Investigating methotrexate toxicity within a randomized double-blinded, placebo-controlled trial: rationale and design of the Cardiovascular Inflammation Reduction Trial-Adverse Events (CIRT-AE) Study

Authors: SPARKS, JEFFREY - Brigham & Women'S Hospital; BARBHAIYA, MEDHA - Brigham & Women'S Hospital; KARLSON, ELIZABETH - Brigham & Women'S Hospital; RITTER, SUSAN - Brigham & Women'S Hospital; RAYCHAUDHURI, SOUMYA - Broad Institute Of Mit/harvard; CORRIGAN, CASSANDRA - Brigham & Women'S Hospital; LU, FENGXIN - Brigham & Women'S Hospital; SELHUB, JACOB - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; CHASMAN, DANIEL - Brigham & Women'S Hospital; PAYNTER, NINA - Harvard University; RIDKER, PAUL - Harvard University; SOLOMON, DANIEL - Brigham & Women'S Hospital

Submitted to: Arthritis and Rheumatism
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/1/2017
Publication Date: 8/1/2017
Citation: Sparks, J., Barbhaiya, M., Karlson, E.W., Ritter, S.Y., Raychaudhuri, S., Corrigan, C.C., Lu, F., Selhub, J., Chasman, D., Paynter, N.P., Ridker, P.M., Solomon, D.H. 2017. Investigating methotrexate toxicity within a randomized double-blinded, placebo-controlled trial: rationale and design of the Cardiovascular Inflammation Reduction Trial-Adverse Events (CIRT-AE) Study. Arthritis and Rheumatism. 47(1):133-142. https://doi.org/10.1016/j.semarthrit.2017.02.003.

Interpretive Summary: The Cardiovascular Inflammation Reduction Trial or CIRT is a multicenter trial involving over 7,000 patients who have cardiovascular disease or are at risk for it. The purpose of the trial is to determine if medicating with low dose methotrexate (LDM) is efficient in preventing the worsening of cardiovascular disease. Methotrexate is a folate-like compound which acts as antifolate. At high doses methotrexate is used for treatment of certain cancers. At low doses (LDM) methotrexate is used for the treatment of autoimmune diseases such as rheumatoid arthritis. It is used for the latter diseases because methotrexate also acts as an anti-inflammatory agent. The theory is that cardiovascular disease is, in part, due to inflammation. Therefore, it is possible to prevent or cure vascular disease by fighting inflammation, and low dose methotrexate administration seems reasonable. However, methotrexate is poisonous to some degree. This additional (ancillary) study in which our lab participates is intended to monitor negative diseases that may be caused by this treatment. Half of the participants are receiving placebo (control,) and therefore it is possible to determine if a specific event is caused by the drug.

Technical Abstract: Background: The role of low dose methotrexate (LDM) in potential serious toxicities remains unclear despite its common use. Prior observational studies investigating LDM toxicity compared LDM to other active drugs. Prior placebo-controlled clinical trials of LDM in inflammatory conditions were not large enough to investigate toxicity. The Cardiovascular Inflammation Reduction Trial (CIRT) is an ongoing NIH-funded, randomized, double-blind, placebo controlled trial of LDM in the secondary prevention of cardiovascular disease. We describe here the rationale and design of the CIRT-Adverse Events (CIRT-AE) ancillary study which aims to investigate adverse events within CIRT. Design: CIRT will randomize up to 7,000 participants with cardiovascular disease and no systemic rheumatic disease to either LDM (target dose 15-20 mg/week) or placebo for an average follow-up period of 3-5 years; subjects in both treatment arms receive folic acid 1 mg daily for six days each week. The primary endpoints of CIRT include recurrent vascular events, incident diabetes, and all-cause mortality, and the ancillary CIRT-AE study has been designed to adjudicate other clinically important adverse events including hepatic, respiratory, hematologic, infectious, mucocutaneous, oncologic, renal, neurologic, and musculoskeletal outcomes. Methotrexate polyglutamate levels and genome-wide single nucleotide polymorphisms will be examined for association with adverse events. Summary: CIRTAE will comprehensively evaluate potential LDM toxicities among subjects with cardiovascular disease within the context of a large, ongoing, double-blind, placebo-controlled trial. This information will lead to a personalized approach to monitoring LDM in clinical practice.