Randomized trial to assess the efficacy and safety of beclomethasone dipropionate breath-actuated inhaler in patients with asthma.

BACKGROUND: Breath-actuated inhalers (BAI) eliminate the need for the hand-breath coordination required with standard metered-dose inhalers (MDI). OBJECTIVE: To evaluate the efficacy and safety of beclomethasone dipropionate (BDP) administered via BAI. METHODS: This 6-week, phase III, double-blind study included patients aged ≥12 years with persistent asthma. During the single-blind run-in, patients discontinued asthma medications and received twice-daily placebo BAI or MDI. At randomization, BAI patients received BDP BAI 320 µg/day, BDP BAI 640 µg/day, or placebo BAI, and MDI patients received BDP MDI 320 µg/day or placebo MDI. Assessments included standardized baseline-adjusted trough morning forced expiratory volume in 1 second (FEV1) area under the effect curve from 0 to 6 weeks (AUEC[0-6 wk]) (obtained by clinic-based spirometry; the primary end point), morning peak expiratory flow (PEF), trough daily morning FEV1 (obtained by handheld spirometry), withdrawals, and tolerability. RESULTS: Of 425 patients randomized, most were white (81%) and female (61%). BDP BAI 320 and 640 µg/day significantly improved FEV1 AUEC(0-6 wk) versus placebo (p < 0.001). The BDP BAI treatment groups exhibited significantly improved morning PEF and daily morning FEV1 versus placebo (p < 0.001). Similar treatment effects were demonstrated for BDP MDI (p < 0.001). Fewer patients withdrew due to worsening asthma while taking BDP BAI 320 µg/day (n = 1), BDP BAI 640 µg/day (n = 0), and BDP MDI 320 µg/day (n = 1) versus placebo (n = 10). BDP BAI was well tolerated. CONCLUSION: BDP BAI demonstrated significant improvements in pulmonary function versus placebo, with results similar to BDP MDI. The safety profile of BDP BAI was comparable to BDP MDI, with no new safety signals.The study was registered on ClinicalTrials.gov (NCT02513160), www.clinicaltrials.gov.

Randomized, double-blind trial evaluating the efficacy and safety of fluticasone propionate and fluticasone propionate/salmeterol delivered via multidose dry powder inhalers in patients with persistent asthma aged 12 years and older.

OBJECTIVE: To assess the efficacy and safety of fluticasone propionate (Fp) and Fp/salmeterol (FS) administered via a novel multidose dry powder inhaler (MDPI) that is easy to use correctly in asthma patients. METHODS: This phase-3, multicenter, double-blind, parallel-group study evaluated asthmatic patients (≥12 years of age) previously treated with either low- or mid-dose inhaled corticosteroids (ICSs) or ICS/long-acting beta agonists. After a 14- to 21-day run-in, patients were randomized to Fp MDPI 50 mcg, Fp MDPI 100 mcg, FS MDPI 50/12.5 mcg, FS MDPI 100/12.5 mcg, or placebo twice daily for 12 weeks. Change from baseline in forced expiratory volume in 1 second (FEV1; primary endpoint) was evaluated at week 12, and serial spirometry was collected at day 1 and week 12 (subset of patients). Safety was assessed by adverse events (AEs). RESULTS: The full analysis and serial spirometry subset included 640 and 312 patients, respectively. At week 12, FS MDPI significantly improved FEV1 from baseline at each dose vs corresponding Fp MDPI doses (p < 0.05). Change from baseline in FEV1 for active treatment groups was significantly greater vs placebo (p < 0.05). After 12 weeks, serial spirometry was significantly greater at all time points in the FS MDPI groups vs corresponding Fp MDPI groups (p < 0.05). Improvements in serial spirometry on day 1 were maintained through week 12. AEs were similar across groups. CONCLUSIONS: Pulmonary function was significantly improved with Fp MDPI and FS MDPI vs placebo and FS MDPI vs Fp MDPI. Active treatments had a safety profile comparable to placebo.

Twelve- and 52-week safety of albuterol multidose dry powder inhaler in patients with persistent asthma.

