Effect of Bronchodilation, Exercise Training, and Behavior Modification on Symptoms and Physical Activity in Chronic Obstructive Pulmonary Disease.

RATIONALE: Bronchodilation and exercise training (ExT) improve exercise tolerance in patients with chronic obstructive pulmonary disease (COPD); however, behavior modification is required to impact daily physical activity (PA). OBJECTIVES: To assess whether tiotropium/olodaterol, with or without ExT, would improve exercise endurance time (EET) and PA compared with placebo in patients participating in a self-management behavior-modification (SMBM) program. METHODS: This was a 12-week, randomized, partially double-blind, placebo-controlled, parallel-group trial in patients with COPD (PHYSACTO; NCT02085161). All patients were enrolled into SMBM and randomized 1:1:1:1 to once-daily placebo, tiotropium 5 µg, tiotropium/olodaterol 5/5 µg, or tiotropium/olodaterol 5/5 µg plus 8 weeks ExT. EET, measured by endurance shuttle walk test after 8 weeks, was the primary endpoint. Additional endpoints assessed downstream effects on PA (measured via accelerometry), and activity-related dyspnea and difficulty (using validated patient-reported questionnaires). MEASUREMENTS AND MAIN RESULTS: SMBM plus tiotropium/olodaterol, with or without ExT, significantly improved EET at Week 8 versus SMBM plus placebo (treatment ratio vs. placebo: with ExT, 1.46; 95% confidence interval, 1.20-1.78; P = 0.0002; without ExT, 1.29; 95% confidence interval, 1.06-1.57; P = 0.0109). No significant increases in steps per day from baseline were observed over SMBM plus placebo at Week 12 (increase of 1,098) when other therapies were added. Adding tiotropium/olodaterol, with or without ExT, to SMBM reduced activity-related dyspnea versus placebo, whereas adding tiotropium/olodaterol plus ExT reduced activity-related difficulty. CONCLUSIONS: Tiotropium/olodaterol, with or without ExT, improved EET in patients with COPD taking part in an SMBM program. Combination bronchodilation, with or without ExT, did not provide additional increases in objective PA compared with SMBM alone but did reduce PA-related dyspnea and difficulty. Clinical trial registered with www.clinicaltrials.gov (NCT02085161).

Enhancing exercise tolerance and physical activity in COPD with combined pharmacological and non-pharmacological interventions: PHYSACTO randomised, placebo-controlled study design.

INTRODUCTION: Chronic obstructive pulmonary disease (COPD) is associated with exercise limitation and physical inactivity, which are believed to have significant long-term negative health consequences for patients. While a number of COPD treatments and exercise training programmes increase exercise capacity, there is limited evidence for their effects on physical activity levels, with no clear association between exercise capacity and physical activity in clinical trials. Physical activity depends on a number of behaviour, environmental and physiological factors. We describe the design of the PHYSACTO trial, which is investigating the effects of bronchodilators, either alone or with exercise training, in combination with a standardised behaviour-change self-management programme, on exercise capacity and physical activity in patients with COPD. It is hypothesised that bronchodilators in conjunction with a behaviour-change self-management programme will improve physical activity and that this effect will be amplified by the addition of exercise training. METHODS AND ANALYSIS: Patients are being recruited from 34 sites in Australia, New Zealand, the USA, Canada and Europe. Patients receiving a multicomponent intervention designed to support behaviour change related to physical activity are randomised to four treatment arms: placebo, tiotropium, tiotropium+olodaterol, and tiotropium+olodaterol+exercise training. The primary outcome is improvement in exercise capacity after 8 weeks, measured by endurance time during a shuttle walk test. The secondary outcome is improvement in physical activity, including objective accelerometer assessment and patient-reported functioning using the Functional Performance Inventory-Short Form and the novel hybrid PROactive instrument. Additionally, the influence of moderating variables (ie, factors influencing a patient's choice to be physically active) on increases in physical activity is also explored. ETHICS AND DISSEMINATION: The study has been approved by the relevant Institutional Review Boards, Independent Ethics Committee and Competent Authority according to national and international regulations. The findings of the trial will be disseminated through relevant peer-reviewed journals and international conference presentations. TRIAL REGISTRATION NUMBER: NCT02085161.

