation and delay joint structural&#xD;
      damage. In patients with rheumatoid arthritis, MTX can reduce suprapatellar bursa synovitis&#xD;
      by 35%, inhibit the inflammatory response of synovial tissue, including reducing the number&#xD;
      of macrophage, inhibiting the expression of intercellular adhesion molecule -1, interleukin&#xD;
      (IL)-1, tumour necrosis factor (TNF)-α and C-reactive protein (CRP), and even reduce bone&#xD;
      marrow lesions (BMLs) and synovitis in very early stages. In patients with early-stage&#xD;
      undifferentiated arthritis, MTX treatment for two months can significantly reduce synovitis&#xD;
      and exudation, alleviate BMLs and reduce serum CRP level. Chronic calcium pyrophosphate&#xD;
      deposition disease is a non-autoimmunity inflammatory arthritis which can be followed by more&#xD;
      severe OA. After 6-81 months of treatment with MTX (5-20 mg/week), the pain intensity,&#xD;
      swelling and the number of involved joints were significantly decreased. Based on all the&#xD;
      evidence as discussed above, MTX may have beneficial effects on OA via a variety of&#xD;
      mechanisms, including reduction of synovitis and effusion, and decreases in inflammatory&#xD;
      cytokines.&#xD;
&#xD;
      The investigators design a multicentre randomized placebo-controlled clinical trial over 12&#xD;
      months. The aim is to determine if MTX can relieve symptom and reduce effusion-synovitis in&#xD;
      patients with advanced knee OA. The investigators will recruit 200 participants who are in&#xD;
      the advanced stage of symptomatic knee OA with effusion-synovitis grade of ≥ 2 (assessed by&#xD;
      MRI). Participants will be randomly allocated to MTX group (start from 5 mg per week for the&#xD;
      first two weeks and increase to 10 mg per week for the second two weeks and 15 mg per week&#xD;
      for the remaining period if tolerated) or placebo group. Intention to treat and per protocol&#xD;
      analyses of primary and secondary outcomes will be performed.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">July 24, 2019</start_date>
  <completion_date type="Anticipated">December 2022</completion_date>
  <primary_completion_date type="Anticipated">December 2022</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Triple (Participant, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Effusion-synovitis</measure>
    <time_frame>12 months</time_frame>
    <description>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.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>VAS knee pain</measure>
    <time_frame>12 months</time_frame>
    <description>Knee pain will be assessed by a 100mm VAS with terminal descriptors of &quot;no pain&quot; and &quot;worst pain possible&quot;.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Infrapatellar fat pad (IPFP) signal intensity alteration</measure>
    <time_frame>12 months</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Western Ontario and McMaster Universities Index (WOMAC) total score</measure>
    <time_frame>12 months</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Outcome Measures in Rheumatology Arthritis Clinical Trials-Osteoarthritis Research Society International (OMERACT-OARSI) responders</measure>
    <time_frame>12 months</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">215</enrollment>
  <condition>Knee Osteoarthritis</condition>
  <condition>Effusion Synovial</condition>
  <condition>Knee Pain</condition>
  <arm_group>
    <arm_group_label>Methotrexate</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Methotrexate 2.5mg/ tablet, oral, once a week, 2-6 tablets each time</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Placebo 2.5mg/ tablet,oral,once a week,2-6 tablets each time</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Methotrexate</intervention_name>
    <description>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.</description>
    <arm_group_label>Methotrexate</arm_group_label>
    <other_name>MTX</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>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.</description>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Meet the America College of Rheumatology (ACR) criteria for clinical knee OA assessed&#xD;
             by a rheumatologist&#xD;
&#xD;
          -  Knee pain, visual analogue scale (VAS) pain at least 40mm&#xD;
&#xD;
          -  Kellgren-Lawrence(K-L) grade of 2-4&#xD;
&#xD;
          -  Physical examination showed signs of inflammation (at least 2 of the following 4&#xD;
             clinical signs of inflammation: warmth around the joint; tenderness around joint&#xD;
             margin; articular cavity effusion; swelling of soft tissue around the knee joint)&#xD;
&#xD;
          -  MRI evaluated effusion synovitis grade of ≥ 2&#xD;
&#xD;
          -  Capable of understanding the study requirements and willing to cooperate with study&#xD;
             instructions, and voluntarily sign informed consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Inflammatory arthritis (such as gout, reactive arthritis, rheumatoid arthritis,&#xD;
             psoriatic arthritis, seronegative spondyloarthropathy), systemic lupus erythematosus&#xD;
&#xD;
          -  Knee surgery or arthroscopic examinations were performed or planned within one year,&#xD;
             Severe valgus knee deformity (angle of genu valgum &gt; 30°) or previous traumatic&#xD;
             history&#xD;
&#xD;
          -  MRI contraindications&#xD;
&#xD;
          -  Intra-articular injection, intramuscular injection or oral glucocorticoid were used&#xD;
             within the last 4 weeks&#xD;
&#xD;
