Safety and tolerability of NVA237, a once-daily long-acting muscarinic antagonist,in COPD patients

NVA237 is a novel once-daily inhaled long-acting muscarinic antagonist administered via a dry powder inhaler. This randomized, double-blind, placebo-controlled study evaluated the safety, tolerability and bronchodilator efficacy of two doses of NVA237 (100 and 200 μg), versus placebo, in patients with moderate-to-severe COPD (forced expiratory volume in 1 s [FEV₁] ≥ 30% and <80% predicted and FEV₁/forced vital capacity [FVC] < 0.7, 30 min after inhalation of 80 μg ipratropium bromide). After appropriate washout periods, patients were randomized to treatment with NVA237 100 μg (n = 92), NVA237 200 μg (n = 98) or placebo (n = 91) for 28 days. The primary objective was evaluation of safety, with efficacy measures included as secondary objectives. NVA237 was generally well tolerated and associated with a frequency and distribution of adverse events similar to placebo. Serious adverse events were uncommon and there was no evidence of adverse cardiovascular effects or unexpected events. Trough FEV₁ was significantly higher in those receiving NVA237 compared with placebo. For NVA237 100 μg the differences were 131 and 161 mL on Days 1 and 28, respectively (p < 0.05), and for NVA237 200 μg the differences were 146 and 151 mL on Days 1 and 28, respectively (p < 0.05). Peak FEV₁, FEV₁ at all timepoints up to 24 h after dosing, and FEV₁ area under the curve during 5 min–5 h post-dosing were also significantly higher in both NVA237 groups, compared with placebo. Patients receiving NVA237 required fewer daily puffs of rescue medication and had a higher percentage of days on which rescue medication was not required. Overall, the present study provides further evidence of the safety, tolerability and bronchodilator efficacy of once-daily treatment with NVA237 100 and 200 μg in patients with moderate-to-severe COPD.     

Vilanterol trifenatate,a novel inhaled long-acting beta2 adrenoceptor agonist,is well tolerated in healthy subjects and demonstrates prolonged bronchodilation in subjects with asthma and COPD

Vilanterol (VI; GW642444M) is a novel inhaled long-acting β2-agonist with inherent 24 h activity in vitro in development as a combination with the inhaled corticosteroid fluticasone furoate for both COPD and asthma. These studies were conducted to determine the safety, tolerability, pharmacodynamics and pharmacokinetics of VI in healthy subjects and subjects with mild to moderate persistent asthma and moderate to severe COPD.Single doses of VI (25–100 μg) were given once daily to subjects with asthma and COPD and repeat doses once daily for 14 days to healthy subjects. Adverse events (AEs), vital signs, ECGs, pharmacodynamic endpoints, FEV₁ and VI plasma pharmacokinetics (AUC, Cmax and Tmax) were determined following dosing.VI (25–100 μg) was well tolerated. The incidence and severity of AEs were comparable to placebo. Following VI administration there were no clinically significant abnormalities in vital signs, 12-lead ECG, Holter ECG, blood glucose or potassium. There were no statistically significant effects on QTc of single and repeat VI doses up to 50 μg; some differences were seen following the 100 μg VI dose after single and repeat dose in healthy subjects and single dose in asthmatic subjects. All VI doses produced increases in FEV₁ from as early as 5 min after dosing which were maintained up to 24 h post-dose in subjects with asthma and COPD. In all subjects VI was rapidly absorbed (healthy subjects median Tmax at 5 min; asthma and COPD subjects median Tmax at 10 min) with systemic exposure increasing in an approximately dose proportional manner across the VI dose range. Marginal accumulation was seen on repeat dosing.Single doses of inhaled VI in subjects with asthma and COPD and repeat doses in healthy subjects were well tolerated with no clinically significant unwanted systemic effects. VI produced a rapid and prolonged bronchodilation over 24 h suggesting the potential for once daily administration.     

Efficacy and safety of indacaterol and tiotropium in COPD patients according to dyspnoea severity

BackgroundGuidelines for chronic obstructive pulmonary disease (COPD) recommend that treatment choices be based partly on symptoms.MethodsA post-hoc analysis of pooled data from clinical studies compared the efficacy and safety of once-daily inhaled bronchodilators indacaterol (150 and 300 μg) and open-label tiotropium (18 μg) according to baseline dyspnoea severity on the modified Medical Research Council (mMRC) scale in patients with COPD (mMRC scores <2 = ‘less dyspnoea’; scores ≥2 = ‘more dyspnoea’). Outcomes were assessed after 26 weeks.ResultsThe analysis included 3177 patients. In patients with less dyspnoea: indacaterol (both doses) improved 24-h post-dose (‘trough’) forced expiratory volume in 1 s (FEV₁), transition dyspnoea index (TDI) and St George's Respiratory Questionnaire (SGRQ) total scores at week 26 and reduced the risk of COPD exacerbations vs placebo; and open-label tiotropium improved trough FEV₁ and TDI total score vs placebo at week 26. In patients with more dyspnoea: indacaterol (both doses) improved trough FEV₁, TDI and SGRQ total scores at week 26; indacaterol 300 μg was the only treatment to improve the TDI total score by more than the minimum clinically important difference (≥1 point) vs placebo; and open-label tiotropium improved trough FEV₁, TDI total score at week 26 and decreased the risk of COPD exacerbations vs placebo. In both subgroups, all treatments were well tolerated.ConclusionsIn patients with less dyspnoea, all treatments had similar effects. Indacaterol 300 μg may be a useful treatment option for patients with COPD who experience more severe breathlessness.     