Efficacy of Tiotropium + Olodaterol in Patients with Chronic Obstructive Pulmonary Disease by Initial Disease Severity and Treatment Intensity: A Post Hoc Analysis.

INTRODUCTION: The once-daily long-acting muscarinic antagonist (LAMA) tiotropium and once-daily long-acting ß2-agonist (LABA) olodaterol have been studied as a once-daily fixed-dose combination (FDC) in patients with chronic obstructive pulmonary disease (COPD). Two large, 52-week, double-blind, parallel-group studies in patients with moderate-very severe COPD demonstrated that tiotropium + olodaterol significantly improved lung function and symptoms versus the monocomponents. This post hoc analysis determined effects on lung function by prior LAMA or LABA maintenance treatment and initial disease severity. METHODS: 5162 patients were randomized and treated with olodaterol 5 µg, tiotropium 2.5 µg, tiotropium 5 µg, tiotropium + olodaterol 2.5/5 µg, or tiotropium + olodaterol 5/5 µg (all once daily via Respimat(®) inhaler). Primary efficacy (lung-function) end points were forced expiratory volume in 1 s (FEV1) area under the curve from 0 to 3 h (AUC0-3) and trough FEV1 responses (i.e., change from baseline). Pooled data are presented for the following subgroups: prior maintenance treatment with LAMA or LABA, Global initiative for chronic Obstructive Lung Disease (GOLD) 2 (predicted FEV1 50% to <80%) and 3 (30% to <50%)/4 (<30%), sex, age, and prior use of inhaled corticosteroids. RESULTS: Tiotropium + olodaterol FDC improved lung function over the monocomponents in patients with GOLD 2 and 3-4 disease, irrespective of prior LAMA or LABA maintenance therapy; most comparisons between FDCs and their respective monocomponents were statistically significant (P < 0.05). FEV1 AUC0-3 and trough FEV1 responses for the individual treatments were generally greater in patients with less severe COPD at baseline. CONCLUSIONS: Tiotropium + olodaterol 5/5 µg significantly improved FEV1 AUC0-3 and trough FEV1 in all GOLD severity groups compared to olodaterol 5 µg and tiotropium 5 µg alone, irrespective of whether patients had received prior LAMA or LABA maintenance treatment. Improvements from baseline in lung function were generally greater in patients with less severe disease. FUNDING: Boehringer Ingelheim. TRIAL REGISTRATION: ClinicalTrials.gov numbers, NCT01431274 and NCT01431287.

A randomised, placebo-controlled, Phase II, dose-ranging trial of once-daily treatment with olodaterol, a novel long-acting ß2-agonist, for 4 weeks in patients with chronic obstructive pulmonary disease.

BACKGROUND: Olodaterol is a novel long-acting ß2-agonist (LABA) with ≥24-h duration of action in preclinical and clinical studies. OBJECTIVE: This Phase II, multicentre, randomised, double-blind, placebo-controlled, parallel-group, dose-finding study evaluated four doses of once-daily olodaterol over 4 weeks in patients with chronic obstructive pulmonary disease (COPD), based on efficacy, safety and pharmacokinetic parameters. METHODS: Patients received olodaterol inhalation solution or placebo via Respimat® Soft Mist™ inhaler once daily for 4 weeks. Pulmonary function testing was performed pre-dose (trough) and up to 3 or 6 h post-dose, depending on visit. Primary end point was change from baseline in trough forced expiratory volume in 1 s (FEV1) after 4 weeks' treatment. Secondary end points included change from baseline in peak FEV1 and FEV1 area under the curve from 0 to 6 h. RESULTS: 405 patients with COPD were randomised and assigned to treatment. Mean baseline post-bronchodilator FEV1 was 1.50 L (54% predicted). All olodaterol doses provided statistically significant increases in trough FEV1 compared to placebo (2 µg: 0.061 L [p = 0.0233]; 5 µg: 0.097 L [p = 0.0003]; 10 µg: 0.123 L [p < 0.0001]; 20 µg: 0.132 L [p < 0.0001]). A clear dose-response relationship was demonstrated regarding pulmonary function; the two highest olodaterol doses (10 and 20 µg) formed the plateau of the dose-response curve. All olodaterol doses were well tolerated, with no dose-dependent safety effects. CONCLUSION: Once-daily olodaterol demonstrated 24-h bronchodilator efficacy, confirming its potential as a once-daily LABA for the management of COPD. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00452400.