OBJECTIVE: Evaluate the safety of albuterol multidose dry powder inhaler (MDPI), a novel, inhalation-driven device that does not require coordination of actuation with inhalation, in patients with persistent asthma. METHODS: We report pooled safety data from two 12-week, multicenter, randomized, double-blind, repeat-dose, parallel-group studies and the 12-week double-blind phase of a 52-week multicenter safety study as well as safety data from the 40-week open-label phase of the 52-week safety study. In each study, eligible patients aged ≥ 12 years with persistent asthma received placebo MDPI or albuterol MDPI 180 µg (2 inhalations × 90 µg/inhalation) 4 times/day for 12 weeks. In the 40-week open-label phase of the 52-week safety study, patients received albuterol MDPI 180 µg (2 inhalations × 90 µg/inhalation) as needed (PRN). RESULTS: During both 12-week studies and the 12-week double-blind phase of the 52-week study, adverse events were more common with placebo MDPI (50%; n = 333) than albuterol MDPI (40%; n = 321); most frequent were upper respiratory tract infection (placebo MDPI 11%, albuterol MDPI 10%), nasopharyngitis (6%, 5%), and headache (6%, 4%). Incidences of ß2-agonist-related events (excluding headache) during the pooled 12-week dosing periods were low (≤ 1%) in both groups. The safety profile with albuterol MDPI PRN during the 40-week open-label phase [most frequent adverse events: nasopharyngitis (12%), sinusitis (11%), upper respiratory tract infection (9%)] was similar to that observed during the 12-week pooled analysis. CONCLUSIONS: The safety profile of albuterol MDPI 180 µg in these studies was comparable with placebo MDPI and consistent with the well-characterized profile of albuterol in patients with asthma.

Efficacy, safety, and optimal dose selection of beclomethasone dipropionate nasal aerosol for seasonal allergic rhinitis in adolescents and adults.

OBJECTIVE: Some patients with allergic rhinitis (AR) may prefer nonaqueous intranasal corticosteroid aerosols because of unwanted attributes of aqueous formulations. The mandatory removal of chlorofluorocarbon-propelled nonaqueous aerosols from the market limited available treatment options. To fulfill this unmet need, a nonaqueous, hydrofluoroalkane-propelled beclomethasone dipropionate (BDP) nasal aerosol was developed and approved for treatment of AR nasal symptoms. As part of the development program, this dose-ranging study evaluated three doses of BDP nasal aerosol to determine the optimally safe and effective dose for adolescent and adult patients (≥12 years old) with seasonal AR (SAR). METHODS: After a 7 to 21 day placebo run-in period, eligible patients with SAR were randomly assigned to once-daily BDP nasal aerosol 80 µg, 160 µg, 320 µg, or placebo. The primary endpoint was the change from baseline in average a.m. and p.m. patient-reported reflective total nasal symptom scores (rTNSS) over 2 weeks. Safety and tolerability were also assessed. A potential study limitation could be lack of objective assessment of AR symptoms. RESULTS: Significant improvements were seen in average a.m. and p.m. rTNSS (least squares [LS] mean treatment difference, -0.63; 95% CI: -1.13, -0.13; p = 0.013) as well as in average a.m. and p.m. instantaneous TNSS (iTNSS; LS mean treatment difference, -0.60; 95% CI: -1.09, -0.11; p = 0.016) with BDP nasal aerosol 320 µg/day compared with placebo. Although there were numerical improvements from baseline in patient-reported rTNSS and iTNSS with BDP nasal aerosol 80 µg and 160 µg, these doses did not achieve statistical significance compared with placebo. BDP nonaqueous nasal aerosol was well tolerated at all doses tested, with a safety profile comparable to that of placebo. CONCLUSIONS: These data indicate that 320 µg/day of BDP nasal aerosol is the optimally safe and effective dose for the treatment of SAR in adolescent and adult patients. Trial registration NCT: #NCT00854360.

A 26-week tolerability study of ciclesonide nasal aerosol in patients with perennial allergic rhinitis.

