<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/NCT04483466</url>
  </required_header>
  <id_info>
    <org_study_id>Chang_MARCH_JUNE2020</org_study_id>
    <nct_id>NCT04483466</nct_id>
  </id_info>
  <brief_title>Methotrexate Treatment of Arthritis Caused by Chikungunya Virus (MARCH)</brief_title>
  <official_title>Methotrexate Treatment of Arthritis Caused by Chikungunya Virus (MARCH): A Phase III Randomized Controlled Clinical Trial of the Efficacy of Methotrexate Monotherapy in the Treatment of Chronic Arthritis After Chikungunya Infection</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>George Washington University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>George Washington University</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      MARCH is the first randomized, double-blind, placebo-controlled evaluation of the efficacy&#xD;
      and pathologic mechanism determined by synovial biopsy of 6 months of methotrexate (n=100)&#xD;
      versus placebo (n=50) therapy for chronic chikungunya (CHIKV) arthritis in Colombia with the&#xD;
      option for open-label use of the medication for up to one year for all participants. Our&#xD;
      central hypothesis is that methotrexate will significantly decrease chronic CHIKV arthritis&#xD;
      disease severity compared to placebo via suppression of leukocyte accumulation in synovial&#xD;
      tissue and decreased expression of inflammatory cytokines from synovial macrophages and&#xD;
      fibroblast-like synoviocytes (FLS).&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      -  In the treatment group, participants will receive methotrexate 15mg by mouth/week with&#xD;
           optional for increase up to 20mg/week in non-responders and folic acid 1mg by mouth&#xD;
           daily for six months in Phase I.&#xD;
&#xD;
        -  In the control group, participants will receive placebo methotrexate tablets by&#xD;
           mouth/week with faux increase optional in non-responders and folic acid 1mg by mouth&#xD;
           daily for six months in Phase I.&#xD;
&#xD;
        -  In Phase II, patients may elect to stop taking the study drug or in those without&#xD;
           clinical remission transition to open label active treatment group for the following six&#xD;
           months.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Enrolling by invitation</overall_status>
  <start_date type="Actual">July 18, 2023</start_date>
  <completion_date type="Anticipated">August 30, 2027</completion_date>
  <primary_completion_date type="Anticipated">August 30, 2027</primary_completion_date>
  <phase>Phase 3</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>
    <intervention_model_description>In the treatment group, participants will receive methotrexate 15mg by mouth/week with optional for increase up to 20mg/week in non-responders and folic acid 1mg by mouth daily for six months in Phase I.&#xD;
In the control group, participants will receive placebo methotrexate tablets by mouth/week with faux increase optional in non-responders and folic acid 1mg by mouth daily for six months in Phase I.&#xD;
In Phase II, any patient may elect to stop taking the study drug or transition to open label active treatment group for the following six months if non-responder.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Double (Participant, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Efficacy of oral methotrexate treatment versus placebo for 6 months in chronic CHIKV arthritis.</measure>
    <time_frame>up to 6 months</time_frame>
    <description>An improvement in the Disease Activity Score-28 response. The DAS-28 is a composite measure including a tender and swollen joint joint of 28 joints, patient reported disease severity measures, and the c-reactive protein</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Inflammation in the synovial tissue measured by synovial inflammatory cell infiltration</measure>
    <time_frame>Up to 6 weeks</time_frame>
    <description>The investigators hypothesize that treatment with methotrexate versus placebo will decrease synovial macrophage and T-cell accumulation.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Inflammatory cytokine levels in synovial tissue</measure>
    <time_frame>Up to 6 weeks</time_frame>
    <description>The investigators hypothesize that treatment with methotrexate versus placebo will dampen production of pathogenic cytokines like with TNF, IL-6, and MCP-1</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">150</enrollment>
  <condition>Investigate the Effect(s) of Methotrexate Treatment on Arthritis Disease Severity</condition>
  <arm_group>
    <arm_group_label>Treatment with methotrexate</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>100 participants will be treated with methotrexate</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo methotrexate</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>50 will receive placebo</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Methotrexate</intervention_name>
    <description>Methotrexate is vibrant yellow-orange colored powder with physical properties of near insolubility in water formulated into methotrexate tablets containing an amount of methotrexate sodium equivalent to 2.5 mg of methotrexate and are round, convex, and yellow. The chemical name is N-[4-[[(2,4-diamino-6pteridinyl)methyl]methyl amino]benzoyl]-L-glutamic acid. Methotrexate is an anti-metabolite that is a folate antagonist that inhibits lymphocyte proliferation and functions as an immunosuppressant in arthritis.</description>
    <arm_group_label>Treatment with methotrexate</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Placebo</description>