A randomised, double-blind, four-way, crossover trial comparing the 24-h FEV1 profile for once-daily versus twice-daily treatment with olodaterol, a novel long-acting ß2-agonist, in patients with chronic obstructive pulmonary disease.

BACKGROUND: This randomised, double-blind, four-way, crossover, Phase II study compared the 24-h forced expiratory volume in 1 s (FEV1) profile of alternative dosing frequencies of two total daily doses of olodaterol (5 and 10 µg) in patients with chronic obstructive pulmonary disease (COPD). METHODS: Patients received olodaterol 2 µg twice daily (BID), 5 µg BID, 5 µg once daily (QD) and 10 µg QD in a randomised sequence over 3-week treatment periods. Co-primary end points were FEV1 area under the curve from 0 to 12 h (AUC0-12) and area under the curve from 12 to 24 h (AUC12-24) responses. Additional lung-function responses, pharmacokinetics and safety were assessed. RESULTS: 47 patients were treated. All olodaterol doses provided significant increases in FEV1 versus baseline (p < 0.001) and FEV1 time profiles were nearly identical for olodaterol 5 and 10 µg QD. Olodaterol 5 µg QD demonstrated improved FEV1 AUC0-12 and similar AUC12-24 versus 2 µg BID. Olodaterol 5 µg QD showed slightly increased FEV1 AUC0-12 but lower AUC12-24 compared to 5 µg BID. Bronchodilation over 24 h was similar for olodaterol 5 µg QD and BID. All doses were well tolerated. CONCLUSIONS: Olodaterol 5 µg QD is efficacious in COPD, with a superior bronchodilatory profile compared to 2 µg BID, which is close to the same total daily dose, and a similar degree of bronchodilation over 24 h compared with double the daily dose (administered as 10 µg QD or 5 µg BID). TRIAL REGISTRATION: ClinicalTrials.gov: NCT00846768.

One-Year Safety of Olodaterol Once Daily via Respimat® in Patients with GOLD 2-4 Chronic Obstructive Pulmonary Disease: Results of a Pre-Specified Pooled Analysis.

The novel long-acting ß2-agonist olodaterol demonstrated an acceptable safety profile in short-term phase II clinical studies. This analysis of four randomized, double-blind, placebo-controlled, parallel-group, phase III studies (1222.11, NCT00782210; 1222.12, NCT00782509; 1222.13, NCT00793624; 1222.14, NCT00796653) evaluated the long-term safety of olodaterol once daily (QD) in a large cohort of patients with moderate to very severe (Global initiative for chronic Obstructive Lung Disease 2-4) chronic obstructive pulmonary disease (COPD). The studies compared olodaterol (5 or 10 µg) QD via Respimat®, formoterol 12 µg twice daily (BID) via Aerolizer® (1222.13 and 1222.14), and placebo for 48 weeks. Patients continued receiving background maintenance therapy, with ∼60% receiving concomitant cardiovascular therapy and 25% having a history of concomitant cardiac disease. Pre-specified analyses of pooled data assessed the adverse events (AEs) and serious AEs in the whole population, and in subgroups with cardiac disease, along with in-depth electrocardiogram and Holter monitoring. In total, 3104 patients were included in the safety analysis: 876 received olodaterol 5 µg, 883 received olodaterol 10 µg, 885 received placebos, and 460 received formoterol 12 µg BID. Overall incidence of on-treatment AEs (71.2%), serious AEs (16.1%), and deaths (1.7%) were balanced across treatment groups. Respiratory and cardiovascular AEs, including major adverse cardiac events, were reported at similar frequencies in placebo and active treatment groups. The safety profiles of both olodaterol 5 µg (marketed and registered dose) and 10 µg QD delivered via Respimat® are comparable to placebo and formoterol BID in this population, with no safety signals identified.