Airway responsiveness to adenosine after a single dose of fluticasone propionate discriminates asthma from COPD

BackgroundRegular treatment with inhaled corticosteroids (ICS) is known to reduce airway hyperresponsiveness (AHR) to adenosine 5′-monophosphate (AMP) in asthma even after a single dose of fluticasone propionate (FP).AimTo determine whether this rapid protective effect of a single dose of FP is also present in COPD.Methods23 mild asthmatic and 24 COPD subjects with documented AHR to both AMP and methacholine took part in a randomized, double-blind, placebo-controlled, crossover study to measure AHR to inhaled AMP and methacholine 2 h after either 1000 μg FP or matched placebo.ResultsIn subjects with asthma, 1000 μg FP in a single dose significantly attenuated the constrictor response to AMP, geometric mean (range) PC20AMP values increasing from a 19.2 (1.3–116.3) to 81.5 (9.6–1600.0) (p < 0.001; post-placebo vs post-FP) mg/ml. Change in the airways response to inhaled AMP after FP was well within test variability in patients with COPD, with PC20AMP values 59.6 (11.3–183.9) and 76.3 (21.0–445.3) (p = 0.022; post-placebo vs post-FP) mg/ml. Additionally, FP failed to significantly attenuate the bronchial response to methacholine in both asthma and COPD subjects. A change in doubling dilution, between placebo and following a single dose of FP, in AMP had a better sensitivity and specificity of 95.8% and 65.2%, compared to methacholine of 79.2% and 43.5% respectively in delineating between COPD and asthma.ConclusionA single dose of 1000 μg FP rapidly improves AHR to AMP in asthmatics but not in COPD subjects. This may provide a convenient way by which provocation challenge with inhaled AMP may help in discriminating asthma from COPD.     

Effects of a FLAP inhibitor,GSK2190915, in asthmatics with high sputum neutrophils

Patients with refractory asthma frequently have neutrophilic airway inflammation and respond poorly to inhaled corticosteroids. This study evaluated the effects of an oral 5-lipoxygenase-activating protein (FLAP) inhibitor, GSK2190915, in patients with asthma and elevated sputum neutrophils.Patients received 14 (range 13–16) days treatment with GSK2190915 100 mg and placebo with a minimum 14 day washout in a double-blind, cross-over, randomised design (N = 14). Sputum induction was performed twice pre-dose in each treatment period to confirm sputum neutrophilia, and twice at the end of each treatment period. The primary endpoint was the percentage and absolute sputum neutrophil count, averaged for end-of-treatment visits.GSK2190915 did not significantly reduce mean percentage sputum neutrophils (GSK2190915-placebo difference [95% CI]: −0.9 [−12.0, 10.3]), or mean sputum neutrophil counts (GSK2190915/placebo ratio [95% CI]: 1.06 [0.43, 2.61]). GSK2190915 resulted in a marked suppression (>90%) of sputum LTB₄ and urine LTE₄, but did not alter clinical endpoints. There were no safety issues.Despite suppressing the target mediator LTB₄, FLAP inhibitor GSK2190915 had no short-term effect on sputum cell counts or clinical endpoints in patients with asthma and sputum neutrophilia.     

24-hour bronchodilation following a single dose of the novel β(2)-agonist olodaterol in COPD

Background

Current guidelines recommend long-acting bronchodilators as maintenance therapy in COPD when symptoms are not adequately controlled with short-acting agents. Olodaterol is a novel long-acting β₂-adrenoceptor agonist with a pre-clinical profile that suggests 24-h bronchodilation may be achieved with once-daily administration.

Objective

To assess dose- and time-response in terms of bronchodilator efficacy, and to evaluate pharmacokinetics, safety and tolerability of single doses of olodaterol administered via Respimat^® Soft Mist™ Inhaler in COPD patients.

Methods

A single-center, double-blind, placebo-controlled, 5-way crossover study including 24-h spirometry (FEV₁, FVC), safety, tolerability and pharmacokinetics (in a subset of patients) following dosing of olodaterol 2 μg, 5 μg, 10 μg and 20 μg; the washout period between test-days was at least 14 days. Primary endpoint of the study was the 24-h post-dosing FEV₁. Patients participating in the pharmacokinetic assessments continued in an open-label extension phase to establish pharmacokinetics of olodaterol 40 μg.

Results

36 patients were assigned to treatment; mean baseline prebronchodilator FEV₁ was 1.01 L (37% predicted normal). All doses of olodaterol provided significantly greater bronchodilation compared to placebo in 24-h FEV₁ post-dose (p < 0.001); a clear dose–response relationship was observed, with values ranging from 0.070 L for olodaterol 2 μg to 0.119 L for olodaterol 20 μg. Similarly, olodaterol was superior to placebo (p < 0.001) in peak FEV₁ (0.121 L to 0.213 L) and average FEV₁ both during the daytime (0–12 h; ranging from 0.099 L to 0.184 L) and night-time (12–24 h; ranging from 0.074 L to 0.141 L). FVC results were consistent with those observed for FEV₁. Pharmacokinetic evaluation of the peak plasma concentrations and renal excretion suggested no obvious deviation from dose-proportionality over the investigated dose range of 2 μg–40 μg; in most patients, no plasma levels could be detected following the 2 μg dose. All treatments were well tolerated with no apparent dose relation in terms of adverse events.

Conclusions

Olodaterol appears to be a promising long-acting β₂-adrenoceptor agonist,with bronchodilation maintained over 24 h that offers an opportunity for once-daily dosing in patients who require maintenance bronchodilator therapy for the management of COPD symptoms.     

