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Background These studies assessed the efficacy and safety of fevipiprant, an oral antagonist of the prostaglandin D2 (PGD2) receptor (DP2), compared with placebo when added to standard-of-care (SoC) asthma therapy in patients with uncontrolled asthma. Methods ZEAL-1 (NCT03215758) and ZEAL-2 (NCT03226392) are two replicate, phase 3, multicentre, randomised, double-blind, placebo-controlled, parallel-group studies in which fevipiprant 150 mg once daily (o.d.) or placebo was added to SoC asthma therapy in patients aged ≥12 years with uncontrolled asthma. Primary endpoint: change from baseline in pre-dose forced expiratory volume in 1 s (FEV1) after 12 weeks’ treatment. Key secondary endpoints: daytime asthma symptom score, short-acting β-agonist (SABA) use and Asthma Quality-of-Life Questionnaire (AQLQ+12) score after 12-weeks treatment. Findings 662 patients in ZEAL-1 and 685 patients in ZEAL-2 completed the treatment period. In ZEAL-1, the least squares (LS) mean change from baseline in pre-dose FEV1 was 112 mL in fevipiprant vs 71 mL in placebo group (difference [∆]:41 mL; 95% CI: −6, 88; adjusted p-value 0·088). In ZEAL-2, the LS mean change in pre-dose FEV1 was 126 mL and 157 mL in the fevipiprant and placebo groups, respectively (∆:−31 mL; 95% CI: −80, 18; adjusted p-value 0·214). For both studies, there were no statistically significant differences in the key secondary objectives between the treatment groups. Interpretation The ZEAL studies did not demonstrate significant improvement in lung function or other clinical outcomes. These results suggest that DP2 receptor inhibition with fevipiprant is not effective in the studied patient population.

Background: GSP301 is an investigational fixed-dose combination nasal spray that contains the antihistamine, olopatadine hydrochloride (HCl), and the corticosteroid, mometasone furoate. Objective: To evaluate the efficacy and safety of GSP301 in patients with seasonal allergic rhinitis (SAR). Methods: In this double-blind, randomized, parallel-group study, patients (≥12 years of age) with SAR were equally randomized to intranasal GSP301 (olopatadine 665 μg and mometasone 25 μg), olopatadine HCl (665 μg), mometasone furoate (25 μg), or placebo for 14 days of twice-daily treatment. The primary end point was the mean change from baseline in the average A.M. and P.M. 12-hour reflective Total Nasal Symptom Score (rTNSS) analyzed by using mixed-effect model repeated measures (p www.clinicaltrials.gov .