Tiotropium and olodaterol fixed-dose combination versus mono-components in COPD (GOLD 2-4).

Efficacy and safety of tiotropium+olodaterol fixed-dose combination (FDC) compared with the mono-components was evaluated in patients with moderate to very severe chronic obstructive pulmonary disease (COPD) in two replicate, randomised, double-blind, parallel-group, multicentre, phase III trials. Patients received tiotropium+olodaterol FDC 2.5/5 µg or 5/5 µg, tiotropium 2.5 µg or 5 µg, or olodaterol 5 µg delivered once-daily via Respimat inhaler over 52 weeks. Primary end points were forced expiratory volume in 1 s (FEV1) area under the curve from 0 to 3 h (AUC0-3) response, trough FEV1 response and St George's Respiratory Questionnaire (SGRQ) total score at 24 weeks. In total, 5162 patients (2624 in Study 1237.5 and 2538 in Study 1237.6) received treatment. Both FDCs significantly improved FEV1 AUC0-3 and trough FEV1 response versus the mono-components in both studies. Statistically significant improvements in SGRQ total score versus the mono-components were only seen for tiotropium+olodaterol FDC 5/5 µg. Incidence of adverse events was comparable between the FDCs and the mono-components. These studies demonstrated significant improvements in lung function and health-related quality of life with once-daily tiotropium+olodaterol FDC versus mono-components over 1 year in patients with moderate to very severe COPD.

The 24-h FEV1 time profile of olodaterol once daily via Respimat® and formoterol twice daily via Aerolizer® in patients with GOLD 2-4 COPD: results from two 6-week crossover studies.

ABSTRACT: These studies evaluated the 24-h forced expiratory volume in 1 sec (FEV1) profile of once-daily (QD) olodaterol compared to placebo and twice-daily (BID) formoterol in patients with moderate to very severe chronic obstructive pulmonary disease. In two replicate, randomized, double-blind, double-dummy, four-way crossover studies, patients received olodaterol 5 and 10 µg QD, formoterol 12 µg BID, or placebo for 6 weeks in addition to usual-care background maintenance therapy. Co-primary end points were FEV1 area under the curve from 0-12 h (AUC0-12) response (change from baseline) and FEV1 AUC from 12-24 h (AUC12-24) response after 6 weeks, with FEV1 AUC from 0-24 h response identified as a key secondary end point. Other secondary end points included FEV1 AUC from 0-3 h and trough FEV1 responses, as well as corresponding forced vital capacity responses. With both olodaterol doses, FEV1 increased to near-maximal 30 min post-morning dose, which was sustained over 24 h. FEV1 also increased within 30 min post-morning dose of formoterol and was sustained over 12 h; the second formoterol dose resulted in a further increase, sustained for an additional 12 h. FEV1 AUC0-12 and AUC12-24 responses with both QD olodaterol doses and BID formoterol were significantly greater than placebo at 6 weeks (P < .0001). Secondary end-point outcomes were consistent with those of the co-primary end points. These data, together with those from the wider phase III clinical program, provide evidence for the 24-h bronchodilator efficacy of olodaterol QD in this patient population. TRIAL REGISTRY: ClinicalTrials.gov; NCT00931385 and NCT00932646.

Lung function efficacy and symptomatic benefit of olodaterol once daily delivered via Respimat® versus placebo and formoterol twice daily in patients with GOLD 2-4 COPD: results from two replicate 48-week studies.

