The high incidence of error reports received by the US Food and Drug Administration (FDA) involving 2-component vaccines led to collaboration between the United States Pharmacopeia (USP) and the Institute for Safe Medication Practices (ISMP). This collaborating group sought to further understand errors associated with all 2-component vaccines (i.e. vaccine components provided by the manufacturer in physically separate containers) and to provide safe practice strategies for storing, preparing, dispensing, and administering these vaccines as intended. Fourteen available 2-component vaccines were identified. The ISMP National Vaccine Errors Reporting Program (VERP) and the FDA Vaccine Adverse Event Reporting System (VAERS) were searched from the initiation of each respective reporting system through December 31, 2019. The three vaccines with the most reported reconstitution errors in the VERP and VAERS are Menveo® (meningococcal), Pentacel® (DTaP, Polio, Haemophilus influenzae type b), and ActHIB® [H. influenzae type b (Hib)]. Manufacturers should design labeling and packaging of vaccines to provide ease of storage and fail-safe preparation to prevent 2-component vaccine errors. Implementing risk reduction strategies, such as training healthcare professionals and affixing storage bin labels, remind healthcare professionals to mix the 2-components and facilitate appropriate administration.

Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality. Early detection and appropriate treatment and management of COPD can lower morbidity and perhaps mortality. Clinicians in the primary care setting provide the majority of COPD care and are pivotal in the diagnosis and management of COPD. In this review, we provide an overview of the Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2020 report, with a focus on the management of COPD in the primary care setting. We discuss the pathophysiology of COPD; describe COPD risk factors, signs, and symptoms that may facilitate earlier diagnosis of COPD; and reinforce the importance of spirometry use in establishing the diagnosis of COPD. Disease monitoring, as well as a review of the 2020 GOLD treatment recommendations, is also discussed. Patients and families are important partners in COPD management; therefore, we outline simple steps that may assist them in caring for those affected by COPD. Finally, we discuss nonpharmacological treatment options for COPD, COPD monitoring tools that may aid in the evaluation of disease progression and response to therapy, and the importance of developing a COPD action plan on an individualized basis.

BACKGROUND: Data are limited on the differential response to long-acting bronchodilators in older versus younger adults with asthma. OBJECTIVE: To determine whether the response to tiotropium Respimat differed in older versus younger patients with asthma. METHODS: Post hoc analyses of 4 randomized, double-blind, placebo-controlled studies in adults with asthma were carried out. Two studies compared tiotropium Respimat 5 mg once daily with placebo, both added to high-dose inhaled corticosteroid (ICS) plus long-acting b2-agonist (ie, severe asthma). The other 2 evaluated tiotropium Respimat 2.5 or 5 mg once daily, salmeterol 50 mg twice daily, or placebo, all added to medium-dose ICS (moderate asthma). Data were analyzed in 2 pools: (1) severe and (2) moderate asthma. Efficacy end points: trough and peak FEV1; trough forced vital capacity; Asthma Control Questionnaire total score and responder percentage, all at week 24. One set of analyses was performed with age as a continuous covariate; the second was conducted in categories less than 40, 40 to 60, and more than 60 years, with treatment-by-age subgroup interaction P values obtained. Safety was analyzed in age categories. RESULTS: Across the age categories, treatment-by-age subgroup interaction P values for trough FEV1 were.13 and.77 for patients with severe and moderate asthma, respectively, not indicating significant impact of age on overall treatment effect, with this observation replicated in the 2 continuum analyses. The other end points (including safety) were also not impacted by age. CONCLUSIONS: Once-daily tiotropium Respimat add-on to ICS or ICS/long-acting b2-agonist therapy was effective and well tolerated in patients with asthma independent of age. (C) 2020 The Authors. Published by Elsevier Inc. on behalf of the American Academy of Allergy, Asthma & Immunology

