Environmental Exposure Chamber Model Research Articles

Effect of olopatadine-mometasone combination nasal spray on seasonal allergic rhinitis symptoms in an environmental exposure chamber study

BackgroundGSP301 nasal spray is a fixed-dose combination of the antihistamine olopatadine hydrochloride and the corticosteroid mometasone furoate intended for seasonal allergic rhinitis (SAR) treatment. ObjectiveTo evaluate the efficacy and safety of once-daily or twice-daily GSP301 in a ragweed pollen environmental exposure chamber. MethodsIn this randomized, double-blind, double-dummy study, adults (18-65 years old) with SAR were equally randomized to 665 μg of olopatadine and 25 μg of mometasone (twice-daily GSP301), 665 μg of olopatadine and 50 μg of mometasone (once-daily GSP301), a US Food and Drug Administration–approved formulation of 137 μg of azelastine and 50 μg of fluticasone twice-daily (AzeFlu), a US Food and Drug Administration–approved formulation of 665 μg of olopatadine twice-daily, or placebo (twice-daily). During 2 visits (baseline and end of 14-day treatment), participants assessed SAR symptoms at specified time points. The primary end point—mean change from baseline in instantaneous total nasal symptom score (iTNSS) for twice-daily or once-daily GSP301 vs placebo—was analyzed by analysis of covariance. Onset of action, ocular symptoms, and adverse events were assessed. ResultsA total of 180 participants were randomized. Treatment with twice-daily or once-daily GSP301 provided statistically significant improvements in iTNSS vs placebo (twice-daily GSP301: least squares mean difference, −3.60; 95% confidence interval [CI], −4.89 to −2.30; once-daily GSP301: least squares mean difference, −3.05; 95% CI, −4.35 to −1.76; P < .0001 for both). Significant improvements in iTNSS with twice-daily GSP301 occurred by 10 minutes after dosing (−1.26; 95% CI, −2.30 to −0.21; P = .02) and were maintained at all later time points except one (2.5 hours). Treatment-emergent adverse events occurred in 22.2%, 30.6%, 25.0%, 22.2%, and 16.7% of participants in the twice-daily GSP301, once-daily GSP301, AzeFlu, olopatadine, and placebo groups, respectively. ConclusionIn an environmental exposure chamber model, twice-daily and once-daily GSP301 treatments were well tolerated and provided statistically significant and clinically meaningful SAR symptom improvement vs placebo. Trial RegistrationClinicalTrials.gov Identifier: NCT03444506

A Pilot Study Investigating Clinical Responses and Biological Pathways of Azelastine/Fluticasone in Nonallergic Vasomotor Rhinitis before and after Cold Dry Air Provocation

Background: Nonallergic vasomotor rhinitis (NAVMR) has been considered a diagnosis by exclusion due to unknown mechanisms or lack of diagnostic biomarkers. Methods: To determine clinical responses and biological pathways in NAVMR subjects challenged to cold dry air (CDA) in an environmental exposure chamber (EEC) pre- and posttreatment with azelastine/fluticasone (AzeFlu), 30 NAVMR subjects, prescreened for CDA-induced symptoms (approx. 14°C, <15% relative humidity, ×1 h) were randomized to treatment with AzeFlu (n = 20) or placebo (n = 10) for 2 weeks. Total nasal symptoms scores, minimum cross-sectional area, cough, and conjunctival redness were recorded at visit 1 (pretreatment) and visit 2 (posttreatment) before, during, and after CDA challenge. At both visits, nasal lavage fluid (NLF) and nasal scrapings (NS) were collected pre- and post-CDA challenge. Substance P, neurokinin-A, and calcitonin gene-related peptide concentrations in NLF were analyzed pre- and postchallenge at each visit. Their relationship with CDA-induced symptoms was determined by statistical analysis. MicroRNA sequencing from NS determined differentially expressed miRNA between the treatment groups post-CDA challenge at each visit. Results: The minimum cross-sectional area (p < 0.05), cough count (p < 0.05), and substance P (p < 0.01) improved posttreatment with AzeFlu versus placebo. Gene targets for differentially expressed miRNAs at visit 1 were enriched for biological pathways regulating epithelial ciliogenesis and cell integrity that were modified in the AzeFlu-treated group versus placebo posttreatment. Conclusions: This study demonstrated the feasibility of an EEC model to investigate CDA-induced clinical responses and pathobiology in NAVMR subjects pre- and posttreatment with AzeFlu. NAVMR disease mechanisms for other nonallergic triggers can be investigated similarly.

