title: A randomized, double-blind dose-ranging study of the novel LAMA GSK573719 in patients with COPD.
abstract: BACKGROUND
  This study evaluated the dose-response and dosing interval of the novel long-acting muscarinic receptor antagonist (LAMA) GSK573719 in patients with COPD.
  
  
  METHODS
  This randomized, double-blind, placebo-controlled, 3-way cross-over, incomplete block study evaluated 5 once-daily doses of GSK573719 (62.5-1000 μg), 3 twice-daily doses (62.5-250 μg), and open-label tiotropium for 14 days in patients (N = 176) with COPD (FEV(1) of 35-70% predicted). The primary endpoint was morning trough FEV(1) at Day 15. Secondary endpoints included 0-24 h weighted mean FEV(1) and serial FEV(1) values over 28 h. Safety measures and pharmacokinetics were assessed.
  
  
  RESULTS
  All once-daily doses of GSK573719 significantly increased trough FEV(1) at Day 15 with improvements ranging from 95 to 186 mL over placebo (p ≤ 0.006), from 79 to 172 mL with twice-daily dosing (p ≤ 0.03), and 105 mL with tiotropium (p = 0.003). No clear dose ordering was observed. Once-daily doses significantly (p < 0.001) increased 0-24 h weighted mean FEV(1) at Day 14 by 131-143 mL over placebo, comparable to increases with the twice-daily doses (120-142 mL) and tiotropium (127 mL). Significant reductions in rescue albuterol use and improvements in FVC were also observed with once-daily dosing. Plasma C(max) occurred within 5-15 min of dosing after which the drug was rapidly cleared and eliminated. GSK573719 was well tolerated, with no apparent treatment-related changes in vital signs, ECG and Holter assessments, or clinical laboratory parameters.
  
  
  CONCLUSIONS
  Once-daily dosing with GSK573719 in COPD provides clinically significant and sustained improvement in lung function over 24 h with similar efficacy to twice-daily dosing.
authors.affiliation: Department of Medicine, University of North Carolina College of Medicine, Chapel Hill, NC 27599, USA. james_donohue@med.unc.edu
authors.forename: James F
authors.initials: JF
authors.lastname: Donohue
authors.forename: Antonio
authors.initials: A
authors.lastname: Anzueto
authors.forename: Jean
authors.initials: J
authors.lastname: Brooks
authors.forename: Rashmi
authors.initials: R
authors.lastname: Mehta
authors.forename: Christopher
authors.initials: C
authors.lastname: Kalberg
authors.forename: Glenn
authors.initials: G
authors.lastname: Crater
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D005541:Forced Expiratory Volume / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D018727:Muscarinic Antagonists / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy* / Q000503:physiopathology; D011812:Quinuclidines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D016896:Treatment Outcome; D014797:Vital Capacity / Q000187:drug effects
chemical_list: C573971:GSK573719; D018727:Muscarinic Antagonists; D011812:Quinuclidines