Randomized study of the effects of Aerochamber Plus ® Flow-Vu ® on the efficacy, pharmacokinetics and safety of glycopyrronium/formoterol fumarate dihydrate metered dose inhaler in patients with chronic obstructive pulmonary disease
Faisal FakihSelwyn SpangenthalBarry SigalPatrick DarkenAndrea MaesShahid SiddiquiMichael GillenColin ReisnerUbaldo J. Martin
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ObjectivesThis study compared the efficacy, pharmacokinetics (PK), and safety of GFF MDI (Bevespi Aerosphere®), a fixed-dose combination of glycopyrronium and formoterol fumarate dihydrate (14.4/10 μg) delivered by a metered dose inhaler (MDI) formulated using innovative co-suspension delivery technology, in patients with moderate-to-very severe chronic obstructive pulmonary disease (COPD) with and without the Aerochamber Plus® Flow-Vu® valved holding chamber (VHC).MethodsIn this multicenter, open-label, crossover, Phase III study (NCT02454959), patients were randomized to receive GFF MDI 14.4/10 μg (equivalent to glycopyrrolate/formoterol fumarate 18/9.6 μg) twice daily for 7 days with and without the VHC. The primary endpoint was forced expiratory volume in 1 s area under the curve from 0 to 12 h (FEV1 AUC0-12) on Day 8. Steady state PK parameters for glycopyrronium and formoterol (AUC0-12, peak concentration [Cmax] and time to peak concentration [tmax]) were estimated from 12-h plasma concentration time data on Day 8. Safety and tolerability were also assessed throughout.ResultsEighty patients were randomized. On Day 8, the ratio (90% confidence interval [CI]) of least squares mean (LSM) FEV1 AUC0-12 for GFF MDI with VHC (LSM = 1538 mL; n = 67) versus without VHC (LSM = 1516 mL; n = 68) was 101.4% (100.1, 102.7). PK parameters were comparable overall with a slightly higher exposure to glycopyrronium with the VHC. The AUC0-12 geometric LSM ratio (90% CI) for GFF MDI with versus without VHC was 115.99% (99.74, 134.89) for glycopyrronium and 96.66% (86.69, 107.78) for formoterol. GFF MDI with and without VHC were well tolerated with a similar adverse event profile.ConclusionsThe magnitude of bronchodilatory effect was similar with and without a VHC following GFF MDI treatment. This, together with the PK and safety profiles, supports the use of the VHC with GFF MDI for the maintenance treatment of COPD, which could be particularly useful for patients who have difficulty with the coordination of an MDI.Keywords:
Metered-dose inhaler
Formoterol Fumarate
Crossover study
Formoterol Fumarate
Onset of action
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Budesonide/formoterol in a single inhaler was compared with budesonide alone, and with concurrent administration of budesonide and formoterol from separate inhalers, in patients with asthma, not controlled with inhaled glucocorticosteroids alone. In this 12-week, double-blind, randomized, double-dummy study, 362 adult asthmatics (forced expiratory volume in one second 73.8% of predicted, inhaled glucocorticosteroid dose 960 µg·day −1 ) received single inhaler budesonide/formoterol (Symbicort® Turbuhaler®) 160/4.5 µg, two inhalations b.i.d. , or corresponding treatment with budesonide, or budesonide plus formoterol via separate inhalers. There was a greater increase in morning peak expiratory flow (PEF) with single-inhaler (35.7 L·min −1 ) and separate-inhaler (32.0 L·min −1 ) budesonide and formoterol, compared with budesonide alone (0.2 L·min −1 ; p<0.001, both comparisons); the effect was apparent after 1 day (p<0.001 versus budesonide, both comparisons). Similarly, evening PEF, use of rescue medication, total asthma symptom scores and percentage of symptom-free days improved more with both single inhaler and separate inhaler therapy than with budesonide alone, as did asthma control days (∼15% more, p<0.001 versus budesonide, both comparisons, with a marked increase in the first week). All treatments were well tolerated and the adverse event profile was similar in all three treatment groups. It is concluded that single inhaler therapy with budesonide and formoterol is a clinically effective and well-tolerated treatment for patients with asthma that is not fully controlled by inhaled glucocorticosteroids alone.
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Objective:To evaluate the efficacy and safety of budesonide/formoterol(B/F)single inhaler therapy versus budesonide inhaler plus formoterol inhaler(B+F)in asthma patients.Methods:A randomized,parallel control,multi-center clinical study recruited 320 patients with asthma,who were ran- domized to administer either B/F(n=158,group A)or B+F(n=162,group B).The primary endpoint was to measure the improvement of morning peak expiratory flow(mPEF),and secondary endpoints includ- ed the changes of evening PEF(ePEF),daytime and night-time asthma symptom scores,short-actingβ_2 agonist usages,awakening number due to shortness of breath at night and lung function during the follow- up pre-and post-therapy.All adverse events were also monitored.Results:Both therapeutic regimens sig- nificantly improved mPEF and ePEF and daytime and nighttime asthma symptom scores,and reduced hum- bers of short-actingβ_2 agonist usages and awakening number due to shortness of breath at night;the P val- ue was no statistical difference between two regimens.No differences in spirometrie measurements and ad- verse events were found between two regimens.Conclusion:Budesonide/formoterol single inhaler therapy was therapeutically equivalent to budesonide inhaler plus formoterol inhaler for patients with asthma.
