Rudolf A. Baumgartner

Effect of nebulized arformoterol on airway function in COPD: Results from two randomized trials

Rationale: Arformoterol, a single isomer long-acting β2-agonist, was developed as an inhalation solution for the maintenance treatment of bronchoconstriction in COPD. Methods: The pulmonary function efficacy of nebulized arformoterol (15 μ g BID, 25 μ g BID, 50 μ g QD) and salmeterol MDI (42 μ g BID) versus placebo was assessed in 1456 subjects (mean FEV1 1.2L, mean predicted 41%). Data were pooled from 2 identical, 12-week, double-blind, randomized trials. The percent change in trough FEV1, percent change in FEV1 average AUC(0 - 12 hrs) and peak percent change FEV1 from predose were analyzed. Results: Improvement in trough FEV1 averaged over 12 weeks was greater for arformoterol and salmeterol versus placebo (mean differences from placebo [95% CI] arformoterol–15 μ g BID: 11.4% [8.4, 14.3]; 25 μ g BID: 15.4% [12.2, 18.6]; 50 μ g QD: 10.9% [7.9, 13.9]); salmeterol: (11.6% [8.8, 14.4]). Greater improvements versus placebo occurred after the first dose (mean differences between arformoterol and placebo for trough FEV1: 13–19%; FEV1 AUC(0 - 12 hrs): 19–24%; peak percent change: 20–25%) and at week 12 (trough FEV1: 10–13%; FEV1 AUC(0 - 12 hrs): 6–13%; peak percent change: 7–14%); all 95% CIs excluded zero. Increases in FEV1 AUC(0 - 12 hrs) and peak percent change were greater for arformoterol than for salmeterol (95% CIs excluded zero). After 12 weeks, 78–87% of arformoterol subjects had ≥ 10% increases in FEV1 from pre-dose (56% salmeterol, 44% placebo); the median time to response was 3–13 minutes (142 minutes salmeterol). Conclusions: In these trials, COPD subjects administered nebulized arformoterol demonstrated significant and sustained improvement in lung function over 12 weeks.

The Safety and Efficacy of Arformoterol and Formoterol in COPD

ABSTRACT This study evaluated the safety and efficacy of arformoterol and formoterol over 6-months in subjects with COPD. In a multi-center, 6-month randomized, double-blind, double-dummy trial, subjects with COPD (mean FEV1 1.21 L, ∼41.0%% predicted) were randomized to receive either nebulized arformoterol (15μg BID [[n == 149]][[ARF 15]], 25μg BID [[n == 147]][[ARF 25]]), or racemic formoterol (12μg BID [[n == 147]][[FORM]]) delivered by DPI. The proportion of subjects with any post-treatment adverse event for ARF 15, ARF 25 μg, and FORM was 67.8%%, 76.2%% and 66.7%%, respectively, and those with at least one COPD exacerbation was 32.2%%, 30.6%%, and 22.4%%, respectively. Pulmonary function improved for all treatment groups and was maintained throughout the study. Mean change from baseline at 6-months for ARF 15, ARF 25 and FORM in peak FEV1 was 0.30L, and 0.34L, and 0.26L, respectively, in 24-hour trough FEV1 was, 0.10L, 0.14L, and 0.09L, and in inspiratory capacity was, 0.20L, 0.37L, and 0.23L. Dyspnea, (mean Transition Dypsnea Index (TDI) focal score) improved in all treatment arms (ARF 15: 1.4, ARF 25: 1.5, and FORM: 1.4) at 6 months, as did rescue short-acting β2-agonists use (mean range: −1.1 to −1.3 actuations/day) and ipratropium bromide (mean range: −0.3 to −0.8 actuations/day). Health status, measured by St Georges Respiratory Questionnaire, improved from baseline at 6-months in all treatment groups (mean change: −3.7 to −6.8). In this 6-month study, arformoterol and formoterol were well-tolerated, and their use was associated with improvement in pulmonary function and health status in subjects with COPD with no apparent development of tolerance.

