Kimberly Denis-Mize

Concomitant treatment with nebulized formoterol and tiotropium in subjects with COPD: A placebo-controlled trial

Adding a long-acting beta(2)-agonist (LABA) by dry powder inhaler (DPI) to tiotropium provides significantly increased and sustained bronchodilation in chronic obstructive pulmonary disease (COPD) patients over either product alone. To demonstrate similar benefits with a nebulized LABA, a placebo-controlled trial was conducted to evaluate the efficacy and safety of formoterol fumarate inhalation solution in subjects receiving tiotropium as a maintenance treatment for COPD. After a 7-14-day screening period using tiotropium 18 microg once daily, subjects with diagnosed COPD (> or = 25% to <65% predicted FEV(1)) were randomized to receive 20 microg formoterol fumarate inhalation solution twice daily for nebulization plus tiotropium (FFIS/TIO) or nebulized placebo twice daily plus tiotropium (PLA/TIO) for 6 weeks. Efficacy was assessed with spirometry at each visit (Day 1, Week 1, 3, 6), the transition dyspnea index (TDI), and St. Georges Respiratory Questionnaire (SGRQ). Baseline characteristics were comparable, including mean FEV(1)% predicted. At Week 6, FEV(1) AUC(0-3) was 1.52 L for FFIS/TIO-treated subjects vs. 1.34 L for PLA/TIO-treated subjects (p<0.0001). The mean TDI scores in the FFIS/TIO and PLA/TIO groups were 2.30 and 0.16, respectively (p=0.0002). SGRQ did not change significantly with 6 weeks treatment, with the exception of FFIS/TIO improvements in symptom score vs. PLA/TIO (p=0.04). More PLA/TIO- than FFIS/TIO-treated subjects experienced AEs (39.7% vs. 22.9%), COPD exacerbations (7.9% vs. 4.5%), and serious AEs (3.2% vs. 1.5%). Nebulized formoterol fumarate in combination with tiotropium provided statistically and clinically significant improvements in bronchodilation and symptom control over tiotropium alone and demonstrated good tolerability.

Efficacy and Safety of Nebulized Formoterol as Add-on Therapy in COPD Patients Receiving Maintenance Tiotropium Bromide Results from a 6-Week, Randomized, Placebo-Controlled, Clinical Trial

AbstractBackground: Current guidelines for the treatment of chronic obstructive pulmonary disease (COPD) recommend the use of long-acting bronchodilators in the maintenance management of COPD. Combining bronchodilators that work through different mechanisms is recommended in patients with continuous symptoms. Objective: We conducted this study to confirm and further investigate the efficacy and safety of nebulized formoterol as an add-on therapy to maintenance tiotropium in patients with COPD. Methods: This randomized, double-blind, placebo-controlled, parallel-group study (NCT00507234) was conducted at 24 US sites from March to October 2007 in 155 patients aged ≥40 years with post-bronchodilator forced expiratory volume in 1 second (FEV1) ≥25% to <65% predicted normal. COPD patients receiving open-label tiotropium bromide 18 μg once daily during a 1- to 2-week run-in period were randomized to receive either formoterol fumarate inhalation solution 20 μg or placebo by nebulization twice daily for 6 weeks while continuing treatment with tiotropium. Outcomes included serial spirometry, inspiratory capacity (IC), baseline dyspnoea index/transition dyspnoea index (BDI/TDI), daily symptom scores, salbutamol (albuterol) use and health status measured by the St George’s Respiratory Questionnaire (SGRQ). Main outcome measures: The primary efficacy endpoint was standardized absolute FEV1 area under the curve over 3 hours (AUC0–3) at week 6. Results: Treatment groups (formoterol plus tiotropium, n = 78; placebo plus tiotropium, n=77) were comparable at baseline. At 6 weeks, FEV1 AUC0–3was significantly greater in the formoterol group compared with the placebo group (1.57 vs 1.38 L [p<0.0001]). Similarly, formoterol plus tiotropium improved other lung function measures, including FEV1, forced vital capacity and post-dose IC at day 1, and maintained efficacy through week 6. Formoterol plus tiotropium decreased rescue albuterol use throughout the study (p<0.05). Mean TDI, SGRQ and most symptom scores did not differ between the two treatment groups. Overall, 37% of formoterol plus tiotropium recipients experienced adverse events versus 51% of those receiving placebo plus tiotropium. Conclusions: The addition of nebulized formoterol to tiotropium in maintenance treatment of COPD provided clinically meaningful, statistically significant and sustained improvements in pulmonary function without additional adverse effects.