BACKGROUND: A new, hydrofluoroalkane nasal aerosol solution formulation of ciclesonide (CIC-HFA) delivered via a metered dose inhaler is currently in clinical development for treatment of allergic rhinitis. OBJECTIVE: To study tolerability and quality of life following administration of CIC-HFA 74- or 148-µg doses once-daily compared with placebo in patients with perennial allergic rhinitis (PAR) over 26 weeks. METHODS: Patients ≥12 years of age with a ≥2 year history of PAR were randomized in a placebo-controlled, double-blind, parallel group, multicenter study to CIC-HFA 74 µg, 148 µg, or placebo QD AM for 26 weeks. Safety was assessed by monitoring treatment-emergent adverse events (TEAEs). Quality of life was assessed by using a rhinoconjunctivitis quality of life questionnaire with standardized activities (RQLQ[S]) in patients with baseline RQLQ ≥3.00. Reflective total nasal symptom scores (rTNSS) and instantaneous total nasal symptom scores (iTNSS) over 26 weeks were also evaluated. RESULTS: In this study, 1111 patients were randomized. The overall incidence of TEAEs was comparable between the treatment groups. Treatment with CIC-HFA 74- or 148-µg doses showed improvements in RQLQ[S] [least squares (LS) mean change 0.40 and 0.37, respectively from baseline, p < 0.01 versus placebo for both], rTNSS (LS mean change 0.65 and 0.52, respectively from baseline; p ≤ 0.01 versus placebo for both), and iTNSS (LS mean change 0.51 and 0.42, respectively from baseline; p < 0.05 versus placebo for both) from baseline. CONCLUSION: In this study, once-daily treatment with CIC-HFA 74- or 148-µg doses over 26 weeks was well tolerated with comparable incidence of TEAEs between the treatment groups.

Efficacy and tolerability study of ciclesonide nasal aerosol in patients with perennial allergic rhinitis.

A new nasal aerosol solution formulation of ciclesonide containing a hydrofluoroalkane propellant (CIC-HFA) delivered via a metered-dose inhaler is currently in clinical development as a potential treatment for allergic rhinitis (AR). This study evaluated the efficacy and tolerability of CIC-HFA 74- or 148-microgram doses compared with placebo in patients with perennial AR (PAR). Patients ≥12 years of age with a ≥ 2-year history of PAR were randomized in a placebo-controlled, double-blind, parallel-group, multicenter study to CIC-HFA 74 micrograms, CIC-HFA 148 micrograms, or placebo q.d. in the morning (A.M.) for 26 weeks. Change from baseline in reflective total nasal symptom score (rTNSS), instantaneous total nasal symptom score (iTNSS), and rhinoconjunctivitis quality-of-life questionnaire with standardized activities (RQLQ[S]) in patients with baseline RQLQ of ≥3.00 were evaluated for the first 6 weeks of treatment. Treatment-emergent adverse events (TEAEs) were monitored throughout the study. Eleven hundred eleven patients were randomized. CIC-HFA 74- and 148-microgram doses showed statistically significant improvements in rTNSS (least squares [LS] mean change, 0.70 and 0.54, respectively; p ≤ 0.001 versus placebo for both), iTNSS (LS mean change, 0.58 and 0.42, respectively; p < 0.05 versus placebo for both), and RQLQ[S] (LS mean change, 0.55 and 0.37, respectively; p < 0.01 versus placebo for both) from baseline. The overall incidence of TEAEs was comparable between the CIC-HFA treatment groups and placebo. In this study, once-daily treatment with CIC-HFA 74- or 148-micrograms showed statistically significant improvements in nasal symptoms of PAR. Both doses were well tolerated. Clinical trial registration URL and registration number: www.clinicaltrials.gov/ct2/show/NCT00953147.

Long-term safety and efficacy of intranasal ciclesonide in adult and adolescent patients with perennial allergic rhinitis.

BACKGROUND: Ciclesonide is a corticosteroid in development for allergic rhinitis that has been shown to be safe and effective in seasonal allergic rhinitis and perennial allergic rhinitis (PAR) trials of up to 6 weeks in duration. However, the long-term safety and efficacy of ciclesonide are unknown. OBJECTIVE: To demonstrate the long-term safety of intranasal ciclesonide, 200 microg once daily, in patients with PAR. METHODS: Patients (> or = 12 years old) with a 2-year or longer history of PAR were randomized in a double-blind fashion to receive ciclesonide, 200 microg, or placebo once daily in the morning for up to 52 weeks. Spontaneous and elicited adverse events were monitored throughout the study. Ear, nose, and throat examinations were performed to evaluate local tolerability. Additionally, 24-hour urinary free cortisol level, morning plasma cortisol level, intraocular pressure, and lens opacification were monitored to evaluate the systemic safety of intranasal ciclesonide. Ciclesonide efficacy was determined by measuring 24-hour reflective total nasal symptom scores. RESULTS: No clinically relevant differences were observed between the ciclesonide and placebo groups in adverse events, ear, nose, and throat examinations, or 24-hour urinary free or morning plasma cortisol levels. Similarly, no clinically relevant differences were found between treatment groups in intraocular pressure, visual acuity, or lens opacification. With regard to efficacy, ciclesonide achieved a significantly greater reduction in 24-hour reflective total nasal symptom score compared with placebo over more than 52 weeks (P < .001). CONCLUSION: In this study, intranasal ciclesonide, 200 microg once daily, was safe and effective for the long-term treatment of PAR, with no evidence of tachyphylaxis.

