Rationale: Short-acting beta 2 -agonists (SABAs) such as albuterol provide rapid relief of asthma symptoms and reduce or prevent exercise-induced bronchoconstriction (EIB).Recent GINA guidelines recommend adding lowdose inhaled corticosteroid (ICS) to a fast-acting bronchodilator as rescue medication as early as GINA Step 1 asthma.PT027 is a fixed dose combination of budesonide and albuterol in a single pressurized metered dose inhaler (pMDI).PT027 is currently in clinical development as an anti-inflammatory rescue/reliever for asthma; these are the first study results.Here, PT027 efficacy and safety was evaluated in subjects with asthma and EIB.Methods: TYREE (NCT04234464) was a randomized, double-blind, single-dose, crossover study to assess the preventative effects of PT027 (2 puffs 80/90µg MDI) compared with placebo pMDI (2 puffs) on EIB in subjects with asthma.Adults and adolescents (≥12 years) with asthma and EIB receiving SABA as needed (prn) alone or in addition to low-to-medium-dose ICS maintenance therapy were enrolled.EIB was defined by a ≥20% decrease from 5-minute pre-exercise challenge test (ECT) best forced expiratory volume in 1 second (FEV 1 ) observed within 60 minutes after ECT.The primary endpoint was maximum percentage fall from post-dose, pre-exercise baseline FEV 1 observed up to 60 minutes post-ECT.Secondary and exploratory endpoints included percentage of subjects with a maximum percentage post-ECT fall in FEV 1 of <10% (full protection) and <20% (partial protection).Safety endpoints were assessed as adverse events (AEs) and serious AEs (SAEs).Results: The study included 60 subjects (mean age 40.5 years, 63% female, mean % predicted FEV 1 5-min pre-ECT at Screening 83%) and met its primary endpoint with LS mean maximum percentage falls from baseline in FEV 1 of 5.45% vs 18.97% for PT027 and placebo, respectively, with a difference of -13.52% (95% CI -16.94, -10.09, p<0.001).The proportion of fully and partially protected subjects, respectively, was 78.3% vs 28.3% and 90.0%vs 51.7% for PT027 vs placebo, with odds ratios of 10.5 (p<0.001) and 10.8 (p<0.001).Similar results were also seen in subgroup analyses of subjects receiving SABA prn only and maintenance ICS plus SABA prn.PT027 was well tolerated.Conclusions: The TYREE study demonstrated efficacy of PT027 to prevent EIB in subjects with asthma, including subjects receiving SABA prn alone or maintenance ICS plus SABA prn, when compared to placebo.These results provide important information towards the evaluation of PT027 as a potential new antiinflammatory rescue/reliever therapy for subjects with asthma.

BACKGROUND:Arformoterol is a single-isomer (R,R-formoterol) nebulized long-acting beta(2)-agonist approved for use in patients with chronic obstructive pulmonary disease (COPD). Exposure (plasma concentrations of (R,R)-formoterol) and forced expiratory volume in 1s (FEV(1)) were compared for 15 microg nebulized arformoterol and 12 and 24 microg racemic formoterol (containing 6 and 12 microg (R,R)-formoterol, respectively) delivered by dry powder inhaler (DPI). METHODS:An open-label, randomized, three-way crossover study in 39 subjects with COPD (FEV(1) 1.4L, 44.4% predicted). Twice-daily treatments included nebulized arformoterol (15 microg) and racemic formoterol DPI (12 and 24 microg) for 14 days. Plasma concentrations of (R,R)- and (S,S)-formoterol were determined on days 1 and 14 of each treatment period. Airway function efficacy endpoints included the percent change in trough FEV(1) from baseline on day 14 of each treatment period. RESULTS:At steady state, exposure to (R,R)-formoterol was similar following nebulized 15 microg arformoterol (C(max): 6.5 pg/mL; AUC(0-tau): 56.5 pgh/mL) and 12 microg racemic formoterol DPI (C(max): 6.2 pg/mL; AUC((0-)(tau)()): 46.3 pgh/mL). The geometric mean ratios between these two treatments (90% confidence intervals) for C(max) and AUC((0-)(tau)()) were 0.91 (0.76, 1.09) and 1.16 (1.00, 1.35), respectively. Treatment with 24 microg racemic formoterol DPI resulted in dose proportionally higher (R,R)-formoterol: C(max) (10.8 pg/mL) and AUC((0-)(tau)()) (83.6 pgh/mL). Detectable (S,S)-formoterol was consistently measured only after treatment with racemic formoterol. The mean percent increase in trough FEV(1) was 19.1% in the arformoterol group, and 16.0% and 18.2% in the 12 and 24 microg racemic formoterol groups, respectively. Changes in (R,R)-formoterol concentrations over time paralleled changes in FEV(1). CONCLUSIONS:In this study, plasma exposure to (R,R)-formoterol was similar for nebulized 15 microg arformoterol and 12 microg racemic formoterol DPI, and 40% lower than 24 microg racemic formoterol DPI. There was no evidence of chiral interconversion following treatment with arformoterol. Finally, temporal changes in airway function in all treatment groups corresponded to changes in (R,R)-formoterol plasma concentrations.