Long-term safety of nebulized formoterol: results of a twelve-month open-label clinical trial.

Formoterol fumarate is a long-acting β2-agonist that is an effective bronchodilator for the maintenance management of patients with chronic obstructive pulmonary disease. The safety profile of the newly developed nebulized formoterol was evaluated over a twelve-month period in an open-label, active-control study. After completing a twelve-week double-blind double-dummy period, 569 subjects with chronic obstructive pulmonary disease entered an open-label extension study and received twice-daily 20 µg formoterol fumarate inhalation solution for nebulization (FFIS) or 12 µg formoterol fumarate dry powder inhalation (FA) for 52 weeks. Most of the FFIS-treated subjects (86%) completed at least six months of open-label treatment with over 90% compliance, comparable to the FA group (88%). Results of safety monitoring for adverse events, laboratory values, and cardiac changes were similar between treatment groups. Three hundred forty (73%) of FFIS-treated subjects and 83 (78%) of FA-treated subjects experienced an adverse event over the course of the study, the majority of which were mild to moderate and considered unrelated to treatment. COPD exacerbation occurred in 15.8% of FFIS-treated and 17.9% of FA-treated subjects. Deaths, serious adverse events, and discontinuations for adverse events occurred in 1.3, 16.2, and 5.4% of the nebulized group versus 1.9, 17.9, and 7.5% of the inhaled group, respectively. There were no clinically important changes from baseline in laboratory tests, including serum potassium and glucose, or vital signs and no treatment-related increases in cardiac arrhythmias, heart rate, or QTc prolongation. We conclude that nebulized formoterol fumarate twice daily is well tolerated over long-term treatment in moderate-to-severe COPD subjects and has a similar safety profile to the DPI formulation.

Nebulized formoterol effect on bronchodilation and satisfaction in COPD patients compared to QID ipratropium/albuterol MDI

ABSTRACT Objective: Bronchodilator maintenance treatment improves pulmonary function and health-related quality of life in COPD patients. Pulmonary function and patient preference/satisfaction were compared before and after treatment with a short-acting ipratropium/albuterol combination and long-acting nebulized formoterol. Methods: A randomized, open-label, crossover trial was conducted at 16 centers in the US. COPD subjects (n = 109, 52.8% predicted FEV1) received nebulized formoterol fumarate inhalation solution (Perforomist**, FFIS 20 μg BID) or ipratropium and albuterol combined in a metered-dose inhaler (MDI) (Combivent**, IPR-ALB, QID) for 2 weeks. After a 1-week washout, subjects were crossed over to the other treatment. Efficacy was assessed with 6-h pulmonary function tests and the transition dyspnea index (TDI). Treatment satisfaction and preference were assessed after treatment. Post-hoc subgroup analyses were conducted by age, gender and COPD severity. ** Perforomist is a registered trademark name of Dey LP, Napa, CA, USA † Combivent is a registered trademark of Boehringer Ingelheim, Ridgefield, CT, USA Main outcome measure: Morning pre-dose FEV1 (trough) after 2 weeks of treatment. Results: FFIS significantly increased morning pre-dose FEV1 relative to IPR-ALB (p = 0.0015). FFIS also improved pre-dose FEV1 beyond that of IPR-ALB in subjects who were older (≥65 years), male, and with both moderate and severe/very severe COPD. Post-dose efficacy at 6 h was maintained in the FFIS group compared with IPR-ALB (p ≤ 0.0001). Patient satisfaction and the perception of disease control were significantly greater with FFIS in the older, male, and severe subgroups. Severe subjects preferred FFIS to IPR-ALB. Both FFIS and IPR-ALB treatments resulted in clinically meaningful changes in dyspnea, but no significant differences were observed between treatments. Conclusions: Following a 2-week treatment period, twice-daily nebulized FFIS was significantly more effective in improving lung function than the IPR-ALB combination MDI delivered four times daily. Although the open-label design may limit interpretation of pulmonary function, the crossover design enabled demonstration of greater treatment satisfaction and perception of disease control following nebulized FFIS treatment. Clinical trial registration: Clinicaltrials.gov NCT00462540

Nebulized formoterol fumarate: Dose selection and pharmacokinetics.