Evaluation of levalbuterol metered dose inhaler in pediatric patients with asthma: a double- blind, randomized, placebo- and active-controlled trial*

ABSTRACT Objective: To evaluate the efficacy and safety of levalbuterol metered dose inhaler (MDI) in children aged 4-11 years (n = 173). Research design and methods: Multicenter, randomized, double-blind 28‐day study of QID levalbuterol 90 µg, racemic albuterol 180 µg, and placebo (2:1:1 ratio). Serial spirometry was performed on Days 0, 14, and 28. The primary endpoint was the double-blind average peak percent (%) change in FEV1 from visit pre-dose; the primary comparison was with placebo. Secondary endpoints included the area under the FEV1 percent change from pre-dose curve and peak % predicted FEV1. Safety endpoints included adverse events, laboratory tests, rescue medication use, and electrocardiograms. Results: Levalbuterol significantly improved the least square mean peak percent change in FEV1 compared with placebo (levalbuterol 25.6% ± 1.3% [p < 0.001]; racemic albuterol 21.8% ± 1.8% [p = ns]; placebo 16.8% ± 1.9%). Results for levalbuterol were similar for the other spirometry endpoints ( p < 0.05 vs. placebo). No levalbuterol-treated patients had a peak percent change in FEV1 < 10% (compared with 15.8% of racemic albuterol-treated patients and 30.3% of placebo-treated patients). The incidence of adverse events was 43.4% for levalbuterol, 56.4% for racemic albuterol, and 51.4% for placebo. The rate of discontinuation was 1.3% for levalbuterol, 2.6% for racemic albuterol, and 8.6% for placebo. The rate of asthma attacks (10.5%, 12.8%, 14.3%, respectively) was similar among treatments. Levalbuterol and racemic albuterol both reduced rescue medication use ( p < 0.01 vs. placebo) and produced changes in ventricular heart rate and QTc‐F that were similar to placebo. Conclusions: In this study, levalbuterol administered via MDI significantly improved airway function in comparison with placebo in asthmatic children aged 4–11 years with a safety profile that was similar to placebo.

A cumulative dose study of levalbuterol and racemic albuterol administered by hydrofluoroalkane-134a metered-dose inhaler in asthmatic subjects.

BACKGROUND The short-acting beta(2)-agonists levalbuterol and racemic albuterol are available for administration through a hydrofluoroalkane-134a (HFA) metered-dose inhaler (MDI). OBJECTIVE This study compared the short-term safety and efficacy of cumulative doses of levalbuterol HFA MDI and racemic albuterol HFA MDI in asthmatic subjects. METHODS This was a randomized, modified-blind, active-controlled, multicenter, 2-way crossover study. Subjects (n = 49) were randomized to 16 cumulative doses (1x, 2x, 4x, 8x, and 16x) of levalbuterol (45 microg per dose) or racemic albuterol (90 microg per dose) administered over a 2-hour period. After a 7-day washout period, subjects were crossed over to the other treatment. After each dose, safety outcomes and pulmonary function were assessed. RESULTS Heart rate and (R)-albuterol exposure increased for both racemic albuterol HFA and levalbuterol HFA. For cumulative doses of 8x or greater, racemic albuterol HFA treatment had greater increases in mean heart rate than levalbuterol HFA (least-squares mean [+/- SD] difference at the 8x dose was 2.8 beats/min [95% CI, 0.3-5.3] and at the 16x dose was 3.5 beats/min [95% CI, 0.6-6.4]). (R)-albuterol plasma levels ranged from 10% to 18% higher after racemic albuterol HFA MDI dosing versus after levalbuterol HFA MDI. FEV(1) improvements were similar for both treatments. The relative potencies of the 2 therapies, based on FEV(1), were similar (ratio, 1.1 [90% CI, 0.9-1.2]; Finney method). CONCLUSION In this study single-day cumulative dosing of asthmatic subjects with levalbuterol HFA MDI or racemic albuterol HFA MDI resulted in similar improvements in FEV(1) and tolerability. Plasma (R)-albuterol levels and mean heart rate were less with levalbuterol HFA MDI.

