TRPV1 inhibition does not prevent cold dry air-elicited symptoms in non-allergic rhinitis.

BACKGROUND: The transient receptor potential vanilloid 1 (TRPV1)-expressing sensory C-fibers may play a role in the development of nasal hyper-responsiveness and symptoms of non-allergic rhinitis (NAR). OBJECTIVE: To evaluate the effects of a TRPV1-antagonist, SB-705498, on cold dry air (CDA)-induced symptoms in patients with NAR. METHODS: This randomized, double-blind, placebo-controlled, crossover study evaluated 14 days of once daily, topical intranasal SB-705498 12 mg in 40 patients with NAR using a CDA challenge experimental model in an environmental exposure chamber (EEC, Cetero Research, Mississauga, Ontario). The primary endpoint was total symptom score (TSS), expressed as weighted mean over 60 minutes (WM0-60) or maximum TSS at 1 hour and 24 hours postdosing. RESULTS: Treatment with SB-705498, relative to placebo, did not improve WM0-60 or maximum TSS at 1 hour and 24 hours post-dosing on days 1 or 14. Mean (95% CI) treatment differences (SB-705498 - placebo) on day 14 were, for WM0-60 at 1 hour: -0.12 (-0.60, 0.36); for maximum TSS at 1 hour: -0.03 (-0.58, 0.51). SB-705498 had no impact on any other efficacy parameters. SB-705498 was well tolerated and pharmacokinetics analysis supported the dosing regimen. CONCLUSION: SB-705498 12 mg for 14 days did not alleviate the CDA-induced symptoms of NAR. Despite engagement of the TRPV1 receptor, there was no translation to clinical efficacy, suggesting redundancy in symptom pathways.

Fel d 1-derived peptide antigen desensitization shows a persistent treatment effect 1 year after the start of dosing: a randomized, placebo-controlled study.

BACKGROUND: Allergic rhinoconjunctivitis is an increasingly common source of morbidity, with sensitivity to cats accounting for 10% to 15% of disease burden. Allergy to cats is also a major risk factor for the development of asthma. OBJECTIVES: We sought to probe the persistence of the treatment effect of a novel F el d 1-derived peptide antigen desensitization (Cat-PAD) 1 year after the start of treatment in subjects with cat allergy-induced rhinoconjunctivitis after standardized allergen challenge. METHODS: In a randomized, double-blind, placebo-controlled, parallel-group clinical trial, subjects attended an environmental exposure chamber in which they were exposed to cat allergen before and after treatment with 2 different regimens of Cat-PAD over a 3-month period. Clinical efficacy was assessed as a change in total rhinoconjunctivitis symptom scores 18 to 22 weeks and 50 to 54 weeks after the start of treatment. RESULTS: Treatment with Cat-PAD showed greater efficacy with 4 administrations of a 6-nmol dose 4 weeks apart than with 8 administrations of a 3-nmol dose 2 weeks apart. The treatment effect of 6 nmol persisted 1 year after the start of treatment and was significantly different from that of 3 nmol (P = .0342) and placebo (P = .0104). The treatment effect was apparent on both nasal and ocular symptoms at 1 year. CONCLUSIONS: A short course of Cat-PAD improves the ocular and nasal components of rhinoconjunctivitis symptoms in subjects with cat allergy, with the treatment effect persisting 1 year after the start of treatment.

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.

Effects of omalizumab on changes in pulmonary function induced by controlled cat room challenge.

BACKGROUND: Environmental exposure to cat allergen is common, and sensitization to cat allergens is strongly associated with asthma. OBJECTIVE: We sought to examine the efficacy of omalizumab in preventing acute bronchoconstriction induced by environmental exposure to cat allergen. METHODS: Patients with a history of cat allergen-induced asthma were randomized to treatment with omalizumab or placebo and exposed to cat allergen in a controlled chamber for up to 1 hour at baseline and after 16 weeks of treatment. The primary efficacy outcome was area under the curve for percentage decrease from prechallenge FEV(1) at week 16 for omalizumab-treated versus placebo-treated patients. FEV(1) was recorded before and every 10 minutes during the 1-hour challenge. Chest, nasal, and ocular symptoms were also monitored during cat chamber exposure as secondary end points. RESULTS: The area under the curve for percentage decrease in FEV(1) was 15.2% per hour for omalizumab-treated patients (n = 32) and 27.3% per hour for placebo-treated patients (n = 33), reflecting 44% less reduction in FEV(1) and a treatment difference of -12.1% per hour (P = .0009; 95% CI, -19.0 to -5.2). Compared with placebo-treated patients, omalizumab-treated patients were also able to tolerate longer allergen exposure (P = .0006) and demonstrated significant reductions from prechallenge values in their chest symptom score (P < .0001) and nasal-ocular symptom score (P = .0002). CONCLUSIONS: The severity of acute airway reactions and symptoms caused by controlled cat room exposure to allergens was significantly reduced by treatment with omalizumab.

