Allergen Challenge Chamber Research Articles

The Efficacy and Tolerability of Two Novel H1/H3 Receptor Antagonists in Seasonal Allergic Rhinitis

Background: A therapeutic role for histamine H₃ receptor antagonism in allergic rhinitis has been proposed and may be complimentary to the well-known benefits of H₁ receptor antagonism. Combined H₁/H₃ blockade has therefore been investigated as a novel therapeutic approach that may enhance symptom relief, particularly nasal blockage. Methods: Two novel H₁/H₃ dual receptor antagonists were investigated in phase I and II safety and efficacy studies. One molecule (GSK1004723) was designed for intranasal administration as a suspension or solution and the other molecule (GSK835726) for oral administration. In phase I and II studies, both molecules were compared with an active control and/or placebo in randomised studies. In phase II studies, efficacy was assessed in an environmental allergen challenge chamber (ECC). Subjects with seasonal allergic rhinitis were exposed to allergen to induce symptoms. Efficacy and safety was measured over 4, 7 and 20–24 h post-dose. The endpoints included total nasal symptom score and nasal blockage. Results: Intranasal suspension of GSK1004723 and oral GSK835726 were well tolerated. Single-dose intranasal suspensions of GSK1004723 (220, 1,100 µg) failed to demonstrate clinically significant attenuation of symptoms of allergic rhinitis induced in the ECC. Single (10, 50, 100 mg) and 3-day repeat (10 mg) dose oral GSK835726 demonstrated clinically significant attenuation of symptoms in the ECC comparable to cetirizine 10 mg. Three-day repeat dosing of the intranasal solution GSK1004723 1,000 µg also demonstrated a statistically significant attenuation of nasal symptoms, but was less than seen with cetirizine and GSK835726 and caused initial nasal discomfort. Conclusions: Combined H₁/H₃ antagonism did not show differentiation from H₁ antagonism in reducing total nasal symptom score or nasal blockage.

Changes in basophil activation during grass-pollen sublingual immunotherapy do not correlate with clinical efficacy

Biomarkers predicting the safety and efficacy of sublingual immunotherapy (SLIT) remain to be established. Eighty-nine patients with allergic rhinoconjunctivitis to grass pollen received either a placebo or five-grass-pollen daily tablet sublingually for 4 months. Following exposure in an allergen challenge chamber, clinical responders and nonresponders were identified individually by evaluating their rhinoconjunctivitis total symptom score (RTSS). Activation of peripheral blood basophils was measured by cytofluorometry before and after 2 or 4 months of immunotherapy, based on CD203c surface expression following allergen stimulation. Patients receiving the grass-pollen tablet had a relative mean improvement of 29.3% vs placebo in the average RTSS after 4 months of SLIT (P < 0.0003). No significant changes in basophil activation were noticed after 2 or 4 months of SLIT despite induction of specific IgGs. Among individual clinical responders, basophil activation was either decreased, increased, or unmodified during SLIT. Levels of basophil activation prior to immunotherapy were not predictive of local adverse reactions associated with immunotherapy. A moderate association was found between basophil activation and allergen-specific IgE levels, skin reactivity, or RTSS, suggesting that the former is, to some extent, indicative of disease severity. As such, patients with the highest level of basophil activation before treatment were more likely to benefit clinically from SLIT. Allergen reactivity of peripheral blood basophils is not a biomarker for adverse events or early onset of clinical responses to SLIT.

Evaluating the Effects of Testing Period on Pollinosis Symptoms Using an Allergen Challenge Chamber

We previously built a pollen challenge test unit (allergen challenge chamber: ACC) to collect objective data about Japanese cedar pollinosis. In this study, we investigated adequate conditions for pollen challenge using the ACC. The study consisted of two parts. The first part was conducted in November, which is not in pollen season. Subjects were exposed to Japanese cedar pollen at a concentration of 50,000 grains/m3 in the chamber for 120 min each day over the course of three consecutive days. The second part was conducted in April, which is just after pollen season. Subjects were exposed to Japanese cedar pollen at the same concentration (50,000 grains/m3) in the chamber for 90 min on a single day. Subjects recorded nasal and ocular symptoms before challenge and every 15 min after challenge initiation. The minimum cross-sectional area in the nasal cavity was measured using acoustic rhinometry before and after challenge as an indicator of nasal obstruction. Inflammatory markers in nasal lavage fluid and serum were also measured before and after challenge. Nasal and ocular symptoms were significantly exacerbated after challenge on all days of the single and 3-consecutive-day challenge tests, particularly on the third day of the consecutive challenge test. Nasal and ocular symptoms were also quickly induced with challenge immediately after the end of pollen season. No significant changes in inflammatory markers were seen. Care is needed with regard to pollen challenge conditions in the ACC, including timing of the challenge, to induce pollinosis symptoms that accurately reflect chronic inflammation.