A proof-of-concept study of the effect of a novel H3-receptor antagonist in allergen-induced nasal congestion

H1-receptor inverse agonists are used effectively for treating several symptoms of allergic rhinitis, including nasal itching, rhinorrhea, and sneezing, although most agents are not very effective in treating nasal congestion. This study evaluated the relative efficacy of a novel selective H3-receptor antagonist, JNJ-39220675, in preventing nasal congestion induced by exposing participants with ragweed allergy to ragweed allergen in an environmental exposure chamber model. In this single-dose, patient-blind, double-dummy, placebo- and active-controlled, phase IIa cross-over study, 53 participants were randomized to JNJ-39220675 plus placebo, placebo plus pseudoephedrine, or only placebo. The primary efficacy assessment was change in nasal patency assessed by measuring the minimal cross-sectional area of the nasal cavity by using acoustic rhinometry. Secondary assessment included total nasal symptom scores (TNSSs) over the 8-hour environmental exposure chamber exposure period. Smaller decreases in minimal cross-sectional area were observed after JNJ-39220675 (least square mean difference, -0.126; P = .06) and pseudoephedrine (least square mean difference, -0.195; P = .004) treatment compared with placebo. The means for the baseline-adjusted area under the curve of TNSSs were significantly smaller for JNJ-39220675 (P = .0003) and pseudoephedrine (P = .04) versus placebo. JNJ-39220675 was significantly effective in treating all 4 individual symptoms (P ≤ .05 for all scores) compared with placebo, whereas pseudoephedrine only showed a trend for improvement in individual symptom scores of the TNSS. Insomnia was the most frequent adverse event (17.3%) associated with JNJ-39220675 treatment. Prophylactic treatment with the H3-antagonist JNJ-39220675 relieved allergen-induced nasal congestion by using standard nasal symptom scoring; however, in contrast to pseudoephedrine, it only showed a trend for increasing nasal patency by using objective measures.

Immunotherapy – 2080. Fel d 1 derived peptide antigen desensitization results in a persistent treatment effect on symptoms of cat allergy 1 year after 4 doses

Background Previously, we identified a series of T-cell epitopes from the major cat allergen Fel d1 and showed these were safe and well-tolerated when administered to cat allergic subjects. In the current study, we evaluated persistence of the treatment effect (tolerance) one year after start of dosing for two treatment regimens with the same cumulative dose. Methods Subjects underwent Baseline Challenge in an Environmental Exposure Chamber (EEC) on 4 consecutive days, consisting of 3-hour allergen exposures (Fel d1 50.19±3.70 ng/m3). Subjects scored four nasal and four ocular symptoms every 30 minutes each on a scale of 0-3. 202 subjects were randomised to placebo, 8x3nmol Cat Peptide Antigen Desensitisation (Cat-PAD) 2weeks(wk) apart or 4x6nmol Cat-PAD 4wk apart. Subjects re-attended the EEC for 4 consecutive days, of 3-hours, 18-22wk after the start of treatment. 50-54wk after commencement of treatment subjects were invited to participate in a blinded follow-on study without further dosing. 89 subjects were enrolled and had a further 4 consecutive days, of 3-hours in the EEC.

Provocation of nonallergic rhinitis subjects in response to simulated weather conditions using an environmental exposure chamber model

Nonallergic rhinitis (NAR) subjects present clinically with similar symptoms to subjects with allergic rhinitis, but which mechanistically are not IgE- mediated. NAR is difficult to study because of multiple, as yet unknown, disease mechanisms and lack of biomarkers and diagnostic tests. The purpose of this proof of concept pilot study was to develop an environmental exposure chamber (EEC) model to simulate weather conditions in a controlled setting to objectively diagnose NAR subjects and ultimately to investigate novel NAR therapies. Thirty-seven subjects with a history of NAR confirmed by negative skin-prick test to a panel of aeroallergens were tested with cold dry air (CDA) and temperature change challenges. Objective (acoustic rhinometry [AcR] and nasal secretions) and subjective measures (total nasal symptom scores [TNSSs]: congestion, rhinorrhea, and postnasal drip [0-3]) were collected. Data was presented as mean ± SEM and statistical significance was assessed by paired t-test. The NAR EEC AcR responders to CDA had a significant decrease in mean minimal cross-sectional area (MCA; a measure of nasal patency) of 22.2 ± 2.43% (p < 0.0001) and 6.7 ± 7.22% (not statistically significant) at 30 and 60 minutes, respectively, with a concomitant increase in TNSS of 1.0 ± 0.24 U and 1.4 ± 0.30 U, respectively. AcR responders to temperature change showed a significant decrease in mean MCA to warm air of 16.0 ± 3.82% (p < 0.001) and 19.4 ± 3.88% (p < 0.0001) at 30 and 60 minutes, respectively, with an increase of TNSS of 0.4 ± 0.25 U and 0.4 ± 0.27 U, respectively. With rapid conversion to cold air, further decrease in mean MCA accompanied by an increase in TNSS was observed at 30 and 60 minutes. Increase in rhinorrhea was highest for CDA and the cold air phase of the temperature change challenge. Using the NAR EEC model, significant symptoms were induced in response to simulated weather changes in NAR patient responders. This proof of concept pilot study shows that the EEC model provides a consistent and reliable method to phenotype weather-induced NAR subjects that could be used to investigate disease mechanisms and novel therapies for NAR.