Summary Background Benralizumab is a humanised, anti-interleukin 5 receptor α monoclonal antibody that directly and rapidly depletes eosinophils, reduces asthma exacerbations, and improves lung function for patients with severe eosinophilic asthma. The objective of this trial was to assess the safety and efficacy of benralizumab for patients with mild to moderate, persistent asthma. Methods In this randomised, double-blind, placebo-controlled, phase 3 trial, we recruited patients aged 18–75 years, weighing at least 40 kg, and with a postbronchodilator reversibility in forced expiratory volume in 1 s (FEV 1 ) of at least 12% at screening, from 52 clinical research centres in six countries. Patients must have been receiving either low- to medium-dosage inhaled corticosteroids (ICS) or low-dosage ICS plus long-acting β 2 agonist fixed-combination therapy at screening, had a morning prebronchodilator FEV 1 of more than 50% to 90% predicted at screening, and had one or more of the following symptoms within the 7 days before randomisation: a daytime or night-time asthma symptom score of at least 1 for at least 2 days, rescue short-acting β 2 agonist use for at least 2 days, or night-time awakenings due to asthma for at least one night. We converted patients' ICS treatments to 180 μg or 200 μg budesonide dry powder inhaler twice daily for the entire duration of the study using the approved dosages in the patients' respective countries and randomly allocated them (1:1; stratified by blood eosinophil count [ vs ≥300 cells per μL] and region [USA vs the rest of the world]) with an interactive web-based voice response system to receive subcutaneous placebo or benralizumab 30 mg injections every 4 weeks for 12 weeks. All patients and investigators involved in patient treatment or clinical assessment and those assessing outcomes were masked to treatment allocation. The primary endpoint was change from baseline prebronchodilator FEV 1 at week 12. Efficacy analyses used an intention to treat approach. This trial is registered with ClinicalTrials.gov, number NCT02322775. Findings Between Feb 2, 2015, and April 24, 2015, we enrolled 351 patients, with 211 (60%) randomly assigned (105 [50%] to placebo and 106 [50%] to benralizumab). Benralizumab resulted in an 80 mL (95% CI 0–150; p=0·04) greater improvement (least-squares mean difference) in prebronchodilator FEV 1 after 12 weeks than did placebo (placebo group: 2246 mL [SD 768] at baseline vs 2261 mL [796] at week 12, change from baseline of 0 mL; benralizumab group: 2248 mL [606] vs 2310 mL [670], 70 mL). 44 (42%) patients in the benralizumab group had adverse events compared with 49 (47%) in the placebo group. The most common adverse events for both groups were nasopharyngitis (eight [8%] patients in each group) and upper respiratory tract infections (five [5%] patients in each group). Serious adverse events occurred in two (2%) patients each in the benralizumab (pancytopenia and a suicide attempt, both considered unrelated to treatment) and placebo (cervix carcinoma and colon adenoma) groups. Interpretation This study suggests that active and modifiable disease processes might be ongoing in patients with mild to moderate, persistent asthma receiving ICS. Although the lung function improvement observed does not warrant use of benralizumab in this population because it did not reach the minimum clinically important difference of 10%, further studies to assess this finding should be considered. Funding AstraZeneca.

MAP0004 (a proprietary formulation of dihydroergotamine mesylate [DHE]) for inhaled delivery is being developed for acute migraine treatment. Because asthma and migraine often occur as co-morbid conditions, it is considered important to study the safety of MAP0004 in a population of asthmatic adults and to confirm that the pharmacokinetics of DHE, when inhaled by asthmatic subjects, were comparable to a population of healthy volunteers. The safety, tolerability, and pharmacokinetics of orally-inhaled MAP0004 administered by the Tempo inhaler were studied in adult asthmatics.This was a randomized, double-blind, placebo-controlled study of two doses of inhaled MAP0004. Eligible subjects were randomized in a 2 : 1 ratio to MAP0004 or placebo and observed for 4 h after each dose. Pharmacokinetic parameters were determined pre-dose and up to 36 h post-dose.Among 19 subjects, geometric mean AUC(0-36) was 6754 pg.h/mL and geometric mean AUC(0-inf) was 7483 pg.h/mL. Geometric mean t(max) was 9.6 min, geometric mean C(max) was 3174 pg/mL, and geometric mean t((1/2)) was 9.5 h. Overall, 13 of 19 (68%) subjects reported at least one adverse event, most commonly nausea, vomiting, dysgeusia, and headache.MAP0004 results in rapid and efficient systemic absorption in asthmatic subjects. Systemic DHE concentrations were similar to those previously reported in healthy subjects, and no clinically relevant safety issues were observed. While this small study was suitable for pharmacokinetic analysis and conclusions, MAP0004 use in migraineurs with concomitant stable asthma should be supported by larger studies of longer duration to confirm that it does not present additional safety risks compared to non-asthmatic migraineurs.

Background: Proinflammatory mediators such as the cysteinyl leukotrienes are important in the pathophysiology of allergic rhinitis. This study evaluated the efficacy and tolerability of montelukast, a cysteinyl leukotriene receptor antagonist, given once daily in the morning for treatment of seasonal (fall) allergic rhinitis for 4 weeks. Methods: This was a randomized, double-blind trial with a placebo run-in and a 4-week treatment period. Patients (n = 1079) with a history of allergic rhinitis and a positive skin test to seasonal pollen allergens were assigned to placebo, montelukast 10 mg, or loratadine 10 mg. Symptoms were assessed with a daily diary. Results: Montelukast was more effective than placebo in improving scores for the primary endpoint of daytime nasal symptoms (P = 0.003) and the secondary endpoints of night-time, composite, and daytime eye symptoms, patient's and physician's global evaluations of allergic rhinitis, and rhinoconjunctivitis quality-of-life (P ≤ 0.006). The positive control loratadine also improved scores for the primary endpoint (P ≤ 0.001) and the majority of the secondary endpoints (P