Two replicate, multicenter, randomized, double-blind, placebo-controlled, parallel-group, Phase III studies investigated the long-term efficacy and safety of once-daily olodaterol via Respimat® versus placebo and formoterol over 48 weeks in patients with moderate to very severe chronic obstructive pulmonary disease receiving usual-care background therapy. Patients received once-daily olodaterol 5 or 10 µg, twice-daily formoterol 12 µg, or placebo. Co-primary end points were forced expiratory volume in 1 second (FEV1) area under the curve from 0-3 hours response, FEV1 trough response, and Mahler transition dyspnea index total score after 24 weeks; secondary end points included St George's Respiratory Questionnaire. Overall, 904 (Study 1222.13) and 934 (Study 1222.14) patients received treatment. Olodaterol significantly improved FEV1 area under the curve from 0-3 hours versus placebo in both studies (with olodaterol 5 µg, 0.151 L and 0.129 L; with olodaterol 10 µg, 0.165 L and 0.154 L; for all comparisons P<0.0001) and FEV1 trough responses versus placebo (0.053-0.085 L; P<0.01), as did formoterol. Primary analysis revealed no significant difference in transition dyspnea index focal score for any active treatment versus placebo. Post hoc analysis using pattern mixture modeling (accounting for discontinuations) demonstrated statistical significance for olodaterol versus placebo. St George's Respiratory Questionnaire total score was significantly improved with olodaterol, but not formoterol, versus placebo. No safety signals were identified from adverse-event or other safety data. Once-daily olodaterol 5 µg and 10 µg is efficacious in patients with moderate to very severe chronic obstructive pulmonary disease on usual-care maintenance therapy, with a satisfactory safety profile.

Efficacy and safety of olodaterol once daily delivered via Respimat® in patients with GOLD 2-4 COPD: results from two replicate 48-week studies.

BACKGROUND: Olodaterol is a long-acting ß2-agonist with a 24-hour bronchodilator profile. Two replicate, randomized, double-blind, placebo-controlled, parallel-group, Phase III trials were performed as part of a comprehensive clinical program to investigate the long-term safety and efficacy of olodaterol in patients with moderate to very severe chronic obstructive pulmonary disease (COPD) receiving usual-care background therapy. METHODS: Patients received olodaterol 5 µg or 10 µg or placebo once daily for 48 weeks. Coprimary end points were forced expiratory volume in 1 second (FEV1) area under the curve from 0 to 3 hours (AUC0-3) response (change from baseline), and trough FEV1 response at 12 weeks. Secondary end points included additional lung function assessments, use of rescue medications, FEV1 AUC response from 0 to 12 hours, and Patient Global Rating over 48 weeks. RESULTS: Overall, 624 and 642 patients were evaluated in studies 1222.11 and 1222.12, respectively. In both studies, olodaterol 5 µg and 10 µg significantly improved the FEV1 AUC0-3 response (P<0.0001) and trough FEV1 (study 1222.11, P<0.0001; study 1222.12, P<0.05, post hoc) at week 12, with an incidence of adverse events comparable with that of placebo. Secondary end points supported the efficacy of olodaterol. CONCLUSION: These studies demonstrate the long-term efficacy and safety of once-daily olodaterol 5 µg and 10 µg in patients with moderate to very severe COPD continuing with usual-care maintenance therapy.

Prolonged bronchoprotection against inhaled methacholine by inhaled BI 1744, a long-acting beta(2)-agonist, in patients with mild asthma.

BACKGROUND: Long-acting ss(2)-agonists are an established controller medication in asthma. BI 1744 is a novel L\long-acting ss(2)-agonist with a preclinical profile that suggests 24-hour bronchodilation and bronchoprotection may be achieved. OBJECTIVE: To examine the bronchoprotective effects of single doses of BI 1744 against methacholine provocation in subjects with mild asthma. METHODS: Thirty-one subjects with mild asthma were randomized to receive single doses of BI 1744 (2, 5, 10, 20 microg) or placebo on separate days according to a double-blind, 5-way crossover design. Methacholine challenges were performed at 30 minutes and at 4, 8, 24, and 32 hours after each single dose of medication, and the results were expressed as PC(20) FEV(1). RESULTS: All doses of BI 1744 produced statistically significant increases in the methacholine PC(20) compared with placebo as long as 32 hours. The mean (geometric SEM) methacholine PC(20) 24 hours after dosing with placebo was 1.73 (1.13) mg/mL, which increased after 2 microg to 3.86 (1.14) mg/mL, after 5 microg to 5.67 (1.14) mg/mL, after 10 microg to 9.42 (1.13) mg/mL, and after 20 microg to 13.71 (1.14) mg/mL (all P < .0001). After 32 hours, the methacholine PC(20) value remained significantly increased for all doses. No safety or tolerability concerns were identified. CONCLUSION: BI 1744 provides significant bronchoprotection against inhaled methacholine for up to 32 hours after single-dose administration.