A pharmacokinetic/pharmacodynamic study comparing arformoterol tartrate inhalation solution and racemic formoterol dry powder inhaler in subjects with chronic obstructive pulmonary disease.

BACKGROUND Arformoterol is a single-isomer (R,R-formoterol) nebulized long-acting beta(2)-agonist approved for use in patients with chronic obstructive pulmonary disease (COPD). Exposure (plasma concentrations of (R,R)-formoterol) and forced expiratory volume in 1s (FEV(1)) were compared for 15 microg nebulized arformoterol and 12 and 24 microg racemic formoterol (containing 6 and 12 microg (R,R)-formoterol, respectively) delivered by dry powder inhaler (DPI). METHODS An open-label, randomized, three-way crossover study in 39 subjects with COPD (FEV(1) 1.4L, 44.4% predicted). Twice-daily treatments included nebulized arformoterol (15 microg) and racemic formoterol DPI (12 and 24 microg) for 14 days. Plasma concentrations of (R,R)- and (S,S)-formoterol were determined on days 1 and 14 of each treatment period. Airway function efficacy endpoints included the percent change in trough FEV(1) from baseline on day 14 of each treatment period. RESULTS At steady state, exposure to (R,R)-formoterol was similar following nebulized 15 microg arformoterol (C(max): 6.5 pg/mL; AUC(0-tau): 56.5 pgh/mL) and 12 microg racemic formoterol DPI (C(max): 6.2 pg/mL; AUC((0-)(tau)()): 46.3 pgh/mL). The geometric mean ratios between these two treatments (90% confidence intervals) for C(max) and AUC((0-)(tau)()) were 0.91 (0.76, 1.09) and 1.16 (1.00, 1.35), respectively. Treatment with 24 microg racemic formoterol DPI resulted in dose proportionally higher (R,R)-formoterol: C(max) (10.8 pg/mL) and AUC((0-)(tau)()) (83.6 pgh/mL). Detectable (S,S)-formoterol was consistently measured only after treatment with racemic formoterol. The mean percent increase in trough FEV(1) was 19.1% in the arformoterol group, and 16.0% and 18.2% in the 12 and 24 microg racemic formoterol groups, respectively. Changes in (R,R)-formoterol concentrations over time paralleled changes in FEV(1). CONCLUSIONS In this study, plasma exposure to (R,R)-formoterol was similar for nebulized 15 microg arformoterol and 12 microg racemic formoterol DPI, and 40% lower than 24 microg racemic formoterol DPI. There was no evidence of chiral interconversion following treatment with arformoterol. Finally, temporal changes in airway function in all treatment groups corresponded to changes in (R,R)-formoterol plasma concentrations.

Long-term safety study of levalbuterol administered via metered-dose inhaler in patients with asthma

BACKGROUND Previous studies have raised concerns regarding the safety of regular use of beta2-agonists for treating asthma. Few studies have explored the safety of at least 1 year of use of racemic albuterol, and none have examined long-term dosing of levalbuterol. OBJECTIVE To examine the long-term safety of levalbuterol hydrofluoroalkane (HFA) vs racemic albuterol HFA administered via metered-dose inhaler (MDI) in patients with stable asthma. METHODS Patients with mild to moderate asthma (mean forced expiratory volume in 1 second [FEVI], 68.3% of predicted) 12 years or older participated in a multicenter, parallel-group, open-label study. Patients were randomized to levalbuterol HFA MDI (90 microg; 2 actuations of 45 microg; n = 496) or racemic albuterol HFA MDI (180 microg; 2 actuations of 90 microg; n = 250) for 52 weeks of 4 times daily dosing. The primary end point was the incidence of postrandomization adverse events. Asthma exacerbations and pulmonary parameters were also assessed. RESULTS The overall incidence of adverse events was similar for levalbuterol (72.0%) and racemic albuterol (76.8%). Rates of beta-mediated adverse events, serious adverse events, and discontinuations because of adverse events were low (<15%) and were comparable between groups. Rates of asthma adverse events for levalbuterol and racemic albuterol were 18.3% and 19.6%, respectively. Mean percentage of predicted FEV1 improved after dosing and was stable for both groups. CONCLUSION In this trial, up to 52 weeks of regular use of levalbuterol HFA MDI or racemic albuterol HFA MDI was well tolerated, and no deterioration of lung function was detected during the study period.