    <arm_group_label>Placebo methotrexate</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Provision of signed and dated informed consent form.&#xD;
&#xD;
          2. Stated willingness to comply with all study procedures and availability for the&#xD;
             duration of the study.&#xD;
&#xD;
          3. Male or female, aged &gt;18 years&#xD;
&#xD;
          4. Ability to take oral medication and be willing to adhere to the methotrexate regimen&#xD;
&#xD;
          5. For females of reproductive potential: use of highly effective contraception for at&#xD;
             least 1 month prior to screening and agreement to use such a method during study&#xD;
             participation and for an additional 3 months after the end of methotrexate&#xD;
             administration.&#xD;
&#xD;
          6. For males of reproductive potential: use of condoms or other methods to ensure&#xD;
             effective contraception with partner.&#xD;
&#xD;
          7. Have a diagnosis of CHIKV by CHIKV IgM or IgG antibody.&#xD;
&#xD;
          8. The disease duration should be greater than 3 months (based on onset of symptoms).&#xD;
&#xD;
          9. Screen laboratory tests must meet the following criteria: Hemoglobin ≥ 9 g/dL, WBCs ≥&#xD;
             3.5 x 109 cells/L, Neutrophils ≥ 1.5 x 109 cells/L, Platelets ≥ 100 x 109 cells/L,&#xD;
             serum transaminase levels not exceeding 1.5 times the upper limit of normal, serum&#xD;
             creatinine ≤ 1.6 mg/dL, and negative for hepatitis B surface antigen and hepatitis C&#xD;
             antibodies.&#xD;
&#xD;
         10. Have a chest radiograph at screening that shows no clear evidence of malignancy or&#xD;
             active infection.&#xD;
&#xD;
         11. Have active moderate arthritis defined as at least 4 tender joints and at least one&#xD;
             joint with definite clinical synovitis (swelling). Joints that may be considered in&#xD;
             the count include the temporomandibular joints (0-2), sternoclavicular joints (0-2),&#xD;
             acromioclavicular joints (0-2), glenohumeral joints (0-2), elbows (0-2), wrists (0-2),&#xD;
             metacarpal phalangeal joints (0-10), finger proximal interphalangeal joints (0-10),&#xD;
             finger distal interphalangeal joints (0-8), hips (0-2), knees (0-2), ankles (0-2),&#xD;
             tarsus/midfoot (0-2), metatarsal phalangeal joints (0-10), toe proximal&#xD;
             interphalangeal joints (0-10).&#xD;
&#xD;
         12. Status-post complete Covid vaccination defined as at least 2 weeks after complete&#xD;
             vaccination series.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Pregnancy or lactation&#xD;
&#xD;
          2. Known allergic reactions to components of methotrexate or folic acid.&#xD;
&#xD;
          3. Treatment with another investigational drug or other intervention within 1 month.&#xD;
&#xD;
          4. History of chronic infection such as hepatitis and HIV. Patients with acute infection&#xD;
             will have enrollment deferred until the infection resolves.&#xD;
&#xD;
          5. Current signs or symptoms of uncontrolled renal, hepatic, hematologic,&#xD;
             gastrointestinal, endocrine, pulmonary, cardiac, neurologic or cerebral disease.&#xD;
&#xD;
          6. Patients with a current diagnosis of class III or IV CHF.&#xD;
&#xD;
          7. History of lymphoproliferative disease including lymphoma.&#xD;
&#xD;
          8. Overt or laboratory evidence of immunodeficiency syndromes.&#xD;
&#xD;
          9. Any opportunistic infections, including but not limited to evidence of active&#xD;
             cytomegalovirus, active Pneumocystis carinii, aspergillosis, histoplasmosis or&#xD;
             atypical mycobacterium infection, within the previous 6 months at screening visit.&#xD;
&#xD;
         10. History of substance abuse (drug or alcohol) within the previous 2 years.&#xD;
&#xD;
         11. Intra-articular, soft tissue or intra-muscular corticosteroid injection during the 4&#xD;
             weeks prior to screening.&#xD;
&#xD;
         12. History of prior use of methotrexate or biologic therapy.&#xD;
&#xD;
         13. Evidence of active infection with fever &gt;38°&#xD;
&#xD;
         14. Current use of any other disease modifying arthritis medication including but not&#xD;
             limited to sulfasalazine, methotrexate, hydroxychloroquine, leflunomide, or biologics&#xD;
             in the previous 2 months. Patients on stable doses of prednisone up to 10 mg per day&#xD;
             for at least 4 weeks prior to enrollment may participate. Non-steroidal&#xD;
             anti-inflammatories (NSAIDS) and acetaminophen are permitted for pain during the&#xD;
             study.&#xD;
&#xD;
         15. Hematuria or proteinuria on urinalysis.&#xD;
&#xD;
         16. The presence of anti-cyclic citrullinated peptide (Anti-CCP) antibodies &gt;2 times the&#xD;
             upper limit of normal.&#xD;
&#xD;
         17. For patients who participate in synovial biopsy substudy the following additional&#xD;
             exclusion criteria apply:&#xD;
&#xD;
        1. Known prior reactions or allergies to local anesthetics or antibiotics (specifically&#xD;
        bupivocaine, lidocaine, or cephalexin) 2. Preexisting advanced structural or functional&#xD;
        damage to joint of interest such as prior history of trauma requiring orthopedic surgery&#xD;
        and hardware placement, and presence of prosthetic devices (artificial joints, pacemakers,&#xD;
        other implantable devices) 3. History of diabetes, skin infections (cellulitis), bleeding&#xD;
        disorders, deep vein thrombosis, pulmonary embolism, history or active cancer of any kind&#xD;
        4. Use of blood thinners (anticoagulants) 5. History of or current chronic pain syndrome&#xD;
