A randomized, controlled, repeat-dose study of batefenterol/fluticasone furoate compared with placebo in the treatment of COPD.

BACKGROUND: Batefenterol (BAT) is a bi-functional molecule with both muscarinic antagonist and ß2-adrenoceptor agonist pharmacology. This Phase II, randomized, placebo-controlled, double-blind study evaluated the safety and tolerability of BAT 300 µg with fluticasone furoate (FF) 100 µg administered via the ELLIPTA inhaler (BAT/FF 300/100). METHODS: Subjects with stable chronic obstructive pulmonary disease were randomized 2:1 to receive BAT/FF 300/100 or placebo once daily for 6 weeks. The primary endpoint was change from baseline in 0-4-h weighted mean (WM) heart rate (HR, measured by electrocardiogram [ECG]) on Day 42. Other endpoints included WM and maximum 0-4-h corrected QT interval (ECG on Days 1, 28, and 42), HR measured by Holter monitoring (Day 42), and standard safety assessments. Study protocol was approved by an Investigational Review Board. RESULTS: Sixty-two patients were randomized and received ≥1 dose of study medication (BAT/FF 300/100 n = 42; placebo n = 20). Mean age was 62.5 years (standard deviation [SD] 8.17). Study completion rates were 83% (BAT/FF 300/100) and 100% (placebo). Screening mean (SD) post-bronchodilator percentage-predicted forced expiratory volume in 1 s was 57.57 (11.42) in the BAT/FF 300/100 group and 55.68 (14.03) in the placebo group. BAT/FF 300/100 was non-inferior to placebo for the primary endpoint, treatment difference: - 2.2 beats per minute (bpm), 95% confidence interval [CI]: - 6.2, 1.7). There were no clinically relevant differences between treatment groups in WM or maximum 0-4-h corrected QT interval, or mean HR based on Holter monitoring on Day 42 (BAT/FF 300/100: 76.3 bpm [SD 11.38]; placebo: 84.8 bpm [SD 9.87]). Adverse events (AEs) occurred in 38% (BAT/FF 300/100) and 35% (placebo) of patients. AEs in ≥2 subjects with BAT/FF 300/100 were dysgeusia (10%), diarrhea (7%), nasopharyngitis (7%), and cough (5%). AEs leading to discontinuation occurred in two subjects who received BAT/FF 300/100: post-treatment severe pneumonia (serious AE) and non-serious AEs of moderate vomiting and severe gastroenteritis; both were not considered drug-related. No deaths occurred. CONCLUSIONS: Six weeks of BAT/FF 300/100 treatment was non-inferior to placebo for change from baseline in HR, with no new clinically relevant general or cardiovascular safety signals. TRIAL REGISTRATION: Clinicaltrials.gov: NCT02573870 (submitted October 12, 2015).

ELLIPTA Versus DISKUS plus HandiHaler in COPD: A Randomized, Open-Label, Crossover Study in a Clinical Trial Setting.

BACKGROUND: Inhaler errors among patients with chronic obstructive pulmonary disease (COPD) can reduce treatment efficacy. METHODS: This randomized, open-label, crossover study evaluated correct use of ELLIPTA versus DISKUS plus HandiHaler. Participants with COPD attended at least 3 study visits (Day 1 [Visit 1], Day 28 [Visit 2], and Day 56 [Visit 3]). Inhalers contained placebo; usual maintenance medication was continued. Participants were randomized to an inhaler sequence (ELLIPTA then DISKUS plus HandiHaler, or the reverse) and preference questionnaire at Visit 1. Participants read the instructions for use in the approved prescribing information for their inhaler(s) and correct use was assessed at Visit 1 (verbal guidance provided if required). Correct use was reassessed at Visit 2, and with the next inhaler(s) at Visit 3. Primary endpoint was the proportion of participants demonstrating correct use (0 errors) with the assigned inhaler(s) after 28 days. RESULTS: A greater proportion of study participants (n = 217) correctly used ELLIPTA (96%) versus DISKUS plus HandiHaler (87%) after 28 days. The odds of demonstrating correct use with ELLIPTA were 6.88 times that of DISKUS plus HandiHaler (p < 0.001). Overall, > 99% of participants made 0 critical errors (errors leading to no or significantly reduced medication inhaled) with ELLIPTA versus 89% with DISKUS plus HandiHaler after 28 days. ELLIPTA was the patient-preferred option versus DISKUS plus HandiHaler or no preference (p < 0.001). CONCLUSIONS: Delivery of COPD maintenance therapy via ELLIPTA demonstrates higher correct use rates and lower critical error rates compared with DISKUS plus HandiHaler.