The use of office spirometry was recommended by the National Lung Health Education Program (NLHEP) consensus conference in 1999 for detection and management of COPD. Since that time, spirometry utilization has increased, but its role in the diagnosis of COPD is still evolving. This update reviews the role of spirometry for screening and case finding in COPD as well as for asthma. Spirometry has been used for disease management in patients with airway obstruction, with varying results. The diagnostic criteria for COPD using spirometry have also evolved in the past 17 years, with differences arising between the Global Initiative for Chronic Obstructive Lung Disease and NLHEP recommendations. More sophisticated spirometers as well as new reference equations are widely available. Standardization guidelines from the American Thoracic Society/European Respiratory Society published in 2005 provide a robust framework for performing and interpreting spirometry, but clinicians still need hands-on training and meaningful feedback to perform high-quality spirometry in the office setting.

To resolve knowledge gaps and further understand asthma in older adults, we assessed the efficacy and safety of once-daily tiotropium Respimat® (tioR) add-on to at least inhaled corticosteroid (ICS) maintenance therapy in patients aged < 65 and ≥65 years with symptomatic asthma.

Acute respiratory compromise describes a deterioration in respiratory function with a high likelihood of rapid progression to respiratory failure and death. Identifying patients at risk for respiratory compromise coupled with monitoring of patients who have developed respiratory compromise might allow earlier interventions to prevent or mitigate further decompensation. The National Association for the Medical Direction of Respiratory Care (NAMDRC) organized a workshop meeting with representation from many national societies to address the unmet needs of respiratory compromise from a clinical practice perspective. Respiratory compromise may arise de novo or may complicate preexisting lung disease. The group identified distinct subsets of respiratory compromise that present similar opportunities for early detection and useful intervention to prevent respiratory failure. The subtypes were characterized by the pathophysiological mechanisms they had in common: impaired control of breathing, impaired airway protection, parenchymal lung disease, increased airway resistance, hydrostatic pulmonary edema, and right-ventricular failure. Classification of acutely ill respiratory patients into one or more of these categories may help in selecting the screening and monitoring strategies that are most appropriate for the patient's particular pathophysiology. Standardized screening and monitoring practices for patients with similar mechanisms of deterioration may enhance the ability to predict respiratory failure early and prevent its occurrence.

Once-daily tiotropium Respimat®, a long-acting anticholinergic bronchodilator, has been shown in a Phase III program to improve lung function and reduce severe exacerbation risk in severe asthma patients who remain symptomatic despite using ICS+LABA. Use of pre-trial leukotriene receptor antagonists (LTRAs) was not restricted; we analyzed whether pre-screening LTRA use affected tiotropium Respimat® efficacy. In two Phase III, replicate, randomized, double-blind, placebo-controlled, parallel-group trials (NCT00772538/NCT00776984), symptomatic patients received high-dose ICS+LABA and once-daily tiotropium Respimat® 5 μg or placebo. LTRAs were permitted during run-in and treatment. Co-primary endpoints were peak and trough FEV1 response (difference from baseline) at 24 weeks. Subgroups were defined by pre-screening LTRA use: "Yes"/"No". Of 912 randomized patients, 205 reported pre-screening LTRA use, 200 reported use during the treatment period, and 187 had efficacy data at week 24. Baseline characteristics were comparable between groups. Mean BMI in LTRA "Yes"/"No" groups: 27.8 kg/m2 and 28.3 kg/m2, respectively. Mean % predicted FEV1 at baseline: 56% in both groups. Lung function responses improved independent of LTRA use: peak FEV1 was 99±50 mL (p=0.049) in the LTRA "Yes" group, and 113±28 mL (p<0.001) in the LTRA "No" group (peak FEV1 improvements independent of concomitant LTRA use [interaction p-value=0.6742]). Trough FEV1 (difference from placebo) was 90±46 mL (p=0.052) in the LTRA "Yes" group and 93±25 mL (p<0.001) in the LTRA "No" group (trough FEV1 improvements independent of concomitant LTRA use [interaction p-value=0.5218]). Once-daily tiotropium Respimat® added to ICS+LABA improves lung function in patients with severe symptomatic asthma, independent of initial LTRA use.