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Formoterol Fumarate
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Eighteen subjects with moderate asthma participated in this double-blind study comparing the bronchodilator response to albuterol or placebo used in conjunction with three inhalation devices; the metered dose inhaler (MDI) actuator alone, the AeroChamber, and the OptiHaler. The principal comparison was the increase in FEV1 over 30 minutes. Also recorded were heart rate, time required to use each device, and patient acceptance of each device. There was a large bronchodilator response with albuterol with each of the devices, but there was no difference in the promptness or the magnitude of the bronchodilator response among the three devices. There was a small but statistically significant increase in heart rate which did not differ among devices. Subject ratings of acceptability were MDI alone best, followed by OptiHaler, then AeroChamber. We conclude (1) the bronchodilator response obtained with use of the MDI alone, the AeroChamber and OptiHaler were not significantly different; (2) patients, as a group, found the MDI required less time to use and they favored it over either spacer; (3) while in subjects employing good MDI technique, the addition of either an AeroChamber or an OptiHaler did not improve bronchodilator response. Spacers may have a role in those with poor inhaler technique or in conjunction with inhaled corticosteroids.
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<i>Background:</i> In contrast to the well-known activity profile in asthma, the precise efficacy and optimum dose schedules of long-acting β<sub>2</sub>-agonists in chronic obstructive pulmonary disease (COPD) are not clear. <i>Objective:</i> In this study, we aimed to compare the onset and the duration of action of a single inhalation of formoterol and salmeterol in COPD patients having partially reversible airway obstruction. <i>Methods:</i> In a double-blind, randomized, crossover and placebo-controlled study design, the respiratory functions of 22 patients (mean age 57.3 ± 5.4 years) having mild to severe COPD (5 mild, 8 moderate and 9 severe) and partially reversible airway obstruction [mean baseline reversibility of forced expiratory volume in 1 s (FEV<sub>1</sub>) 19.3 ± 3.1%] were evaluated after inhalation of 12 μg formoterol and 50 μg salmeterol. <i>Results:</i> Regarding the onset of bronchodilator action, the mean absolute increase of 0.20 liters in FEV<sub>1</sub> 10 min after inhalation of formoterol was significantly higher than baseline and that of placebo (0.04 liters), whereas that of salmeterol (0.11 liters) did not reach statistical significance. At 20 min, both formoterol (0.25 liters) and salmeterol (0.20 liters) produced a significant increase in FEV<sub>1</sub> compared with baseline and with that of placebo (0.04 liters). The peak bronchodilator effects occurring at 60 and 120 min following formoterol (0.39 liters) and salmeterol (0.40 liters) inhalation, respectively, were significantly higher than the corresponding levels of placebo (0.02 and –0.12 liters, respectively). Concerning the duration of action, the 12-hour values of both formoterol (0.25 liters) and salmeterol (0.22 liters) were significantly higher than that of placebo (–0.12 liters). The area under the curve values of FEV<sub>1</sub> of formoterol (3.5 ± 1.3 l·h) and salmeterol (3.2 ± 1.2 l·h) averaged over 12 h were comparable and higher than placebo values (1.2 ± 0.5 l·h). After formoterol inhalation 2 patients experienced tremor and 1 had palpitation; 1 tremor and 1 headache attack were noted after salmeterol. For the pharmacologically predictable side effects, there was no difference between the drugs. <i>Conclusions: </i>In conclusion, this study revealed that a single dose of 12 μg formoterol and 50 μg salmeterol provided comparable bronchodilation within 12 h and had tolerable side effects in patients with mild to severe COPD having partially reversible airway obstruction.
