Relationship between handheld and clinic-based spirometry measurements in asthma patients receiving beclomethasone.

INTRODUCTION: Handheld spirometers for home use by patients allow longitudinal spirometry data to be collected daily and may overcome some of the limitations of in-clinic spirometry (long intervals between measurements, results can be affected by site-based coaching and patient's asthma status during a given visit). OBJECTIVES: To determine the relationship between spirometry values measured by clinic-based and handheld spirometers during a clinical trial. METHODS: A post hoc correlation analysis of data from a 6-week phase 3 study of beclomethasone dipropionate (BDP; delivered by breath-actuated inhaler: BAI) versus placebo in patients aged ≥12 years with persistent asthma. During the study, forced expiratory volume in 1 s (FEV1) was assessed by both office-based spirometry at Weeks 2, 4 and 6, and daily by handheld spirometer as a secondary study endpoint. RESULTS: There was a high correlation between FEV1 values measured at home and in-clinic (overall correlation coefficient = 0.8393, R = 0.81921, 0.85927, 0.85369 and 0.83734 for BAI 320 µg/day, BAI 640 µg/day, BDP metered dose inhaler 320 µg/day and placebo treatment groups, respectively), with the scatterplot showing an upward trend for all treatment groups. Nearly all patients achieved home FEV1 values close to clinic FEV1 values, with very few outliers. CONCLUSIONS: Clinic-based and handheld spirometry demonstrated comparable treatment effects relative to placebo, suggesting that home spirometry could be used to help patients monitor their asthma severity. Daily measurement of FEV1 provides more comprehensive data than can be achieved through clinic visits, and may lead to a new approach to clinical trial design.

Device mechanics and evaluation of inspiratory flow rate required of the beclomethasone dipropionate breath-actuated inhaler.

Background: Approximately 80% of patients with asthma and chronic obstructive pulmonary disease incorrectly use a metered-dose inhaler and, therefore, fail to obtain full benefit from their inhaler medication. Beclomethasone dipropionate (BDP) hydrofluoroalkane, an inhalation aerosol administered via a breath-actuated inhaler (BAI) has been designed to improve ease of use over press-and-breathe metered-dose inhalers by eliminating the need for hand-breath coordination. Objective: To present the mechanics of the BAI device, assess the minimum reliable inspiratory flow rate required to trigger an actuation, and evaluate if intended users can safely and effectively use the BDP BAI according to the instructions for use (IFU). Methods: Six random batches (three batches each of 40 µg and 80 µg) of 10 inhalers were evaluated for the minimum inspiratory flow rate required for actuation trigger. Each inhaler was tested for actuation at five flow rates: 12, 14, 16, 18, and 20 L/min. Simulated-use testing was conducted with 91 participants from six representative user groups in the United States to assess the use of a placebo-filled production-equivalent BDP BAI according to the IFU. Results: Across the 40-µg batches, 83% of the devices actuated at 16 L/min and 100% actuated at 18 and 20 L/min. For the 80-µg batches, 67% and 100% actuated at 18 L/min and 20 L/min, respectively. All the participants demonstrated successful use of the BDP BAI during the study session. Isolated safety-critical errors with the potential for no-dose delivery were recorded for 15 participants but were considered unrelated to the design of the IFU. Conclusion: The BDP BAI consistently triggered actuation at an airflow rate of 20 L/min and was successfully used based on guidance from the IFU only. This device provides an alternative for patients who find it difficult to use metered-dose inhaler devices correctly.

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.

Pharmacokinetics of Beclomethasone Dipropionate Delivered by Breath-Actuated Inhaler and Metered-Dose Inhaler in Healthy Subjects.

