Add-on histamine receptor-3 antagonist for allergic rhinitis: a double blind randomized crossover trial using the environmental exposure unit

Michelle L North, Terry J Walker, Lisa M Steacy, Barnaby G Hobsbawn, Richard J Allan, Frances Hackman, Xiaoqun Sun, Andrew G Day, Anne K Ellis, Michelle L North, Terry J Walker, Lisa M Steacy, Barnaby G Hobsbawn, Richard J Allan, Frances Hackman, Xiaoqun Sun, Andrew G Day, Anne K Ellis

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.

Keywords: Allergic rhinitis; Decongestant; Environmental exposure unit; Fexofenadine; H1 receptor; H3 receptor; Nasal congestion; PF-03654764; Ragweed; pseudoephedrine.

Figures

Figure 1
Figure 1
Time-course of change in symptom scores post-treatment. Exploratory visualization of the change in symptom scores (Δ to baseline) are shown for A) Congestion, and B) Total Nasal Symptom Score (TNSS) from time of drug administration (0 hours) to 6 hours post-treatment. Lines and error bars represent the raw means and standard errors of the means for each of the treatments over time. It includes all participant study periods in which a participant was administered a treatment and remained in the EEU for the entire study period (excludes those periods where a participant discontinued the study without completing the visit). The y-intercept represents baseline, defined as the mean of the last two pre-treatment symptom scores (-0.5H and 0H). Samples sizes were; n = 86, 96, 28 and 14 for PF-03654764 + fexofenadine, fexofenadine + pseudoephedrine, PF-03654764, and placebo, respectively.

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