title: A 2-year randomised, double-blind, placebo-controlled, multicentre study of oral selective iNOS inhibitor, cindunistat (SD-6010), in patients with symptomatic osteoarthritis of the knee.
abstract: OBJECTIVE
  To determine if inhibition of inducible nitric oxide synthase (iNOS) with cindunistat hydrochloride maleate slows progression of osteoarthritis (OA)   METHODS:  This 2-year, multinational, double-blind, placebo-controlled trial enrolled patients with symptomatic knee OA (Kellgren and Lawrence Grade (KLG) 2 or 3). Standard OA therapies were permitted throughout. Patients were randomly assigned to cindunistat (50 or 200 mg/day) or placebo. Randomisation was stratified by KLG. Radiographs to assess joint space narrowing (JSN) were acquired using the modified Lyon-schuss protocol at baseline, week 48 and 96.
  
  
  RESULTS
  Of 1457 patients (50 mg/day, n=485; 200 mg/day, n=486; placebo, n=486), 1048 (71.9%) completed the study. Patients were predominantly women; 56% had KLG3. The primary analysis did not demonstrate superiority of cindunistat versus placebo for rate of change in JSN. In KLG2 patients, JSN after 48 weeks was lower with cindunistat 50 mg/day versus placebo (p=0.032). Least-squares mean±SE JSN with cindunistat 50 mg/day ( -0.048±0.028 mm) and 200 mg/day (-0.062±0.028 mm) were 59.9% (95% CI 6.8% to 106.9%) and 48.7% (95% CI -8.4% to 93.9%) of placebo, improvement was not maintained at 96 weeks. No improvement was observed for KLG3 patients at either time-point. Cindunistat did not improve joint pain or function, but was generally well tolerated.
  
  
  CONCLUSIONS
  Cindunistat (50 or 200 mg/day) did not slow the rate of JSN versus placebo. After 48-weeks, KLG2 patients showed less JSN; however, the improvement was not sustained at 96-weeks. iNOS inhibition did not slow OA progression in KLG3 patients.   CLINICAL TRIAL LISTING:  NCT00565812.
authors.affiliation: Medicines Development Group, Primary Care Business Unit, Pfizer Inc., 445 Eastern Point Road, Groton, CT 06340, USA. helliomp@pfizer.com
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Hellio le Graverand
authors.forename: Ray S
authors.initials: RS
authors.lastname: Clemmer
authors.forename: Patricia
authors.initials: P
authors.lastname: Redifer
authors.forename: Robert M
authors.initials: RM
authors.lastname: Brunell
authors.forename: Curtis W
authors.initials: CW
authors.lastname: Hayes
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Brandt
authors.forename: Steven B
authors.initials: SB
authors.lastname: Abramson
authors.forename: Pamela T
authors.initials: PT
authors.lastname: Manning
authors.forename: Colin G
authors.initials: CG
authors.lastname: Miller
authors.forename: Eric
authors.initials: E
authors.lastname: Vignon
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000578:Amidines / Q000627:therapeutic use*; D003545:Cysteine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004311:Double-Blind Method; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors*; D020370:Osteoarthritis, Knee / Q000000981:diagnostic imaging / Q000188:drug therapy*; D010919:Placebos; D011859:Radiography; D016896:Treatment Outcome
chemical_list: D000578:Amidines; D004791:Enzyme Inhibitors; D010919:Placebos; C578791:cindunistat; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II; D003545:Cysteine