Background: Long-term corticosteroid use may increase cataract risk. The Lens Opacities Classification System (LOCS) III ranked lens opacities as Class 1: 0.5-0.9 unit; Class 2: 1.0 -1.4 units; or Class 3: >= 1.5 units in clinical trials of combined mometasone furoate and formoterol (MF/F) administered by metered-dose inhaler (MDI). We examined retrospectively shifts in lenticular opacity in patients with chronic obstructive pulmonary disease (COPD) or asthma.Methods: We analyzed pooled LOCS III data from two COPD studies and separately analyzed LOCS III data from an asthma study. COPD subjects were randomized to twice daily MF/F 200/10 mu g, MF/F 400/10 mu g, MF 400 mu g, F 10 mu g, and placebo; asthma subjects were randomized to MF/F 200/10 mu g, MF/F 400/10 mu g, fluticasone propionate/salmeterol (FP/S) 250/50 mu g, and FP/S 500/50 mu g. Lenticular opacity changes were analyzed post hoc for proportions of subjects with LOCS III grade increases >= 0.5, >= 1.0, or >= 1.5 units at weeks 26 and 52.Results: Proportions of subjects in the COPD studies with Class 1 (>= 0.5 unit), 2 (>= 1.0 unit), or 3 (>= 1.5 units) increases in LOCS III at week 26 (N = 1675) ranged from 15.5 to 18.6%, 3.3-6.0%, and 0.9-2.2%, respectively. At week 52 (N = 1085), proportions of active-treated subjects with Class 1, 2, or 3 increases in LOCS III ranged from 26.6 to 28.9%, 6.3-10.7%, and 2.6 -5.9%, respectively. Treatment differences in lenticular shifts were generally small and nonsignificant in the asthma study.Conclusion: No clinically relevant trends were observed in the LOCS III assessment of lenticular shifts during treatment of COPD and asthma patients, although further study may be needed to confirm the findings presented here. In these trials, MF/F effects on lens opacity were not observed. (Clinicaltrials.gov numbers: NCT00383435, NCT00383721, and NCT00379288.) (C) 2014 Elsevier Ltd. All rights reserved.

SESSION TITLE: Tiotropium and Asthma

Rationale: The purpose of this study was to investigate the clinical efficacy and safety of a fixed-dose combination of mometasone furoate/formoterol fumarate (MF/F) administered via a metered-dose inhaler in subjects with moderate-to-very severe chronic obstructive pulmonary disease (COPD).Methods: This multicenter, double-blind, placebo-controlled trial had a 26-week treatment period and a 26-week safety extension. Subjects (n = 1196), at least 40 years old, were current or ex-smokers randomized to twice-daily inhaled MF/F 400/10 mu g, MF/F 200/10 mu g, MF 400 mu g, F 10 mu g, or placebo. The trial's co-primary endpoints were mean changes from baseline, as area under the curve (AUC), in forced expiratory volume (FEV1) over 0-12 hours (AUC(0-12 h) FEV1) with MF/F versus MF, and in morning (AM) pre-dose (trough) FEV1 with MF/F versus F after 13 weeks of treatment. Key secondary endpoints were the effects of MF/F on respiratory health status using the Saint George's Respiratory Questionnaire (SGRQ), symptom-free nights, partly stable COPD at 26 weeks, and time to first COPD exacerbation.Results: The largest improvements in AUC(0-12 h) FEV1 were observed with MF/F 400/10 mu g and MF/F 200/10 mu g. Serial spirometry results demonstrated that bronchodilator effects with MF/F occurred rapidly (within 5 minutes), persisted for 12 hours after dosing, and were sustained over the 26-week treatment period. Similar findings were observed for AM pre-dose FEV1, for which effects were further investigated, excluding subjects whose AM FEV1 data were incorrectly collected after 2 days from the last dose of study treatment. Improvements in SGRQ scores surpassed the minimum clinically important difference of more than four units with both MF/F treatments. At 26 weeks, no notable between-treatment differences in the occurrence and nature of adverse events (AEs) were reported. No unexpected AEs were observed. Overall, 90 subjects reported AEs considered to be treatment-related, the most common of which were lenticular opacities, dysphonia, and oral candidiasis.Discussion: In conclusion, MF/F treatments improved lung function and respiratory health status, reduced exacerbations, and were well tolerated in subjects with moderate-to-very severe COPD.