Formoterol

Abstract

Inhaled formoterol is a long-acting selective β₂-adrenoceptor agonist, with an onset of action of 5 minutes postdose and a bronchodilator effect that lasts for at least 12 hours.Statistically significant and clinically relevant (> 120ml) improvements in lung function [assessed using standardized/normalized area under the forced expiratory volume in 1 second (FEV₁) versus time curve (AUC FEV₁)] were observed with inhaled formoterol 12μg twice daily (the approved dosage in the US) compared with placebo in 12-week and 12-month, randomized, double-blind trials in patients with chronic obstructive pulmonary disease (COPD).The bronchodilator efficacy of formoterol 12μg twice daily was greater than that of oral slow-release theophylline (individualized dosages) in a 12-month trial or inhaled ipratropium bromide 40μg four times daily in a 12-week trial. Improvement in AUC FEV₁ with formoterol, but not theophylline, compared with placebo was observed in patients with irreversible or poorly-reversible airflow obstruction. Formoterol also significantly improved health-related quality of life compared with ipratropium bromide or placebo and significantly reduced symptoms compared with placebo. Combination therapy with formoterol 12μg twice daily plus ipratropium bromide 40μg four times daily was significantly more effective than albuterol (salbutamol) 200μg four times daily plus the same dosage of ipratropium bromide in a 3-week, randomized, double-blind, double-dummy, crossover trial.Inhaled formoterol was well tolerated in clinical trials. The incidence of investigator-determined drug-related adverse events with inhaled formoterol 12μg twice daily was similar to that with placebo and inhaled ipratropium bromide 40μg four times daily but lower than that with oral slow-release theophylline (individualized dosages). Importantly, there were no significant differences between formoterol and placebo or comparator drugs in cardiovascular adverse events in patients with COPD and corrected QT interval values within the normal range.In conclusion, inhaled formoterol improved lung function and health-related quality of life and reduced symptoms relative to placebo in clinical trials in patients with COPD. The drug had greater bronchodilator efficacy than oral slow-release theophylline or inhaled ipratropium bromide and showed efficacy in combination with ipratropium bromide. The adverse events profile (including cardiovascular adverse events) with formoterol was similar to that with placebo. Thus, inhaled formoterol may be considered as a first-line option for the management of bronchoconstriction in patients with COPD who require regular bronchodilator therapy for the management of symptoms.

Pharmacodynamic Properties

Inhaled formoterol is a long-acting selective β₂-adrenoceptor agonist (β₂-agonist); it has a rapid onset of action (5 minutes in single- and multiple-dose studies) and, like salmeterol, maintains a bronchodilator effect for at least 12 hours. The onset of postdose bronchodilator action was faster with formoterol 12μg than with salmeterol 100μg in a double-blind, randomized, placebo-controlled trial.Formoterol 6 to 24μg improved forced expiratory volume in 1 second (FEV₁) compared with baseline and placebo in single-dose crossover trials in patients with chronic obstructive pulmonary disease (COPD), and was at least as effective as salmeterol 50 or 100μg or albuterol (salbutamol) 400μg at improving FEV₁. Mean peak FEV₁ was reached 1 hour after inhalation of formoterol 12μg; values for this parameter were 1 hour after albuterol 200μg, and 2 to 5 hours after salmeterol 50μg.Formoterol 4.5 to 18μg twice daily for 1 week prolonged the time to exhaustion on a bicycle ergometer test compared with placebo; results were similar to those for ipratropium bromide 80μg three times daily.All β₂-agonists have the potential to increase heart rate and plasma glucose concentrations, and to decrease plasma potassium concentrations, through effects on extrapulmonary β₂ receptors. Dose-dependent increases in heart rate, corrected QT (QTc) interval and plasma glucose concentrations, and dose-dependent decreases in plasma potassium concentrations, were observed with inhaled formoterol 24 to 96μg or salmeterol 100 to 400μg in a double-blind, placebo-controlled, crossover trial in 16 healthy volunteers. In patients with COPD, pre-existing mild to moderate cardiac arrhythmias and hypoxemia [PaO₂ (arterial oxygen pressure) <60mm Hg], formoterol 12μg had similar systemic effects to salmeterol 50μg. Complex ventricular arrhythmias were observed in formoterol 12 and 24μg recipients, but not in salmeterol 50μg or placebo recipients.

Pharmacokinetic Properties

The maximum plasma concentration (92 ng/L) of formoterol was reached within 5 minutes of inhalation of a single supraoptimal dose (120μg) in 12 healthy volunteers. Urinary excretion data suggest that absorption was linear with inhaled formoterol 12 to 96μg in ten healthy volunteers. In vitro plasma protein binding of formoterol was 61 to 64% at concentrations 0.1 to 100 μg/L.Mean plasma concentrations of the drug at 10 minutes to 6 hours postinhalation were 4.0 to 8.8 ng/L and 8.0 to 17.3 ng/L, respectively, after multiple doses of formoterol 12 or 24μg administered twice daily for 12 weeks in patients with COPD, with some evidence of accumulation of formoterol in the plasma (accumulation index 1.19 to 1.38).Formoterol is metabolized primarily in the liver by four cytochrome P450 (CYP) isoenzymes (CYP2D6, CYP2C19, CYP2C9 and CYP2A6). These enzymes were not inhibited by the drug at therapeutic concentrations. Following inhalation of formoterol 12 or 24μg by 18 patients with COPD, 7% of the total dose was excreted in the urine as unchanged drug and 6 to 9% of the total dose was eliminated as direct conjugates of formoterol. The mean terminal elimination half-life was determined to be 10 hours (based on plasma concentrations) following inhalation of single-dose formoterol 120μg by 12 healthy volunteers.Currently, there are no pharmacokinetic data for the use of formoterol in patients with hepatic or renal impairment or in elderly individuals.

