title: Efficacy and safety of budesonide and formoterol in one pressurized metered-dose inhaler in patients with moderate to very severe chronic obstructive pulmonary disease: results of a 6-month randomized clinical trial.
abstract: BACKGROUND
  The combination of an inhaled corticosteroid (ICS) and a long-acting bronchodilator is recommended in the treatment of patients with chronic obstructive pulmonary disease (COPD) who have frequent exacerbations. Budesonide/formoterol dry powder inhaler (DPI) has demonstrated efficacy and tolerability in patients with COPD.
  
  
  OBJECTIVE
  To evaluate the efficacy and tolerability of budesonide/formoterol administered via one hydrofluoroalkane pressurized metered-dose inhaler (pMDI) in patients with COPD.
  
  
  METHODS
  This was a 6-month, randomized, double-blind, double-dummy, placebo-controlled, parallel-group, multicentre study (NCT00206154) of 1704 patients aged > or =40 years with moderate to very severe COPD conducted in 194 centres in the US, Czech Republic, the Netherlands, Poland and South Africa. After 2 weeks of treatment based on previous therapy (ICSs and short-acting bronchodilators allowed during the run-in period), patients received one of the following treatments administered twice daily: budesonide/formoterol pMDI 160/4.5 microg x two inhalations (320/9 microg); budesonide/formoterol pMDI 80/4.5 microg x two inhalations (160/9 microg); budesonide pMDI 160 microg x two inhalations (320 microg) plus formoterol DPI 4.5 microg x two inhalations (9 microg); budesonide pMDI 160 microg x two inhalations (320 microg); formoterol DPI 4.5 microg x two inhalations (9 microg); or placebo.
  
  
  METHODS
  The co-primary efficacy variables were pre-dose forced expiratory volume in 1 second (FEV(1)) and 1-hour post-dose FEV(1).
  
  
  RESULTS
  Budesonide/formoterol 320/9 microg demonstrated significantly greater improvements in pre-dose FEV(1) versus formoterol (p = 0.026; pre-specified primary comparator) and 1-hour post-dose FEV(1) versus budesonide (p < 0.001; pre-specified primary comparator); budesonide/formoterol 160/9 microg demonstrated significantly greater improvements versus budesonide (p < 0.001) for 1-hour post-dose FEV(1) but not versus formoterol for pre-dose FEV(1). Dyspnoea (measured using the Breathlessness Diary) and health-related quality-of-life (HR-QOL) scores (based on the St George's Respiratory Questionnaire total score) were significantly improved with both dosage strengths of budesonide/formoterol compared with budesonide, formoterol and placebo (p < or = 0.044 for all). Although not powered a priori for comparisons, the number of exacerbations per patient-treatment year requiring treatment with oral corticosteroids and/or hospitalization was numerically (20-25%) lower with the budesonide-containing treatments (0.710-0.884) versus formoterol (1.098) and placebo (1.110). This result was driven by the exacerbations requiring treatment with oral corticosteroids (79-120 events). The number of exacerbations resulting in hospitalization was very low across treatment groups (11-22); the number per patient-treatment year was significantly different for budesonide/formoterol 320/9 microg (0.158) versus other treatment groups (0.081-0.108) except budesonide/formoterol 160/9 microg (0.139), and for budesonide/formoterol 160/9 microg versus formoterol (0.081) [p < or = 0.05]. All treatments were generally well tolerated. The incidence of individual non-fatal serious adverse events was similar across all treatment groups, except COPD, which was highest in the budesonide/formoterol 320/9 microg group (6.1%) and lowest in the budesonide (3.6%) and formoterol (3.9%) groups, with a range of 4.3-4.6% in the budesonide/formoterol 160/9 microg, budesonide plus formoterol and placebo groups. Budesonide/formoterol had a safety profile comparable with that of the monocomponents and placebo. There was no increase in the incidence of pneumonia in the active treatment groups relative to placebo.
  
