title: Add-on histamine receptor-3 antagonist for allergic rhinitis: a double blind randomized crossover trial using the environmental exposure unit.
abstract: BACKGROUND
  Oral antihistamines that target the histamine receptor-1, such as fexofenadine, offer suboptimal relief of allergic rhinitis-associated nasal congestion. Combinations with oral sympathomimetics, such as pseudoephedrine, relieve congestion but produce side effects. Previous animal and human studies with histamine receptor-3 antagonists, such as PF-03654764, demonstrate promise.
  
  
  METHODS
  Herein we employ the Environmental Exposure Unit (EEU) to conduct the first randomized controlled trial of PF-03654764 in allergic rhinitis. 64 participants were randomized in a double-blind, placebo-controlled 4-period crossover study. Participants were exposed to ragweed pollen for 6 hours post-dose in the EEU. The primary objective was to compare the effect of PF-03654764 + fexofenadine to pseudoephedrine + fexofenadine on the subjective measures of congestion and Total Nasal Symptom Score (TNSS). The objectives of our post-hoc analyses were to compare all treatments to placebo and determine the onset of action (OA). This trial was registered at ClinicalTrials.gov (NCT01033396).
  
  
  RESULTS
  PF-03654764 + fexofenadine was not superior to pseudoephedrine + fexofenadine. In post-hoc analyses, PF-03654764 + fexofenadine significantly reduced TNSS, relative to placebo, and OA was 60 minutes. Pseudoephedrine + fexofenadine significantly reduced congestion and TNSS, relative to placebo, with OA of 60 and 30 minutes, respectively. Although this study was not powered for a statistical analysis of safety, it was noted that all PF-03654764-treated groups experienced an elevated incidence of adverse events.
  
  
  CONCLUSIONS
  PF-03654764 + fexofenadine failed to provide superior relief of allergic rhinitis-associated nasal symptoms upon exposure to ragweed pollen compared to fexofenadine + pseudoephedrine. However, in post-hoc analyses, PF-03654764 + fexofenadine improved TNSS compared to placebo. Side effects in the PF-03654764-treated groups were clinically significant compared to the controls.
authors.affiliation: Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada ; Allergy Research Unit, Kingston General Hospital, Kingston, Ontario, Canada.
authors.forename: Michelle L
authors.initials: ML
authors.lastname: North
authors.affiliation: Allergy Research Unit, Kingston General Hospital, Kingston, Ontario, Canada.
authors.forename: Terry J
authors.initials: TJ
authors.lastname: Walker
authors.affiliation: Allergy Research Unit, Kingston General Hospital, Kingston, Ontario, Canada.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Steacy
authors.affiliation: Allergy Research Unit, Kingston General Hospital, Kingston, Ontario, Canada.
authors.forename: Barnaby G
authors.initials: BG
authors.lastname: Hobsbawn
authors.affiliation: Pfizer Ltd., Sandwich, UK.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Allan
authors.affiliation: Pfizer Ltd., Sandwich, UK.
authors.forename: Frances
authors.initials: F
authors.lastname: Hackman
authors.affiliation: Clinical Research Centre, Kingston General Hospital, Kingston, Ontario, Canada.
authors.forename: Xiaoqun
authors.initials: X
authors.lastname: Sun
authors.affiliation: Clinical Research Centre, Kingston General Hospital, Kingston, Ontario, Canada.
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Day
authors.affiliation: Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada ; Allergy Research Unit, Kingston General Hospital, Kingston, Ontario, Canada ; Division of Allergy and Immunology, Department of Medicine, Queen's University, Doran 1, Kingston General Hospital, 76 Stuart Street, Kingston, ON K7L 2 V7, Canada.
authors.forename: Anne K
authors.initials: AK
authors.lastname: Ellis
keywords: Allergic rhinitis; Decongestant; Environmental exposure unit; Fexofenadine; H1 receptor; H3 receptor; Nasal congestion; PF-03654764; Ragweed; pseudoephedrine