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Methotrexate Treatment of Arthritis Caused by Chikungunya Virus (MARCH)

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.
 
ClinicalTrials.gov Identifier: NCT04483466
Recruitment Status : Not yet recruiting
First Posted : July 23, 2020
Last Update Posted : July 23, 2020
Sponsor:
Information provided by (Responsible Party):
Aileen Chang, George Washington University

Tracking Information
First Submitted Date  ICMJE June 23, 2020
First Posted Date  ICMJE July 23, 2020
Last Update Posted Date July 23, 2020
Estimated Study Start Date  ICMJE August 1, 2020
Estimated Primary Completion Date July 30, 2025   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 20, 2020)
Efficacy of oral methotrexate treatment versus placebo for 6 months in chronic CHIKV arthritis. [ Time Frame: up to 6 months ]
An improvement in the American College of Rheumatology (ACR 20) response. The ACR20 is a composite measure defined as both improvement of 20% in the number of tender and number of swollen joints, and a 20% improvement in three of the following five criteria: patient global assessment, physician global assessment, functional ability measure [most often Health Assessment Questionnaire (HAQ)], visual analog pain scale, and erythrocyte sedimentation rate or C-reactive protein (CRP). For the purposes of our study we will use the number of tender and number of swollen joints, and a 20% improvement in three of the following five criteria: patient global assessment, physician global assessment, functional ability measured by the Health Assessment Questionnaire (HAQ)], visual analog pain scale, C-reactive protein (CRP).
Original Primary Outcome Measures  ICMJE Same as current
Change History No Changes Posted
Current Secondary Outcome Measures  ICMJE
 (submitted: July 20, 2020)
  • Inflammation in the synovial tissue measured by synovial inflammatory cell infiltration [ Time Frame: Up to 6 weeks ]
    The investigators hypothesize that treatment with methotrexate versus placebo will decrease synovial macrophage and T-cell accumulation.
  • Inflammatory cytokine levels in synovial tissue [ Time Frame: Up to 6 weeks ]
    The investigators hypothesize that treatment with methotrexate versus placebo will dampen production of pathogenic cytokines like with TNF, IL-6, and MCP-1
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Methotrexate Treatment of Arthritis Caused by Chikungunya Virus (MARCH)
Official Title  ICMJE 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
Brief Summary 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=134) versus placebo (n=67) 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).
Detailed 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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE 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.
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Investigate the Effect(s) of Methotrexate Treatment on Arthritis Disease Severity
Intervention  ICMJE
  • Drug: Methotrexate
    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.
  • Drug: Placebo
    Placebo
Study Arms  ICMJE
  • Experimental: Treatment with methotrexate
    134 participants will be treated with methotrexate
    Intervention: Drug: Methotrexate
  • Placebo Comparator: Placebo methotrexate
    76 will receive placebo
    Intervention: Drug: 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: July 20, 2020)
201
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 30, 2025
Estimated Primary Completion Date July 30, 2025   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Provision of signed and dated informed consent form.
  2. Stated willingness to comply with all study procedures and availability for the duration of the study.
  3. Male or female, aged >18 years
  4. Ability to take oral medication and be willing to adhere to the methotrexate regimen
  5. For females of reproductive potential: use of highly effective contraception for at least 1 month prior to screening and agreement to use such a method during study participation and for an additional 4 weeks after the end of methotrexate administration.
  6. For males of reproductive potential: use of condoms or other methods to ensure effective contraception with partner.
  7. Have a diagnosis of CHIKV by CHIKV IgM or IgG antibody.
  8. Have a diagnosis of arthritis as defined by having at least one joint with definite clinical synovitis (swelling)
  9. The disease duration should be greater than 3 months (based on onset of symptoms).
  10. Have active disease at the time of screening; active disease is defined as at least 4 swollen and 4 tender joints (using the 66-joint count).
  11. Screen laboratory tests must meet the following criteria: Hemoglobin ≥ 9 g/dL, WBCs ≥ 3.5 x 109 cells/L, Neutrophils ≥ 1.5 x 109 cells/L, Platelets ≥ 100 x 109 cells/L, serum transaminase levels not exceeding 1.5 times the upper limit of normal, serum creatinine ≤ 1.6 mg/dL, and negative for hepatitis B surface antigen and hepatitis C antibodies.
  12. Have a chest radiograph either at screening or within the past year that shows no evidence of malignancy or active infection.
  13. Must have at least moderate Disease Activity Score.

Exclusion Criteria:

  1. Pregnancy or lactation
  2. Known allergic reactions to components of methotrexate or folic acid.
  3. Treatment with another investigational drug or other intervention within 1 month.
  4. History of chronic infection such as hepatitis, pneumonia, or pyelonephritis.
  5. Current signs or symptoms of uncontrolled renal, hepatic, hematologic, gastrointestinal, endocrine, pulmonary, cardiac, neurologic or cerebral disease.
  6. Patients with a current diagnosis of class III or IV CHF.
  7. History of lymphoproliferative disease including lymphoma.
  8. Active TB or evidence of latent TB (positive PPD skin test or a history of old or latent TB on chest x-ray) without adequate therapy for TB.
  9. Overt or laboratory evidence of immunodeficiency syndromes.
  10. Any opportunistic infections, including but not limited to evidence of active cytomegalovirus, active Pneumocystis carinii, aspergillosis, histoplasmosis or atypical mycobacterium infection, within the previous 6 months at screening visit.
  11. History of substance abuse (drug or alcohol) within the previous 2 years.
  12. Intra-articular, soft tissue or intra-muscular corticosteroid injection during the 4 weeks prior to screening.
  13. History of prior use of methotrexate or biologic therapy.
  14. Evidence of active viral infection with fever >38°
  15. Current use of any other disease modifying arthritis medication including but not limited to sulfasalazine, methotrexate, hydroxychloroquine, leflunomide, or biologics in the previous 2 months. Patients on stable doses of prednisone up to 10 mg per day for at least 4 weeks prior to enrollment may participate. Non-steroidal anti-inflammatories (NSAIDS) and acetaminophen are permitted for pain during the study.
  16. Hematuria or proteinuria on urinalysis.
  17. Diagnosis of rheumatoid arthritis prior to chikungunya infection or the presence of anti-cyclic citrullinated peptide (anti-CCP) antibodies >2 times the upper limit of normal.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Aileen Chang, MD, MSPH 2022742437 chang@email.gwu.edu
Contact: Holly Liu, MBA, MS 2022742437 hliu@mfa.gwu.edu
Listed Location Countries  ICMJE Not Provided
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04483466
Other Study ID Numbers  ICMJE Chang_MARCH_JUNE2020
Has Data Monitoring Committee Yes
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 Aileen Chang, George Washington University
Study Sponsor  ICMJE George Washington University
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account George Washington University
Verification Date July 2020

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