Solubilized nasal steroid (CDX-947) when combined in the same solution nasal spray with an antihistamine (CDX-313) provides improved, fast-acting symptom relief in patients with allergic rhinitis.

Studies indicate that allergy sufferers remain dissatisfied with available antiallergic therapies. A new convenient formulation of solubilized steroid combined in the same nasal spray solution with antihistamine may provide added symptom relief. The objective was to evaluate effects of CDX-947 (solubilized budesonide) and CDX-313 (solubilized azelastine + budesonide) against their suspension-type comparators (budesonide [Rhinocort Aqua {RA}] or azelastine + budesonide [Astelin] {AS} + RA]) and placebo on nasal allergy symptoms of patients exposed to controlled levels of ragweed pollen in an environmental exposure chamber (EEC). Two separate EEC studies that enrolled 173 patients were analyzed. Total nasal symptom score (TNSS) and onset of action were captured. Mean change from baseline of TNSS was compared with analysis of covariance and the onset of action determined. Meta-analysis was performed to allow cross-comparisons between studies. All active treatments significantly reduced TNSS when compared with placebo and both CDX-947 and CDX-313 showed increased improvement over the suspension-type comparators. CDX-313 provided significantly faster onset of action for itchy nose and sneezing. No clinically significant adverse events were reported in this study. The novel combination product, CDX-313, provided fast, long-lasting relief for allergic rhinitis symptoms. Compared with products where corticosteroid remains suspended, the new solubilized nasal spray formulation provides added benefit including faster onset of action and superior, convenient dosing of two therapeutics in one convenient product.

Efficacy comparison of levocetirizine vs montelukast in ragweed sensitized patients.

BACKGROUND: To date, no adequate data are available on direct comparison of the efficacy of levocetirizine, a recently approved histamine1-antihistamine, with that of a leukotriene antagonist in the treatment of seasonal allergic rhinitis (SAR) symptoms. OBJECTIVE: To compare the efficacy of therapeutic doses of 5 mg of levocetirizine and 10 mg of montelukast in ragweed sensitized patients. METHODS: A randomized, double-blind, placebo-controlled, parallel-group study was conducted between July and October 2006. Symptomatic patients with SAR were exposed to ragweed pollen under controlled conditions in an environmental exposure chamber for 4 to 5 hours after treatment with 5 mg of levocetirizine, 10 mg of montelukast, or matched placebo on 2 consecutive days. The mean change from baseline in pollen-induced rhinitis symptoms, expressed as a major symptoms complex (MSC) score (sum of scores for rhinorrhea, itchy nose, sniffles, nose blows, sneezes, and watery eyes), in period 1 (first 5 hours after first drug intake) was the primary efficacy outcome. RESULTS: A total of 611 patients were screened, of whom 403 were randomized to receive treatment (102 placebo, 152 levocetirizine, and 149 montelukast). The MSC score in period 1 was progressively decreased to a significantly greater extent in the levocetirizine group compared with the montelukast and placebo groups (adjusted mean differences, -2.18 [95% confidence interval, -3.35 to -1.01; P < .001] and -2.22 [95% confidence interval, -3.51 to -0.92; P < .001] for levocetirizine vs montelukast and vs placebo, respectively). The effect of 10 mg of montelukast was not significantly different compared with placebo. Levocetirizine also achieved a significantly faster onset of action within 2.5 hours of administration. Both products were well tolerated. CONCLUSIONS: This study in an environmental exposure chamber confirms the therapeutic efficacy of 5 mg of levocetirizine in improving symptoms of SAR, which was superior to 10 mg of montelukast.

Onset of action of ciclesonide once daily in the treatment of seasonal allergic rhinitis.