Therapeutic Efficacy

Inhaled formoterol has been evaluated as monotherapy or combination therapy for the management of patients with COPD. In clinical trials, COPD was diagnosed using the American Thoracic Society guidelines.The bronchodilator effect [measured as normalized area under the FEV₁ versus time curve (AUC FEV₁)] with formoterol 12μg twice daily (n = 194) was significantly greater than that with ipratropium bromide 40μg four times daily (n = 194; p = 0.001) or placebo (n = 200; p < 0.001) in a randomized, double-blind, 12-week trial in patients with COPD. Significant improvements were also observed in mean morning premedication peak expiratory flow (PEF; p < 0.001) and health-related quality of life [all three subsections of the St. George’s Respiratory Questionnaire (SGRQ); p ≤ 0.036], and significant reductions were reported for the use of rescue medication (p ≤ 0.014) and the percentage of ‘bad days’ (days with at least two individual symptom scores of ≥2 and/or a reduction in PEF from baseline of >20%; p < 0.001) in formoterol compared with ipratropium bromide recipients. The differences in health-related quality of life between the two treatments were clinically relevant (exceeding 4 points) for the Activity and the Impacts domains of the SGRQ.Compared with oral slow-release theophylline (individualized dosages targeted at plasma concentrations of 8 to 20 mg/L), formoterol 12μg twice daily significantly increased standardized AUC_12h FEV₁ (primary end-point; p = 0.026) and mean morning premedication PEF (p ≤ 0.020) and reduced the percentage of ‘bad days’ (p ≤ 0.035) in a randomized, double-blind (with the exception of the theophylline arm), 12-month trial. A subgroup analysis in this trial indicated that at 3 (p = 0.007) and 12 months (p = 0.002), formoterol (n = 118), but not oral slow-release theophylline (n = 105), produced significant bronchodilation compared with placebo (n = 117) in patients with irreversible or poorly-reversible airflow obstruction (i.e. patients whose FEV₁ values increased <15% after receiving albuterol). Both formoterol (p ≤ 0.026) and oral slow-release theophylline (p ≤ 0.013) were significantly more effective than placebo at managing COPD during the night (measured as morning premedication FEV₁).In these two monotherapy trials, inhaled formoterol 24μg twice daily did not provide any additional benefit over the 12μg twice daily dosage in patients with COPD.The combined efficacy of inhaled formoterol 12μg twice daily plus inhaled ipratropium bromide 40μg four times daily for 3 weeks has been compared with that of albuterol 200μg four times daily for 3 weeks via a pressurized metered-dose inhaler plus inhaled ipratropium bromide 40μg four times daily in a randomized, double-blind, double-dummy, crossover trial in 172 patients with COPD. Formoterol combination therapy was significantly more effective than albuterol combination therapy at increasing mean morning premedication PEF (primary endpoint; p = 0.0003). Combination therapy with formoterol was also more effective according to secondary endpoints, significantly increasing postmedication FEV₁ to 6 hours (p< 0.0001), peak postmedication FEV₁ (p < 0.0001) and AUC FEV₁ (p < 0.0001) and improving symptoms of COPD (measured as mean total symptoms score, p = 0.0042) and the SGRQ symptoms score (p = 0.0408) relative to albuterol combination therapy.

Tolerability

Inhaled formoterol was well tolerated in clinical trials in patients with COPD. The percentage of patients experiencing at least one adverse event with inhaled formoterol 12μg twice daily was similar to that with placebo, inhaled ipratropium bromide 40μg four times daily or oral slow-release theophylline (individualized dosages targeted at plasma concentrations of the drug of 8 to 20 mg/L) in randomized, double-blind, comparative trials of 12 weeks’ and 12 months’ duration. Viral infection, exacerbation of COPD, bronchitis, upper respiratory tract infection, dyspnea and headache were the most commonly reported adverse events (i.e. occurring in >5% of formoterol 12μg twice daily recipients); however, the incidence of these events was not significantly different compared with oral slow-release theophylline or placebo.Drug-related adverse events, serious adverse events and events leading to withdrawal from the study occurred with a similar incidence with inhaled formoterol, placebo or ipratropium bromide. In contrast, drug-related adverse events and withdrawal because of adverse events occurred with a higher incidence in patients receiving oral slow-release theophylline in the 12-month trial.There were no significant differences in the incidence of cardiovascular adverse events with inhaled formoterol (0.5% of patients) compared with inhaled placebo (2.5%) or ipratropium bromide (2.6%) after 12 weeks’ treatment or in the incidence of serious cardiovascular adverse events with inhaled formoterol (2.4% of patients) compared with placebo (0.9%) or oral slow-release theophylline (2.4%) after 12 months’ treatment in patients with COPD and QTc interval values within the normal range; heart rate and rhythm disorders were infrequent. The incidences of QTc interval prolongation (>0.46s), ECG abnormalities or clinically relevant changes in serum potassium or fasting plasma glucose concentrations were similar with inhaled formoterol 12μg twice daily compared with placebo, inhaled ipratropium bromide or oral slow-release theophylline in clinical trials.

Dosage and Administration

Formoterol, inhaled orally using an Aerolizer?1 inhaler, is indicated in the US for the long-term maintenance treatment of bronchoconstriction associated with COPD (including chronic bronchitis and emphysema). The recommended dosage of formoterol in this patient group is 12μg twice daily approximately 12 hours apart; the total daily dose should not exceed 24μg.Formoterol should be used with caution in patients with cardiovascular disorders (especially coronary insufficiency, cardiac arrhythmias or hypertension), convulsive disorders or thyrotoxicosis, or hypersensitivity to sympathomimetic amines. Extreme caution is advised if formoterol is used concomitantly with monoamine oxidase inhibitors, tricyclic antidepressants or drugs that are known to prolong the QTc interval, and caution is recommended with the concomitant use of formoterol and non-potassium-sparing diuretics.

     

Integrating indacaterol dose selection in a clinical study in COPD using an adaptive seamless design

BackgroundThe drug development process can be streamlined by combining the traditionally separate stages of dose-finding (Phase IIb) and confirmation of efficacy and safety (Phase III) using an adaptive seamless design. This approach was used in a clinical study of indacaterol, a novel once-daily (od) inhaled long-acting β₂-adrenoreceptor agonist bronchodilator for the treatment of COPD (chronic obstructive pulmonary disease).MethodsThe study comprised a dose-finding stage with dose selection after 14 days of treatment, and a second stage evaluating efficacy and safety during 26 weeks of treatment. The dose-finding stage included seven randomized treatment arms: double-blind indacaterol 75 μg, 150 μg, 300 μg or 600 μg od, the β₂-adrenoceptor agonist formoterol 12 μg twice-daily or placebo, or the anticholinergic tiotropium 18 μg od open-label. An independent data monitoring committee selected two indacaterol doses based on unblinded results of an interim analysis performed by an independent statistician. The sponsor, investigators and patients remained blinded to the results. The indacaterol doses were selected using pre-set efficacy criteria for trough (24-h post-dose) and early (1–4 h post-dose) bronchodilator effect after 14 days, and all safety data. To qualify for selection, the doses had to exceed a threshold for clinical relevance or be superior to either tiotropium or formoterol, whichever was the highest value. Selected doses were continued into the second, 26-week stage. The two other indacaterol doses not selected, and formoterol, were discontinued following dose selection.Results801 patients with moderate-to-severe COPD were evaluated. Indacaterol 150 μg was the lowest effective dose, exceeding criteria for trough FEV₁ (reference value 140 mL vs placebo) and FEV₁ AUC_1–4h (reference value 220 mL vs placebo). No safety signal was observed with any dose of indacaterol. Thus, indacaterol 150 and 300 μg were selected to continue into the second, 26-week stage.ConclusionThe adaptive seamless design is a novel and efficient way to combine dose selection with efficacy evaluation and safety confirmation in a single trial.     

