title: Effects of low- versus high-dose fluticasone propionate/formoterol fumarate combination therapy on AMP challenge in asthmatic patients: A double-blind, randomised clinical trial.
abstract: The dose-response relationship between two dose levels of fluticasone/formoterol (flutiform(®), 100/10 μg and 500/20 μg) was evaluated in asthmatic patients. Non-invasive inflammatory markers were used including adenosine monophosphate (AMP) challenge (primary endpoint), and sputum eosinophils and fractional exhaled nitric oxide (FeNO) (secondary endpoints).
  
  
  
  Patients aged ≥18 years with forced expiratory volume in 1 s (FEV1) ≥60% predicted and who required a dose of <60 mg AMP to elicit a 20% drop in FEV1 (AMP PD20) were randomised in this incomplete block, crossover study to receive 2 of 3 treatments b.i.d.: fluticasone/formoterol 500/20 μg (high dose), 100/10 μg (low dose) or placebo, during 2 periods of 28 ± 3 days each, separated by 2-3 weeks. AMP challenges were performed pre-dose and 12 h after last dose at the end of each treatment period. A series of post hoc analyses were performed only in patients allocated to both fluticasone/formoterol doses, who completed the study and had evaluable AMP PD20 data for both treatments ("fluticasone/formoterol subgroup"). Changes in AMP PD20 FEV1, percentage sputum eosinophils and FeNO levels (Day 1 vs Day 28) between treatments were compared by an analysis of covariance (ANCOVA).
  
  
  
  Sixty-two patients were randomised and 46 completed the study. Fifteen patients received both high- and low-dose fluticasone/formoterol (post hoc subgroup). The difference in AMP PD20 for the overall population was not statistically significant between high- and low-dose fluticasone/formoterol (LS mean fold difference: 1.3; p = 0.489), although both dose levels were superior to placebo: high-dose vs placebo LS mean fold difference: 4.4, p < 0.001; low-dose vs placebo LS mean fold difference: 3.5, p < 0.001. In the post hoc subgroup, the difference in AMP PD20 between the doses was statistically significant in favour of the high-dose (LS mean fold difference: 2.4, p = 0.012). Other inflammatory parameters (sputum eosinophil counts and FeNO) showed small differences and statistically non-significant changes between high- and low-dose fluticasone/formoterol.
  
  
  
  A significant dose-response was found between low- and high-dose fluticasone/formoterol in the post hoc subgroup (patients who received both doses), but not in the overall population, with the higher dose demonstrating a greater reduction in airway responsiveness to AMP.
authors.affiliation: Practice for Allergy and Family Medicine, Reinfeld, Germany. Electronic address: f.kanniess@gpr-reinfeld.de.
authors.forename: Frank
authors.initials: F
authors.lastname: Kanniess
authors.affiliation: Department of Respiratory Medicine and Allergology, Skane University Hospital, Institute for Clinical Science, Lund University, Lund, Sweden; University of Groningen, University Medical Centre Groningen, Department of General Practice, Department of Clinical Pharmacy & Pharmacology, Groningen, Netherlands; QPS-Netherlands, Groningen, Netherlands. Electronic address: z.diamant@gems.demon.nl.
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Diamant
authors.affiliation: Mundipharma Research Ltd, Cambridge, UK. Electronic address: Mark.Lomax@mundipharma-rd.eu.
authors.forename: Mark
authors.initials: M
authors.lastname: Lomax
mesh_terms: D000249:Adenosine Monophosphate / Q000008:administration & dosage; D000328:Adult; D000730:Androstadienes / Q000008:administration & dosage* / Q000627:therapeutic use; D018927:Anti-Asthmatic Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D001249:Asthma / Q000188:drug therapy* / Q000503:physiopathology; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004338:Drug Combinations; D004804:Eosinophils / Q000378:metabolism; D004983:Ethanolamines / Q000008:administration & dosage* / Q000627:therapeutic use; D005260:Female; D000068298:Fluticasone; D005541:Forced Expiratory Volume; D000068759:Formoterol Fumarate; D006801:Humans; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide / Q000378:metabolism; D013183:Sputum / Q000378:metabolism
chemical_list: D000730:Androstadienes; D018927:Anti-Asthmatic Agents; D004338:Drug Combinations; D004983:Ethanolamines; C586520:fluticasone-formoterol; D009569:Nitric Oxide; D000249:Adenosine Monophosphate; D000068298:Fluticasone; D000068759:Formoterol Fumarate
keywords: AMP bronchoprovocation test; Asthma; Dose-response; Fluticasone propionate; Formoterol fumarate; ICS/LABA