Methotrexate Alone Versus Combination of Methotrexate and Subcutaneous Fludarabine for Severe Rheumatoid Arthritis: Safety, Tolerance and Efficacy

This study has been completed.
Sponsor:
Information provided by:
National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov Identifier:
NCT00001677
First received: November 3, 1999
Last updated: March 3, 2008
Last verified: May 1999
  Purpose

The safety profile and efficacy of combination therapy will be evaluated using methotrexate (MTX) and the nucleoside analog fludarabine in 40 patients with severe refractory rheumatoid arthritis. The patients enrolled will be those who have experienced inadequate disease control with MTX alone or in combination with other immunosuppressive drugs such as sulfasalazine (SSZ), cyclosporin A (CsA), or hydroxychloroquine (HCQ). In this randomized, double-blind, placebo controlled trial, patients will be maintained on oral MTX at 17.5 mg/week to which either placebo or subcutaneous fludarabine at 30 mg/m(2) daily for three consecutive days per month will be added for four months. The fludarabine (or placebo) treatment period will be followed by two months of follow-up, at which time patients will be evaluated for response. Patients will be monitored for adverse effects/tolerability, disease activity, and changes in synovial volume as measured by magnetic resonance imaging (MRI). Additionally synovial biopsies will be obtained before and after treatment for investigation of infiltrating cell numbers and phenotypes, cytokine profiles, Th1 versus Th2 responses, and angiogenesis.


Condition Intervention Phase
Arthritis, Rheumatoid
Synovitis
Drug: Methotrexate
Drug: Fludarabine
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Primary Purpose: Treatment
Official Title: Methotrexate Alone Versus Combination of Methotrexate and Subcutaneous Fludarabine for Severe Rheumatoid Arthritis: Safety, Tolerance and Efficacy

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Estimated Enrollment: 40
Study Start Date: June 1998
Estimated Study Completion Date: April 2000
Detailed Description:

The safety profile and efficacy of combination therapy will be evaluated using methotrexate (MTX) and the nucleoside analog fludarabine in 40 patients with severe refractory rheumatoid arthritis. The patients enrolled will be those who have experienced inadequate disease control with MTX alone or in combination with other immunosuppressive drugs such as sulfasalazine (SSZ), cyclosporin A (CsA), or hydroxychloroquine (HCQ). In this randomized, double-blind, placebo controlled trial, patients will be maintained on oral MTX at 17.5 mg/week to which either placebo or subcutaneous fludarabine at 30 mg/m(2) daily for three consecutive days per month will be added for four months. The fludarabine (or placebo) treatment period will be followed by two months of follow-up, at which time patients will be evaluated for response. Patients will be monitored for adverse effects/tolerability, disease activity, and changes in synovial volume as measured by magnetic resonance imaging (MRI). Additionally synovial biopsies will be obtained before and after treatment for investigation of infiltrating cell numbers and phenotypes, cytokine profiles, Th1 versus Th2 responses, and angiogenesis.

  Eligibility

Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Ability to provide informed consent to all aspects of the study after full information is provided.

Age equal to or older than 18.

A diagnosis of Rheumatoid Arthritis (RA) of more than 6 months as defined by the revised American College of Rheumatology criteria.

Active RA defined as: 6 or more swollen joints;

6 or more tender joints;

ESR greater than 28 mm/hr (or CRP greater than 0.8) or morning stiffness greater than 45 minutes.

Incomplete response (defined as persistently active disease as described above) to treatment with at least one of the following regimens for over 3 months:

MTX alone (greater than or equal to 17.5 mg/week);

MTX (greater than or equal to 17.5 mg/week) plus HCQ (greater than or equal to 200 mg/day);

MTX (greater than or equal to 17.5 mg/week) plus SSZ (greater than or equal to 1 gm/d);

MTX (greater than or equal to 17.5 mg/week) plus CsA (1-3 mg/kg/day);

MTX (greater than or equal to 17.5 mg/week) plus SSZ (greater than 1 gm/day) plus HCQ (greater than or equal to 200 mg/day);

No requirement of corticosteroids in doses equivalent to over 10 mg/d prednisone nor other immunosuppressive agents required for the control of extraarticular manifestations at the time of study entry.

No active acute or chronic infections requiring antibiotic therapy, serious viral infections (such as hepatitis, herpes zoster, or HIV), or serious fungal infections. Patients with a positive PPD who have not received INH or other antituberculous therapy will be excluded.

No pregnant women, nursing mothers, or patients of childbearing age not practicing birth control.

No preexisting malignancy other than basal cell carcinoma.

No history of stroke, seizure disorder, or chronic neurologic disease.

No unstable coronary artery disease, cardiomyopathy, conduction heart block greater than first degree, or a dysrhythmia requiring therapy.

No confounding medical illness that in the judgment of the investigators would pose added risk for study participants (e.g., chronic hepatic, renal, or pulmonary disease or bone marrow hypoplasia).

No presence of seronegative spondyloarthropathy, systemic lupus erythematosus, systemic sclerosis, inflammatory myopathy, systemic vasculitis, psoriasis, or inflammatory bowel disease.

No serum creatinine greater than 2.0 mg/dL on at least 2 different occasions which is sustained for at least 1 month.

No hematocrit less than 28% (or hemoglobin less than 9.0 mg/dL), or platelet count less than 100,000, or white blood count less than 3,500/dL.

No patients with active lung disease, patients with a chronic and progressive lung disease, or patients with a chronic but stable lung disease with pulmonary function tests of less than 70% of predicted (DLCO less than 60%).

No patients with hypogammaglobulinemia (IgG count less than 300).

No patients treated with alkylating agents for over 1 year at any time or treated with a purine nucleoside analog at any time.

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00001677

Locations
United States, Maryland
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Bethesda, Maryland, United States, 20892
Sponsors and Collaborators
  More Information

Publications:
ClinicalTrials.gov Identifier: NCT00001677     History of Changes
Other Study ID Numbers: 980117, 98-AR-0117
Study First Received: November 3, 1999
Last Updated: March 3, 2008
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
Immunosuppression
Lymphocytes
Magnetic Resonance
Synovial Biopsy
Synovitis
Rheumatoid Arthritis

Additional relevant MeSH terms:
Synovitis
Arthritis
Arthritis, Rheumatoid
Joint Diseases
Musculoskeletal Diseases
Rheumatic Diseases
Connective Tissue Diseases
Autoimmune Diseases
Immune System Diseases
Methotrexate
Fludarabine phosphate
Fludarabine
Abortifacient Agents, Nonsteroidal
Abortifacient Agents
Reproductive Control Agents
Physiological Effects of Drugs
Pharmacologic Actions
Therapeutic Uses
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

ClinicalTrials.gov processed this record on August 21, 2014