The allergen challenge chamber: a valuable tool for optimizing the clinical development of pollen immunotherapy

The clinical development of allergen immunotherapy for allergic rhinoconjunctivitis because of pollen is complicated by seasonal, geographical and subject-related variability in allergen exposure. Using an allergen challenge chamber (ACC), a room that enables reproducible challenges with controlled levels of inhalant allergens for several hours, these factors can be controlled. The ACC has often been used to evaluate symptomatic medications but is underexploited in the field of allergen immunotherapy. When used in conjunction with a programme of natural-exposure trials, the ACC enables researchers to (i) facilitate the allergen immunotherapy dose-finding process, (ii) accelerate the transition from Phase I/II to Phase III trials, (iii) characterize the onset and maintenance of action, (iv) avoid the confounding effects of rescue medication, (v) better characterize the baseline or pretreatment characteristics of trial subjects, (vi) perform better-standardized physical and laboratory measurements during an acute challenge, (vii) simplify trial logistics and use smaller numbers of subjects than would be required in equivalent natural-exposure studies and (viii) support (but not replace) Phase III natural-exposure trials for the investigation into long-term and disease-modifying effects. ACC studies can further increase levels of evidence for allergen immunotherapy--the only current therapy potentially capable of modifying the underlying allergic disease.

Preliminary study of a challenge test to the patients with Japanese cedar pollinosis using an environmental exposure unit

Objective Although clinical studies on pollinosis have been performed employing placebo-controlled double-blind comparative and field techniques, accurate evaluation is difficult because the scattering pollen count and climatic conditions vary between years and regions, leading to a bias in the results. Thus, we prepared a pollen challenge test unit (allergen challenge chamber: ACC) which facilitates quantitative pollen challenge at any time, and, so, the acquisition of objective data. Methods The control of constant conditions and maintenance of specified pollen concentrations in ACC were investigated. In addition, the pollen distribution in ACC was measured while maintaining the level at 10,000 counts/m 3. The pollen levels were measured employing the aspiration and Durham methods, and the measured values were compared. Furthermore, whether symptoms are adequately induced in the chamber during the non-cedar pollen-scattering season was investigated in 14 volunteers with cedar pollinosis. Results When the pollen level in ACC was set at 6000 counts/m 3 or higher, the rate of variation was ±15%, within the adjustable range, and that of the pollen distribution in the chamber was within ±20%. When the volunteers with cedar pollinosis were exposed to cedar pollen in ACC, pollinosis symptoms were induced, and challenge for 2 consecutive days significantly induced symptoms. Conclusions The temporal and spatial variations of the pollen level in ACC were small, facilitating stable pollen challenge, and pollinosis symptoms were induced in the volunteers with cedar pollinosis. The challenge chamber may be useful to judge the effects of therapy against pollinosis.

Early onset of action of a 5-grass-pollen 300-IR sublingual immunotherapy tablet evaluated in an allergen challenge chamber