        such as fibromyalgia, chronic back pain, migraines, and history of current complex regional&#xD;
        pain syndrome, and /or current or past chronic opiate treatment 6. Significant other&#xD;
        comorbidities and /or medication use which in physician's clinical judgment may pause&#xD;
        procedure or post-procedure complication risk.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Clinica de la Costa</name>
      <address>
        <city>Barranquilla</city>
        <country>Colombia</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Colombia</country>
  </location_countries>
  <verification_date>August 2023</verification_date>
  <study_first_submitted>June 23, 2020</study_first_submitted>
  <study_first_submitted_qc>July 20, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 23, 2020</study_first_posted>
  <last_update_submitted>August 18, 2023</last_update_submitted>
  <last_update_submitted_qc>August 18, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">August 22, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>George Washington University</investigator_affiliation>
    <investigator_full_name>Aileen Y Chang</investigator_full_name>
    <investigator_title>Associate Professor of Medicine</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Chikungunya Fever</mesh_term>
    <mesh_term>Arthritis</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/NCT04483466
org study id: Chang_MARCH_JUNE2020
nct id: NCT04483466
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
MARCH is the first randomized, double-blind, placebo-controlled evaluation of the efficacy
      and pathologic mechanism determined by synovial biopsy of 6 months of methotrexate (n=100)
      versus placebo (n=50) therapy for chronic chikungunya (CHIKV) arthritis in Colombia with the
      option for open-label use of the medication for up to one year for all participants. Our
      central hypothesis is that methotrexate will significantly decrease chronic CHIKV arthritis
      disease severity compared to placebo via suppression of leukocyte accumulation in synovial
      tissue and decreased expression of inflammatory cytokines from synovial macrophages and
      fibroblast-like synoviocytes (FLS).
-  In the treatment group, participants will receive methotrexate 15mg by mouth/week with
           optional for increase up to 20mg/week in non-responders and folic acid 1mg by mouth
           daily for six months in Phase I.

        -  In the control group, participants will receive placebo methotrexate tablets by
           mouth/week with faux increase optional in non-responders and folic acid 1mg by mouth
           daily for six months in Phase I.

        -  In Phase II, patients may elect to stop taking the study drug or in those without
           clinical remission transition to open label active treatment group for the following six
           months.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: In the treatment group, participants will receive methotrexate 15mg by mouth/week with optional for increase up to 20mg/week in non-responders and folic acid 1mg by mouth daily for six months in Phase I.
In the control group, participants will receive placebo methotrexate tablets by mouth/week with faux increase optional in non-responders and folic acid 1mg by mouth daily for six months in Phase I.
In Phase II, any patient may elect to stop taking the study drug or transition to open label active treatment group for the following six months if non-responder.
primary purpose: Treatment
masking: Double (Participant, Investigator)
measure: Efficacy of oral methotrexate treatment versus placebo for 6 months in chronic CHIKV arthritis.
time frame: up to 6 months
description: An improvement in the Disease Activity Score-28 response. The DAS-28 is a composite measure including a tender and swollen joint joint of 28 joints, patient reported disease severity measures, and the c-reactive protein
measure: Inflammation in the synovial tissue measured by synovial inflammatory cell infiltration
time frame: Up to 6 weeks
description: The investigators hypothesize that treatment with methotrexate versus placebo will decrease synovial macrophage and T-cell accumulation.
measure: Inflammatory cytokine levels in synovial tissue
time frame: Up to 6 weeks
description: The investigators hypothesize that treatment with methotrexate versus placebo will dampen production of pathogenic cytokines like with TNF, IL-6, and MCP-1
arm group label: Treatment with methotrexate
arm group type: Experimental
description: 100 participants will be treated with methotrexate
arm group label: Placebo methotrexate
arm group type: Placebo Comparator
description: 50 will receive placebo
intervention type: Drug
intervention name: Methotrexate
description: Methotrexate is vibrant yellow-orange colored powder with physical properties of near insolubility in water formulated into methotrexate tablets containing an amount of methotrexate sodium equivalent to 2.5 mg of methotrexate and are round, convex, and yellow. The chemical name is N-[4-[[(2,4-diamino-6pteridinyl)methyl]methyl amino]benzoyl]-L-glutamic acid. Methotrexate is an anti-metabolite that is a folate antagonist that inhibits lymphocyte proliferation and functions as an immunosuppressant in arthritis.
arm group label: Treatment with methotrexate
intervention type: Drug
intervention name: Placebo
description: Placebo
arm group label: Placebo methotrexate
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
facility: 
country: Colombia
responsible party type: Principal Investigator
investigator affiliation: George Washington University
investigator full name: Aileen Y Chang
investigator title: Associate Professor of Medicine
mesh term: Chikungunya Fever
mesh term: Arthritis
mesh term: Methotrexate