To determine a dose of nebulized formoterol fumarate inhalation solution (FFIS) comparable to that of the marketed formoterol fumarate dry powder inhaler (FA, 12microg), two crossover studies were conducted in subjects with COPD. Study 1 was a single-dose, double-blind, double-dummy dose-ranging study in which 47 subjects were randomly assigned to treatment sequences that evaluated the bronchodilatory effects of FFIS 2.5, 5, 10, 20, and 40microg, FA, and placebo over 12h. Mean FEV(1) AUC(0-12) following FFIS treatment ranged from 1.3 to 3.0l/h in a dose-related manner, with equivalent values (2.3l/h) for FFIS 20microg and FA. Results for other spirometric measures, including peak and trough FEV(1) and absolute change in FEV(1) by timepoint, confirmed the comparability of FFIS 20microg and FA. Study results with the nebulized formulation supported the rapid time to onset of bronchodilation with FFIS 20microg (3.9 and 2.2min imputed for 15% and 12%/200ml response, respectively). Study 2, a single-dose, open-label crossover study, was conducted to establish the pharmacokinetic (PK) profile of nebulized formoterol and confirm comparability to FA. Thirteen subjects were randomly assigned to treatment sequences with FFIS 10, 20, and 244microg and FA with a 5-14-day washout period between each treatment. Formoterol levels were assessed from blood and urine collected pre-dose and over a 24-36-h period after dosing. Pharmacodynamic (PD) measures included clinical laboratory and ECG measures pre-dose and over a 24-h period post-dose. FFIS 244mug was rapidly absorbed with a T(max) of 12min and t(1/2) of 6.1h. Data from other doses were sporadic due to assay sensitivity. The mean amount excreted (Ae) in urine suggested linear kinetics and confirmed the comparability of FFIS 20microg and FA. Mean serum potassium decreased and mean serum glucose increased transiently in a dose-dependent manner following treatment. No clinically significant ECG changes were observed; mean heart rate increased after treatment with FFIS 244mug by up to 6bpm. Findings from dose-ranging and PK/PD studies confirmed that a 20microg dose of FFIS was comparable to formoterol fumarate delivered by dry powder inhalation (12microg) and established the dose proportionality and linear kinetics of formoterol fumarate delivered by nebulization.

Nebulized formoterol provides added benefits to tiotropium treatment in chronic obstructive pulmonary disease

IntroductionThe use of one or more long-acting bronchodilators is key in the maintenance therapy of chronic obstructive pulmonary disease (COPD). This analysis pooled the results of two double-blind studies evaluating the efficacy and safety of adding nebulized formoterol fumarate inhalation solution (FFIS) to maintenance tiotropium (TIO) treatment.MethodsFollowing a run-in period of 7–14 days with once-daily TIO 18 µg, COPD subjects (≥25% to <65% predicted forced expiratory volume in 1 second [FEV1]) were randomized to twice-daily FFIS 20 µg (n=145) or nebulized placebo (PLA, n=140) while continuing on maintenance TIO for 6 weeks. Efficacy was measured using serial spirometry, transition dyspnea index (TDI), rescue albuterol use, and St. George’s Respiratory Questionnaire (SGRQ).ResultsThe mean standardized area under the curve for FEV1 over 3 hours (FEV1AUC0–3), the primary efficacy variable, was significantly higher in the FFIS/TIO group than the PLA/TIO group on day 1 (140 mL difference, P<0.0001) and week 6 (192 mL difference, P<0.0001). Mean TDI scores in the FFIS/TIO and PLA/TIO groups were 1.97 and 0.67, respectively (P=0.0001). Mean albuterol use declined in the FFIS/TIO group from 2.6 to 1.5 puffs/day compared with little change in the PLA/TIO group (P<0.0001). SGRQ scores were similar between treatment groups with the exception of the symptoms score, which improved in the FFIS/TIO group (−5.8) compared with PLA/TIO (−1.0), and more FFIS/TIO-treated subjects experienced a clinically significant improvement in total SGRQ score. More PLA/TIO-treated subjects than FFIS/TIO-treated subjects experienced adverse events (AEs) (45.7% vs. 31.0%) and COPD exacerbations (7.9% vs. 3.4%).ConclusionsThe addition of FFIS to maintenance TIO treatment for moderate to severe COPD results in significantly improved FEV1 and dyspnea, decreased rescue medication use, and a lower incidence of AEs and COPD exacerbations. The addition of FFIS to TIO yields clinically and statistically significant benefits for COPD patients and might be of long-term benefit.