Clinical validation of controlled exposure to birch pollen in the Environmental Exposure Unit (EEU).

BACKGROUND: The Environmental Exposure Unit (EEU) in Kingston, Ontario, Canada is a controlled allergen challenge facility (CACF) that has been previously clinically validated for the use of ragweed and grass pollen in clinical studies. In this study we aim to validate the use of birch pollen to challenge allergic participants. METHODS: A total of 59 volunteers were screened and 38 birch allergic participants and ten non-allergics completed the study, outside of tree pollen season. Participants had to have a minimum of 2-year history of allergic rhinoconjunctivitis during the typical tree pollen season and have a positive skin prick test to birch allergen ≥5 mm from the control. Qualified participants were exposed to birch (Betula pendula) pollen for 4 h in the EEU and recorded their symptoms of sneezing, rhinorrhea, nasal congestion, nasal itch which comprised the total nasal symptom score (TNSS), as well as itchy/watery eyes, red/burning eyes and itching of ears/palate/throat which along with the TNSS comprised the total rhinoconjunctival symptom score (TRSS) along with Peak Nasal Inspiratory Flow (PNIF) at baseline and at 30 min intervals for the duration of exposure, then hourly for up to 12 h from the start of exposure. RESULTS: Allergic participants reported a gradual rise in TNSS and TRSS, reaching a mean and standard error of the mean of 7.08 ± 0.45 and 11.58 ± 0.93 respectively by 180 min from the start of exposure. Symptoms gradually declined to near baseline values following departing from the unit, reaching 1.9 and 2.7 by 450 min. Allergic participants reported significantly higher TNSS than non-allergics starting from 30 min (p < 0.01, two-way ANOVA with Bonferroni corrections), maintaining maximum significance from 60 to 300 min (p < 0.0001) and losing significance by 420 min. TRSS and PNIF followed similar trends as those seen with TNSS. Participants were phenotyped using previously published definitions using the TNSS into Early Phase Responders (EPR, 57.8 %), protracted EPR (pEPR, 39.5 %), and Dual Phase Responders (DPR, 2.7 %). CONCLUSIONS: The EEU can competently challenge birch allergic participants and achieve statistically significant changes in symptoms and nasal airflow, while such changes are not reported in non-allergic controls. Trial registration NCT02351830 clinicaltrials.gov.

Clinical validation of controlled grass pollen challenge in the Environmental Exposure Unit (EEU).

RATIONALE: The Environmental Exposure Unit (EEU), a controlled allergen exposure model of allergic rhinitis (AR), has traditionally utilized ragweed pollen. We sought to clinically validate the use of grass pollen in the EEU. METHODS: Healthy volunteers with a history of AR symptoms during grass pollen season and supportive skin test responses attended the EEU for 3 hrs of rye grass pollen exposure (Lolium Perenne). Non-atopic controls were also recruited. Participants assessed individual rhinoconjunctivitis symptoms to generate Total Nasal Symptom Score (TNSS; max 12) and Total Symptom Score (TSS; max 24) and recorded Peak Nasal Inspiratory Flow (PNIF) q30min while in the EEU. Participants returned the following day for an additional 3 hrs of pollen exposure. Two separate groups allowed for the exploration of lower vs. higher pollen concentrations and subsequent effects on symptoms. RESULTS: 78 participants were screened, of whom 39 were eligible and attended the 2x3h EEU visits, plus 8 non-atopic controls. Mean TSS, TNSS and PNIF values amongst participants in the higher pollen concentration group (target 3500 grains/m3) after the first 3 hr exposure were 18.9, 9.7 and 68 L/min, respectively. In comparison, mean TSS, TNSS and PNIF values in the lower pollen concentration (2500 grains/m3) group were only 13.3, 7.6, and 82 L/min, respectively. The subsequent day of pollen exposure did not appreciably alter the maximal TSS/TNSSs, but rather resulted in a more rapid onset of symptomatology, with higher mean scores at the 30 min, 60 min and 90 min timepoints. The non-atopic controls remained asymptomatic. CONCLUSIONS: This study provides clinical validation of the ability to generate allergic rhinoconjunctivitis symptoms amongst grass-allergic individuals in the EEU.

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

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.