Background Mometasone furoate nasal spray (MFNS) 400 μg, twice daily, as adjunctive treatment with oral antibiotic significantly improved symptoms of recurrent rhinosinusitis. Objective To evaluate the effectiveness and safety of MFNS 200 μg, twice daily, and 400 μg, twice daily, compared with placebo as adjunctive treatment with oral antibiotic for acute rhinosinusitis. Methods In this multicenter, double-blind, placebo-controlled study, 967 outpatients with computed tomographic scan-confirmed moderate to severe rhinosinusitis received amoxicillin/clavulanate potassium (Augmentin, GlaxoSmithKline, Research Triangle Park, NC) 875 mg, twice daily, for 21 days with adjunctive twice daily MFNS 200 μg, MFNS 400 μg, or placebo nasal spray. Patients recorded scores of six rhinosinusitis symptoms and any adverse events twice daily. Pre- and postcosyntropin–stimulation plasma cortisol levels were measured in a subset of patients at selected study sites. Results Treatment with MFNS 200 μg or 400 μg, twice daily, produced significantly greater improvements in total symptoms score (primary efficacy variable) day 1 to day 15 average (50% and 51%, respectively) than placebo (44%, P ≤0.017). Both doses of MFNS produced significant total symptoms score improvement over placebo by day 4, and maintained efficacy over the entire 21-day study. Relief of individual symptoms showed a similar pattern. Both doses of MFNS were well tolerated, and adverse events were similar to that of placebo. Cosyntropin stimulation showed no evidence of hypothalamic-pituitary-adrenal axis suppression. Conclusions As adjunctive therapy to oral antibiotic treatment, MFNS at doses of 200 μg or 400 μg, twice daily, was well tolerated and significantly more effective in reducing the symptoms of rhinosinusitis than antibiotic therapy alone.

OBJECTIVE The Pediatric Asthma Diary was developed and validated to assess efficacy of interventions in children with asthma. DESIGN, PATIENTS, AND SETTING Diary validation was performed in a three week, prospective study of 106 children aged 6–14 years with asthma. Children were classified at baseline as either stable (requiring no additional asthma treatment) or new onset/worse (requiring either addition of or increase in anti-inflammatory treatment). RESULTS A daytime symptom scale and “day without asthma” were defined from diary questions. Both measures demonstrated significant validity and responsiveness to anti-inflammatory treatment. The stable group experienced a higher percentage of days without asthma during week 1 compared with the new onset/worse group (39.6% v 11.6%, respectively). The new onset/worse patients experienced significant improvement in days without asthma (24.5%) compared with stable patients (6.4%). CONCLUSIONS The Pediatric Asthma Diary daytime symptom scale and day without asthma are acceptable measures for use in asthma intervention studies of children aged 6–14 years.

Background:Mometasone furoate nasal spray (MFNS, NASONEX®), is a new synthetic corticosteroid with considerable efficacy in the treatment of seasonal and perennial rhinitis and less than 0.1% systemic absorption. This study was designed to evaluate the time of onset of action of MFNS. The subjects were evaluated over the course of 2 weeks during the spring allergy season. Methods:The effects of MFNS 200 μg given once daily for 2 weeks were evaluated in a randomized, multicenter, double-blind, placebo-controlled study in 201 patients with seasonal allergic rhinitis. Clinically significant onset of action was assessed prospectively by special patient diary cards kept during the first 3 days of treatment. Results:By 12 h after initial dosage (the earliest evaluation), 28% of patients in the MFNS group experienced clinically significant relief, compared with 13% of those given placebo (P=0.01). Median time to at least moderate symptom relief in patients who received MFNS was 35.9 h, compared with more than 72 h in patients given placebo (P

