Onset of Action of the Fixed Combination Intranasal Azelastine-Fluticasone Propionate in an Allergen Exposure Chamber.

BACKGROUND: A fixed-dose combination of intranasal azelastine hydrochloride and fluticasone propionate (MP-AzeFlu) is the most effective treatment of allergic rhinitis, but its onset of action requires further investigation. OBJECTIVE: To compare the onset of action of MP-AzeFlu with the free combination of oral loratadine (LORA) and intranasal fluticasone propionate (INFP). METHODS: In this single-center, randomized, placebo-controlled, double-blind, double-dummy, 3-period crossover trial, allergic rhinitis symptoms were induced in asymptomatic patients by ragweed pollen challenge in an allergen environmental exposure chamber. Patients received single-dose MP-AzeFlu, LORA/INFP, or placebo and were monitored for 4 hours. The primary outcome was onset of action measured by total nasal symptom score (TNSS). Secondary measures were total ocular symptom score (TOSS), total score of the 7 nasal and ocular symptoms (T7SS), and the global visual analog scale (VAS). RESULTS: The full analysis set included 82 patients, of which 78 completed all treatments. TNSS was significantly reduced versus placebo from 5 minutes for MP-AzeFlu and 150 minutes for LORA/INFP onward (both P < .05) till the end of assessment (0-4 hours). MP-AzeFlu reduced TNSS to a greater extent at each time point from 5 to 90 minutes (P < .05) and over the entire assessment interval (P ≤ .005) versus LORA/INFP or placebo. No statistically significant difference between LORA/INFP and placebo was observed over the assessment interval (P = .182). The onset of action of MP-AzeFlu assessed by TOSS, T7SS, and VAS was 10 minutes, 2 hours earlier than with LORA/INFP. CONCLUSION: MP-AzeFlu had a more rapid onset of action (5 minutes) and was more effective than LORA/INFP.

Validation of the Global Allergy and Asthma European Network (GA2LEN) chamber for trials in allergy: Innovation of a mobile allergen exposure chamber.

BACKGROUND: Field clinical trials of pollen allergy are affected by the impossibility of predicting and determining individual allergen exposure because of many factors (eg, pollen season, atmospheric variations, pollutants, and lifestyles). Environmental exposure chambers, delivering a fixed amount of allergen in a controlled environmental setting, can overcome these limitations. Environmental exposure chambers are currently already used in phase 2, 3, and even 4 trials. Unfortunately, few chambers exist in the world, and this makes it difficult to perform large, multicenter clinical trials. The new Global Allergy and Asthma European Network (GA2LEN) mobile exposure chamber is a step forward because the mobility of the chamber makes it convenient for patients to participate in clinical testing. OBJECTIVE: This study was made to validate the reproducibility, sensitivity, and specificity of the results obtained in the new GA2LEN chamber. METHODS: Seventy-two adult patients (19-61 years old) with allergic rhinitis with or without asthma caused by grass pollen were included in different clinical validation tests. Total symptom scores and total nasal symptom scores were recorded at time zero (0) and every 10 minutes during exposures, along with nasal and respiratory parameters. RESULTS: Exposure tests confirmed the reproducibility between subsequent runs and the sensitivity (P < .00001 vs patients exposed to placebo) and specificity (very low score in nonallergic subjects) in the GA2LEN chamber. No adverse reactions were recorded during the tests. CONCLUSIONS: The mobility of the GA2LEN chamber provides a new, potentially effective, and safe way of generating reliable data in allergy multicenter clinical trials.

Method for a homogeneous distribution of pollens in an environmental exposure chamber.