BACKGROUND: Breath-actuated inhalers (BAIs) eliminate the need for hand-breath coordination required of pressurized metered-dose inhalers (MDIs). This pharmacokinetic study compared systemic exposure following beclomethasone dipropionate delivery through BAI versus MDI. METHODS: This open-label, three-period crossover, single-dose study randomized healthy subjects aged 18-45 years (N = 72) to 1 of 6 treatment sequences containing beclomethasone dipropionate BAI 160 mcg (40 mcg/inhalation, 4 inhalations), beclomethasone dipropionate BAI 320 mcg (80 mcg/inhalation, 4 inhalations), and beclomethasone dipropionate MDI 320 mcg (80 mcg/inhalation, 4 inhalations). Blood samples were collected predose through 24 hours postdose for determination of plasma concentrations of beclomethasone-17-monopropionate (17-BMP), the active metabolite of beclomethasone dipropionate. The primary pharmacokinetic parameters were area under the plasma drug concentration-time curve (AUC) from time 0 (predose) until the last measurable drug concentration (AUC0-t) and maximum plasma drug concentration (Cmax) for 17-BMP. Safety was assessed by adverse events, vital signs, clinical laboratory tests, and physical examinations. RESULTS: Plasma concentrations of 17-BMP peaked at a median of 10 minutes after the last inhalation of all study treatments and remained measurable for at least 18 hours in most subjects. Mean elimination half-life was ∼4 hours. The AUC0-t and Cmax for 17-BMP were 11% and 14% higher, respectively, when beclomethasone dipropionate 320 mcg was administered through BAI versus MDI, but the 90% confidence intervals of the geometric least squares mean BAI:MDI ratio for each parameter were fully contained within the bioequivalence boundaries of 0.80-1.25. Plasma concentrations of 17-BMP following beclomethasone dipropionate 160 mcg BAI were approximately half those with 320 mcg through BAI or MDI. All treatments were safe and generally well tolerated. CONCLUSIONS: Systemic availability of 17-BMP following administration of beclomethasone dipropionate was bioequivalent between BAI and MDI at the 320-mcg dose, and approximately dose proportional at the 160- and 320-mcg doses using the BAI.

Evaluation of beclomethasone dipropionate (80 and 160 micrograms/day) delivered via a breath-actuated inhaler for persistent asthma.

BACKGROUND: Breath-actuated inhalers (BAI) may simplify the delivery of inhaled medications compared with other devices. OBJECTIVE: To evaluate the efficacy and safety of beclomethasone dipropionate BAI versus matching placebo in adolescent and adult patients with persistent asthma. METHODS: This phase III, 12-week, double-blind study enrolled patients with asthma aged ≥12 years who were previously treated with a stable dose of inhaled corticosteroid or noncorticosteroid therapy. After a run-in period of 14 to 21 days, patients were randomly assigned in a 1:1:1 ratio to beclomethasone dipropionate BAI 80 or 160 micrograms/day (40 or 80 micrograms twice daily) or placebo BAI. The primary end point was the standardized baseline-adjusted trough morning forced expiratory volume in 1 second (FEV1) area under the effect curve from time 0 to 12 weeks (AUEC[0-12 weeks]). Secondary end points included peak expiratory flow, rescue medication use, asthma symptoms, and the time to withdrawal due to meeting predefined criteria for worsening asthma. Additional end points evaluated quality of life, instructions for use, and safety. RESULTS: The full analysis and the safety sets included 270 and 273 patients, respectively. Patients who received beclomethasone dipropionate BAI 80 or 160 micrograms/day had significant improvements in FEV1 AUEC(0-12 weeks) versus placebo (p ≤ 0.001). Improvements in secondary end points were also apparent in patients who received beclomethasone dipropionate BAI 80 or 160 micrograms/day compared with placebo. Patients who received beclomethasone dipropionate BAI 80 or 160 micrograms/day had greater increases in Asthma Quality of Life Questionnaire scores versus placebo patients at week 12. Of 98 patients who participated in the instructions-for-use substudy, 87 (88.8%) used the inhaler successfully on their first attempt. Treatment was generally safe and well tolerated. CONCLUSION: Beclomethasone dipropionate BAI 80 and 160 micrograms/day were effective and well-accepted treatments in patients with asthma, with safety comparable to beclomethasone dipropionate delivered via a metered-dose inhaler.Clinical trial NCT02040779, www.clinicaltrials.gov.