RATIONALE: Sensory attributes of nasal sprays may affect patient compliance with treatment regimens. This study compared patient perceptions of sensory attributes including taste and aftertaste of olopatadine nasal spray (OLO) to azelastine nasal spray (AZ) (Astelin®). METHODS: Patients 18 years or older with a 2-year history of allergic rhinitis who were symptomatic at enrollment were treated with OLO and AZ nasal sprays in a prospective, randomized, double-masked, multi-site, crossover study. Patients received one dose (two sprays per nostril) of each test article, with 24±2 hours washout between the treatments. Patients self-rated the attributes of each treatment (immediately and 45 minutes post-dose) and completed a product comparison at the end of study using a validated questionnaire. Primary endpoint was the aftertaste preference at the end of study. Secondary endpoints included satisfaction with sensory attributes (immediate taste, aftertaste) and product preference (overall preference, likelihood of use). Safety evaluation was based on adverse events. RESULTS: One hundred ten patients of ages 18 to 72 years were enrolled into the study. OLO was statistically superior to AZ (p=0.0005) for aftertaste at the end of study, with 60.6% preferring OLO over AZ. OLO was also superior to AZ for satisfaction with immediate taste (p<0.0001), overall preference (p=0.0001), and preference for likelihood of use of the product (p=0.0004). OLO was numerically, but not statistically (p=0.3150) superior to AZ for satisfaction with aftertaste 45 minutes post-dose. CONCLUSIONS: Patients preferred OLO over AZ based on taste and aftertaste and would be more likely to use OLO nasal spray given the choice.

BACKGROUND:Inhaled corticosteroids (ICSs) delivered by metered-dose inhalers that contain chlorofluorocarbon propellants are being discontinued because of the harmful effects of chlorofluorocarbon on the ozone layer. Therefore, some metered-dose inhaler products are being reformulated with "ozone-friendly" hydrofluoroalkane propellants. OBJECTIVE:To evaluate treatment with fluticasone propionate hydrofluoroalkane inhalation aerosol, 88, 220, and 440 microg twice daily, vs placebo in patients with asthma receiving an ICS. METHODS:Randomized, double-blind, parallel-group, 12-week study. RESULTS:Mean morning predose percent predicted forced expiratory volume in 1 second increased by 2.2%, 3.2%, and 4.6% in the fluticasone propionate, 88-, 220-, and 440-microg twice-daily, groups, respectively, compared with an 8.3% decrease for placebo (P < .001 vs placebo for all groups). Secondary pulmonary function end points and asthma symptoms showed similar improvements compared with placebo. Discontinuation from the study due to lack of efficacy was 50% in the placebo group and 11%, 10%, and 6% in the fluticasone propionate, 88-, 220-, and 440-microg twice-daily, groups, respectively. At week 12, the probability of remaining in the study was 0.89, 0.90, and 0.94 for the fluticasone propionate, 88-, 220-, and 440-microg twice-daily, groups, respectively, vs 0.45 for the placebo group (P < .001 for all). Changes in 24-hour urinary cortisol excretion rates were similar among treatment groups. CONCLUSIONS:Fluticasone propionate hydrofluoroalkane, previously shown to be a clinically suitable alternative to fluticasone propionate chlorofluorocarbon, was effective and well tolerated. The ability to switch from fluticasone propionate chlorofluorocarbon and other chlorofluorocarbon-containing ICSs to fluticasone propionate hydrofluoroalkane without sacrificing asthma control or tolerability will facilitate a smooth transition to this nonchlorofluorocarbon-containing medicinal.

