title: 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.
abstract: 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.
  
  
  
  CIRT will randomize up to 7000 participants with cardiovascular disease and no systemic rheumatic disease to either LDM (target dose: 15-20mg/week) or placebo for an average follow-up period of 3-5 years; subjects in both treatment arms receive folic acid 1mg daily for 6 days each week. The primary endpoints of CIRT include recurrent cardio 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, gastrointestinal, 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.
  
  
  
  CIRT-AE 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 may lead to a personalized approach to monitoring LDM in clinical practice.
authors.affiliation: Department of Medicine, Division of Rheumatology, Immunology and Allergy, Brigham and Women׳s Hospital, Boston, MA; Harvard Medical School, Boston, MA. Electronic address: jsparks@bwh.harvard.edu.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Sparks
authors.affiliation: Department of Medicine, Division of Rheumatology, Immunology and Allergy, Brigham and Women׳s Hospital, Boston, MA; Harvard Medical School, Boston, MA. Electronic address: mbarbhaiya@partners.org.
authors.forename: Medha
authors.initials: M
authors.lastname: Barbhaiya
authors.affiliation: Department of Medicine, Division of Rheumatology, Immunology and Allergy, Brigham and Women׳s Hospital, Boston, MA; Harvard Medical School, Boston, MA.
authors.forename: Elizabeth W
authors.initials: EW
authors.lastname: Karlson
authors.affiliation: Department of Medicine, Division of Rheumatology, Immunology and Allergy, Brigham and Women׳s Hospital, Boston, MA; Harvard Medical School, Boston, MA.
authors.forename: Susan Y
authors.initials: SY
authors.lastname: Ritter
authors.affiliation: Department of Medicine, Division of Rheumatology, Immunology and Allergy, Brigham and Women׳s Hospital, Boston, MA; Harvard Medical School, Boston, MA; Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA.
authors.forename: Soumya
authors.initials: S
authors.lastname: Raychaudhuri
authors.affiliation: Department of Medicine, Division of Rheumatology, Immunology and Allergy, Brigham and Women׳s Hospital, Boston, MA.
authors.forename: Cassandra C
authors.initials: CC
authors.lastname: Corrigan
authors.affiliation: Department of Medicine, Division of Rheumatology, Immunology and Allergy, Brigham and Women׳s Hospital, Boston, MA.
authors.forename: Fengxin
authors.initials: F
authors.lastname: Lu
authors.affiliation: Jean Mayer USDA, Human Nutrition Center on Aging, Tufts University, Boston, MA.
authors.forename: Jacob
authors.initials: J
authors.lastname: Selhub
authors.affiliation: Harvard Medical School, Boston, MA; Department of Medicine, Center for Cardiovascular Disease Prevention, Brigham and Women׳s Hospital, Boston, MA.
authors.forename: Daniel I
authors.initials: DI
authors.lastname: Chasman
authors.affiliation: Harvard Medical School, Boston, MA; Department of Medicine, Center for Cardiovascular Disease Prevention, Brigham and Women׳s Hospital, Boston, MA.
authors.forename: Nina P
authors.initials: NP
authors.lastname: Paynter
authors.affiliation: Harvard Medical School, Boston, MA; Department of Medicine, Center for Cardiovascular Disease Prevention, Brigham and Women׳s Hospital, Boston, MA.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Ridker
authors.affiliation: Department of Medicine, Division of Rheumatology, Immunology and Allergy, Brigham and Women׳s Hospital, Boston, MA; Harvard Medical School, Boston, MA.
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Solomon
mesh_terms: D018501:Antirheumatic Agents / Q000008:administration & dosage / Q000009:adverse effects*; D002318:Cardiovascular Diseases / Q000517:prevention & control; D004311:Double-Blind Method; D005492:Folic Acid / Q000627:therapeutic use; D006397:Hematinics / Q000627:therapeutic use; D006801:Humans; D008727:Methotrexate / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D057285:Precision Medicine; D012107:Research Design; D012307:Risk Factors
chemical_list: D018501:Antirheumatic Agents; D006397:Hematinics; D005492:Folic Acid; D008727:Methotrexate
keywords: Genetics; Methotrexate; Pharmacovigilance; Polyglutamate; Toxicity