BACKGROUND: A variety of different environmental exposure chambers (EECs) have been used to evaluate treatments for allergic rhinitis. OBJECTIVE: To describe and test a system for a homogenous distribution of grass pollen, Phleum Pratense, in an EEC to be used for controlled pollen exposure studies in allergic participants. METHODS: A chamber made of stainless steel with completely rounded corners, seating four individuals at a time, was used. Room pressure, temperature, humidity and the air change rate were kept constant throughout the study period. A rotating pipette dispensed a uniform supply of pollen into a turntable's v-shaped grooves. A stainless steel capillary tube sucked the pollens into a venturi throat at which time the pollens were mixed with a high-pressure airstream of compressed high-efficiency particulate arrestance filtered air and then transported to a spreading plate inside the EEC. To achieve uniform concentrations in the EEC, the turntable's rotating speed was continuously adjusted using information from video-coupled feedback and feed forward mechanisms. Pollen levels were detected using standard volumetric air samplers and laser particle counters. The target pollen exposure level was 1000 pollens/m(3) . Twenty-one participants were exposed to pollens in the EEC twice for 210 min. Participants evaluated their symptoms every 30 min using a total nasal symptom score (TNSS) consisting of blocked nose, runny nose, nasal itching and sneezing. RESULTS: Across fifteen study days, the average pollen level was 982 pollens/m(3) (SD, 102 pollens/m(3) ). On average, participants experienced a 10% difference in overall pollen levels between their two visits to the EEC. The mean TNSSs rose throughout the exposure period, with a low at baseline of 0.43 (SD, 0.68) to a high of 4.71 (SD, 2.43) just before exiting the EEC. CONCLUSION AND CLINICAL RELEVANCE: This EEC provides a reproducible, precise and homogenous distribution of pollens making it suitable for single-centre allergy clinical trials.

Environmental exposure chambers in allergen immunotherapy trials: Current status and clinical validation needs.

As required by the European Medicines Agency and the US Food and Drug Administration for pivotal trials involving allergen immunotherapy (AIT) products, clinical efficacy assessment is currently based on double-blind, placebo-controlled field studies with natural allergen exposure during the allergen season. However, this study design is associated with several drawbacks, such as the high variability of allergen exposure in different trial sites or seasons and the presence of confounding environmental factors. On the contrary, environmental exposure chambers (EECs) aim to operate with a stable and reproducible allergen exposure under highly standardized environmental conditions. Technical validation parameters for different EECs worldwide have been published by several groups. However, full clinical validation of EEC study outcomes is required for their classification as an appropriate alternative to natural allergen exposure for AIT product efficacy assessment. Some clinical validation parameters have already been addressed for EEC units. The reliability of provoked symptoms in repeated EEC sessions is high, but the predictive power of EEC settings for the clinical response on natural exposure and the impact of seasonal priming on test results still have to be validated systematically, as does the inter-EEC variability. Thus the authors recommend a continued in-depth validation of EECs to exploit the potential of this technology for future AIT product development.

Efficacy of a short course of specific immunotherapy in patients with allergic rhinoconjunctivitis to ragweed pollen.

BACKGROUND: Specific immunotherapy acts to modify the underlying cause of allergic rhinoconjunctivitis. Addition of adjuvants, such as monophosphoryl lipid A (MPL), might allow for efficacious and safe treatment with only 4 injections administered preseasonally, which is in contrast to most available schedules requiring long injection courses. OBJECTIVE: The primary objective was to assess the clinical efficacy of Ragweed MATA MPL (short ragweed pollen allergoid adsorbed to L-Tyrosine + MPL) versus placebo in reducing allergic rhinoconjunctivitis symptoms caused by ragweed pollen in an environmental exposure chamber (EEC) 3 weeks after treatment. METHODS: This was a randomized, double-blind, placebo-controlled phase IIb study to evaluate the clinical efficacy and safety of Ragweed MATA MPL compared with placebo by using controlled ragweed pollen exposure in an EEC. Two hundred twenty-eight patients with a history of ragweed allergy and positive skin prick test responses to ragweed were randomized and received 4 weekly injections of active treatment or placebo. Total nasal and nonnasal symptom scores were obtained in the EEC before and after treatment. RESULTS: Mean improvement in total symptom scores in the Ragweed MATA MPL group was statistically significantly greater than in the placebo group (relative mean improvement of active vs placebo, 48%; P < .05; median improvement, 82%). The majority of adverse events (AEs) experienced by subjects were mild injection-site reactions. No severe systemic AEs or serious AEs occurred during the study. CONCLUSION: This study demonstrated that an ultrashort course of Ragweed MATA MPL is efficacious in reducing allergy symptoms in patients with seasonal allergic rhinitis and that it is well tolerated.