title: Efficacy and safety of CH-1504, a metabolically stable antifolate, in patients with active rheumatoid arthritis: results of a phase II multicenter randomized study.
abstract: OBJECTIVE
  To investigate the potential efficacy, safety, and tolerability of daily use of CH-1504 in patients with active rheumatoid arthritis (RA). US National Institutes of Health database no. NCT00658047.
  
  
  METHODS
  In our phase II randomized double-blind double-dummy study, patients naive to methotrexate (MTX; n = 201) and having moderate to severe RA received either CH-1504 (0.25 mg, 0.5 mg, or 1.0 mg once-daily oral doses) or MTX (titrated to 20.0 mg once-weekly oral doses). All received weekly 10-mg folate supplementation. Efficacy and safety were assessed at 2, 4, 8, and 12 weeks, with a treatment-free followup at 16 weeks. Safety and tolerability were assessed. Primary efficacy endpoint was proportion of patients achieving ACR20 response at Week 12. Secondary endpoints included difference from baseline in the 28-joint Disease Activity Score (DAS28) and individual components of the American College of Rheumatology (ACR) composite index.
  
  
  RESULTS
  Demographic characteristics were similar in all treatment groups: mean age 54.3 ± 11.4 years, female sex 87%, mean baseline DAS28 6.6 ± 0.9. At Week 12, CH-1504 demonstrated comparable efficacy compared to MTX as measured by ACR20, DAS28, and ACR composite core-set measures, including tender and swollen joints. No dose-response relationship was observed. Adverse events across treatment groups were mild. Liver enzyme levels increased from baseline to Week 16 in the MTX group, with qualitatively lesser increases in the CH-1504 groups. Two patients in the MTX group withdrew because of gastrointestinal-related adverse events. CH-1504 appeared safe and well tolerated at all dose levels.
  
  
  CONCLUSIONS
  CH-1504 has comparable efficacy to MTX and is safe and well tolerated. Metabolically stable antifolates are a promising therapeutic option that warrants further study.
authors: Rebecca MacDonald Centre for Arthritis and Autoimmune Disease, Mount Sinai Hospital, Joseph and Wolf Lebovic Building, 60 Murray Street, Room 2-006, PO Box 4, Toronto, Ontario M5G 1X5, Canada. ksnow@mtsinai.on.ca
authors: Edward C
authors: EC
authors: Keystone
authors: Valery S
authors: VS
authors: Shirinsky
authors: Lee S
authors: LS
authors: Simon
authors: Simon
authors: S
authors: Pedder
authors: L Arthur
authors: LA
authors: Hewitt
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000630:Aminopterin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D018501:Antirheumatic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D005260:Female; D005493:Folic Acid Antagonists / Q000008:administration & dosage* / Q000009:adverse effects; D006801:Humans; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage / Q000009:adverse effects; D008875:Middle Aged; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: C512248:4'-methylene-5,8,10-trideazaaminopterin; D018501:Antirheumatic Agents; D005493:Folic Acid Antagonists; D000630:Aminopterin; D008727:Methotrexate