Methotrexate Treatment of Arthritis Caused by Chikungunya Virus (MARCH)

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

Study Description

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).

Condition or disease	Intervention/treatment	Phase
Investigate the Effect(s) of Methotrexate Treatment on Arthritis Disease Severity	Drug: Methotrexate; Drug: Placebo	Phase 3

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 201 participants
• 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
• 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
• Estimated Study Start Date: August 1, 2020
• Estimated Primary Completion Date: July 30, 2025
• Estimated Study Completion Date: December 30, 2025

Arms and Interventions

Arm	Intervention/treatment
Experimental: Treatment with methotrexate; 134 participants will be treated with methotrexate	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.
Placebo Comparator: Placebo methotrexate; 76 will receive placebo	Drug: Placebo; Placebo

Outcome Measures

Primary Outcome Measures :

1. 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).

Secondary Outcome Measures :

1. 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.
2. 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

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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.

Contacts and Locations

Contacts

Contact: Aileen Chang, MD, MSPH; 2022742437; chang@email.gwu.edu

Contact: Holly Liu, MBA, MS; 2022742437; hliu@mfa.gwu.edu

Sponsors and Collaborators

George Washington University

More Information

• Responsible Party: Aileen Chang, Assistant Professor of Medicine, George Washington University
• ClinicalTrials.gov Identifier: NCT04483466
• Other Study ID Numbers: Chang_MARCH_JUNE2020
• First Posted: July 23, 2020
• Last Update Posted: July 23, 2020
• Last Verified: July 2020

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Chikungunya Fever; Arthritis; Joint Diseases; Musculoskeletal Diseases; Alphavirus Infections; Togaviridae Infections; RNA Virus Infections; Virus Diseases; Methotrexate; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Reproductive Control Agents; Physiological Effects of Drugs; Antimetabolites, Antineoplastic; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Dermatologic Agents; Enzyme Inhibitors; Folic Acid Antagonists; Immunosuppressive Agents; Immunologic Factors; Antirheumatic Agents; Nucleic Acid Synthesis Inhibitors