Efficacy and safety of glycopyrrolate/formoterol fumarate metered dose inhaler delivered using co-suspension delivery technology in Japanese patients with moderate-to-very severe chronic obstructive pulmonary disease

BackgroundPINNACLE-4 evaluated the efficacy and safety of the long-acting muscarinic antagonist/long-acting β₂-agonist fixed-dose combination glycopyrrolate/formoterol fumarate metered dose inhaler (GFF MDI) in patients from Asia, Europe, and the USA with moderate-to-very severe chronic obstructive pulmonary disease (COPD). This pre-specified analysis included Japanese patients in PINNACLE-4.MethodsIn this double-blind randomized study (NCT02343458), patients received GFF MDI (18/9.6 μg), glycopyrrolate (GP) MDI (18 μg), formoterol fumarate (FF) MDI (9.6 μg), or placebo MDI twice daily for 24 weeks. The primary endpoint was change from baseline in morning pre-dose trough forced expiratory volume in 1 s (FEV₁) over Weeks 12–24. Secondary lung function endpoints, patient-reported outcomes, and safety were assessed. The Japanese subpopulation (n = 150) analyses were exploratory.ResultsGFF MDI improved change from baseline in morning pre-dose trough FEV₁ over Weeks 12–24 versus GP MDI, FF MDI, and placebo MDI (least squares mean [LSM] differences [95% confidence interval]: 69 [8–131], 60 [–1 to 121], and 275 [180–370] mL, respectively). GFF MDI numerically improved Transition Dyspnea Index focal score and change from baseline in St George's Respiratory Questionnaire total score versus placebo MDI (LSM differences 0.19 and ?3.78, respectively). Treatment-related adverse events occurred in ≤4.5% of patients in any treatment group.ConclusionsGFF MDI improved lung function versus monocomponents and placebo MDI in the Japan subpopulation of PINNACLE-4. The efficacy and safety results were generally consistent with those of the global study population, supporting the use of GFF MDI in Japanese patients with moderate-to-very severe COPD.     

28-Day safety and tolerability of umeclidinium in combination with vilanterol in COPD: A randomized placebo-controlled trial

BackgroundUmeclidinium (UMEC; GSK573719) is a new long-acting muscarinic antagonist (LAMA) currently in development in combination with vilanterol (VI), an inhaled, long-acting beta₂ agonist for the treatment of chronic obstructive pulmonary disease (COPD). The primary aim of this study was to evaluate the safety and tolerability of repeat dosing of UMEC and VI in combination once daily for 28 days in patients with COPD.MethodsThis was a multicenter, double-blind, placebo-controlled, parallel group study. Patients aged ≥40 years with post-bronchodilator FEV₁ ≤80% of predicted normal values and FEV₁/FVC ratio ≤0.70, and a smoking history of ≥10 pack-years, were randomized 4:1 to once-daily UMEC/VI (500/25 mcg; n = 42) or placebo (n = 9).ResultsUMEC/VI was non-inferior to placebo in weighted mean pulse rate over 0–6 h at Day 28 (primary endpoint: difference of ?0.5 bpm, 95% CI: ?5.5 to 4.5). There was no evidence of a difference between UMEC/VI compared with placebo in blood pressure, minimum and maximum pulse rate, or QTcF assessments. Adverse events (AEs) were reported by 11 (26%) patients in the UMEC/VI group and one (11%) patient in the placebo group. No serious AEs were reported. Both UMEC and VI showed rapid absorption (median t_max ～6 min for both drugs) with no evidence of accumulation for AUC or C_max on Day 28 compared with Day 1 for UMEC or VI. There was no correlation between individual steady-state C_max and pulse rate on Day 28. Change from baseline in trough FEV₁ on Day 29 showed numerically greater improvements with UMEC/VI compared with placebo.ConclusionOnce-daily dosing with UMEC in combination with VI in patients with moderate-to-very-severe COPD was well tolerated over 28 days.     

Bronchodilation and safety of supratherapeutic doses of salbutamol or ipratropium bromide added to single dose GSK961081 in patients with moderate to severe COPD

