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

Brian J O'Connor, Sara Collarini, Gianluigi Poli, Caterina Brindicci, Monica Spinola, Daniela Acerbi, Peter J Barnes, Brian Leaker, Brian J O'Connor, Sara Collarini, Gianluigi Poli, Caterina Brindicci, Monica Spinola, Daniela Acerbi, Peter J Barnes, Brian Leaker

Abstract

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.

Figures

Figure 1
Figure 1
Study design.
Figure 2
Figure 2
FENO levels at 4 hours post-administration after 3 days of treatment with extrafine BDP/F low dose (100/6 μg, 1 actuation), high dose (100/6 μg, 4 actuations), or placebo. Columns and bars represent LS mean and 95% CI.
Figure 3
Figure 3
AMP PC20 at 4 hours post-administration after 3 days of treatment with extrafine BDP/F low dose (100/6 μg, 1 actuation), high dose (100/6 μg, 4 actuations), or placebo. Columns and bars represent LS mean and 95% CI.
Figure 4
Figure 4
Mean FEV1 on the first day of treatment with extrafine BDP/F low dose (100/6 μg, 1 actuation), high dose (100/6 μg, 4 actuations), or placebo.

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