Background: National and international guidelines recommend the use of inhaled antiinflammatory medications in patients with all but the mildest forms of asthma. Twice daily dosing may increase compliance with therapy. Objective: We sought to evaluate the safety and efficacy of 400 μg twice daily triamcinolone acetonide (TAA) compared with placebo in adult patients with mild-to-moderate asthma who were poorly controlled by β 2 -agonist therapy. Methods: We performed a multicenter, randomized, double-blind, placebo-controlled study, including a screening visit, a 7- to 21-day pretreatment baseline phase, and a 6-week double-blind treatment phase. Efficacy was measured by weekly spirometry and daily diary recordings of peak flow rates, asthma symptom scores, and albuterol use. Eligible patients used albuterol four or more times per day, had total asthma symptom scores of 15 or greater (possible total, 60) over 5 of 7 baseline days, and had FEV 1 measurements of 60% of predicted value or greater. Results: One hundred twenty-one patients were randomized to treatment. TAA was superior to placebo for all efficacy measures, with significant improvements in asthma symptoms, albuterol use, morning and evening peak flow rates, and forced vital capacity evident at Treatment Week 1. Significant improvements in other pulmonary function measurements were observed after 2 or more weeks. All efficacy variables improved progressively throughout the study. Conclusions: Twice daily TAA (400 μg) decreased asthma symptoms and improved lung function in patients with mild-to-moderate asthma compared with placebo. Therapeutic benefit was evident within 1 week and increased throughout treatment.

Topical nasal corticosteroids have become a mainstay of treatment for the symptoms of seasonal allergic rhinitis (SAR). It is likely that topical corticosteroids, by blocking an initial influx of inflammatory cells in the nasal mucosa induced by aeroallergens, may have a preventive effect on nasal allergy symptoms when administered before the pollen season.This study was designed to assess the efficacy and safety of an 8-week course of mometasone furoate nasal spray (MFNS), 200 micrograms once daily, in the treatment of SAR compared with beclomethasone dipropionate aqueous nasal spray (BDP), 168 micrograms twice daily, and placebo vehicle, when treatment is initiated before the anticipated onset of the ragweed season.Three hundred forty-nine patients with SAR to ragweed pollen from nine centers in the Northeast and Midwest of the United States were randomized to one of the three intranasal study medications (MFNS, 200 micrograms once daily, BDP, 168 micrograms twice daily, or placebo vehicle), starting 4 weeks before the estimated start of the ragweed season.The proportion of "minimal symptom" days (total nasal symptom scoreor = 2) was statistically significantly higher in both the MFNS and BDP groups when compared with the placebo vehicle group (p0.01). The two active treatment groups were not statistically significantly different from each other. MFNS and BDP displayed a similar safety profile that did not differ from placebo.This suggests that MFNS, 200 micrograms (once daily), is a useful therapy in the prophylactic treatment of SAR.

The efficacy of oral montelukast has been well established in asthma and allergic rhinitis in adults and children. The purpose of this study was to evaluate dose-related bronchodilation and tolerability of inhaled montelukast.Randomized, double-blind, crossover, adaptive-design study comparing single-dose administration of inhaled montelukast versus placebo in patients age 15-65 years with chronic asthma (n = 68). Montelukast was delivered as a witnessed dose through dry powder inhaler at doses of 25, 250, or 1000 μg, and doses of 50, 100, and 500 μg could be used if needed based on a prespecified dose-response algorithm. Each administration was followed by a 4- to 7-day washout period before crossing over to the next treatment. The primary endpoint was the change from baseline in a forced expiratory volume in 1 second (FEV₁) over the first 4 hours after administration, calculated as a time-weighted average (ΔFEV₁ [0-4 hours]). Other endpoints included the onset and duration of bronchodilation and the effect of albuterol when added to inhaled montelukast.Over 4 hours postdose, and compared with placebo (least-squares [LS] mean 0.03 L), inhaled montelukast 100 μg (0.13 L; p ≤ .001), 250 μg (0.10 L; p.01), and 1000 μg (0.12 L; p ≤ .001) had significantly greater ΔFEV₁ (0-4 hours). At 24 hours postdose, inhaled montelukast 100 μg (0.10 L) and 1000 μg (0.09 L) had significantly greater bronchodilation compared with placebo (0.02 L; p.05 vs. montelukast). Montelukast 1000 μg provided significant bronchodilation versus placebo within 20 minutes of administration (0.03 L vs. -0.05 L), whereas montelukast 100 μg provided significant bronchodilation relative to placebo within 2 hours of dosing (0.09 L vs. 0.01 L). Montelukast (pooled doses) plus albuterol was significantly more effective than montelukast plus placebo for ΔFEV₁ (0-90 minutes) (0.34 L vs. 0.15 L; p = .015). The tolerability of inhaled montelukast was similar to that of placebo. No serious adverse experiences were reported.Inhaled montelukast provided significant bronchodilation compared with placebo as early as 20 minutes after the administration that persisted for 24 hours and provided additive bronchodilation to albuterol.