The Role of Guaifenesin in the Management of Chronic Mucus Hypersecretion Associated with Stable Chronic Bronchitis: A Comprehensive Review.

Chronic obstructive pulmonary disease is the third leading cause of death and disease burden worldwide. It includes a spectrum of diseases including chronic bronchitis which is characterized by overproduction, hypersecretion and decreased elimination of mucus. Chronic bronchitis has numerous clinical consequences, including predisposition to lower respiratory tract infections, accelerated decline in lung function, increased exacerbation rate and decreased health-related quality of life.Although the inflammatory mechanisms responsible for mucus cell metaplasia in chronic obstructive pulmonary disease and stable chronic bronchitis are poorly understood, the main goals of therapy are to decrease mucus hypersecretion by controlling inflammation and to increase mucus clearance. Non-pharmacological measures include smoking cessation and chest physiotherapy. Pharmacological interventions include expectorants and mucolytics together with long-acting beta2-adrenergic receptor agonists, anticholinergics, glucocorticoids, phosphodiesterase-4 inhibitors, antioxidants, and antibiotics.Guaifenesin is an expectorant that is thought to increase hydration and decrease viscosity of mucus leading to improved clearance of accumulated secretions from the upper and lower airway. Although guaifenesin has a Food and Drug Administration Over-the-Counter (OFC) Monograph indication to "help loosen phlegm (mucus) and thin bronchial secretions in patients with stable chronic bronchitis," there is limited published evidence of either mechanism of action or clinical efficacy in this disease state. Here we review the pathophysiology and consequences of chronic mucus hypersecretion and examine the evidence for the use of guaifenesin in patients with stable chronic bronchitis.

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.

OBJECTIVES: This 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). METHODS: In 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. RESULTS: Eighty 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. CONCLUSIONS: The 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.

A phase IIb randomized, chronic-dosing, incomplete block, cross-over study of glycopyrronium, delivered via metered dose inhaler, compared with a placebo and an active control in patients with moderate-to-severe COPD.

BACKGROUND: Long-acting muscarinic antagonist (LAMA) and long-acting ß2-agonist (LABA) bronchodilators are key to the pharmacologic treatment of chronic obstructive pulmonary disease (COPD). This Phase IIb study investigated the safety and efficacy of four doses of the LAMA glycopyrronium (GP) delivered using co-suspension delivery technology via metered dose inhaler (MDI). The study was part of a wider clinical trial program performed to determine the optimal dose of GP MDI, the LABA formoterol fumarate dihydrate (FF) MDI, and glycopyrronium/formoterol fumarate dihydrate (GFF) MDI fixed-dose combination to be taken forward into Phase III studies. METHODS: In this randomized, double-blind, 7-day chronic-dosing, three-period incomplete block, cross-over study, patients with moderate-to-severe COPD received two of the four doses of GP MDI (28.8 µg, 14.4 µg, 7.2 µg, and 3.6 µg) twice daily (BID), and either placebo MDI BID or open-label ipratropium MDI 34 µg four times daily. The primary efficacy endpoint was forced expiratory volume in 1 s (FEV1) area under the curve from 0 to 12 h (AUC0-12) relative to baseline on Day 7. Secondary and exploratory efficacy endpoints were assessed on Days 1 and 7. Safety and tolerability were evaluated throughout the study. RESULTS: All GP MDI treatments were superior to placebo MDI for the primary efficacy endpoint (all p < 0.0001). However, only GP MDI 28.8 µg and 14.4 µg demonstrated statistical superiority to placebo MDI for all secondary efficacy endpoints analyzed in this study, with the exception of GP MDI 14.4 µg versus placebo MDI for the proportion of patients achieving ≥12% improvement in FEV1. No nominally significant differences were observed between GP MDI 28.8 µg and GP MDI 14.4 µg for any of the endpoints. All doses of GP MDI were well tolerated, with no unexpected safety findings. CONCLUSIONS: This study indicated that there was no advantage of GP MDI 28.8 µg compared with GP MDI 14.4 µg. It therefore added to the evidence from the Phase I/II clinical trial program, which identified GP MDI 14.4 µg as the most appropriate dose for use in the Phase III clinical studies. TRIAL REGISTRATION: ClinicalTrials.gov (NCT01350128). Registered May 09, 2011.

