title: Maraviroc, a chemokine receptor-5 antagonist, fails to demonstrate efficacy in the treatment of patients with rheumatoid arthritis in a randomized, double-blind placebo-controlled trial.
abstract: BACKGROUND
  The purpose of this study was to determine whether maraviroc, a human CC chemokine receptor 5 (CCR5) antagonist, is safe and effective in the treatment of active rheumatoid arthritis (RA) in patients on background methotrexate (MTX).
  
  
  METHODS
  This phase IIa study comprised two distinct components: an open-label safety study of the pharmacokinetics (PK) of MTX in the presence of maraviroc, and a randomized, double-blind, placebo-controlled, proof-of-concept (POC) component. In the PK component, patients were randomized 1:1 to receive maraviroc 150 or 300 mg twice daily (BID) for four weeks. In the POC component, patients were randomized 2:1 to receive maraviroc 300 mg BID or placebo for 12 weeks. Patients were not eligible for inclusion in both components.
  
  
  RESULTS
  Sixteen patients were treated in the safety/PK component. Maraviroc was well tolerated and there was no evidence of drug-drug interaction with MTX. One hundred ten patients were treated in the POC component. The study was terminated after the planned interim futility analysis due to lack of efficacy, at which time 59 patients (38 maraviroc; 21 placebo) had completed their week 12 visit. There was no significant difference in the number of ACR20 responders between the maraviroc (23.7%) and placebo (23.8%) groups (treatment difference -0.13%; 90% CI -20.45, 17.70; P = 0.504). The most common all-causality treatment-emergent adverse events in the maraviroc group were constipation (7.8%), nausea (5.2%), and fatigue (3.9%).
  
  
  CONCLUSIONS
  Maraviroc was generally well tolerated over 12 weeks; however, selective antagonism of CCR5 with maraviroc 300 mg BID failed to improve signs and symptoms in patients with active RA on background MTX.
  
  
  BACKGROUND
  ClinicalTrials.gov:  NCT00427934.
authors.affiliation: Pfizer Inc, 700 Chesterfield Parkway, St, Louis, MO, 63017, and Eastern Point Road, Groton, CT, 06340 USA. dona.l.fleishaker@pfizer.com
authors.forename: Dona L
authors.initials: DL
authors.lastname: Fleishaker
authors.forename: Juan A
authors.initials: JA
authors.lastname: Garcia Meijide
authors.forename: Andriy
authors.initials: A
authors.lastname: Petrov
authors.forename: Michael David
authors.initials: MD
authors.lastname: Kohen
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.forename: Sujatha
authors.initials: S
authors.lastname: Menon
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Stock
authors.forename: Charles A
authors.initials: CA
authors.lastname: Mebus
authors.forename: James M
authors.initials: JM
authors.lastname: Goodrich
authors.forename: Howard B
authors.initials: HB
authors.lastname: Mayer
authors.forename: Bernhardt G
authors.initials: BG
authors.lastname: Zeiher
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018501:Antirheumatic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D019540:Area Under Curve; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000378:metabolism; D065100:CCR5 Receptor Antagonists; D003248:Constipation / Q000139:chemically induced; D003510:Cyclohexanes / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008297:Male; D000077592:Maraviroc; D008657:Metabolic Clearance Rate; D008727:Methotrexate / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D017211:Treatment Failure; D014230:Triazoles / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D055815:Young Adult
chemical_list: D018501:Antirheumatic Agents; D065100:CCR5 Receptor Antagonists; D003510:Cyclohexanes; D014230:Triazoles; D000077592:Maraviroc; D008727:Methotrexate