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Crossover study
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Bronchodilator Agents
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Background Traditionally inhaled treatment for asthma has been considered as preventer and reliever therapy. The combination of formoterol and budesonide in a single inhaler introduces the possibility of using a single inhaler for both prevention and relief of symptoms (single inhaler therapy). Objectives The aim of this review is to compare formoterol and corticosteroid in single inhaler for maintenance and relief of symptoms with inhaled corticosteroids for maintenance and a separate reliever inhaler. Search methods We last searched the Cochrane Airways Group trials register in September 2008. Selection criteria Randomised controlled trials in adults and children with chronic asthma. Data collection and analysis Two review authors independently assessed studies for inclusion and extracted the characteristics and results of each study. Authors or manufacturers were asked to supply unpublished data in relation to primary outcomes. Main results Five studies on 5,378 adults compared single inhaler therapy with current best practice, and did not show a significant reduction in participants with exacerbations causing hospitalisation (Peto OR 0.59; 95% CI 0.24 to 1.45) or treated with oral steroids (OR 0.83; 95% CI 0.66 to 1.03). Three of these studies on 4281 adults did not show a significant reduction in time to first severe exacerbation needing medical intervention (HR 0.96; 95% CI 0.85 to 1.07). These trials demonstrated a reduction in the mean total daily dose of inhaled corticosteroids with single inhaler therapy (mean reduction ranged from 107 to 267 micrograms/day, but the trial results were not combined due to heterogeneity). The full results from four further studies on 4,600 adults comparing single inhaler therapy with current best practice are awaited. Three studies including 4,209 adults compared single inhaler therapy with higher dose budesonide maintenance and terbutaline for symptom relief. No significant reduction was found with single inhaler therapy in the risk of patients suffering an asthma exacerbation leading to hospitalisation (Peto OR 0.56; 95% CI 0.28 to 1.09), but fewer patients on single inhaler therapy needed a course of oral corticosteroids (OR 0.54; 95% CI 0.45 to 0.64). These results translate into an eleven month number needed to treat of 14 (95% CI 12 to 18), to prevent one patient being treated with oral corticosteroids for an exacerbation. The run‐in for these studies involved withdrawal of long‐acting beta2‐agonists, and patients were recruited who were symptomatic during run‐in. One study included children (N = 224), in which single inhaler therapy was compared to higher dose budesonide. There was a significant reduction in participants who needed an increase in their inhaled steroids with single inhaler therapy, but there were only two hospitalisations for asthma and no separate data on courses of oral corticosteroids. Less inhaled and oral corticosteroids were used in the single inhaler therapy group and the annual height gain was also 1 cm greater in the single inhaler therapy group, [95% CI 0.3 to 1.7 cm]. There was no significant difference found in fatal or non‐fatal serious adverse events for any of the comparisons. Authors' conclusions Single inhaler therapy can reduce the risk of asthma exacerbations needing oral corticosteroids in comparison with fixed dose maintenance inhaled corticosteroids. Guidelines and common best practice suggest the addition of regular long‐acting beta2‐agonist to inhaled corticosteroids for uncontrolled asthma, and single inhaler therapy has not been demonstrated to significantly reduce exacerbations in comparison with current best practice, although results of five large trials are awaiting full publication. Single inhaler therapy is not currently licensed for children under 18 years of age in the United Kingdom.
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Terbutaline
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This trial was performed in a randomized double-blind manner on four different days in 13 asthmatic patients in order to compare the bronchodilator efficacy of two different inhalation devices, Inspirease (IP) and Aerochamber (AC), to the conventional metered dose inhaler (MDI). The results showed that clenbuterol determined a significant FEV1 increase inhaled either via MDI or via IP and AC. IP caused a greater bronchodilatation than AC, 30 min after clenbuterol administration. IP caused a greater mean increase (P less than 0.05) in FEV1 than the MDI at all time intervals; AC provided an improvement in bronchodilator response over directly administered MDI. Such responses are only marginally clinically relevant when patients use MDI correctly. These devices are mainly indicated in patients with poor hand-lung coordination.
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BACKGROUND The metered dose inhaler is difficult to use correctly, synchronising actuation with inhalation being the most important problem. A breath actuated pressurised inhaler, designed to help patients with poor inhaler technique, was compared with a conventional metered dose inhaler in terms of aerosol deposition and bronchodilator response. METHODS Radioaerosol deposition and bronchodilator response to 100 micrograms salbutamol were measured in 18 asthmatic patients, who inhaled from a conventional metered dose inhaler by their own chosen metered dose inhaler technique, from a conventional metered dose inhaler by a taught metered dose inhaler technique, and from a breath actuated pressured inhaler (Autohaler). RESULTS In the 10 patients who could coordinate actuation and inhalation of the inhaler on their own deposition of aerosol in the lungs and bronchodilator response were equivalent on the three study days. By contrast, in the eight patients who could not coordinate the mean (SEM) percentage of the dose deposited in the lungs with their own inhaler technique (7.2% (3.4%] was substantial lower than those attained by the taught metered dose inhaler technique (22.8% (2.5%] and by Autohaler (20.8% (1.7%]. CONCLUSION Although of little additional benefit to asthmatic patients with good coordination, the Autohaler is potentially a valuable aid to those with poor coordination, and should be considered in preference to a conventional metered dose inhaler in any patient whose inhaler technique is not known to be satisfactory.
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Salmeterol
Bronchodilatation
Metered-dose inhaler
Formoterol Fumarate
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