A randomized, seven-day study to assess the efficacy and safety of a glycopyrrolate/formoterol fumarate fixed-dose combination metered dose inhaler using novel Co-Suspension™ Delivery Technology in patients with moderate-to-very severe chronic obstructive pulmonary disease.

BACKGROUND: Long-acting muscarinic antagonist/long-acting ß2-agonist combinations are recommended for patients whose chronic obstructive pulmonary disease (COPD) is not managed with monotherapy. We assessed the efficacy and safety of glycopyrrolate (GP)/formoterol fumarate (FF) fixed-dose combination delivered via a Co-Suspension™ Delivery Technology-based metered dose inhaler (MDI) (GFF MDI). METHODS: This was a Phase IIb randomized, multicenter, placebo-controlled, double-blind, chronic-dosing (7 days), crossover study in patients with moderate-to-very severe COPD ( NCT01085045 ). Treatments included GFF MDI twice daily (BID) (GP/FF 72/9.6 µg or 36/9.6 µg), GP MDI 36 µg BID, FF MDI 7.2 and 9.6 µg BID, placebo MDI, and open-label formoterol dry powder inhaler (FF DPI) 12 µg BID or tiotropium DPI 18 µg once daily. The primary endpoint was forced expiratory volume in 1 s area under the curve from 0 to 12 h (FEV1 AUC0-12) on Day 7 relative to baseline FEV1. Secondary endpoints included pharmacokinetics and safety. RESULTS: GFF MDI 72/9.6 µg or 36/9.6 µg led to statistically significant improvements in FEV1 AUC0-12 after 7 days' treatment versus monocomponent MDIs, placebo MDI, tiotropium, or FF DPI (p ≤ 0.0002). GFF MDI 36/9.6 µg was non-inferior to GFF MDI 72/9.6 µg and monocomponent MDIs were non-inferior to open-label comparators. Pharmacokinetic results showed glycopyrrolate and formoterol exposure were decreased following administration via fixed-dose combination versus monocomponent MDIs; however, this was not clinically meaningful. GFF MDI was well tolerated. CONCLUSIONS: GFF MDI 72/9.6 µg and 36/9.6 µg BID improve lung function and are well tolerated in patients with moderate-to-very severe COPD. TRIAL REGISTRATION: ClinicalTrials.gov NCT01085045 . Registered 9 March 2010.

Efficacy and Safety of Glycopyrrolate/Formoterol Metered Dose Inhaler Formulated Using Co-Suspension Delivery Technology in Patients With COPD.