Past asthma surveys have shown suboptimal management and control of asthma in the United States. No major survey of asthma management has been conducted since the Third Expert Panel Report for the National Asthma Education and Prevention Program (NAEPP) guidelines on diagnosis and treatment of asthma (August 2007). This study was designed to report asthma management and control results from the Asthma Insight and Management survey of U.S. patients and physicians. A telephone-based survey was conducted during 2009 in 2500 patients with asthma, aged >= 12 years, and 309 physicians (104 allergists, 54 pulmonologists, 101 family practitioners, and 50 internists). Patients' asthma control perceptions (71% "completely controlled" or "well controlled") were inconsistent with their NAEPP control level as determined by self-reported symptoms (29% well controlled). Patients and physicians had low expectations for effective asthma management; patients considered asthma well managed if rescue medication was used three times per week (46%), urgent care visits occurred twice per year (67%), or emergency department visits occurred once per year (60%). Asthma-related syncope, seizure, intensive care unit admission, and intubation were associated with uncontrolled asthma based on NAEPP guidelines. Respiratory specialists (allergists/pulmonologists) implemented asthma management recommendations more than other physicians surveyed. However, only 22% of patients visited a specialist for usual asthma care and 48% had never visited a specialist. Despite detailed NAEPP guidance, asthma management and control in U.S. patients is unsatisfactory. Improved asthma control assessment (impairment and risk) and implementation of NAEPP management recommendations are needed to improve asthma control and outcomes. (Allergy Asthma Proc 33:54-64, 2012; doi: 10.2500/aap.2011.32.3518)

