title: 28-Day safety and tolerability of umeclidinium in combination with vilanterol in COPD: a randomized placebo-controlled trial.
abstract: BACKGROUND
  Umeclidinium (UMEC; GSK573719) is a new long-acting muscarinic antagonist (LAMA) currently in development in combination with vilanterol (VI), an inhaled, long-acting beta₂ agonist for the treatment of chronic obstructive pulmonary disease (COPD). The primary aim of this study was to evaluate the safety and tolerability of repeat dosing of UMEC and VI in combination once daily for 28 days in patients with COPD.
  
  
  METHODS
  This was a multicenter, double-blind, placebo-controlled, parallel group study. Patients aged ≥40 years with post-bronchodilator FEV₁ ≤80% of predicted normal values and FEV₁/FVC ratio ≤0.70, and a smoking history of ≥10 pack-years, were randomized 4:1 to once-daily UMEC/VI (500/25 mcg; n = 42) or placebo (n = 9).
  
  
  RESULTS
  UMEC/VI was non-inferior to placebo in weighted mean pulse rate over 0-6 h at Day 28 (primary endpoint: difference of -0.5 bpm, 95% CI: -5.5 to 4.5). There was no evidence of a difference between UMEC/VI compared with placebo in blood pressure, minimum and maximum pulse rate, or QTcF assessments. Adverse events (AEs) were reported by 11 (26%) patients in the UMEC/VI group and one (11%) patient in the placebo group. No serious AEs were reported. Both UMEC and VI showed rapid absorption (median t(max) ∼6 min for both drugs) with no evidence of accumulation for AUC or C(max) on Day 28 compared with Day 1 for UMEC or VI. There was no correlation between individual steady-state C(max) and pulse rate on Day 28. Change from baseline in trough FEV₁ on Day 29 showed numerically greater improvements with UMEC/VI compared with placebo.
  
  
  CONCLUSIONS
  Once-daily dosing with UMEC in combination with VI in patients with moderate-to-very-severe COPD was well tolerated over 28 days.
authors.affiliation: S. Carolina Pharmaceutical Research, Spartanburg, SC, USA. gfeld3232@aol.com
authors.forename: Gregory
authors.initials: G
authors.lastname: Feldman
authors.forename: Robert R
authors.initials: RR
authors.lastname: Walker
authors.forename: Jean
authors.initials: J
authors.lastname: Brooks
authors.forename: Rashmi
authors.initials: R
authors.lastname: Mehta
authors.forename: Glenn
authors.initials: G
authors.lastname: Crater
mesh_terms: D000280:Administration, Inhalation; D058666:Adrenergic beta-2 Receptor Agonists / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019540:Area Under Curve; D001592:Benzyl Alcohols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D002722:Chlorobenzenes / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D003692:Delayed-Action Preparations; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004338:Drug Combinations; D005260:Female; D005500:Follow-Up Studies; D005541:Forced Expiratory Volume; D006801:Humans; D008297:Male; D008875:Middle Aged; D018727:Muscarinic Antagonists / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy* / Q000503:physiopathology; D011812:Quinuclidines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D012720:Severity of Illness Index; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D001592:Benzyl Alcohols; D002722:Chlorobenzenes; D003692:Delayed-Action Preparations; D004338:Drug Combinations; C573971:GSK573719; D018727:Muscarinic Antagonists; D011812:Quinuclidines; C550468:vilanterol