Evaluation of the Efficacy and Safety of Levalbuterol in Subjects with COPD

The efficacy and safety of nebulized levalbuterol in adults with chronic obstructive pulmonary disease (COPD) was evaluated in this multicenter, randomized, double-blind, parallel design study. Randomized subjects (n = 209) received levalbuterol (LEV) 0.63 mg or 1.25 mg, racemic albuterol (RAC) 2.5 mg, or placebo (PBO) TID for 6 weeks. Serial spirometry was completed in-clinic after study drug alone (weeks 0, 2, and 6) or in combination with ipratropium bromide 0.5 mg (week 4). The primary endpoint was the averaged FEV1 AUC(0–8 hrs) over weeks 0, 2 and 6 compared with placebo. Other endpoints included rescue medication use, safety parameters, COPD exacerbations, and global evaluations. All active treatments demonstrated improvements in the percent change in FEV1 AUC(0–8 hrs) over the double-blind period and at each visit vs PBO (p < 0.05). Rescue medication use vs. baseline (doses/day) changed over time: PBO +0.38 ± 3.3; LEV 0.63 mg +0.07 ± 3.3; LEV 1.25 mg −0.84 ± 3.8 (p = 0.02 vs. RAC); RAC +0.97 ± 2.5. The overall rate of adverse events was PBO 56.4%, LEV 0.63 mg 56.6%, LEV 1.25 mg 67.3%, and RAC 65.4%. Protocol-defined COPD exacerbations occurred in all groups (PBO 12.7%, LEV 0.63 mg 11.3%; LEV 1.25 mg 18.4%; RAC 21.2%). Withdrawals due to COPD exacerbations were significantly higher in the RAC group compared with PBO (PBO 0%; LEV 0.63 mg 1.9%; LEV 1.25 mg 4.1%; RAC 9.6% p = 0.01 vs. PBO). In this study, levalbuterol treatment in subjects with COPD was generally well tolerated, produced significant bronchodilation compared with PBO, and improved clinical control of COPD as evidenced by reductions in rescue medication use compared with PBO and/or RAC.

Efficacy of Trabodenoson in a Mouse Keratoconjunctivitis Sicca (KCS) Model for Dry-Eye Syndrome

Purpose To determine the efficacy of trabodenoson, an adenosine mimetic with highly selective adenosine A1 receptor binding properties, in a preclinical mouse model for dry-eye disease. Methods Dry-eye disease was induced in adult male C57BL/6 mice using a combination of desiccating environment and transdermal administration of scopolamine. Mice were treated concurrently and twice daily with either vehicle, 6% trabodenoson, or 0.05% cyclosporine (Restasis). Efficacy (P < 0.05 versus vehicle) was determined by clinical assessment of dry-eye symptoms using corneal fluorescein staining and tear volumes and histopathologically by quantifying lacrimal gland pathology and conjunctival goblet cells. Results Twice-daily topical (ocular) administration of trabodenoson increased tear levels and reduced corneal fluorescein staining (P < 0.05) as compared with vehicle-treated eyes in a mouse model of dry-eye disease. Furthermore, significant infiltration of immune cells in the lacrimal gland and reduced number of mucin-producing conjunctival goblet cells were noted in both untreated and vehicle-treated eyes. Comparatively, trabodenoson treatment significantly reduced lacrimal gland infiltration and increased the number of goblet cells (P < 0.05 for both versus vehicle). These trabodenoson-related effects on lacrimal gland pathology and goblet cells were similar to or better than the effects observed with cyclosporine treatment. Conclusions Topical ocular delivery of trabodenoson significantly improves the clinical and histopathological signs associated with dry-eye disease in mice. This improvement appears to be related to anti-inflammatory effects from targeting adenosine signaling and represents a novel therapeutic approach to develop for the management of dry-eye disease.