Efficacy and safety of beclomethasone dipropionate breath-actuated or metered-dose inhaler in pediatric patients with asthma.

BACKGROUND: Breath-actuated inhalers (BAI) eliminate the need for hand-breath coordination and, therefore, simplify the delivery of inhaled medication. OBJECTIVE: To evaluate the efficacy and safety of beclomethasone dipropionate BAI and metered-dose inhaler (MDI) versus placebo in pediatric patients ages 4-11 years with persistent asthma. METHODS: In this double-blind, double-dummy, phase III study, 628 children with persistent asthma were randomly assigned (1:1:1:1:1) to twice-daily beclomethasone dipropionate (BAI 80 µg/day, BAI 160 µg/day, MDI 80 µg/day, or MDI 160 µg/day) or to placebo. Efficacy over 12 weeks was assessed by spirometry, peak expiratory flow (PEF) measurements and other clinical end points. The primary efficacy end point was the baseline-adjusted trough morning percent predicted forced expiratory volume in 1 second (PPFEV1) area under the effect curve from 0 to 12 weeks (AUEC[0-12 weeks]). RESULTS: PPFEV1 AUEC(0-12 weeks) showed numerical improvements from baseline in the BAI 80 µg/day and BAI 160 µg/day groups and MDI 80 µg/day and MDI 160 µg/day groups; however, these improvements were not significant versus placebo for any group after hierarchical testing was applied. Consistent improvements were noted in the active treatment groups versus placebo for the weekly average trough morning and evening PEFs, and with BAI 80 µg/day versus placebo for rescue albuterol/salbutamol use and the total daily asthma symptom score. Most patients indicated that the BAI device was easy or very easy to use. Adverse events were comparable across the groups; the incidence of oral candidiasis ranged from 0.8 to 3.2%. CONCLUSIONS: Although the primary efficacy end point was not demonstrated, consistent improvements in PEF and other clinical end points were observed with beclomethasone dipropionate BAI, particularly at the 80 µg/day dose. These clinical benefits, combined with the need for better symptom control in children with asthma, supported the development of beclomethasone dipropionate BAI.

Safety and efficacy of beclomethasone dipropionate delivered by breath-actuated or metered-dose inhaler for persistent asthma.

BACKGROUND: Breath-actuated inhalers (BAI) have been developed to simplify the delivery of inhaled medication. OBJECTIVE: To evaluate the safety and efficacy of beclomethasone dipropionate hydrofluoroalkane BAI and metered-dose inhaler (MDI) versus placebo in patients who previously used a mid- to high-dose inhaled corticosteroid or inhaled corticosteroid/long-acting beta agonist for persistent asthma. METHODS: This phase III study included five treatment groups: placebo, and four beclomethasone dipropionate groups (BAI 320 µg/day, BAI 640 µg/day, MDI 320 µg/day, and MDI 640 µg/day). Efficacy over 12 weeks was assessed by spirometry, peak flow measurements, and other clinical end points. Safety was assessed by adverse events. RESULTS: Baseline-adjusted trough morning forced expiratory volume in 1 second area under the effect curve from time 0 to 12 weeks (primary end point) was increased in the BAI 320 and BAI 640 µg/day groups and the MDI 640 µg/day group versus placebo (not significant). Clinically important improvements were noted in morning and evening peak expiratory flow and decreased rescue medications. More patients who received placebo than patients in active treatment groups withdrew due to meeting the stopping criteria for worsening asthma. Patients in the active treatment groups experienced a greater decrease in asthma symptoms than patients in the placebo group. Quality of life and Asthma Control Test scores improved in the active treatment groups compared with the placebo group (p ≤ 0.0074). The most common adverse events (>5% in any group) were oral candidiasis and upper respiratory tract infection. CONCLUSION: Clinical benefits for patients who used BAI 320 and 640 µg/day and MDI 640 µg/day were demonstrated. The safety profiles of BAI 320 and 640 µg/day were comparable with that of the MDI. These benefits and the continued need for better symptom control among patients with asthma support the continued development of this controller medication. ClinicalTrials.gov identifier NCT02031640.

