Randomized study of the safety, pharmacokinetics, and bronchodilatory efficacy of a proprietary glycopyrronium metered-dose inhaler in study patients with chronic obstructive pulmonary disease.

BACKGROUND: Bronchodilator medications are central to the symptomatic management of chronic obstructive pulmonary disease (COPD). Metered-dose inhalers (MDIs) are the most commonly used devices to deliver treatment to patients with COPD and asthma, comprising approximately 70% of bronchodilator prescriptions. Proprietary porous-particle technology permits the formulation of long-acting muscarinic antagonists, long-acting ß2-agonists, and a combination of both in hydrofluoroalkane (HFA) MDIs, providing a solution to formulation challenges inherent to the development of HFA MDIs, which have contributed to the development of dry-powder inhalers. METHODS: In this randomized, double-blind, 4-period, 6-treatment, placebo- and active-controlled, multicenter, crossover study, 4 ascending single doses of a proprietary glycopyrronium (GP) MDI were evaluated compared with Placebo MDI and open-label tiotropium (TIO) in study patients with COPD. Thirty-three study patients were enrolled and received single-dose administration of 4 of the 6 treatments (Placebo MDI, TIO 18 µg, or GP MDI at 14.4, 28.8, 57.6, and 115.2 µg ex-actuator) with an interval of 1 to 3 weeks between doses. The primary efficacy endpoint was peak change in forced expiratory volume in 1 second (FEV1). RESULTS: All 4 doses of GP MDI showed statistically superior efficacy compared with Placebo MDI for peak FEV1 (differences of 146 to 248 mL; P<.001), with a clear dose ordering of the response. Statistically significant differences compared with Placebo MDI were noted at almost all doses for the secondary FEV1 parameters (P ≤ .049) except 24-hour trough FEV1 at 28.8 µg. All doses were safe and well tolerated in this study; the most frequently reported adverse event was dry mouth (0-14.3% across doses; 9.5% for Placebo MDI, and 9.1% for TIO). CONCLUSIONS: This study demonstrated superior bronchodilatory efficacy of GP MDI compared with Placebo MDI at all doses tested, and no serious adverse events were reported. This study supports the further evaluation of GP MDI in study patients with COPD. In addition, these findings indicate that the correct dosage of glycopyrronium is no more than 115.2 µg total daily dose, or 57.6 µg twice daily based on comparisons with the active comparator. TRIAL REGISTRATION: This clinical trial was registered on ClinicalTrials.gov, Identifier: NCT00871182.

A randomized study of formoterol fumarate in a porous particle metered-dose inhaler in patients with moderate-to-severe COPD.

BACKGROUND: Formoterol fumarate (FF) is a well-established long-acting ß2-agonist. This represents the first clinical study of FF in a metered-dose inhaler (FF MDI) based on proprietary lipid-based porous-particle engineering technology. METHODS: In this randomized, double-blind, 5-period, crossover study (NCT00880490), subjects received 2.4, 4.8, and 9.6 µg of FF MDI, open-label Foradil(®) Aerolizer(®) (FA) 12 µg, and placebo. Spirometry was performed at baseline, 15 and 30 min, and 1, 2, 4, 6, 8, 10, 11.5, and 12 h post-dose. RESULTS: Thirty-four subjects were enrolled. Improvement in forced expiratory volume in 1 s (FEV1) was similar between FF MDI 9.6 µg and FA. Change in FEV1 area under the curve for 0-12 h (AUC0-12) for each FF MDI dose demonstrated superior efficacy versus placebo (P < .001 for all 3 doses). Over 12 h and at each time point, FF MDI 9.6 µg was non-inferior to FA for FEV1 AUC0-12 with the 95% CI's supporting a maximum difference of approximately 45 mL. Peak and trough FEV1, forced vital capacity, peak expiratory flow rate, peak inspiratory capacity, and pharmacokinetics confirmed the primary endpoint, with dose ordering of the FF MDI 2.4, 4.8, and 9.6 µg, and comparability of FF MDI 9.6 µg to FA. All 3 doses of FF MDI were safe and well-tolerated, with a safety profile similar to that of placebo and FA. CONCLUSIONS: The efficacy and pharmacokinetic profile of FF MDI 9.6 µg were comparable to FA 12 µg and with similar safety to placebo and FA. TRIAL REGISTRATION: This clinical trial was registered on ClinicalTrials.gov, Identifier: NCT NCT00880490.