BackgroundThere are few data on the bronchodilatory effects of adding short-acting bronchodilators (SABA) to maintenance, long-acting bronchodilator therapy. This study assessed the additional bronchodilation and safety of adding supratherapeutic doses of salbutamol (SALB) or ipratropium bromide (IPR) to the novel bi-functional molecule (or dual pharmacophore) GSK961081 400 μg (MABA 400) or 1200 μg (MABA 1200).MethodsThis randomised, double-blind, complete, crossover study in 44 patients with moderate to severe COPD, evaluated 6 treatments with a washout of at least 7 days between treatments: single doses of MABA 400 or MABA 1200 followed by cumulative doses of either SALB (3× 200 μg at 20 min intervals), IPR (20 μg, 20 μg and 40 μg at 20 min intervals) or placebo (PLA) (three doses at 20 min intervals) at 1 h, 12 h and 24 h post-MABA dose. The primary endpoint was maximal increase in FEV₁, from pre-dose bronchodilator (SABA/PLA), measured 15 min after each cumulative dose of SALB, IPR or PLA. Systemic pharmacodynamics (potassium, heart rate, glucose and QTc), adverse events and systemic pharmacokinetics were also assessed.ResultsThe additional bronchodilatory effects at 12 h and 24 h for both SALB and IPR were of a similar magnitude and statistically significant relative to PLA; mean differences (SE) (L) following MABA 400 dosing: 0.139 (0.023) after SALB at 12 h; 0.123 (0.022) after SALB at 24 h; 0.124 (0.023) after IPR at 12 h; 0.141 (0.021) after IPR at 24 h; and after MABA 1200 dosing: 0.091 (0.023) after SALB at 12 h; 0.126 (0.022) after SALB at 24 h; 0.055 (0.023) after IPR at 12 h; 0.122 (0.022) after IPR at 24 h. Any additional bronchodilator effects at 1 h were small and not clinically significantly different from PLA. There were small, non-clinically significant increases in mean heart rate after both MABA doses plus SALB, and decreased potassium levels in four patients after MABA 1200 plus SALB (×3) or PLA (×1) were observed but overall all treatments were well tolerated and raised no significant safety signals.ConclusionThe additional bronchodilation achieved following supratherapeutic doses of SALB and IPR on top of single doses of MABA 400 or 1200 was comparable for the two agents and neither were associated with any clinically relevant systemic pharmacodynamic effects other than the small transient hypokalemic effect in a 3 out of 41 patients receiving additional high dose salbutamol and MABA 1200. Either short-acting bronchodilator could potentially be used as rescue medication on top of MABA therapy.     

Pharmacodynamics of GSK961081, a bi-functional molecule,in patients with COPD

GSK961081 is an inhaled bi-functional molecule with both muscarinic antagonism and β₂-agonism (MABA) properties.This randomised, double-blind, double-dummy, crossover study evaluated 14 days treatment with the MABA GSK961081 400 μg and 1200 μg once daily and tiotropium 18 μg once daily plus salmeterol 50 μg twice daily (TIO + SAL), versus placebo in 50 patients with moderate COPD. The primary endpoint was forced expiratory volume in 1 s (FEV₁) at 24 h on Days 1 and 14.MABA 400 (n = 29), MABA 1200 (n = 32) and TIO + SAL (n = 41) resulted in significant increases in FEV₁ over 24 h. Mean (95% CI) 24 h trough FEV₁ (L) values relative to placebo (n = 43) were, for Day 1, MABA 400: 0.141 (0.060, 0.222); MABA 1200: 0.184 (0.105, 0.263); TIO + SAL: 0.162 (0.092, 0.231); for Day 14, MABA 400: 0.115 (0.024, 0.205); MABA 1200: 0.168 (0.080, 0.255); TIO + SAL: 0.103 (0.026, 0.180). Onset of bronchodilation was faster for both MABA doses versus TIO + SAL. No clinically relevant systemic pharmacodynamic effects were observed. Adverse events were similar across groups; however tremor (n = 2, MABA 1200), dysgeusia (n = 2, MABA 1200; n = 2, MABA 400) and dry mouth (n = 1, MABA 1200) were reported after GSK961081 only.GSK961081 demonstrated sustained bronchodilation similar to TIO + SAL, but with a more rapid onset, and was well tolerated at the tested doses.     

Efficacy and safety of roflumilast in patients with stable chronic obstructive pulmonary disease: A meta-analysis

BackgroundCurrently, several large studies showed that roflumilast has been demonstrated efficacy during treatment chronic obstructive pulmonary disease (COPD) patients, but also caused some side effects.AimTo assess the efficacy and safety of roflumilast in COPD patients.MethodsA computerized search through electronic databases included PubMed, EMBASE, CINAHL, the Cochrane clinical trials database, Physiotherapy Evidence Database and ClinicalTrials.gov was performed to identify randomized controlled trials. The primary outcomes were trough forced expiratory volume in 1 s (FEV₁) (reported pre-bronchodilator values) and exacerbation rate. Secondary outcomes included other spirometric parameters, health-related quality of life, the overall mortality rate and adverse events. Weighted mean differences (WMDs), relative risks (RRs) and 95% confidence intervals (CIs) were calculated and pooled using a random effects model.ResultsEleven trials involving 9675 patients met the inclusion criteria. Roflumilast significantly reduced the mean exacerbation rate (mild, moderate or severe) (WMD = −0.23; 95% CI = −0.33 to −0.13; p < 0.00001) and improved trough FEV₁ (WMD = 53.52 ml; 95% CI = 42.49 to 64.55; p < 0.00001), and other post-bronchodilator spirometric parameters (e.g., forced vital capacity, etc.). Roflumilast did not improve St George's Respiratory Questionnaire total score (WMD = −0.70 units; 95% CI = −2.65 to 1.26; p = 0.49) and decrease the overall mortality rate (RR = 0.90; 95% CI = 0.63 to 1.29; p = 0.56). Roflumilast increased some adverse events including diarrhea, headache, nausea, weight loss, and insomnia.ConclusionsRoflumilast significantly reduces the mean exacerbation rate in COPD patients. Although there are insufficient clinical evidence on other clinical endpoints and high risk of some adverse events, roflumilast therapy may benefit COPD patients. Further studies are needed to pay more attention to the long-term efficacy and safety of roflumilast.     

