Purpose: The purpose of this study is to evaluate the efficacy and safety of chronic Anti-tumor necrosis factor (TNF) Chimeric Monoclonal Antibody (cA2) treatment in patients with active rheumatoid arthritis (RA) despite treatment with methotrexate (MTX). Additional objectives of the study are to determine the efficacy and safety of cA2 treatment in providing continued reduction in signs and symptoms, reduction of disability, slowing of joint damage, promotion of disease remission and improvement in quality of life at 1 year following the onset of treatment. RA is a chronic autoimmune disorder of unknown etiology that occurs in approximately 1% of the population. MTX has become the drug of choice for many rheumatologists because of its superior efficacy and faster mode of action. However, despite treatment with MTX, many patients only experience partial relief of symptoms and continue to exhibit active disease. Cytokines such as TNF-a are abundant in inflamed joints and promote the influx of neutrophils into synovial fluid and entry of lymphocytes and monocytes into the synovial tissue. TNF appears to be a key mediator since it regulates other proinflammatory cytokines. Methods: Patients will be randomized into one of five treatment groups: Group I receives placebo infusions, Group II receives 3 mg/kg at weeks 0, 2 and 6 and every 8 weeks through week 54 (with placebo infusions at the interim visits), Group III receives 3 mg/kg cA2 infusions at each visit, Group IV receives 10 mg/kg cA2 infusions at weeks 0, 2 and 6 and every 8 weeks through week 54 (with placebo infusions at the interim visits), and Group V receives 10 mg/kg cA2 infusions at each visit. The study was extended to allow for an additional 12 infusions of the same blinded dose regimen patients were randomized to in the first 54 weeks of treatment. Patients will be required to make 2 safety follow-up visits after their last infusion. Results: Study enrollment began in April of 1997 and is now complete with 25 patients randomized. Thirty-six patients were screened for the study. By race and gender, they include: 21 Caucasian females; 12 Caucasian males and 3 African American females. There were two adverse events leading to patient withdrawals in 2 cases. One patient was withdrawn due to a decrease in the number of white blood cells. This event was judged possibly related to the study medication. Follow-up studies show an improvement in this laboratory finding since termination of the study agent. This patient will not receive further treatments of the study medication under this protocol. This patient is participating in follow-up evaluations. Another patient was withdrawn because they were unable to return for the required visits after a partial lumbar hemilaminectomy on November 6, 1997. This patient was allowed, by the sponsor, to continue in the study despite the surgical event. However, a slow recovery period made this too difficult for the patient. This patient agreed to return periodically for safety evaluations, however, she has not returned for follow-up. Her husband gave permission to contact her local physician to request follow-up information on her condition. On 9/8/98, her physician informed me that he had terminated this patient from his care because of abuse of pain medications. At the time of contact this patient was in a hospital's de-tox unit for abuse of pain meds and alcohol. Her physician informed me that to his knowledge, the patient has not been diagnosed with any other autoimmune diseases, has not developed a malignancy, or developed a serious infection requirring hospitalization, and the patient was alive. No other follow-up information has been obtained since that time. Four patients were withdrawn from the study because of worsening of their arthritis or no clinical improvement in their arthritis. All four patients are participating in follow-up evaluations. An analysis of the week 30 data from the study reveals improvement of joint count tenderness and swelling as well as quality of life changes. Data also show a significant response to treatment at both dose levels. Significance: Current treatment of RA is often unsuccessful and has not been shown to prevent joint damage. The proposed study is potentially an effective treatment for RA because of its ability to bind to human TNF and neutralize its biologic activity. Future Plans: The sponsor of the study plans to file for FDA approval of this drug in 1999.
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