Background Nighttime problems constitute a significant burden on the quality of life of patients with seasonal allergic rhinitis (SAR). The aim of this study was to evaluate the effectiveness of montelukast on nighttime AR symptoms. Methods In seven multicenter, double-blind, parallel-group trials, nighttime problems were assessed as the nighttime symptoms score (NSS), an average of three individual symptom scores: difficulty going to sleep, nighttime awakening, and nasal congestion on awakening (each rated 0 = none to 3 = severe). Patients (aged 15–82 years) were randomized to receive montelukast, 10 mg (n = 1751), placebo (n = 1557), or the positive control loratadine, 10 mg (n = 1616). Results In a combined analysis, changes from baseline (mean ± SE) in NSS were -0.28 ± 0.01, -0.16 ± 0.01, and —0.24 ± 0.01 for the montelukast, placebo, and loratadine groups, respectively. Difference versus placebo in least-squares mean change from baseline were —0.11 (95% confidence interval, -0.14, -0.08; p ≤ 0.001) for montelukast and -0.09 (-0.12, -0.06; p ≤ 0.001) for loratadine. Strong baseline correlations (R > 0.70; p < 0.001) of NSS and two of its individual symptoms with the sleep domain of the validated Rhinoconjunctivitis Quality of Life Questionnaire support the validity and importance of measuring nighttime morbidity in SAR. Furthermore, a clinically important benefit of montelukast on the nighttime impact of SAR was shown using an analysis anchored on the Patient's Global Evaluation. Conclusion These data underscore the importance of nighttime problems in patients with SAR and the need to treat nighttime symptoms. In these studies, montelukast significantly improved the NSS, a clinically relevant and valid measure in patients with SAR.

Background: Despite their proven efficacy in the treatment and prevention of asthma exacerbations, current inhaled corticosteroids carry safety concerns, especially adrenal suppression. Ciclesonide (hydrofluoroalkane propellant) is a novel inhaled corticosteroid with few, if any, clinical adverse events.Objective: To evaluate the potential effects of ciclesonide therapy on the dynamic cortisol response to sequential low- and high-dose cosyntropin Stimulation in adults with mild-to-moderate persistent asthma.Methods: This was a double-blind, randomized, placebo-controlled, 12-week study in adults with mild-to-moderate asthma. One hundred sixty-four patients were randomized and treated; 148 patients completed the study. Fluticasone propionate (chlorofluorocarbon propellant) was used as an active comparator. The doses administered were 320 mu g of ciclesonide once daily, 320 mu g of ciclesonide twice daily, and 440 mu g of fluticasone propionate twice daily, all doses ex-actuator.Results: For both ciclesonide groups, changes in mean low- and high-dose peak serum cortisol levels and in 24-hour urinary free cortisol levels corrected for creatinine were small vs baseline and comparable with placebo. For the fluticasone propionate group, significant reductions vs placebo in serum cortisol levels in response to high-dose cosyntropin stimulation and in 24-hour urinary free cortisol levels were observed. Oral candidiasis rates were 2.5% for 320-mu g/d ciclesonide, 2.4% for 640-mu g/d ciclesonide, and 22.0% for 880-mu g/d fluticasone propionate.Conclusions: These findings confirm the safety of ciclesonide therapy, dernonstrating that at doses up to 640 mu g/d, the drug does not affect sensitive markers of adrenal function.

