title: Efficacy and safety of CE-224,535, an antagonist of P2X7 receptor, in treatment of patients with rheumatoid arthritis inadequately controlled by methotrexate.
abstract: OBJECTIVE
  To evaluate efficacy and safety of CE-224,535, a selective P2X(7) receptor antagonist, versus placebo, in patients with active rheumatoid arthritis (RA) and inadequate response to methotrexate (MTX).
  
  
  METHODS
  In our phase IIA study (ClinicalTrials.gov no. NCT00628095; A6341009), patients aged ≥ 18 years with active RA were randomized to receive either CE-224,535 (500 mg bid) or placebo for 12 weeks; all patients continued a stable background dose of ≥ 7.5 mg MTX.
  
  
  RESULTS
  The American College of Rheumatology 20% (ACR20) response rate (primary efficacy endpoint) was not significantly different from placebo for CE-224,535 (34.0% vs 36.2%; p = 0.591) at Week 12, or at any timepoint over the 12-week treatment period. There was no significant difference at Week 12 for the ACR20 response rate following subgroup analyses by age, sex, baseline disease activity, baseline duration of disease, geographic region, or concomitant use of steroids. ACR50/ACR70 response rates and change from baseline in Disease Activity Score 28-joint C-reactive protein (DAS28-3-CRP) and Health Assessment Questionnaire-Disability Index for CE-224,535 were not significant at Week 12 versus placebo. Treatment-emergent adverse events (AE) were reported by 62.3% (CE-224,535) and 55.3% (placebo) of patients; the most common AE were nausea (11.3%, CE-224,535; 4.3%, placebo) and diarrhea (7.5%, CE-224,535; 4.3%, placebo). The proportion of patients discontinuing due to an AE was 9.4% (CE-224,535) and 6.4% (placebo); no deaths were reported. Serious AE occurred in 3.8% (CE-224,535) and 2.1% (placebo) of patients; none was considered treatment-related.
  
  
  CONCLUSIONS
  CE-224,535 was not efficacious, compared with placebo, for the treatment of RA in patients with an inadequate response to MTX. CE-224,535 demonstrated an acceptable safety and tolerability profile.
authors.affiliation: Pfizer Global Research and Development, 500 Arcola Road, F3212, Collegeville, PA 19426, USA. thomas.stock@pfizer.com
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Stock
authors.forename: Bradley J
authors.initials: BJ
authors.lastname: Bloom
authors.forename: Nathan
authors.initials: N
authors.lastname: Wei
authors.forename: Saliha
authors.initials: S
authors.lastname: Ishaq
authors.forename: Won
authors.initials: W
authors.lastname: Park
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.forename: Pankaj
authors.initials: P
authors.lastname: Gupta
authors.forename: Charles A
authors.initials: CA
authors.lastname: Mebus
mesh_terms: D000328:Adult; D000368:Aged; D018501:Antirheumatic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D001549:Benzamides / Q000008:administration & dosage* / Q000009:adverse effects; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D015990:Placebo Effect; D058920:Purinergic P2X Receptor Antagonists / Q000008:administration & dosage* / Q000009:adverse effects; D014498:Uracil / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D055815:Young Adult
chemical_list: D018501:Antirheumatic Agents; D001549:Benzamides; C562356:CE 224,535; D058920:Purinergic P2X Receptor Antagonists; D014498:Uracil