  
  CONCLUSIONS
  Budesonide/formoterol pMDI 320/9 microg demonstrated significantly greater efficacy for pulmonary function on both co-primary endpoints versus the pre-specified comparators (formoterol DPI 9 microg for pre-dose FEV(1) and budesonide pMDI 320 microg for 1-hour post-dose FEV(1)). Budesonide/formoterol pMDI 160/9 microg demonstrated significantly greater efficacy for 1-hour post-dose FEV(1) versus budesonide pMDI 320 microg. Dyspnoea scores and HR-QOL were significantly improved with both budesonide/formoterol pMDI dosage strengths versus both monocomponents and placebo. Both budesonide/formoterol pMDI dosage strengths were well tolerated relative to the monocomponents and placebo.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, University of California, Los Angeles, California, USA. dtashkin@mednet.ucla.edu
authors.forename: Donald P
authors.initials: DP
authors.lastname: Tashkin
authors.forename: Stephen I
authors.initials: SI
authors.lastname: Rennard
authors.forename: Paula
authors.initials: P
authors.lastname: Martin
authors.forename: Sulabha
authors.initials: S
authors.lastname: Ramachandran
authors.forename: Ubaldo J
authors.initials: UJ
authors.lastname: Martin
authors.forename: Philip E
authors.initials: PE
authors.lastname: Silkoff
authors.forename: Mitchell
authors.initials: M
authors.lastname: Goldman
mesh_terms: D000328:Adult; D000335:Aerosol Propellants; D000368:Aged; D000369:Aged, 80 and over; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use*; D001993:Bronchodilator Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use*; D019819:Budesonide / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use*; D004311:Double-Blind Method; D004338:Drug Combinations; D004417:Dyspnea / Q000139:chemically induced; D004983:Ethanolamines / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use*; D005260:Female; D005541:Forced Expiratory Volume; D000068759:Formoterol Fumarate; D006801:Humans; D008297:Male; D036501:Metered Dose Inhalers; D008875:Middle Aged; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy*; D011788:Quality of Life; D012129:Respiratory Function Tests
chemical_list: D000335:Aerosol Propellants; D000893:Anti-Inflammatory Agents; D001993:Bronchodilator Agents; D004338:Drug Combinations; D004983:Ethanolamines; D019819:Budesonide; D000068759:Formoterol Fumarate
references.citation: Chest. 2007 Mar;131(3):648-9
references.pmid: 17356076
references.citation: Chest. 2007 Mar;131(3):682-689
references.pmid: 17356080
references.citation: Am J Respir Crit Care Med. 2008 Jan 1;177(1):19-26
references.pmid: 17916806
references.citation: Am J Respir Crit Care Med. 2002 Oct 15;166(8):1084-91
references.pmid: 12379552
references.citation: Am J Respir Crit Care Med. 2001 Sep 1;164(5):778-84
references.pmid: 11549532
references.citation: Respir Med. 2003 Jan;97 Suppl A:S59-70
references.pmid: 12564612
references.citation: Am J Respir Crit Care Med. 2007 Jan 15;175(2):144-9
references.pmid: 17053207
references.citation: Lancet. 2003 Feb 8;361(9356):449-56
references.pmid: 12583942
references.citation: BMJ. 2000 May 13;320(7245):1297-303
references.pmid: 10807619
references.citation: COPD. 2005 Mar;2(1):157-65
references.pmid: 17136977
references.citation: Am Rev Respir Dis. 1992 Jun;145(6):1321-7
references.pmid: 1595997
references.citation: Eur Respir J. 2002 Oct;20(4):819-25
references.pmid: 12412670
references.citation: Am J Respir Crit Care Med. 1996 Dec;154(6 Pt 1):1726-34
references.pmid: 8970362
references.citation: Am J Respir Crit Care Med. 2001 Aug 15;164(4):580-4
references.pmid: 11520719
references.citation: Ann Fam Med. 2006 May-Jun;4(3):253-62
references.pmid: 16735528
references.citation: Am J Med. 2002 Jul;113(1):59-65
references.pmid: 12106623
references.citation: N Engl J Med. 2007 Feb 22;356(8):775-89
references.pmid: 17314337
references.citation: COPD. 2005 Mar;2(1):75-9
references.pmid: 17136966
references.citation: Eur Respir J. 2003 Dec;22(6):912-9
references.pmid: 14680078
references.citation: Contemp Clin Trials. 2008 Mar;29(2):114-24
references.pmid: 17625985
references.citation: Eur Respir J. 2002 May;19(5):936-43
references.pmid: 12030736
references.citation: Eur Respir J. 2003 Jan;21(1):74-81
references.pmid: 12570112
references.citation: Chest. 1999 Apr;115(4):957-65
references.pmid: 10208192
references.citation: Am Rev Respir Dis. 1981 Jun;123(6):659-64
references.pmid: 7271065
references.citation: Eur Respir J. 2002 Nov;20(5):1138-46
references.pmid: 12449166
references.citation: Eur Respir J. 2003 Feb;21(2):260-6
references.pmid: 12608439
references.citation: Am J Respir Crit Care Med. 2001 Apr;163(5):1087-92
references.pmid: 11316640
references.citation: COPD. 2008 Jun;5(3):187-200
references.pmid: 18568843