Background: Currently available oral second-generation antihistamines do not provide adequate symptom relief for many allergy patients.Objective: To determine the ability of azelastine nasal spray to improve rhinitis symptoms in patients with seasonal allergic rhinitis who remained symptomatic after treatment with fexofenadine.Methods: This was a multicenter, randomized, double-blind, placebo-controlled, 2-week study in patients with moderate-to-severe seasonal allergic rhinitis. The study began with a 1-week, open-label lead-in period, during which patients received fexofenadine, 60 mg twice daily. Patients who improved less than 25% to 33% with fexofenadine were randomized to treatment with (1) azelastine nasal spray, 2 sprays per nostril twice daily; (2) azelastine nasal spray, 2 sprays per nostril twice daily, plus fexofenadine, 60 mg twice daily; or (3) placebo (saline) nasal spray and placebo capsules twice daily. The primary efficacy variable was the change from baseline to day 14 in the total nasal symptom score (TNSS), consisting of runny nose, sneezing, itchy nose, and nasal congestion symptom scores.Results: A total of 334 patients who remained symptomatic after treatment with fexofenadine were included in the efficacy analysis. After 2 weeks of treatment, azelastine nasal spray (P = .007) and azelastine nasal spray plus fexofenadine (P = .003) significantly improved the TNSS compared with placebo. Azelastine nasal spray monotherapy was as effective as the combination of azelastine nasal spray plus fexofenadine as measured by the TNSS and individual symptoms of the TNSS.Conclusions: Azelastine nasal spray is effective monotherapy for patients who remain symptomatic after treatment with fexofenadine and should be considered in the initial management of patients with seasonal allergic rhinitis.

RATIOANLE: HPA-axis function is an indicator of systemic effect for inhaled corticosteroids.The effects of inhaled ciclesonide (CIC) on cortisol suppression were evaluated as measured by low-dose (1 lag) cosyntropin-stimulated serum cortisol.METHODS: Patients (N=164, ->18 y), with 6 months of mild to moderate asthma and normal HPA-axis function were randomized to 12 weeks of treatment with metered dose inhalations of CIC 320 lag qd PM (CIC320), CIC 320 lag bid (CIC640), fluticasone propionate 440 lag bid (FP880), or placebo in a multicenter, double-blind, double-dummy study.Primary endpoint was mean change from baseline in low-dose (1 lag) cosyntropin-stimulated peak serum cortisol (max of 20-, 30-, and 60-min measurements) at study-end.RESULTS: After 12 weeks, both CIC320 and CIC640 showed no significant difference in mean change in low-dose (1 lag) cosyntropin-stimulated peak serum cortisol when compared with placebo (P=0.383 for CIC320; P=0.911 for CIC640).The FP880 group showed a significant decrease in low-dose (1 lag) cosyntropin-stimulated peak serum cortisol when compared with the CIC320 group (P<0.0I).

BACKGROUND:Symptoms of allergic rhinitis are mediated in part by cysteinyl leukotrienes.OBJECTIVE:To evaluate the clinical benefit of montelukast, a cysteinyl leukotriene receptor antagonist, administered once daily for treating seasonal allergic rhinitis.METHODS:This multicenter, randomized, double-blind, placebo- and active-controlled study enrolled 1,214 healthy, nonsmoking outpatients aged 15 to 85 years with spring allergic rhinitis, positive skin test to a spring allergen, and predefined daytime nasal symptoms. After a 3- to 5-day placebo run-in period, patients were randomly assigned to treatment with montelukast 10 mg (n = 522), loratadine 10 mg (n = 171), or placebo (n = 521) once daily at bedtime for 2 weeks. During the run-in and treatment periods, symptoms were evaluated in a daily diary using a 0 (best) to 3 (worst) scale.RESULTS:Baseline characteristics of randomized patients were clinically similar in the three treatment groups. Montelukast was significantly more effective than placebo (P = 0.003) in improving the daytime nasal symptoms score (difference in least square means, -0.09; 95% confidence interval, -0.16, -0.03) averaged over 2 weeks of therapy. The treatment effect of montelukast was significantly greater (P < 0.05), relative to placebo, for all secondary endpoints, including nighttime symptoms and daytime eye symptoms, patient and physician global evaluations of allergic rhinitis, and rhinoconjunctivitis quality of life. Loratadine, which served as a positive control, was significantly more effective than placebo for most endpoints, validating the study results. Both montelukast and loratadine were well tolerated.CONCLUSION:Therapy with montelukast significantly improves assessments of symptom severity as well as quality-of-life parameters for patients with seasonal allergic rhinitis.

Background Cysteinyl leukotrienes are important proinflammatory mediators believed to have a role in allergic rhinitis.