No hypothalamic-pituitary-adrenal function effect with beclomethasone dipropionate nasal aerosol, based on 24-hour serum cortisol in pediatric allergic rhinitis.

BACKGROUND: Intranasal corticosteroids are the mainstay of allergic rhinitis (AR) treatment. Their potential to suppress the hypothalamic-pituitary-adrenal axis should be evaluated, especially after long-term daily use in children. OBJECTIVE: To evaluate the effects of treatment with non-aqueous beclomethasone dipropionate (BDP) nasal aerosol on hypothalamic-pituitary-adrenal axis function in children with perennial AR. METHODS: In this double-blinded, placebo-controlled, parallel-group study, patients (6-11 years old) with perennial AR were randomized (2:1) to BDP nasal aerosol at 80 µg/day (n = 67) or placebo (n = 32). The primary end point was change from baseline in 24-hour serum cortisol (SC) weighted mean for BDP nasal aerosol and placebo after 6 weeks of treatment, which was analyzed in the per-protocol population. RESULTS: The per-protocol population included 97 patients (BDP nasal aerosol, n = 66; placebo, n = 31). Baseline geometric mean SC weighted mean values were similar in the 80-µg/day BDP nasal aerosol and placebo groups (5.97 and 6.47 µg/dL, respectively). After 6 weeks' treatment, geometric mean values were 6.19 and 7.13 µg/dL, respectively, with no decrease from baseline in either group. Geometric mean SC ratio of BDP nasal aerosol at 80 µg/day to placebo was 0.91 (95% confidence interval 0.81-1.03), indicating predefined noninferiority. SC concentration-time profiles were similar for the placebo and 80-µg/day BDP nasal aerosol groups at baseline and week 6. BDP nasal aerosol at 80 µg/day was generally well tolerated. CONCLUSION: In pediatric patients with perennial AR, 24-hour SC profiles were comparable for BDP nasal aerosol and placebo, indicating that once-daily BDP nasal aerosol treatment did not significantly affect hypothalamic-pituitary-adrenal axis function. TRIAL REGISTRATION: ClinicalTrials.gov; NCT01697956.

Efficacy and safety of beclomethasone dipropionate nasal aerosol in children with perennial allergic rhinitis.

BACKGROUND: Beclomethasone dipropionate (BDP) nasal aerosol (non-aqueous) is approved for management of seasonal and perennial allergic rhinitis (PAR) in adolescents and adults. OBJECTIVE: To evaluate the efficacy and safety of BDP nasal aerosol at 80 µg/day in children with PAR. METHODS: This 12-week, phase 3, double-blinded, placebo-controlled, parallel-group study randomized 547 children (4-11 years old) with PAR to once-daily BDP nasal aerosol at 80 µg/day or placebo. The primary end point was change from baseline in average morning and evening reflective total nasal symptom score (rTNSS) during the first 6 weeks of treatment in patients 6 to 11 years old. Changes from baseline in average morning and evening instantaneous TNSS (iTNSS) in children 6 to 11 years old and average rTNSS and iTNSS in children 4 to 11 years old were assessed during the first 6 weeks of treatment. RESULTS: Improvements were significantly greater with BDP nasal aerosol than with placebo during the first 6 weeks of treatment in children 6 to 11 years old in average morning and evening rTNSS and iTNSS (mean treatment difference -0.66 [P = .002] and -0.58 [P = .004], respectively). Improvements in average morning and evening rTNSS and iTNSS also were significantly greater in patients 4 to 11 years receiving BDP nasal aerosol than with placebo during the first 6 weeks of treatment (P = .002 and P = .004, respectively). Similar improvements were seen during 12 weeks of treatment. The safety profile of BDP nasal aerosol was comparable to that of placebo. CONCLUSION: The BDP nasal aerosol at 80 µg/day in children 4 to 11 years old was well tolerated and effective in controlling nasal symptoms of PAR. TRIAL REGISTRATION: www.clinicaltrials.gov, identifier NCT01783548.