Comparison of the effect of beclometasone/formoterol in asthma patients after methacholine-induced bronchoconstriction: A noninferiority study using metered dose vs. dry powder inhaler.

AIMS: To demonstrate the noninferiority of extrafine beclomethasone/formoterol fumarate (BDP/FF) dry powder inhaler (DPI) vs. extrafine BDP/FF pressurized metered dose inhaler (pMDI; Foster® 100/6 µg NEXThaler and pMDI, respectively) in the onset of reliever effect after methacholine induced bronchospasm in asthmatic patients, evaluated in terms of forced expiratory volume in 1 s (FEV1 ) at 5 min postdose. The DPI provides an alternative device option for patients who cannot use a pMDI properly during an acute asthma attack. METHODS: Sixty-five patients received one inhalation of BDP/FF DPI, BDP/FF pMDI or placebo after methacholine challenge, according to a double-blind, double-dummy, cross-over design. Lung function and Borg dyspnoea score were assessed up to 30 min postdose. RESULTS: FEV1 adjusted mean difference between BDP/FF DPI and BDP/FF pMDI at 5 min postdose was 2 ml (95% confidence interval: -0.060; 0.065). A similar result was observed at the other time points. Median time to 85% recovery in FEV1 was 8 min for BDP/FF DPI, 7.5 min for BDP/FF pMDI and 28 min for placebo (P = 0.554 DPI vs. pMDI). The Borg score improved after treatment with both BDP/FF DPI and pMDI and the effect was greater than after placebo. Median time to reach 50% recovery was 4.2 min for BDP/FF DPI, 4.0 min for BDP/FF pMDI and 10.0 min for placebo (P = 0.609 DPI vs. pMDI). CONCLUSIONS: Extrafine Foster® NEXThaler, a flow-independent DPI, is comparable to extrafine Foster® pMDI when administered as reliever therapy after methacholine challenge, thus supporting the maintenance and reliever therapy approach also with Foster® NEXThaler.

Effect of AeroChamber Plus™ on the lung and systemic bioavailability of beclometasone dipropionate/formoterol pMDI.

AIM: To assess the effect of AeroChamber Plus™ on lung deposition and systemic exposure to extra-fine beclometasone dipropionate (BDP)/formoterol (100/6 µg) pMDI (Foster®). The lung deposition of the components of the combination given with the pMDI was also evaluated using the charcoal block technique. METHODS: Twelve healthy male volunteers received four inhalations of extra-fine BDP/formoterol (100/6 µg) using (i) pMDI alone, (ii) pMDI and AeroChamber Plus™ and (iii) pMDI and charcoal ingestion. RESULTS: Compared with pMDI alone, use of AeroChamber Plus™ increased the peak plasma concentrations (C(max)) of BDP (2822.3 ± 1449.9 vs. 5454.9 ± 3197.1 pg ml(-1)), its active metabolite beclometasone 17-monopropionate (17-BMP) (771.6 ± 288.7 vs. 1138.9 ± 495.6 pg ml(-1)) and formoterol (38.4 ± 17.8 vs. 54.7 ± 20.0 pg ml(-1)). For 17-BMP and formoterol, the AUC(0,30 min), indicative of lung deposition, was increased in the AeroChamber Plus™ group by 41% and 45%, respectively. This increase was mainly observed in subjects with inadequate inhalation technique. However, use of AeroChamber Plus™ did not increase the total systemic exposure to 17-BMP and formoterol. Results after ingestion of charcoal confirmed that AUC(0,30 min) can be taken as an index of lung bioavailability and that more than 30% of the inhaled dose of extra-fine BDP/formoterol 100/6 µg was delivered to the lung using the pMDI alone. CONCLUSIONS: The use of AeroChamber Plus™ optimizes the delivery of BDP and formoterol to the lung in subjects with inadequate inhalation technique. The total systemic exposure was not increased, supporting the safety of extra-fine BDP/formoterol pMDI with AeroChamber Plus™.

Rapid effects of extrafine beclomethasone dipropionate/formoterol fixed combination inhaler on airway inflammation and bronchoconstriction in asthma: a randomised controlled trial.