Inhaled corticosteroids (ICSs) are a first-line treatment for persistent asthma. This study was designed to compare the efficacy and safety of ciclesonide (CIC) in subjects with mild-to-moderate persistent asthma not using an ICS. This was a multicenter, double-blind, parallel-group, placebo-controlled, 16-week study in subjects who were > or =12 years old, had a > or =6-month history of persistent asthma, a forced expiratory volume in 1 second (FEV(1)) of > or =60 to < or =85% predicted, and who were not using an ICS < or =30 days before study entry. Subjects were randomized to CIC, 80 microg twice daily (CIC80 b.i.d.; n = 170); CIC, 160 microg once daily in the morning (CIC160 q.d. in the A.M.; n = 173); CIC80 b.i.d. for 4 weeks followed by CIC160 q.d. for 12 weeks (CIC80 b.i.d./CIC160 q.d.; n = 171); or placebo (n = 177). Change in FEV(1) from baseline to the average of weeks 12 and 16 (primary end point) and to week 16, A.M. peak expiratory flow, rescue albuterol use, nighttime awakenings, asthma symptom scores, and safety were evaluated. FEV(1) improved from baseline to the average of weeks 12 and 16 for CIC80 b.i.d. (+0.30L; p < 0.0001), CIC160q.d. (+0.19L; p < 0.0001), CIC80 b.i.d./CIC160 q.d. (+0.19L; p < 0.0001), and placebo (+0.06L; p = 0.0251); improvement was greatest for CIC80 b.i.d. (p < 0.01). At week 16, all CIC treatments significantly improved FEV(1) and A.M. PEF from baseline (p < 0.0001) and compared with placebo (p < or = 0.015). All treatments reduced albuterol use and nighttime awakenings and improved asthma symptom scores (p < or = 0.05 versus baseline); these improvements were greater for CIC80 b.i.d. than for placebo (p < 0.01). The incidence of adverse events was similar among treatment groups (range, 53-58%). In this study, CIC80 b.i.d. improved disease control in subjects with mild-to-moderate persistent asthma not using an ICS and provided greater improvements than CIC160 q.d.

Patients with seasonal allergic rhinitis experience many nasal and concomitant nonnasal symptoms. Many patients also experience headaches and facial pain, pressure, or discomfort. Standard over-the-counter therapy with antihistamines and nasal decongestants often does not completely relieve all symptoms associated with allergic rhinitis.To establish the contribution of ibuprofen when used with pseudoephedrine and chlorpheniramine, a standard over-the-counter regimen, to relieve the symptoms of seasonal allergic rhinitis.In this 7-day, multicenter, randomized, placebo-controlled, double-blind, double-dummy, parallel-group trial, qualified subjects were randomly assigned to 1 of 4 treatment groups that received combined ibuprofen/pseudoephedrine/chlorpheniramine (200/30/2 mg or 400/60/4 mg), combined pseudoephedrine/chlorpheniramine (30/2 mg), or placebo. Therapy began when the subject experienced a minimum of moderate allergy-associated pain, and it continued 3 times a day for 7 consecutive days.Mean pain intensity reduction in both ibuprofen/pseudoephedrine/chlorpheniramine treatment groups was 40% greater than in the placebo group and 33% greater than in the pseudoephedrine/chlorpheniramine treatment group (P.001). Mean changes from baseline in total and nonpain symptom scores for both ibuprofen/pseudoephedrine/chlorpheniramine doses were significantly greater than for placebo (P.001) and pseudoephedrine/chlorpheniramine (P.001-.05) but were not different from each other. Ibuprofen enhanced the chlorpheniramine and pseudoephedrine effects, resulting in incremental 33% to 34% pain relief and 17% to 22% allergy symptom relief compared with pseudoephedrine/chlorpheniramine.In both doses of the triple combination, ibuprofen added to the effects of chlorpheniramine and pseudoephedrine, resulting in superior relief of pain and all nonpain allergy symptoms compared with pseudoephedrine/chlorpheniramine treatment. Furthermore, the superior efficacy of the lower dose of the triple combination allowed for a decrease in the incidence of adverse effects.