RationaleWe report findings from a phase 3 trial evaluating the effects of mometasone furoate/formoterol (MF/F), administered via metered-dose inhaler, on pulmonary function in moderate-very severe COPD.MethodsThis 26-wk, multicenter, randomized, double-blind, placebo (PBO)-controlled trial evaluated MF/F 400/10μg twice daily (BID) and 200/10μg BID in current/ex-smokers (≥10 pack-y) ages ≥40y with moderate−very severe COPD (mean baseline [BL] % predicted FEV1, 38.7%). Subjects received BID treatment with MF/F 400/10μg, MF/F 200/10μg, MF 400μg, F 10μg, or PBO. Lung function was analyzed for mean changes from BL in FEV1 over 0−12hrs (AUC0−12 FEV1) and pre-dose AM FEV1 at endpoint (EP) after 13wks or 26wks of treatment.Results1193 subjects received treatment. At 13wks, changes from BL in AUC0−12 FEV1 with MF/F 400/10μg, MF/F 200/10μg, MF 400μg, F 10μg, PBO were 179mL,*†‡ 139mL,*† 53mL, 92mL,* 18mL, respectively (*P≤.004 vs PBO; †P≤.001 vs MF 400μg ‡P≤.001 vs F 10μg). At 26wks, changes from BL in AUC0−12 FEV1 with MF/F 400/10μg, MF/F 200/10μg, MF 400μg, F 10μg, PBO were 152mL,*† 120mL,*‡ 33mL, 63mL,§ 8mL, respectively (*P<.001 vs PBO; †P≤.001 vs MF 400μg, F 10μg; ‡P≤.027 vs MF 400μg, F 10μg; §P=.038 vs PBO). At 26wks, changes from BL in pre-dose AM FEV1 with MF/F 400/10μg, MF/F 200/10μg, MF 400μg, F 10μg, PBO were 92mL,*† 69mL,* 27mL, 10mL, 3mL (*P≤.030 vs PBO, F 10μg; †P=.017 vs MF 400μg). No unexpected AEs were observed; MF/F was generally well tolerated.ConclusionsMF/F treatments significantly improved lung function and were well tolerated in subjects with moderate to very severe COPD. RationaleWe report findings from a phase 3 trial evaluating the effects of mometasone furoate/formoterol (MF/F), administered via metered-dose inhaler, on pulmonary function in moderate-very severe COPD. We report findings from a phase 3 trial evaluating the effects of mometasone furoate/formoterol (MF/F), administered via metered-dose inhaler, on pulmonary function in moderate-very severe COPD. MethodsThis 26-wk, multicenter, randomized, double-blind, placebo (PBO)-controlled trial evaluated MF/F 400/10μg twice daily (BID) and 200/10μg BID in current/ex-smokers (≥10 pack-y) ages ≥40y with moderate−very severe COPD (mean baseline [BL] % predicted FEV1, 38.7%). Subjects received BID treatment with MF/F 400/10μg, MF/F 200/10μg, MF 400μg, F 10μg, or PBO. Lung function was analyzed for mean changes from BL in FEV1 over 0−12hrs (AUC0−12 FEV1) and pre-dose AM FEV1 at endpoint (EP) after 13wks or 26wks of treatment. This 26-wk, multicenter, randomized, double-blind, placebo (PBO)-controlled trial evaluated MF/F 400/10μg twice daily (BID) and 200/10μg BID in current/ex-smokers (≥10 pack-y) ages ≥40y with moderate−very severe COPD (mean baseline [BL] % predicted FEV1, 38.7%). Subjects received BID treatment with MF/F 400/10μg, MF/F 200/10μg, MF 400μg, F 10μg, or PBO. Lung function was analyzed for mean changes from BL in FEV1 over 0−12hrs (AUC0−12 FEV1) and pre-dose AM FEV1 at endpoint (EP) after 13wks or 26wks of treatment. Results1193 subjects received treatment. At 13wks, changes from BL in AUC0−12 FEV1 with MF/F 400/10μg, MF/F 200/10μg, MF 400μg, F 10μg, PBO were 179mL,*†‡ 139mL,*† 53mL, 92mL,* 18mL, respectively (*P≤.004 vs PBO; †P≤.001 vs MF 400μg ‡P≤.001 vs F 10μg). At 26wks, changes from BL in AUC0−12 FEV1 with MF/F 400/10μg, MF/F 200/10μg, MF 400μg, F 10μg, PBO were 152mL,*† 120mL,*‡ 33mL, 63mL,§ 8mL, respectively (*P<.001 vs PBO; †P≤.001 vs MF 400μg, F 10μg; ‡P≤.027 vs MF 400μg, F 10μg; §P=.038 vs PBO). At 26wks, changes from BL in pre-dose AM FEV1 with MF/F 400/10μg, MF/F 200/10μg, MF 400μg, F 10μg, PBO were 92mL,*† 69mL,* 27mL, 10mL, 3mL (*P≤.030 vs PBO, F 10μg; †P=.017 vs MF 400μg). No unexpected AEs were observed; MF/F was generally well tolerated. 1193 subjects received treatment. At 13wks, changes from BL in AUC0−12 FEV1 with MF/F 400/10μg, MF/F 200/10μg, MF 400μg, F 10μg, PBO were 179mL,*†‡ 139mL,*† 53mL, 92mL,* 18mL, respectively (*P≤.004 vs PBO; †P≤.001 vs MF 400μg ‡P≤.001 vs F 10μg). At 26wks, changes from BL in AUC0−12 FEV1 with MF/F 400/10μg, MF/F 200/10μg, MF 400μg, F 10μg, PBO were 152mL,*† 120mL,*‡ 33mL, 63mL,§ 8mL, respectively (*P<.001 vs PBO; †P≤.001 vs MF 400μg, F 10μg; ‡P≤.027 vs MF 400μg, F 10μg; §P=.038 vs PBO). At 26wks, changes from BL in pre-dose AM FEV1 with MF/F 400/10μg, MF/F 200/10μg, MF 400μg, F 10μg, PBO were 92mL,*† 69mL,* 27mL, 10mL, 3mL (*P≤.030 vs PBO, F 10μg; †P=.017 vs MF 400μg). No unexpected AEs were observed; MF/F was generally well tolerated. ConclusionsMF/F treatments significantly improved lung function and were well tolerated in subjects with moderate to very severe COPD. MF/F treatments significantly improved lung function and were well tolerated in subjects with moderate to very severe COPD.

