title: Rapid effects of extrafine beclomethasone dipropionate/formoterol fixed combination inhaler on airway inflammation and bronchoconstriction in asthma: a randomised controlled trial.
abstract: BACKGROUND
  The dose-dependent anti-inflammatory effects of a recent fixed combination of extrafine beclomethasone dipropionate/formoterol (BDP/F) were investigated using non-invasive markers of inflammation, exhaled nitric oxide (NO) and adenosine monophosphate (AMP) provocative challenge. The aim was to assess the onset of the anti-inflammatory action of low and high doses and evaluate the suitability of non-invasive assessments to demonstrate dose response.
  
  
  METHODS
  Steroid naïve adult out-patients with mild asthma, sensitive to AMP with baseline exhaled NO > 25 parts per billion entered a double-blind, placebo-controlled, 3-way, cross-over study. Patients were randomised to low dose (1 actuation) or high dose (4 actuations) extrafine BDP/F 100/6 μg, or placebo administered twice daily on Days 1 and 2 and once in the morning on Day 3 of each period. Exhaled NO was measured pre-dose on Day 1, then 2 and 4 hours post-administration on Day 3. The AMP challenge was performed 4 hours post-administration on Day 3 and forced expiratory volume in 1 second (FEV1, L) was measured from 0 to 4 hours post-dose on Day 1. Endpoints were NO at 2 and 4 hours, AMP challenge at 4 hours after the fifth dose on Day 3 and FEV1 area under the curve from 0 to 4 h post-dose on Day 1. Analysis of covariance was performed for NO and FEV1 and analysis of variance for AMP challenge.
  
  
  RESULTS
  Eighteen patients were randomised and completed the study. Exhaled NO was significantly lower for both doses of extrafine BDP/F versus placebo at 2 and 4 hours (high dose LS mean difference: -22.5 ppb, p < 0.0001 and -20.5 ppb, p < 0.0001; low dose: -14.1 ppb, p = 0.0006 and -12.1 ppb, p = 0.0043) with a significant dose response (p = 0.0342 and p = 0.0423). Likewise, AMP challenge revealed statistically significant differences between both doses of extrafine BDP/F and placebo (high dose LS mean difference: 4.8 mg/mL, p < 0.0001; low dose: 3.7 mg/mL, p < 0.0001), and a significant dose response (p = 0.0185). FEV1 was significantly improved versus placebo for both doses (high dose LS mean difference: 0.2 L, p = 0.0001; low dose: 0.2 L p = 0.0001), but without a significant dose response.
  
  
  CONCLUSIONS
  The fixed combination inhaler of extrafine BDP/F has early dose-dependent anti-inflammatory effects with a rapid onset of bronchodilatation in mild asthmatic patients.
  
  
  BACKGROUND
  ClinicalTrials.gov: NCT01343745.
authors.affiliation: Chiesi Farmaceutici S.p.A., Via Palermo 26/A, Parma, Italy.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: O'Connor
authors.forename: Sara
authors.initials: S
authors.lastname: Collarini
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Poli
authors.forename: Caterina
authors.initials: C
authors.lastname: Brindicci
authors.forename: Monica
authors.initials: M
authors.lastname: Spinola
authors.forename: Daniela
authors.initials: D
authors.lastname: Acerbi
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Barnes
authors.forename: Brian
authors.initials: B
authors.lastname: Leaker
mesh_terms: D000280:Administration, Inhalation; D000293:Adolescent; D000328:Adult; D018927:Anti-Asthmatic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001249:Asthma / Q000188:drug therapy*; D001507:Beclomethasone / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D016084:Bronchoconstriction / Q000187:drug effects*; D001993:Bronchodilator Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004338:Drug Combinations; D004983:Ethanolamines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D005541:Forced Expiratory Volume; D000068759:Formoterol Fumarate; D006801:Humans; D036501:Metered Dose Inhalers; D008875:Middle Aged; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D018927:Anti-Asthmatic Agents; D001993:Bronchodilator Agents; D004338:Drug Combinations; D004983:Ethanolamines; D001507:Beclomethasone; D000068759:Formoterol Fumarate