Bronchodilator efficacy of indacaterol, a novel once-daily beta2-agonist, in patients with persistent asthma.

BACKGROUND: Indacaterol is a novel once-daily inhaled beta2-agonist in development for the treatment of patients with asthma or chronic obstructive pulmonary disease. OBJECTIVE: To investigate the bronchodilator efficacy of indacaterol in patients with persistent asthma. METHODS: Patients received a randomized sequence of single doses of indacaterol, 400 microg, via single-dose dry powder inhaler (SDDPI); indacaterol, 200 microg, via multidose dry powder inhaler (MDDPI); and placebo. At each visit, the forced expiratory volume in 1 second (FEV1) was recorded at a series of time points during a 24-hour period. RESULTS: Of 33 patients screened, 25 were randomized to treatment. Adjusted mean FEV1 was significantly higher (P < or = .005) for both indacaterol doses vs placebo at most time points. The first time points at which statistically significant treatment differences were observed for indacaterol and placebo in FEV1 were 0.17 L at 5 minutes after dosing for 400 microg of indacaterol (SDDPI) and 0.21 L at 10 minutes for 200 microg of indacaterol (MDDPI) (both P < .001 vs placebo). Differences relative to placebo at the final time point, 24 hours after dosing, were 0.29 L and 0.15 L for indacaterol, 400 microg and 200 microg, respectively (both P < or = .003 vs placebo). Overall, FEV1 was significantly higher for the 400-microg dose compared with the 200-microg dose from 15 minutes to 2 hours after dosing (P < or = .013) and from 5 hours onward (P < or = .022). Indacaterol was associated with good tolerability and safety. CONCLUSIONS: Indacaterol demonstrates sustained bronchodilator efficacy throughout the full 24-hour period, with a rapid onset of action and a good overall safety profile.

Cardiac safety of formoterol 12 microg twice daily in patients with chronic obstructive pulmonary disease.

BACKGROUND: Some evidence suggests an increased risk of myocardial infarction and dysrhythmia events associated with beta(2)-agonist use in patients with chronic obstructive pulmonary disease (COPD). This prospective, multicenter, randomized, double-blind, placebo-controlled study compared the cardiac safety of formoterol and placebo in patients with COPD. METHODS: After a 3-14-day run-in, 204 patients were randomized to receive formoterol 12 microg dry powder inhalation or matching placebo twice daily for 8 weeks. Twenty four-hour continuous electrocardiography (Holter monitoring) was performed at screening and after 2 and 8 weeks of treatment. RESULTS: Only a small number of patients met the predefined criteria for a proarrhythmic event (4 formoterol and 2 placebo patients). No patients had sustained postbaseline ventricular tachycardia events, postbaseline run of ventricular ectopic beats associated with relevant symptoms (e.g. hypotension, syncope), or an episode of ventricular flutter or fibrillation. Holter monitoring data were variable but showed no clinically meaningful differences between the formoterol and placebo groups, respectively, for variables such as (mean+/-SD at end of treatment): heart rate (80+/-8.6 vs. 80+/-10.6 bpm), number and rate of ventricular premature beats (total 732+/-2685.4 vs. 650+/-2090.6; rate 35+/-131.0 vs. 30+/-101.3 per h), ventricular tachycardia events (total 0.4+/-1.70 vs. 1.0+/-9.23; rate 0.02+/-0.082 vs. 0.05+/-0.479 per h), and supraventricular premature beats (total 504+/-1844.1 vs. 823+/-2961.8; rate 22+/-80.6 vs. 37+/-129.6 per h). Vital signs and electrocardiogram data, including corrected QT intervals (Bazett and Fridericia), were similar across treatment groups. The overall adverse event experience was similar in the formoterol (n=26 [27%]) and placebo (n=33 [31%]) groups. The most common adverse events, infections and respiratory events, were expected for this patient population. The incidence of cardiac adverse events was low (1 formoterol and 4 placebo patients). CONCLUSIONS: The results of this study confirm the good cardiovascular safety profile of formoterol in patients with COPD.