BACKGROUND: The dose-dependent anti-inflammatory effects of a recent fixed combination of extrafine beclomethasone dipropionate/formoterol (BDP/F) were investigated using non-invasive markers of inflammation, exhaled nitric oxide (NO) and adenosine monophosphate (AMP) provocative challenge. The aim was to assess the onset of the anti-inflammatory action of low and high doses and evaluate the suitability of non-invasive assessments to demonstrate dose response. METHODS: Steroid naïve adult out-patients with mild asthma, sensitive to AMP with baseline exhaled NO > 25 parts per billion entered a double-blind, placebo-controlled, 3-way, cross-over study. Patients were randomised to low dose (1 actuation) or high dose (4 actuations) extrafine BDP/F 100/6 µg, or placebo administered twice daily on Days 1 and 2 and once in the morning on Day 3 of each period. Exhaled NO was measured pre-dose on Day 1, then 2 and 4 hours post-administration on Day 3. The AMP challenge was performed 4 hours post-administration on Day 3 and forced expiratory volume in 1 second (FEV1, L) was measured from 0 to 4 hours post-dose on Day 1. Endpoints were NO at 2 and 4 hours, AMP challenge at 4 hours after the fifth dose on Day 3 and FEV1 area under the curve from 0 to 4 h post-dose on Day 1. Analysis of covariance was performed for NO and FEV1 and analysis of variance for AMP challenge. RESULTS: Eighteen patients were randomised and completed the study. Exhaled NO was significantly lower for both doses of extrafine BDP/F versus placebo at 2 and 4 hours (high dose LS mean difference: -22.5 ppb, p < 0.0001 and -20.5 ppb, p < 0.0001; low dose: -14.1 ppb, p = 0.0006 and -12.1 ppb, p = 0.0043) with a significant dose response (p = 0.0342 and p = 0.0423). Likewise, AMP challenge revealed statistically significant differences between both doses of extrafine BDP/F and placebo (high dose LS mean difference: 4.8 mg/mL, p < 0.0001; low dose: 3.7 mg/mL, p < 0.0001), and a significant dose response (p = 0.0185). FEV1 was significantly improved versus placebo for both doses (high dose LS mean difference: 0.2 L, p = 0.0001; low dose: 0.2 L p = 0.0001), but without a significant dose response. CONCLUSIONS: The fixed combination inhaler of extrafine BDP/F has early dose-dependent anti-inflammatory effects with a rapid onset of bronchodilatation in mild asthmatic patients. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01343745.

Bronchodilator efficacy of extrafine glycopyrronium bromide: the Glyco 2 study.

An extrafine formulation of the long-acting muscarinic antagonist glycopyrronium bromide (GB) is in development for chronic obstructive pulmonary disease (COPD), in combination with beclometasone dipropionate and formoterol fumarate - a "fixed triple". This two-part study was randomized, double blind, placebo controlled in patients with moderate-to-severe COPD: Part 1: single-dose escalation, GB 12.5, 25, 50, 100 or 200 µg versus placebo; Part 2: repeat-dose (7-day), four-period crossover, GB 12.5, 25 or 50 µg twice daily (BID) versus placebo, with an open-label extension in which all patients received tiotropium 18 µg once daily. On the morning of Day 8 in all five periods, patients also received formoterol 12 µg. In study Part 1, 27 patients were recruited. All GB doses significantly increased from baseline forced expiratory volume in 1 second (FEV1) area under the curve (AUC0-12h) and peak FEV1, with a trend toward greater efficacy with higher GB dose. All adverse events were mild-moderate in severity, with a lower incidence with GB than placebo and no evidence of a dose-response relationship. In study Part 2, of 38 patients recruited, 34 completed the study. Adjusted mean differences from placebo in 12 h trough FEV1 on Day 7 (primary) were 115, 142 and 136 mL for GB 12.5, 25 and 50 µg BID, respectively (all P<0.001). GB 25 and 50 µg BID were superior (P<0.05) to GB 12.5 µg BID for pre-dose morning FEV1 on Day 8. For this endpoint, GB 25 and 50 µg BID were also superior to tiotropium. Compared with Day 7, addition of formoterol significantly increased Day 8 FEV1 peak and AUC0-12h with all GB doses and placebo (all P<0.001). All adverse events were mild-moderate in severity and there was no indication of a dose-related relationship. This study provides initial evidence on bronchodilation, safety and pharmacokinetics of extrafine GB BID. Overall, the results suggest that GB 25 µg BID is the optimal dose in patients with COPD.