Background: Antihistamines have been shown to have a variety of therapeutic effects in asthma. Although nasal obstruction may play an important role in modulating lower airway function, no prior trial has used a decongestant in combination with an antihistamine in patients with allergic rhinitis and concomitant asthma. Objective: We sought to determine the efficacy and safety of loratadine (5 mg) plus pseudoephedrine (120 mg) (L/P) twice daily in patients with seasonal allergic rhinitis and mild asthma. Methods: We conducted a randomized, double-blind, placebo-controlled trial of L/P in 193 subjects during the fall allergy season. Nasal and chest symptoms, albuterol use, and peak expiratory flow rates were recorded daily for 6 weeks. Spirometry was measured at baseline and after 1, 2, 4, and 6 weeks of therapy, and health-related quality of life was rated at the beginning and end of the study. Results: Total rhinitis and asthma symptom severity scores were significantly reduced in patients receiving active therapy compared with those receiving placebo throughout the 6-week study. Peak expiratory flow rates improved significantly in patients treated with L/P during weeks 2 through 6 (peak effect [mean ± SEM]: L/P, 26.23 ± 4.64 L/min vs placebo, 8.52 ± 3.53 L/min, p = 0.002) as did FEV 1 (peak effect [mean ± SEM]: L/P, 170 ± 53 ml vs placebo, 20 ± 40 ml, p = 0.01) at all clinic visits. In addition, select measures of asthma-specific quality of life improved significantly relative to placebo. Conclusions: L/P significantly improved nasal and asthma symptoms, pulmonary function, and quality of life in patients with seasonal allergic rhinitis and concomitant mild asthma. (J Allergy Clin Immunol 1997;100:781-8)

Background: Few clinical trials have directly compared the efficacy of antihistamines with topical nasal corticosteroids. Objective: The study was performed to compare the efficacy and safety of triamcinolone acetonide nasal spray at a dose of 110 μg in each nostril once daily with 10 mg of oral astemizole once daily for the treatment of seasonal allergic rhinitis. Methods: A multicenter, double-blind, parallel-group study was conducted in 239 patients who were randomized to receive either triamcinolone acetonide or astemizole. A 5-day, drug-free, lead-in period was followed by 4 weeks of double-blind treatment. One hundred four patients treated with triamcinolone acetonide and 105 patients treated with astemizole could be evaluated. Results: Overall, triamcinolone acetonide was more effective than astemizole in reducing total nasal symptoms, nasal stuffiness, nasal itching, and sneezing ( p ≤0.01). Triamcinolone acetonide was superior to astemizole at weeks 1, 2, and 3 in reduction of the total nasal symptom score ( p ≤0.0401) and in reduction of nasal stuffiness ( p ≤0.05). Improvements in individual nasal symptoms (itching, postnasal drip, runny nose, and sneezing) were greater for triamcinolone acetonide at week 2 ( p ≤0.01). Ocular symptoms improved from baseline in both groups. When pollen counts were correlated to mean nasal rhinitis scores, the triamcinolone acetonide group showed continued improvement from week 1 to week 2 in nasal symptoms when pollen counts were at their highest. During the same period, patients treated with astemizole failed to show improvement from week 1 to week 2. This study demonstrated that once daily administration of triamcinolone acetonide was more effective than astemizole for controlling nasal symptoms of seasonal allergic rhinitis, especially during the peak pollination period.