          -  Other anti-synovitis agents (such as hydroxychloroquine and sulfasalazine) were&#xD;
             applied in the past 3 months&#xD;
&#xD;
          -  Clinical significant conditions, such as (but not limited to) active malignant tumor,&#xD;
             abnormal renal function (assessed by GFR), hepatic abnormalities [active hepatitis B,&#xD;
             hepatitis C, abnormal liver function (ALT is more than twice the upper limit)],&#xD;
             respiratory diseases (lung infection, pulmonary fibrosis), hematological changes (e.g&#xD;
             white blood cell (WBC) count &lt; 4 x 10^9 /L, platelet &lt; 100 x 10^9 /L or hemoglobin &lt;&#xD;
             100 g/L), serious diseases of gastrointestinal, endocrine, heart, nerve or brain&#xD;
             assessed by clinical physicians&#xD;
&#xD;
          -  Infectious history such as HIV infection&#xD;
&#xD;
          -  Hypersensitivity to methotrexate&#xD;
&#xD;
          -  Pregnant and Lactating women&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>45 Years</minimum_age>
    <maximum_age>70 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Changhai Ding, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Clinical Research Center of Zhujiang Hospital</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>The 1st Affiliated Hospital of Anhui Medical University</name>
      <address>
        <city>Hefei</city>
        <state>Anhui</state>
        <zip>230000</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Zhujiang Hospital</name>
      <address>
        <city>Guangzhou</city>
        <state>Guangdong</state>
        <zip>510280</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Peking University People's Hospital</name>
      <address>
        <city>Beijing</city>
        <zip>100044</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Xuanwu Hospital Capital Medical University</name>
      <address>
        <city>Beijing</city>
        <zip>100053</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Peking Union Medical College University</name>
      <address>
        <city>Beijing</city>
        <zip>10032</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>China</country>
  </location_countries>
  <verification_date>November 2022</verification_date>
  <study_first_submitted>January 21, 2019</study_first_submitted>
  <study_first_submitted_qc>January 21, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 24, 2019</study_first_posted>
  <last_update_submitted>November 4, 2022</last_update_submitted>
  <last_update_submitted_qc>November 4, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">November 9, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Zhujiang Hospital</investigator_affiliation>
    <investigator_full_name>Ding Changhai</investigator_full_name>
    <investigator_title>Director,Clinical Research Center</investigator_title>
  </responsible_party>
  <keyword>Methotrexate</keyword>
  <keyword>knee osteoarthritis</keyword>
  <keyword>Magnetic Resonance imaging</keyword>
  <keyword>pain</keyword>
  <keyword>synovitis</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Osteoarthritis</mesh_term>
    <mesh_term>Osteoarthritis, Knee</mesh_term>
    <mesh_term>Synovitis</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Methotrexate</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03815448
org study id: 2018-FSMYK-001
nct id: NCT03815448
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
is fda regulated drug: No
is fda regulated device: No
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).
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.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Triple (Participant, Investigator, Outcomes Assessor)
measure: Effusion-synovitis
time frame: 12 months
description: 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.
measure: VAS knee pain
time frame: 12 months
description: Knee pain will be assessed by a 100mm VAS with terminal descriptors of "no pain" and "worst pain possible".
measure: Infrapatellar fat pad (IPFP) signal intensity alteration
time frame: 12 months
description: 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.
measure: Western Ontario and McMaster Universities Index (WOMAC) total score
time frame: 12 months
description: 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.
measure: Outcome Measures in Rheumatology Arthritis Clinical Trials-Osteoarthritis Research Society International (OMERACT-OARSI) responders
time frame: 12 months
description: 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.
arm group label: Methotrexate
arm group type: Experimental
description: Methotrexate 2.5mg/ tablet, oral, once a week, 2-6 tablets each time
arm group label: Placebo
arm group type: Placebo Comparator
description: Placebo 2.5mg/ tablet,oral,once a week,2-6 tablets each time
intervention type: Drug
intervention name: Methotrexate
description: 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.
arm group label: Methotrexate
other name: MTX
intervention type: Other
intervention name: Placebo
description: 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 group label: Placebo
criteria: 
gender: All
minimum age: 45 Years
maximum age: 70 Years
healthy volunteers: No
last name: Changhai Ding, MD
role: Principal Investigator
affiliation: Clinical Research Center of Zhujiang Hospital
facility: 
facility: 
facility: 
facility: 
facility: 
country: China
responsible party type: Principal Investigator
investigator affiliation: Zhujiang Hospital
investigator full name: Ding Changhai
investigator title: Director,Clinical Research Center
mesh term: Osteoarthritis
mesh term: Osteoarthritis, Knee
mesh term: Synovitis
mesh term: Methotrexate