Efficacy and safety of the long-acting muscarinic antagonist GSK233705 delivered once daily in patients with COPD

Introduction: GSK233705 is a recently developed inhaled anticholinergic being investigated for the potential treatment of chronic obstructive pulmonary disease (COPD). Objectives: This dose‐ranging, parallel‐group, double‐blind study compared the bronchodilator efficacy, safety and pharmacokinetics of GSK233705 with placebo in patients with moderate‐to‐severe COPD. Methods: Patients were randomised to receive 12.5 µg, 25 µg, 50 µg, 100 µg or 200 µg of GSK233705 or placebo once daily for 28 days. The primary endpoint was change from baseline in trough forced expiratory volume in 1 s (FEV₁) on day 29. Results: The intent‐to‐treat population consisted of 576 patients (mean predicted FEV₁ 51%; mean age 62 years). Treatment with GSK233705 produced statistically significant improvements in pulmonary function compared with placebo. Only the 200 µg dose exceeded the predefined target threshold of 130‐mL difference compared with placebo for the primary endpoint of change from baseline in trough FEV₁ on day 29. No clear pattern of dose response was observed for the other doses. Serial FEV₁ (0–24 h) showed a peak effect around 2 h postdose and tended to decline to clinically insignificant levels compared with placebo at 23 and 24 h. Each dose of GSK233705 was well tolerated. The incidence of adverse events was low and similar across all treatment groups. There were no clinically significant effects on laboratory parameters, vital signs or electrocardiograms. Conclusion: All doses of GSK233705 demonstrated bronchodilatory activity and were well tolerated. Although the onset of bronchodilation was rapid, it was not sustained over 24 h making it unsuitable for once‐daily dosing. Please cite this paper as: Bateman E, Feldman G, Kilbride S, Brooks J, Mehta R, Harris S, Maden C and Crater G. Efficacy and safety of the long‐acting muscarinic antagonist GSK233705 delivered once daily in patients with COPD. Clin Respir J 2012; DOI:10.1111/j.1752‐699X.2011.00278.x.     

Metered dose inhaler delivery of treprostinil for the treatment of pulmonary hypertension

BackgroundThe stable prostanoid analogue treprostinil is approved as continuous infusion for treatment of pulmonary arterial hypertension. Unique drug characteristics may render this prostanoid feasible for inhalation therapy with a metered dose inhaler.Methods and resultsRandomised open label investigation of acute haemodynamic effects, safety and tolerability of inhaled treprostinil delivered in seconds by a metered dose inhaler (MDI-TRE). Inhaled nitric oxide (NO) and MDI-TRE were applied once during right heart catheter investigation to 39 consecutive patients with pre-capillary pulmonary hypertension. Doses of 30 μg, 45 μg and 60 μg MDI-TRE were investigated in separate groups of patients. Haemodynamics and blood gases were measured for 2 h following treprostinil application. Acute haemodynamic responses to NO and MDI-TRE were comparable. MDI-TRE significantly improved haemodynamics compared to placebo inhalation. MDI-TRE induced effects were comparable to a historical control group that inhaled treprostinil from an ultrasonic nebuliser. The 120 min area under the curve for PVR changes due to placebo, 30 μg, 45 μg or 60 μg MDI-TRE was 1114 ± 998, ?870 ± 940, ?2450 ± 2070 and ?2000 ± 900 min*%. Reduction of systemic vascular resistance and pressure were not clinically relevant. No significant side effects were observed. No impact on ventilation/perfusion matching by treprostinil was demonstrated in 5 patients with pre-existing gas exchange limitations by use of the multiple inert gas elimination technique.ConclusionsThe application of inhaled treprostinil with a metered dose inhaler is feasible and well tolerated. It induced a sustained pulmonary selective vasodilatation.     

Effectiveness and Safety of Inhaled Antibiotics in Patients With Chronic Obstructive Pulmonary Disease. A Multicentre Observational Study

BackgroundWe aimed to describe the effectiveness and safety of inhaled antibiotics in chronic obstructive pulmonary disease (COPD) patients, as well as the patient profile in which they are usually prescribed and the patient groups that can most benefit from this treatment.MethodsMulticentre retrospective observational cohort study in COPD patients who had received ≥1 dose of inhaled antibiotics in the last 5 years. Clinical data from the two years prior to and subsequent to the start of the treatment were compared. Primary outcome: COPD exacerbations. Secondary outcomes: side effects, symptomatology (sputum purulence, dyspnoea), microbiological profile and pathogen eradication.ResultsOf 693 COPD patients analyzed (aged 74.1; 86.3% men; mean FEV₁ = 43.7%), 71.7% had bronchiectasis and 46.6% presented chronic bronchial infection (CBI) by Pseudomonas aeruginosa (PA). After 1 year of treatment with inhaled antibiotics, there was a significant decrease in the number of exacerbations (?33.3%; P < .001), hospital admissions (?33.3%; P < .001) and hospitalization days (?26.2%; P = .003). We found no difference in effectiveness between patients with or without associated bronchiectasis. Positive patient outcomes were more pronounced in PA-eradicated patients. We found a significant reduction in daily expectoration (?33.1%; P = .024), mucopurulent/purulent sputum (?53.9%; P < .001), isolation of any potentially pathogenic microorganisms (PPM) (?16.7%; P < .001), CBI by any PPM (?37.4%; P < .001) and CBI by PA (?49.8%; P < .001). CBI by any PPM and ≥three previous exacerbations were associated with a better treatment response. 25.4% of patients presented non-severe side-effects, the most frequent of these being bronchospasm (10.5%), dyspnoea (8.8%) and cough (1.7%).ConclusionsIn COPD patients with multiple exacerbations and/or CBI by any PPM (especially PA), inhaled antibiotics appear to be an effective and safe treatment, regardless of the presence of bronchiectasis.     

Real-world Safety and Efficacy of Indacaterol Maleate in Patients with Chronic Obstructive Pulmonary Disease: Evidence from the Long-term Post-marketing Surveillance in Japan

Objective Evidence concerning the safety and efficacy of indacaterol maleate in a real-life setting is limited. The objective of this post-marketing surveillance was to evaluate the real-life safety and efficacy of indacaterol maleate in Japanese patients with chronic obstructive pulmonary disease (COPD). Methods This was a 52-week post-marketing surveillance conducted between April 2012 and December 2018. The safety endpoints included the incidence of adverse events (AEs), serious adverse events (SAEs), and adverse drug reactions (ADRs). The efficacy endpoints included the physician-reported global evaluation of treatment effectiveness (GETE), change from baseline in the COPD assessment test (CAT) results, forced vital capacity (FVC), forced expiratory volume in 1 second (FEV₁), and %FEV₁ following 4, 12, 26, and 52 weeks of indacaterol administration. Results Of the 1,846 enrolled patients, 1,726 were included in the safety and efficacy analyses. The mean age of the patients was 72.5 years old. Cough, pneumonia and COPD worsening were the most common AEs reported, while pneumonia (1.04%) was the most common SAE, and cough (1.68%) was the most common ADR. GETE showed that 69.70% of patients achieved an excellent/good/moderate response following indacaterol treatment. The CAT score decreased, and lung function parameters (FVC, FEV₁ and %FEV₁) improved across all the COPD stages following treatment with indacaterol. Conclusion Indacaterol showed a favorable safety and tolerability profile in Japanese patients with COPD without new safety signals observed in real-life settings. These findings demonstrated that indacaterol is an effective maintenance treatment in real-life practice for Japanese patients with COPD.     