55 Ocular Signs and Symptoms Elicited by a Naturalistic Allergen Challenge in an Environmental Exposure Chamber Model Versus a Direct Allergen Instillation Model

BackgroundDirect-instillation ocular models are well established for eliciting allergic responses in research and clinical testing. This study compared direct ocular instillation of allergen to a more naturalistic airborne allergen exposure.MethodsThirteen subjects with histories of ragweed allergy and positive skin prick responses attended screening, dose-finding, dose, confirmation, and analysis study visits. For conjunctival allergen provocation testing (CAPT), 1 drop of ragweed allergen was administered to each eye, at the lowest possible subject-specific concentration between 1.6 and 100 protein nitrogen units per 25 μl drop. For environmental exposure chamber (EEC) testing, subjects were exposed to continual airborne ragweed pollen at 3500 ± 500 particles/m3. Symptoms of itching and tearing were self-assessed on diary cards by subjects. Signs of hyperemia, swelling, and mucous discharge were assessed by clinicians. Assessment time points started at 30 minutes before exposure and continued through 180 minutes after exposure.ResultsAt baseline, there were minimal signs and symptoms. Maximum mean hyperemia with CAPT was 2.3 ± 0.6 units (between moderate and severe) and with EEC was 1.9 ± 0.5 units (approximately moderate); these maxima occurred after 30 minutes with CAPT (rapid spike) and after 180 minutes with EEC (gradual increase). Mean swelling was <1 unit out of 4 units at all times (CAPT and EEC), and mucous discharge was observed in only 1 subject during the study (with CAPT). Maximum mean itching with both CAPT and EEC was 2.8 ± 1.0 units (approximately severe), but this maximum occurred after 20 minutes with CAPT (rapid spike) and after 180 minutes with EEC (gradual increase). Maximum mean tearing with CAPT was 1.2 ± 0.7 units (approximately mild) and with EEC was 1.6 ± 0.6 units (between mild and moderate); these maxima occurred after 15 minutes with EEC (rapid spike) and after 120 minutes with EEC (gradual increase).ConclusionsThe time courses of allergic signs and symptoms differed between CAPT and EEC models; however, both models evoked similar maximum response levels. This demonstrates that the EEC model is a useful challenge model for mimicking natural airborne ocular allergen exposure.

Ectoin ®, a Novel, Non-Drug, Extremophile-Based Device, Relieves Allergic Rhinoconjunctivitis Symptoms in Patients in an Environmental Exposure Chamber Model

RATIONALE: Despite the many pharmaceutical treatments available, allergy patients remain dissatisfied due to deleterious side-effects and ineffective symptom relief. A new, naturally-sourced, extremophile derived, anti-allergic device, Ectoin®, was investigated in this study. The objective was to assess the relative efficacy of Ectoin® Nasal Spray and Eye Drops compared to placebo on the complex of rhinoconjuntivitis symptoms in subjects exposed to highly controlled ragweed levels in an Environmental Exposure Chamber.

Seasonal allergic rhinitis symptoms correlate with the quality of life in patients with ragweed allergy in the environmental exposure chamber model

Seasonal allergic rhinitis symptoms correlate with the quality of life in patients with ragweed allergy in the environmental exposure chamber model

Effect of ‘priming’ on predose symptom scores in environmental exposure chamber (EEC) study design

RATIONALE: Study designs utilizing EEC model commonly involve several EEC sessions prior to the main treatment EEC session to 'Prime' the patient. The rationale for this is to initiate the late phase allergic response, which theoretically results in higher predose symptoms on treatment day. We wanted to investigate and quantify the effect of ‘priming’ on the Total Nasal Symptom Scores (TNSS- sneezing, runny, itchy and stuffy nose on a 0-3 rating scale) on treatment day.