BACKGROUND: Long-acting muscarinic antagonist (LAMA)/long-acting ß2-agonist (LABA) combinations are a treatment option for patients with COPD who continue to have symptoms despite treatment with a LAMA or a LABA alone. The Efficacy and Safety of PT003, PT005, and PT001 in Subjects with Moderate-to-Very Severe COPD (PINNACLE-1) (NCT01854645) and the Multi-Center Study to Assess the Efficacy and Safety of PT003, PT005, and PT001 in Subjects with Moderate-to-Very Severe COPD (PINNACLE-2) (NCT01854658) trials investigated the efficacy and safety of a novel glycopyrrolate [GP]/formoterol [FF] 18/9.6-µg (GFF) metered dose inhaler (MDI) formulated using the Co-Suspension Delivery Technology in patients with moderate-to-very severe COPD. METHODS: These two phase III trials took place over 24 weeks and were randomized, double blind, and placebo controlled; 2,103 and 1,615 patients (40-80 years of age), respectively, were randomized. Patients received GFF MDI, GP MDI 18 µg, FF MDI 9.6 µg, or placebo MDI (all twice daily), or tiotropium 18 µg dry powder inhaler (once daily in PINNACLE-1 only [open-label active comparator]). Efficacy and safety were assessed. RESULTS: At week 24, differences in change from baseline in the morning predose trough FEV1 for GFF MDI vs placebo MDI, GP MDI, and FF MDI were 150 mL, 59 mL, and 64 mL in PINNACLE-1 (all P < .0001) and 103 mL, 54 mL, and 56 mL in PINNACLE-2 (all P < .001), respectively. There were no significant safety findings (incidence of adverse events was similar between treatment arms). CONCLUSIONS: We conclude that GFF MDI 18/9.6 µg demonstrated superiority over placebo and monocomponent MDIs and was well tolerated, thus providing an additional treatment option for patients with moderate-to-very severe COPD. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01854645 and No. NCT01854658; URL: www.clinicaltrials.gov.

Dose-response to inhaled glycopyrrolate delivered with a novel Co-Suspension™ Delivery Technology metered dose inhaler (MDI) in patients with moderate-to-severe COPD.

BACKGROUND: This study forms part of the first complete characterization of the dose-response curve for glycopyrrolate (GP) delivered using Co-Suspension™ Delivery Technology via a metered dose inhaler (MDI). We examined the lower GP MDI dose range to determine an optimal dose for patients with moderate-to-severe chronic obstructive pulmonary disease (COPD). METHODS: This randomized, double-blind, chronic-dosing, balanced incomplete-block, placebo-controlled, crossover study compared six doses of GP MDI (18, 9, 4.6, 2.4, 1.2, and 0.6 µg, twice daily [BID]) with placebo MDI BID and open-label tiotropium dry powder inhaler (18 µg, once daily [QD]) in patients with moderate-to-severe COPD. Patients were randomized into 1 of 120 treatment sequences. Each sequence included 4 of 8 treatments administered for 14-day periods separated by 7- to 21-day washout periods. The primary efficacy endpoint was change from baseline in forced expiratory volume in 1 s area under the curve from 0 to 12 h (FEV1 AUC0-12) on Day 14. Secondary efficacy endpoints included peak change from baseline (post-dose) in FEV1 and inspiratory capacity (IC) on Days 1, 7, and 14; change from baseline in morning pre-dose trough FEV1 on Days 7 and 14; change from baseline in 12-h post-dose trough FEV1 on Day 14; time to onset of action (≥10 % improvement in mean FEV1) and the proportion of patients achieving ≥12 % improvement in FEV1 on Day 1; and pre-dose trough IC on Days 7 and 14. Safety and tolerability were also assessed. RESULTS: GP MDI 18, 9, 4.6, and 2.4 µg demonstrated statistically significant and clinically relevant increases in FEV1 AUC0-12 compared with placebo MDI following 14 days of treatment (modified intent-to-treat population = 120). GP MDI 18 µg was non-inferior to open-label tiotropium for peak change in FEV1 on Day 1 and morning pre-dose trough FEV1 on Day 14. All doses of GP MDI were well tolerated with no unexpected safety findings. CONCLUSIONS: These efficacy and safety results support GP MDI 18 µg BID as the most appropriate dose for evaluation in Phase III trials in patients with moderate-to-severe COPD. TRIAL REGISTRATION: ClinicalTrials.gov NCT01566773 . Registered 27 March 2012.

Efficacy and safety of twice-daily glycopyrrolate in patients with stable, symptomatic COPD with moderate-to-severe airflow limitation: the GEM1 study.