Long-term achievement of asthma control is dependent in part on the use of mutually understandable asthma terminology in all verbal and written patient-physician communications. Using data from the Asthma Insight and Management (AIM) survey, the objective of this analysis is to provide a contemporary depiction of asthma deterioration terminology as used by current asthma patients and physicians in the United States. As part of the 2009 AIM survey, current asthma patients (≥12 years of age; weighted n = 2499) and physicians (n = 309) were queried about their recognition, understanding, and/or use of the terms "asthma attack," "asthma flare-up," and "asthma exacerbation" in telephone interviews. Nearly all patients had heard the term "asthma attack" (97%), but relatively few had heard the term "asthma exacerbation" (24%); 71% had heard "asthma flare-up." In contrast, physicians reported using the term "asthma attack" least (65%) and the term "asthma exacerbation" most (77%) when discussing asthma with their patients; 70% reported using "asthma flare-up." Among patients familiar with "asthma flare-up" and "asthma exacerbation" (n = 502), only 38% said that the terms mean the same thing; nearly all physicians (94%) said that the terms mean the same thing. Collectively, data from the AIM survey suggest that patients and physicians use different asthma deterioration terminology and, more importantly, that they do not necessarily understand each other's terms. Standardizing asthma deterioration terminology may help optimize asthma patient-physician communication to improve patient understanding of written asthma action plans and therefore, enhance patient outcomes.

Significant changes in asthma treatment guidelines and therapies occurred between the period of time in which the Asthma in America (AIA) and Asthma Insight and Management (AIM) surveys were conducted: 1998 and 2009, respectively. This study compares asthma burden and management in 1998 and 2009. Both surveys were telephone based and conducted across the United States. The AIA survey included 2509 patients with asthma (aged <1 year to 89 years old), 512 physicians, and 1000 adults from the general population. The AIM survey included 2500 patients (aged ≥12 years), 309 physicians, and 1090 adults from the general population. Patient responses were weighted to match the entire population of U.S. patients with asthma. The impact of asthma burden and care on the general population and on asthma patients was slightly lower or unchanged in the AIM survey versus the AIA survey. Acute care use (hospitalizations, emergency department visits, or other urgent care visits) was common in AIA (36%) and AIM (34%) surveys. Most physicians were aware of guidelines in AIA (90%) and AIM (96%), but fewer "always" followed them (AIA, 36%; AIM, 28%). Spirometry was often used to aid in diagnosis by asthma care specialists (AIA, 73%; AIM, 76%) but infrequently by nonsubspecialists (AIA, 27%; AIM, 38%). Most physicians prescribed inhaled corticosteroids (ICSs) for mild (AIA, 70%; AIM, 83%) or moderate (AIA, 89%; AIM, 83%) persistent asthma. In the AIM survey, 38% of specialists prescribed ICSs combined with a long-acting β2-agonist for moderate asthma. The state of U.S. asthma care and clinical outcomes changed little from 1998 to 2009.