The efficacy and safety of a 5-grass-pollen sublingual immunotherapy (SLIT) tablet (Stallergènes SA, Antony, France) have been evaluated in clinical studies during the pollen season. The allergen challenge chamber (ACC) has been developed as a pharmacodynamic assessment tool to control the environmental allergens and to avoid all problems associated with unpredictable pollen seasons. We sought to evaluate the onset of action and efficacy of 300-IR (index of reactivity) SLIT tablets by using an ACC. Patients with grass pollen-induced rhinoconjunctivitis were randomized into the active or placebo groups. A standardized allergen challenge with grass pollen and symptom evaluation every 15 minutes was performed at baseline, 1 week, and 1, 2, and 4 months of treatment. The primary end point was the average rhinoconjunctivitis total symptom score (ARTSS). Allergen-specific basophil activation, T-cell proliferation, and plasmatic IgE and IgG responses were assessed before and after treatment. In the intention-to-treat population (n = 89) a significant treatment effect was achieved after the first month (P = .0042) and second month (P = .0203) and was maintained through to the fourth month (P = .0007). In the active group the ARTSS (means +/- SDs) decreased at each challenge: week 1, 7.40 +/- 2.682; month 1, 5.89 +/- 2.431; month 2, 5.09 +/- 2.088; and month 4, 4.85 +/- 1.999. An improvement (vs placebo) of 29.3% for the mean ARTSS (median, 33.3%) was observed at end point. Furthermore, the induction of grass pollen allergen-specific IgGs was associated with clinical response. The most frequent adverse reactions were local: oral pruritus, ear pruritus, and throat irritation. In this ACC study the 300-IR 5-grass-pollen SLIT tablets had a significant effect on rhinoconjunctivitis symptoms (vs placebo) from the first month of treatment onward.

The concept of receptor occupancy to predict clinical efficacy: A comparison of second generation H1 antihistamines

Second generation H1 antihistamines are considered first-line therapy for allergic rhinitis and chronic idiopathic urticaria, largely because of their nonsedating effects. Evaluating pharmacokinetic and pharmacodynamic parameters and clinical efficacy of a drug is important, but models to predict clinical efficacy are lacking. Receptor occupancy (RO), a predictor for human pharmacodynamics and antihistamine potency that takes into account the affinity of the drug for the receptor and its free plasma concentration, may be a more accurate way to predict a drug's clinical efficacy. This study was designed to assess the concept of RO as a surrogate for clinical efficacy, using examples of second generation oral antihistamines. A literature review was conducted using MEDLINE. Search terms included allergy, allergic rhinitis, drug efficacy, over-the-counter drugs, perennial allergic rhinitis, seasonal allergic rhinitis, second generation antihistamines, chronic idiopathic urticaria, and treatment outcomes. Abstracts and posters from recent allergy-related society meetings were also used. RO of several second generation H1 antihistamines was derived from noncomparative and head-to-head studies. Fexofenadine and levocetirizine showed similar RO at 4 hours, both higher than that of desloratadine. Levocetirizine established higher RO than fexofenadine or desloratadine at 12 and 24 hours. RO for these agents appeared to correlate with pharmacodynamic activity in skin wheal and flare studies and with efficacy in allergen challenge chamber studies. Parameters affecting RO included time from dosing, pH, and dosing regimen. RO did not appear to be linearly related to drug concentration. Results indicate that RO is an accurate predictor of in vivo pharmacodynamic activity and clinical efficacy.

Onset of Action of a Five Grass Pollen 300IR SLIT Tablet Evaluated in an Allergen Challenge Chamber (ACC)

Onset of Action of a Five Grass Pollen 300IR SLIT Tablet Evaluated in an Allergen Challenge Chamber (ACC)

A sublingual grass pollen allergy vaccine tablet [Oralair Grasses] has shown positive results in an allergen challenge chamber study.

A sublingual grass pollen allergy vaccine tablet [Oralair Grasses] has shown positive results in an allergen challenge chamber study.

Levocetirizine

Levocetirizine (Xyzal) is a selective, potent, oral histamine H(1) receptor antagonist of the latest generation that is licensed for the symptomatic treatment of allergic rhinitis (including persistent allergic rhinitis [PER]) and chronic idiopathic urticaria (CIU). Large, well designed trials indicate that levocetirizine is effective and generally well tolerated in the treatment of allergic rhinitis and CIU. Its pharmacological profile offers many positive aspects: a rapid onset and long duration of antihistaminic effect; rapid absorption and high bioavailability; a low potential for drug interactions; a low volume of distribution; and a lack of effect on cognition, psychomotor function and the cardiovascular system. Allergen challenge chamber studies suggest that levocetirizine has better efficacy than desloratadine, loratadine or fexofenadine. Well controlled, long-term studies with other later-generation H(1) receptor antagonists are required to fully define its clinical profile relative to other agents in this class. Overall, levocetirizine is a valuable addition to the oral H(1) receptor antagonists available for the treatment of allergic rhinitis and as first-line therapy in patients with CIU.