BACKGROUND: The purpose of this study was to confirm the efficacy and safety of twice-daily glycopyrrolate 15.6 µg, a long-acting muscarinic antagonist, in patients with stable, symptomatic, chronic obstructive pulmonary disease (COPD) with moderate-to-severe airflow limitation. METHODS: The GEM1 study was a 12-week, multicenter, double-blind, parallel-group, placebo-controlled study that randomized patients with stable, symptomatic COPD with moderate-to-severe airflow limitation to twice-daily glycopyrrolate 15.6 µg or placebo (1:1) via the Neohaler(®) device. The primary objective was to demonstrate superiority of glycopyrrolate versus placebo in terms of forced expiratory volume in 1 second area under the curve between 0 and 12 hours post morning dose at week 12. Other outcomes included additional spirometric end points, transition dyspnea index, St George's Respiratory Questionnaire, COPD Assessment Test, rescue medication use, and symptoms reported by patients via electronic diary. Safety was also assessed during the study. RESULTS: Of the 441 patients randomized (glycopyrrolate, n=222; placebo, n=219), 96% of patients completed the planned treatment phase. Glycopyrrolate demonstrated statistically significant (P<0.001) improvements in lung function versus placebo. Glycopyrrolate showed statistically significant improvement in the transition dyspnea index focal score, St George's Respiratory Questionnaire total score, COPD Assessment Test score, rescue medication use, and daily total symptom score versus placebo at week 12. Safety was comparable between the treatment groups. CONCLUSION: Significant improvement in lung function, dyspnea, COPD symptoms, health status, and rescue medication use suggests that glycopyrrolate is a safe and effective treatment option as maintenance bronchodilator in patients with stable, symptomatic COPD with moderate-to-severe airflow limitation.

Once-daily indacaterol 75 µg in moderate- to-severe COPD: results of a Phase IV study assessing time until patients' perceived onset of effect.

BACKGROUND: Indacaterol 75 µg once daily is a long-acting ß2 agonist approved for maintenance bronchodilator treatment in patients with chronic obstructive pulmonary disease (COPD). The purpose of this study was to evaluate patients' perception of onset of effect with a single dose. METHODS: In this double-blind, crossover, Phase IV study, 40 patients were randomized to receive a single dose of indacaterol 75 µg or placebo via a dry powder inhaler device. The primary variable was time until patient's perception of onset of effect, using a simple self-administered (nonvalidated) questionnaire that patients answered at nine protocol-specified time points. Exploratory variables included change in forced expiratory volume in 1 second (FEV1) and change in percent predicted FEV1 from predose to postdose (determined 60-75 minutes postdose). RESULTS: The least-squares mean time to patient's perception of onset of effect was 25.4 minutes and 23.9 minutes for indacaterol and placebo, respectively. There was no significant effect for treatment, period, or sequence on the time to patient's perception. In addition, no statistically significant differences between treatments were observed for patient's global satisfaction with onset of effect and global expectation of treatment adherence. For the exploratory variable change in FEV1 from predose to postdose, indacaterol showed superiority over placebo with a clinically relevant least-squares mean treatment difference of 0.12 L (P<0.0001). There was little or no association between patient's perception of time to onset of effect and change in FEV1, or change in percent predicted FEV1. Both treatments were well tolerated. CONCLUSION: A single dose of indacaterol 75 µg did not separate from placebo in terms of patient perception of onset, although there was an improvement in FEV1 for indacaterol compared with placebo. Development and use of a validated questionnaire may be needed to address the inconsistency in evaluating this patient-related outcome.

Safety and tolerability of inhaled loxapine in subjects with asthma and chronic obstructive pulmonary disease--two randomized controlled trials.