Background: A clinical trial of mometasone furoate/formoterol fumarate (MF/F) administered via a metered-dose inhaler in subjects with moderate to very severe chronic obstructive pulmonary disease (COPD) investigated the efficacy and safety of a fixed-dose combination of MF/F.Methods: This multicenter, double-blind, placebo-controlled trial had a 26-week treatment period and a 26-week safety extension. Subjects (n = 1055; >= 40 years) were current or ex-smokers randomized to twice-daily treatment with inhaled MF/F 400/10 mu g, MF/F 200/10 mu g, MF 400 mu g, F 10 mu g, or placebo. The coprimary endpoints of the trial were mean changes from baseline in forced expiratory volume in 1 second (FEV1) over 0-12 hours (AUC(0-12) FEV1) with MF/F versus MF, and in morning predose FEV1 with MF/F versus F. Key secondary endpoints were quality of life (Saint George's Respiratory Questionnaire [SGRQ]), symptom-free nights, and partly stable COPD at 26 weeks, as well as time to first COPD exacerbation.Results: Significant improvements in FEV1 AUC(0-12) occurred at endpoint with MF/F 400/10 and MF/F 200/10 versus MF 400 (P <= 0.007). Significant bronchodilation occurred in 5 minutes with MF/F, and serial spirometry demonstrated sustained FEV1 improvements with MF/F over the treatment period. Significant improvements in morning predose FEV1 occurred with both MF/F doses, and these effects were further investigated by excluding results for subjects whose morning FEV1 data were collected >2 days after the last dose of study treatment. Improvements in SGRQ total scores surpassed the minimum clinically important difference of at least 4 units with MF/F 400/10. MF/F 400/10 significantly reduced the time-to-first COPD exacerbation. Similar proportions of subjects in all five treatment groups reported treatment-emergent adverse events. Rates of pneumonia were low (<= 1.0%) across treatment groups.Conclusion: MF/F 400/10 mu g twice daily was shown to be an effective therapy for patients with moderate to very severe COPD, and both MF/F 400/10 mu g twice daily and MF/F 200/10 mu g twice daily were well tolerated.

Background: The clinical efficacy and safety of a mometasone furoate/formoterol fumarate (MF/F) fixed-dose combination formulation administered via a metered-dose inhaler was investigated in patients with moderate to very severe chronic obstructive pulmonary disease (COPD).Methods: Two 52-week, multicenter, double-blind, placebo-controlled trials with identical study designs were conducted in current or ex-smokers (aged >= 40 years), and pooled study results are presented herein. Subjects (n = 2251) were randomized to 26 weeks of twice-daily treatment with MF/F 400/10 mu g, MF/F 200/10 mu g, MF 400 mu g, F 10 mu g, or placebo. After the 26-week treatment period, placebo subjects completed the trial and 75% of subjects on active treatment entered a 26-week safety extension. Coprimary efficacy variables were mean changes in forced expiratory volume in one second (FEV1), area under the curve from 0 to 12 hours postdose (AUC(0-12 h)), and morning predose/trough FEV1 from baseline to the week 13 endpoint. Key secondary efficacy variables were St George's Respiratory Questionnaire scores, symptom-free nights, time-to-first exacerbation, and partly stable COPD at the week 26 endpoint.Results: In the 26-week treatment period, significantly greater increases in FEV1 AUC(0-12 h) occurred with MF/F 400/10 versus MF 400 and placebo at the week 13 and week 26 endpoints (P <= 0.032). These increases were over three-fold greater with MF/F 400/10 than with MF 400. Also, significantly greater increases in morning predose/trough FEV1 occurred with MF/F 400/10 versus F 10 and placebo at the week 13 endpoint (P < 0.05). The increase was four-fold greater with MF/F 400/10 than with F 10. All active treatment groups achieved minimum clinically important differences from baseline (>4 units) in St George's Respiratory Questionnaire scores at week 26. Symptom-free nights increased by >= 14% in the MF/F 400/10, MF 400, and F 10 groups (P <= 0.033 versus placebo). The incidence of exacerbations was lower in the MF/F groups (<= 33.3%) than it was in the MF, formoterol, and placebo groups (>= 33.8%) over the 26-week treatment period. The incidence of adverse events was similar in the active-treated and placebo-treated subjects across 26 weeks of treatment. Over the 1-year study period, there were no notable differences in the incidence or types of adverse events between the MF/F 400/10 and MF/F 200/10 groups compared with the MF or formoterol groups. Differences in rates of individual treatment-emergent adverse events were <3% between treatment groups. Rates of pneumonia were low (<= 2%) across all treatment groups.Conclusion: Patients treated with MF/F demonstrated significant improvements in lung function, health status, and exacerbation rates. Although significant improvements were seen with both doses, a trend showing a dose-response effect was observed in the lung function measurements.