Background: Flovent Diskus is a powder formulation of the inhaled corticosteroid fluticasone propionate (FP) delivered via a breath-actuated, multidose inhaler.Objective: To determine the efficacy and safety of dry powder FP administered once or twice daily (200 mug per day) to children with persistent asthma.Methods: Twelve-week, randomized, double-blind, placebo-controlled, multicenter trial with a 52-week, open-label extension. Children aged 4 to 11 were required to have pulmonary function 50% to 85% of predicted values. The population was stratified for baseline therapy (inhaled corticosteroid/cromolyn or bronchodilators only). After a 2-week placebo run-in, 242 patients received dry powder EP 200 mug each morning, dry powder FP 100 mug BID, or placebo for 12 weeks; 192 were rerandomized to the QD or BID regimen for an additional 52 weeks of open-label treatment. Primary endpoints were mean changes in FEV1 and morning PEF recorded at clinic visits.Results: Both dry powder FP regimens significantly improved FEV1, evening PEF, and asthma symptoms at the double-blind phase endpoint (P less than or equal to .017 compared with placebo). The BID regimen also significantly improved morning PEF and nighttime awakenings due to asthma (P less than or equal to .005). Among patients previously treated with inhaled corticosteroids/cromolyn, improvements observed with the QD and BID regimens were similar. Patients switched from BID to open-label QD treatment showed additional improvements at week 52 generally comparable to patients who received the BID regimen during both phases. Fluticasone propionate was well tolerated for up to 64 weeks with few reports of drug-related adverse events or morning plasma cortisol abnormalities,Conclusions: Once daily dosing of dry powder FP 200 mug is an effective and convenient alternative for children whose asthma is controlled with a more frequent dosing regimen of inhaled corticosteroids.

Objective: To determine whether inhaled fluticasone propionate has long-term effects on growth in children with persistent asthma.Study design: In a double-blind, randomized, parallel-group, multicenter study, 325 prepubescent children with persistent asthma and normal growth rates were treated with placebo or inhaled fluticasone propionate powder 50 mu g or 100 mu g administered twice daily by a breath-actuated device for 1 year. Growth was evaluated monthly, whereas other safety variables and pulmonary function were evaluated periodically.Results: The prepubescent patients showed no statistically significant differences in mean height, mean growth velocity, or mean skeletal age between any of the treatment groups at any time. Over a period of 1 year, mean height (+/- SE) increased 6.15 +/- 0.17 cm in the placebo group, 5.94 +/- 0.16 cm in the fluticasone propionate 50 mu g group, and 5.73 +/- 0.13 cm in the fluticasone propionate 100 mu g group (p = 0.308, overall).Conclusions: Prepubescent children treated with fluticasone propionate 50 mu g and 100 mu g administered twice daily for 1 year grew at rates similar to placebo-treated control subjects and at rates equal to expected growth velocity for age.

Objective: To determine the efficacy and safety of budesonide delivered by an inhalation-driven dry powder inhaler (Turbuhaler) in children with moderate to severe persistent asthma. Study design: In our randomized, double-blind, placebo-controlled, parallel-group, multicenter study, a total of 404 children with asthma, who were aged 6 to 18 years and who had been receiving inhaled glucocorticosteroid therapy, were randomly assigned to receive either 100, 200, or 400 μg of budesonide or placebo twice daily for 12 weeks. At baseline, mean forced expiratory volume in 1 second (FEV1) was 74.6% (range, 30.7% to 123.3%) of the predicted normal value. Results: Patients in each of the three budesonide treatment groups showed significant dose-related improvements in lung function (morning peak expiratory flow and FEV1), in asthma symptoms, and with a significant decrease in inhaled β2-agonist use in comparison with placebo. Improvements were evident within 2 weeks and were maintained throughout the 12 weeks. Budesonide treatment had no significant effect on hypothalamic–pituitary–adrenal axis function, and the incidence of reported adverse events was similar in all treatment groups. Conclusion: Budesonide administered via a dry powder inhaler provided dose-related improvements in lung function and clinical status and was well tolerated by children (6 to 18 years of age) with moderate to severe persistent asthma. (J Pediatr 1998;132:976-82.)