BACKGROUND: Loxapine, a first-generation antipsychotic, delivered with a novel inhalation delivery device developed for the acute treatment of agitation in patients with schizophrenia or bipolar disorder was evaluated in subjects with asthma or chronic obstructive pulmonary disease (COPD). METHODS: Separate randomized, double-blind, parallel-arm, placebo-controlled trials compared two administrations of inhaled loxapine (10 mg) 10 hr apart with placebo in 52 subjects with asthma and in 53 subjects with COPD. A thermally-generated drug aerosol of loxapine was delivered to the deep lung for rapid systemic absorption. Controller medications were continued throughout the study, but quick-relief bronchodilators were withheld from 6-8 hr before through 34 hr after dose 1, unless indicated as rescue. RESULTS: All airway adverse events (AEs) were of mild or moderate severity. Symptomatic bronchospasm occurred in 53.8% of subjects with asthma after inhaled loxapine and 11.5% after placebo; and in 19.2% of COPD subjects after inhaled loxapine and 11.1% after placebo. Subjects required inhaled albuterol as follows: asthma: 53.8% after inhaled loxapine and 11.5% after placebo; and COPD: 23.1% after inhaled loxapine and 14.8% after placebo. Respiratory signs/symptoms requiring treatment responded to rescue bronchodilator [forced expiratory volume in 1 sec (FEV(1)) return to within 10% of baseline] within 1 hr in 11 of 15 events in asthma subjects and four of seven events in COPD subjects, the remainder by the last spirometry. CONCLUSIONS: In subjects with either asthma or COPD, FEV(1) decline and bronchospasm can occur following inhaled loxapine, but more frequently in asthmatic subjects. Most subjects with bronchospasm responded to rescue bronchodilator within 1 hr. No treatment-related serious AE occurred. Although inhaled loxapine is contraindicated in patients with active airways disease per the current approved US labeling, these studies demonstrated that rescue bronchodilator mitigated the symptomatic bronchospasms that may occur in case of inadvertent use.

Faster onset of action of formoterol versus salmeterol in patients with chronic obstructive pulmonary disease: a multicenter, randomized study.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a growing public health problem that has increased in recent years. It similarly affects men and women, especially those who smoke. The goals of COPD pharmacotherapy are to improve lung function, reduce symptoms, prevent exacerbations, and improve patients' health status. Bronchodilators are the foundation of treatment for COPD, and the long-acting beta2-agonists formoterol and salmeterol are both indicated for regular use by patients with stable COPD. OBJECTIVE: A clinical study was conducted to compare the onset of bronchodilator effects following treatment with formoterol 12 microg administered twice-daily (BID) or salmeterol 50 microg BID. The trial also assessed whether the bronchodilator effects of treatment resulted in significant differences in clinical response. METHODS: This was a randomized, multicenter, open-label, parallel-group study of formoterol 12 microg BID versus salmeterol 50 microg BID, both administered for 28 days. Patients were current or previous smokers aged>or=40 years, with a diagnosis of stable COPD. The primary efficacy variable was change from baseline in forced expiratory volume in 1 s (FEV1) 5 min after drug administration on day 28. Secondary efficacy variables included changes from baseline in the 6-min walk test (6MWT) and rescue medication use. The primary variable was assessed by analysis of covariance, with baseline FEV1 as the covariate. RESULTS: A total of 270 patients were randomized to formoterol 12 microg BID (n=137) or salmeterol 50 microg BID (n=133). In the intent-to-treat population the least square (LS) mean change from baseline in FEV1 at 5 min postdose on day 28 was 0.13 L in the formoterol group compared with 0.07 L in the salmeterol group (P=0.022). At 30 min postdose on day 28, the LS mean change from baseline in FEV1 was 0.17 L in the formoterol group compared with 0.07 L in the salmeterol group (P<0.001). Similar changes were reported at 60 min postdose (0.19 L for the formoterol group versus 0.13 L for the salmeterol group, P=0.069). Patients in the formoterol group walked longer distances in the 6MWT and used less rescue medication compared with patients in the salmeterol group, although the differences were not statistically significant. CONCLUSIONS: Significantly greater improvements from baseline in FEV1 were observed at 5 and 30 min postdose with formoterol 12 microg compared with salmeterol 50 microg after 28 days of treatment. Numeric improvements in the 6MWT and rescue medication use were also observed with formoterol.