title: Ultrasonographic measures of synovitis in an early phase clinical trial: a double-blind, randomised, placebo and comparator controlled phase IIa trial of GW274150 (a selective inducible nitric oxide synthase inhibitor) in rheumatoid arthritis.
abstract: OBJECTIVE
  To test the sensitivity to change of ultrasonographic endpoints in early phase clinical trials in subjects with active rheumatoid arthritis (RA).
  
  
  METHODS
  A double-blind, placebo and comparator controlled, randomised, two-centre study investigated the effect on synovial thickness and vascularity of 28 days repeat daily oral dosing of 60 mg of the inducible nitric oxide synthase inhibitor GW274150 or 7.5 mg prednisolone in RA. Fifty patients with DAS28 scores ≥4.0 were assigned to 3 treatment arms of 17, 19 and 14 (on placebo, GW274150 and prednisolone respectively). Synovial thickness and vascularity of all 10 metacarpophalangeal joints were assessed by ultrasonography using a semi-quantitative scale at baseline (Day 1), Day 15 and Day 28. Vascularity was also measured quantitatively by power Doppler area.
  
  
  RESULTS
  At Day 28, the GW274150 group showed a trend towards reduction in synovial thickness compared with placebo, with an adjusted mean decrease of 33% (p=0.072); the prednisolone group decreased significantly by 44% (p=0.011). Similarly, there was a trend to reduced synovial vascularity with GW274150 by 42% compared with placebo (p=0.075); prednisolone resulted in a statistically significant decrease of 55% (p=0.012). There was a 55% decrease in power Doppler area for GW274150, compared with placebo although the result was not statistically significant (p=0.375). Prednisolone 7.5 mg resulted in a highly statistically significant decrease of 95% (p=0.003).
  
  
  CONCLUSIONS
  This study advocates the use of ultrasonographic measures of metacarpophalangeal joint synovitis as an endpoint for clinical studies assessing therapeutic potential of new compounds in small patient cohorts over 28 days.
authors.affiliation: Kennedy Institute of Rheumatology, London, UK. m.seymour@imperial.ac.uk
authors.forename: Matthew
authors.initials: M
authors.lastname: Seymour
authors.forename: Frank
authors.initials: F
authors.lastname: Pétavy
authors.forename: Flaminia
authors.initials: F
authors.lastname: Chiesa
authors.forename: Hayley
authors.initials: H
authors.lastname: Perry
authors.forename: Pauline T
authors.initials: PT
authors.lastname: Lukey
authors.forename: Michael
authors.initials: M
authors.lastname: Binks
authors.forename: Philippe D
authors.initials: PD
authors.lastname: Donatien
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Freidin
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Eckersley
authors.forename: Catherine
authors.initials: C
authors.lastname: McClinton
authors.forename: Kathleen
authors.initials: K
authors.lastname: Heath
authors.forename: Slavica
authors.initials: S
authors.lastname: Prodanovic
authors.forename: Goran
authors.initials: G
authors.lastname: Radunovic
authors.forename: Nada
authors.initials: N
authors.lastname: Pilipovic
authors.forename: Nemanja
authors.initials: N
authors.lastname: Damjanov
authors.forename: Peter C
authors.initials: PC
authors.lastname: Taylor
mesh_terms: D000328:Adult; D000368:Aged; D018501:Antirheumatic Agents / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000201:enzymology; D004185:Disability Evaluation; D004311:Double-Blind Method; D004739:England; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008297:Male; D008662:Metacarpophalangeal Joint / Q000098:blood supply / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000201:enzymology; D008875:Middle Aged; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010919:Placebos; D011237:Predictive Value of Tests; D011239:Prednisolone / Q000627:therapeutic use*; D055771:Serbia; D013440:Sulfides / Q000627:therapeutic use*; D013585:Synovitis / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000201:enzymology; D013997:Time Factors; D016896:Treatment Outcome; D018608:Ultrasonography, Doppler
chemical_list: D018501:Antirheumatic Agents; D004791:Enzyme Inhibitors; D010919:Placebos; D013440:Sulfides; C409004:GW 274150; D011239:Prednisolone; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II