Fractional Exhaled Nitric Oxide Guided-Therapy in Chronic Obstructive Pulmonary Disease: A Stratified,Randomized, Controlled Trial

IntroductionChronic obstructive pulmonary disease (COPD) with eosinophilic airway inflammation represents a distinct phenotype that might respond to treatment with inhaled corticosteroids. Fractional exhaled nitric oxide (FENO) might predict eosinophilic inflammation and guide treatment option. We hypothesized that COPD patients with different baseline levels of FENO might have differentiated response to treatment with salmeterol/fluticasone (SFC) or tiotropium (TIO).MethodsThis open-label, randomized-controlled trial enrolled treatment-naïve COPD patients who were stratified into high- (≥23.5 ppb) and low-FENO group, followed by 12-week treatment with SFC or TIO. A linear mixed model with repeated measures was applied to analyze the changes in FENO (primary outcome), COPD assessment test (CAT) score, FEV₁, and parameters in induced sputum and blood after treatment.Results134 patients were divided into 4 subgroups: low-FENO/SFC (n = 30), low-FENO/TIO (n = 29), high-FENO/SFC (n = 37), and high-FENO/TIO (n = 38). At baseline, FENO 23.5 ppb clearly differentiated between eosinophilic and non-eosinophilic inflammation groups based on the eosinophils in induced sputum and blood. FENO significantly correlated with sputum and blood eosinophils at baseline. High-FENO/SFC (vs. high-FENO/TIO) subgroup had significant reduction in FENO and sputum inflammation profiles (including eosinophils, macrophages, matrix metalloproteinase-9, and interlukin-8) after treatment. These differences were not replicated between low-FENO/SFC and low-FENO/TIO subgroups. The improvement in CAT and FEV₁ after treatment was indiscriminate between SFC and TIO in the low- and high-FENO groups.ConclusionHigh baseline FENO can serve as an indicator of eosinophilic airway inflammation in COPD patients who may respond favorably to treatment with inhaled corticosteroids/long-acting β₂-agonists.Trial registration numberClinicalTrials.gov Identifier: NCT02546349.     

The contribution of sublingual immunotherapy to the achievement of control in birch-related mild persistent asthma: A real-life randomised trial

BackgroundAsthma control represents the main goal of asthma management and different strategies aim to avoid the long term downsides of inhaled corticosteroids. We investigated in real-life conditions the contribution of sublingual immunotherapy in achieving the control of birch-related mild persistent asthma compared to two usual step-up therapeutic options.MethodsA three-year open randomised study included 84 asthmatics, uncontrolled during the previous birch pollen season, despite a treatment with budesonide 400 μg/day. Patients randomly received budesonide 800 μg/day, budesonide 1600 μg/day, budesonide 400 μg/day plus montelukast 10 μg/day and budesonide 400 μg/day plus carbamylated allergoid of betulaceae pre-coseasonally. Asthma Control test, combined allergy symptoms and medications score, albuterol consumption, lung function, nasal eosinophils and nasal steroids usage were assessed as changes from the first to last pollen season.ResultSeventy-six patients concluded the study. All options, except budesonide 800 μg/day, produced an improvement of mean monthly Asthma Control test (p < 0.05). Patients undergoing low-dose budesonide plus immunotherapy achieved, after three years, an appreciable control (ACT mean score 24). A significant improvement was seen in all groups for allergy symptoms plus medications and bronchial reactivity. Albuterol consumption and lung function improved in all but the first group. Only budesonide plus immunotherapy reduced nasal eosinophils and nasal steroids usage. Two mild self-resolving adverse events were reported.ConclusionsFor patients with respiratory allergy due to birch pollen and mild persistent asthma, sublingual immunotherapy added to low-dose inhaled corticosteroids appears effective in maintaining long-term seasonal asthma control, representing a safe opportunity to reduce the cumulative amount of delivered corticosteroids.     

Aclidinium bromide provides long-acting bronchodilation in patients with COPD

Aclidinium bromide is a novel, long-acting, muscarinic antagonist in phase III development for the maintenance treatment of COPD. This phase IIb study investigated the efficacy and safety of aclidinium for the treatment of moderate to severe COPD to establish the optimal dose for phase III studies. A total of 464 patients with moderate to severe stable COPD were randomised to double-blind, once-daily treatment with aclidinium (25, 50, 100, 200, or 400 μg), placebo, or open-label tiotropium (18 μg) for 4 weeks. Spirometric measurements were performed at 22–24 h after the first dose and then at weekly intervals, and from 0.5 to 6 h post-dose on day 1 and day 29. Compared with placebo, aclidinium 200 μg and 400 μg significantly increased trough FEV₁ on day 29 versus baseline. During the first 6 h post-dose, the bronchodilatory effect of aclidinium (all doses) on day 1 was comparable to that on day 29. Time to peak FEV₁ was 3 h for aclidinium 100–400 μg. Aclidinium was well tolerated, with no dose-dependent effect on ECG, laboratory parameters, or adverse events. The incidence of AEs was generally comparable to placebo. Aclidinium produced sustained bronchodilation over 24 h and was well tolerated during this short-term study. Based on these data, aclidinium 200 μg was selected as the investigational dose for future clinical trials in COPD.