Ciclesonide is an intranasal corticosteroid approved for the treatment of allergic rhinitis. We conducted a randomized, double-blind, parallel-group, placebo-controlled study to evaluate the time to onset of action of ciclesonide 200 microg once daily in 502 adults with seasonal allergic rhinitis of at least 2 years' duration. To trigger immunologic priming, patients underwent between one and five priming sessions with exposure to 3,500 grains/m(3) (+/-500) of ragweed pollen in an environmental exposure chamber. The criteria for a successful priming session were a patient-assessed instantaneous total nasal symptom score of at least 6 (of a possible 12) and a nasal congestion or rhinorrhea score of at least 2 (of a possible 3) 90 minutes after allergen exposure during at least two consecutive priming sessions. Patients were then randomly assigned to receive either a single dose of ciclesonide 200 microg (n = 251) or placebo (n = 251) administered intranasally. The difference in the change from baseline total nasal symptom scores in the two groups was assessed hourly for 12 hours after administration. Onset of action was determined to have taken place the first time that the effects of ciclesonide, as reflected in the total nasal symptom score, were significantly greater than those of placebo at a particular hourly assessment, provided that the subsequent hourly assessment also showed a statistically significant difference. The onset of action of ciclesonide occurred within 1 hour of administration (p = 0.01 vs. placebo), and the significant difference in total nasal symptom scores between ciclesonide and placebo was maintained through post-treatment hour 12 (p = 0.018).

Lack of effect on adult and adolescent hypothalamic-pituitary-adrenal axis function with use of fluticasone furoate nasal spray.

BACKGROUND: Intranasal corticosteroids are recommended as first-line therapy for allergic rhinitis (AR), and because of their pharmacologic class, hypothalamic-pituitary-adrenal (HPA) axis function is evaluated. OBJECTIVE: To evaluate whether cortisol production was suppressed (as a measure of HPA axis function) by 6 weeks of treatment with fluticasone furoate nasal spray, 110 microg once daily, in patients with perennial AR. METHODS: A double-blind, randomized, placebo- and active-controlled (prednisone), parallel-group study. Outpatients aged 12 to 65 years with perennial AR for 2 years or more were from 1 center in the United States and 1 center in Canada. Pharmacodynamic and pharmacokinetic samples were collected during 24-hour domiciled visits (overnight in clinic). Measurements included change from baseline in 24-hour serum cortisol weighted mean and 24-hour urinary free cortisol excretion, total 24-hour urinary free cortisol excretion and 6-beta hydroxycortisol excretion, and plasma concentration of fluticasone furoate. RESULTS: A total of 112 of 183 patients were randomized. Fluticasone furoate was noninferior to placebo with respect to the ratio from baseline in serum cortisol weighted mean (treatment ratio, 0.98; 95% confidence interval, 0.89 to 1.07). In contrast, use of prednisone, 10 mg once daily, significantly reduced the ratio from baseline compared with placebo. Change from baseline in 24-hour urinary cortisol excretion was similar in the fluticasone furoate and placebo groups. Plasma levels of fluticasone furoate were undetectable after 6 weeks of treatment. CONCLUSION: Fluticasone furoate nasal spray, 110 microg once daily, was not associated with HPA axis suppression in patients 12 years and older with perennial AR.

Onset and duration of action of nasal sprays in seasonal allergic rhinitis patients: olopatadine hydrochloride versus mometasone furoate monohydrate.

Rapid relief of symptoms should be one of the primary goals of treatment for allergic rhinitis (AR). The onset and duration of action of olopatadine hydrochloride nasal spray, 665 mcg (OLO; Patanese), for seasonal AR (SAR) was evaluated in this study. This study was performed to determine the onset and duration of action of OLO compared with placebo spray, with mometasone furoate monohydrate, 50 mcg (MM; Nasonex), as a reference standard. This was a single center, single-dose, randomized, double-blinded parallel-group environmental exposure chamber study. Patients were primed at two 2-hour priming visits. Eligible patients were randomized to OLO, placebo spray, or MM, 2 sprays/nostril. Allergy symptoms (sneezing, runny, itchy, and stuffy nose) were rated by patients at 16 time points during 12 hours after dosing and patient satisfaction was assessed at 4 and 12 hours postdose. Safety was assessed by a review of adverse events, cardiovascular and nasal examination parameters. Four hundred twenty-five adult patients were randomized. OLO was superior to placebo spray in reducing total nasal symptoms (TNSS) within 30 minutes after dosing and maintained superiority for at least 12 hours (p < 0.05). The onset of MM was not observed until 150 minutes postdose and was smaller in magnitude compared with OLO. OLO was superior to both placebo spray (p < 0.0001) and MM (p < 0.05) in patient satisfaction. Treatment was well-tolerated with no safety concerns. OLO is superior to placebo spray and MM in reducing allergy symptoms; OLO has a rapid onset of action and a duration of effect of at least 12 hours.