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Evaluation of Rapid Onset of Action of ICS/LABA Combination Therapies on Respiratory Function in Asthma Patients: A Single-Center, Open-Label, Randomized, Crossover Trial.

ABSTRACT: INTRODUCTION:Products based on inhaled corticosteroid (ICS)/long-acting β2 agonist (LABA) combinations may provide different clinical benefits. This study was conducted to compare the rapid effects of three such combination products: formoterol/fluticasone (FFC) aerosol (pMDI), formoterol/budesonide (FBC) dry powder inhaler (DPI), and vilanterol/fluticasone furoate (VFC) DPI. METHODS:The study design was a three-armed, randomized, crossover study. Patients included in the study had stable moderate asthma, defined as an Asthma Control Questionnaire (ACQ) score ≤ 0.75, and were undergoing step 2 or 3 asthma treatment as defined by JGL2015. Subjects were treated with fluticasone propionate inhaled via Diskus® during a 2-week washout period before randomization. At visit 2, subjects were randomly assigned in a 1:1:1 ratio to FFC, FBC, or VFC, and evaluated for changes in pulmonary function over time. At visits 3 and 4, the treatment was switched to another ICS/LABA combination in a crossover manner after a 1-week washout period. Spirometry was performed pre-dose and at 3, 10, and 30 min post-dose, and forced oscillation was implemented pre-dose and at 1, 7, 15, and 60 min post-dose. RESULTS:Fifteen outpatients (63.3 ± 9.5 years, ACQ: 0.13 ± 0.19) completed the study. ∆FEV1 at 3 min did not significantly differ among the three groups. Significant increases in FEV1 and %FEV1 from baseline were observed in the FFC (p = 0.004, 0.003), FBC (p = 0.014, 0.011), and VFC (p = 0.032, 0.023) groups at 30 min. Improvements in respiratory resistance at 5-20 Hz from baseline at 60 min, resonant frequency, respiratory system reactance at 5 Hz, and low-frequency reactance area from baseline were observed at 1 min in the FFC group (p = 0.014, 0.002, 0.027, 0.018, respectively). CONCLUSION:FFC administered using a pMDI showed favorable delivery to peripheral airways and significantly more rapid action promptly after inhalation as compared with other ICS/LABA preparations inhaled using a DPI, thus broadening the potential therapeutic options for asthma. TRIAL REGISTRATION NUMBER:UMIN000029379. FUNDING:Kyorin Pharmaceutical Co., Ltd.

SUBMITTER: Ohbayashi H

PROVIDER: S-EPMC6967249 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:Loss of bronchoprotection (LOBP) with a regularly used long-acting ?2-adrenergic receptor agonist (LABA) is well documented. LOBP has been attributed to ?2-adrenergic receptor (B2AR) downregulation, a process requiring farnesylation, which is inhibited by alendronate. OBJECTIVE:We sought to determine whether alendronate can reduce LABA-associated LOBP in inhaled corticosteroid (ICS)-treated patients. METHODS:We conducted a randomized, double-blind, placebo-controlled, parallel-design, proof-of-concept trial. Seventy-eight participants with persistent asthma receiving 250 ?g of fluticasone twice daily for 2 weeks were randomized to receive alendronate or placebo while initiating salmeterol for 8 weeks. Salmeterol-protected methacholine challenges (SPMChs) and PBMC B2AR numbers (radioligand binding assay) and signaling (cyclic AMP ELISA) were assessed before randomization and after 8 weeks of ICS plus LABA treatment. LOBP was defined as a more than 1 doubling dose reduction in SPMCh PC20 value. RESULTS:The mean doubling dose reduction in SPMCh PC20 value was 0.50 and 0.27 with alendronate and placebo, respectively (P = .62). Thirty-eight percent of participants receiving alendronate and 33% receiving placebo had LOBP (P = .81). The after/before ICS plus LABA treatment ratio of B2AR number was 1.0 for alendronate (P = .86) and 0.8 for placebo (P = .15; P = .31 for difference between treatments). The B2AR signaling ratio was 0.89 for alendronate (P = .43) and 1.02 for placebo (P = .84; P = .44 for difference). Changes in lung function and B2AR number and signaling were similar between those who did and did not experience LOBP. CONCLUSION:This study did not find evidence that alendronate reduces LABA-associated LOBP, which relates to the occurrence of LOBP in only one third of participants. LOBP appears to be less common than presumed in concomitant ICS plus LABA-treated asthmatic patients. B2AR downregulation measured in PBMCs does not appear to reflect LOBP.

Project description:Patients with COPD show a significant reduction of the lobar hyperinflation at the functional residual capacity level in the patients who improved >120 mL in forced expiratory volume in 1 second (FEV1) after 6 months of treatment with roflumilast in addition to inhaled corticosteroids (ICSs)/long-acting beta-2 agonists (LABAs)/long-acting muscarinic antagonists (LAMAs).Functional respiratory imaging was used to quantify lobar hyperinflation, blood vessel density, ventilation, aerosol deposition, and bronchodilation. To investigate the exact mode of action of roflumilast, correlations between lobar and global measures have been tested using a mixed-model approach with nested random factors and Pearson correlation, respectively.The reduction in lobar hyperinflation appears to be associated with a larger blood vessel density in the respective lobes (t=-2.154, P=0.040); lobes with a higher percentage of blood vessels reduce more in hyperinflation in the responder group. Subsequently, it can be observed that lobes that reduce in hyperinflation after treatment are better ventilated (t=-5.368, P<0.001). Functional respiratory imaging (FRI)-based aerosol deposition showed that enhanced ventilation leads to more peripheral particle deposition of ICS/LABA/LAMA in the better-ventilated areas (t=2.407, P=0.024). Finally, the study showed that areas receiving more particles have increased FRI-based bronchodilation (t=2.564, P=0.017), leading to an increase in FEV1 (R=0.348, P=0.029).The study demonstrated that orally administered roflumilast supports the reduction of regional hyperinflation in areas previously undertreated by inhalation medication. The local reduction in hyperinflation induces a redistribution of ventilation and aerosol deposition, leading to enhanced efficacy of the concomitant ICS/LABA/LAMA therapy. FRI appears to be a sensitive tool to describe the mode of action of novel compounds in chronic obstructive pulmonary disease. Future studies need to confirm the enhanced sensitivity and the potential of FRI parameters to act as surrogates for clinically relevant, but more difficult to measure, end points such as exacerbations.

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Evaluation of Rapid Onset of Action of ICS/LABA Combination Therapies on Respiratory Function in Asthma Patients: A Single-Center, Open-Label, Randomized, Crossover Trial.

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