Efficacy of diphenhydramine vs desloratadine and placebo in patients with moderate-to-severe seasonal allergic rhinitis.

BACKGROUND: Previous studies have shown that diphenhydramine and desloratadine effectively relieve symptoms of seasonal allergic rhinitis (SAR). OBJECTIVE: To compare the relative efficacy of 50 mg of diphenhydramine hydrochloride, 5 mg of desloratadine, and placebo in relieving symptoms in patients with moderate-to-severe SAR. METHODS: In this 1-week, multicenter, parallel-group, randomized, double-blind, double-dummy, placebo-controlled study, 610 patients with moderate-to-severe SAR received 50 mg of diphenhydramine hydrochloride 3 times daily, 5 mg of desloratadine once daily, or placebo. Daily 24-hour reflective total nasal symptom scores (TNSSs) (primary end point), total symptom scores, and individual symptom scores were evaluated. A global evaluation of response to treatment was conducted at 2 posttreatment visits. RESULTS: The mean reduction from baseline in 24-hour reflective TNSSs relative to the placebo response was 77.6% for the diphenhydramine group (P < .001) and 21.0% for the desloratadine group (P = .12). A TNSS between-treatment difference of -1.81 (46.7%; P < .001) was observed when comparing diphenhydramine with desloratadine. A similar between-treatment difference was observed for the 24-hour reflective total symptom score comparing diphenhydramine to desloratadine (-3.35; 45.5%; P < .001). Diphenhydramine provided clinically and statistically significant reductions vs placebo and desloratadine in all individual symptoms, including nasal congestion. Desloratadine had a tendency toward improvement compared with placebo for most individual symptom scores. However, a statistically significant result was reached only for sneezing (-0.27; 33.9%; P = .04). CONCLUSIONS: Diphenhydramine, 50 mg, given for 1 week provided statistically significant and clinically superior improvements in symptoms compared with 5 mg of desloratadine in patients with moderate-to-severe SAR. Somnolence occurred more frequently with diphenhydramine (22.1%) compared with desloratadine (4.5%) and placebo (3.4%).

Efficacy and safety of low-dose fluticasone propionate compared with zafirlukast in patients with persistent asthma.

To compare the efficacy and safety of fluticasone propionate and zafirlukast in patients with relatively stable persistent asthma who were previously treated with inhaled corticosteroids and short-acting beta(2)-agonists.A total of 440 patients (> or =12 years of age) previously treated with inhaled corticosteroids (beclomethasone dipropionate or triamcinolone acetonide) and short-acting beta(2)-agonists were included in this randomized double-blind study. After an 8-day run-in period, patients were treated with fluticasone (88 microg) or zafirlukast (20 mg) twice daily for 6 weeks. Outcome measures included pulmonary function (forced expiratory volume in 1 second [FEV(1)], peak expiratory flow [peak flow]), albuterol use, asthma symptoms, withdrawals due to lack of efficacy, and asthma exacerbations. Patients treated with fluticasone (n = 224) experienced greater mean increases in FEV(1) (0.24 L vs. 0.08 L, P <0.001), morning peak flow (30 L/min vs. 6 L/min, P <0.001), and evening peak flow (23 L/min vs. 5 L/min, P <0.001) during the study than did those treated with zafirlukast (n = 216). Fluticasone-treated patients had significantly greater increases in the mean percentages of symptom-free days (22% vs. 8%, P <0.001), rescue-free days (23% vs. 10%, P = 0.002), nights with uninterrupted sleep (<1% vs. -5%, P = 0.006), and fewer asthma exacerbations (1% vs. 6%, P = 0.005). Fewer fluticasone-treated patients were withdrawn due to lack of efficacy (2% vs. 13%, P <0.001).Inhaled fluticasone was more effective than zafirlukast in maintaining or improving asthma control in patients with relatively stable asthma who were switched from low-dose inhaled corticosteroids.