Older patients with chronic obstructive pulmonary disease (COPD) may be at increased risk of adverse events (AEs) due to decreased protective organ function and increased comorbidities. TONADO® 1 + 2 were replicate, randomized, double-blind, parallel-group, 52-week, Phase III trials comparing the efficacy and safety of tiotropium/olodaterol (5/5 µg) versus the monocomponents via the Respimat® inhaler in patients with moderate-to-very-severe COPD. In this prespecified safety analysis, patients were grouped by age. Of 3100 patients, 1585 (51.1%) were aged <65 years, 1198 (38.7%) 65–<75 years, 309 (10.0%) 75–<85 years, and eight (0.3%) ≥85 years. At baseline, 23.4% had a pre-existing cardiac disorder, 45.6% had hypertension, and 13.3% had glucose metabolism disorders, including diagnosed diabetes. Overall, there was no increase in major adverse cardiac events, other AEs, or serious AEs with tiotropium/olodaterol versus the monocomponents in any age group, supporting the safety of tiotropium/olodaterol in older patients with COPD.

Chronic obstructive pulmonary disease is associated with significant morbidity and mortality. Trials of maintenance chronic obstructive pulmonary disease treatments focus on improvement in lung function and reductions in exacerbations, while patients are much more concerned about symptoms and health status. Our aim was to investigate the effects of tiotropium + olodaterol on patient-reported health outcomes, breathlessness and night-time rescue medication use in patients with chronic obstructive pulmonary disease, compared to placebo, tiotropium or olodaterol monotherapy. Two pairs of replicate, phase III studies of 12 (OTEMTO 1 + 2) and 52 weeks’ (TONADO 1 + 2) duration were evaluated, in which patients received either tiotropium + olodaterol 2.5/5 or 5/5 μg, tiotropium 2.5 or 5 μg, olodaterol 5 μg or placebo, all delivered once daily via Respimat inhaler. Patient-reported outcomes included breathlessness assessed by transition dyspnoea index focal score, health status assessed by St George’s Respiratory Questionnaire total score and night-time rescue medication use at 12 or 24 weeks. Outcomes from the pooled study data are reported. Overall, 1621 and 5162 patients were treated in the OTEMTO and TONADO trials, respectively. Significantly larger improvements in St George’s Respiratory Questionnaire and transition dyspnoea index focal scores were observed and a greater proportion of patients were responders to therapy (based on minimum clinically important differences in St George’s Respiratory Questionnaire and transition dyspnoea index) with tiotropium + olodaterol compared to either monotherapy or to placebo. Tiotropium + olodaterol 5/5 µg significantly reduced night-time rescue medication usage.

Background Increasing age is associated with poor prognosis in patients with COPD. Objective This analysis from the replicate Phase III OTEMTO® and TONADO® studies examined the efficacy and safety of tiotropium, a long-acting anticholinergic, combined with olodaterol, a long-acting β2-agonist, compared to monotherapies and placebo in patients with COPD aged 40 years to <65 years, 65 years to <75 years, 75 years to <85 years, and ≥85 years. Methods In these double-blind, parallel-group, active-controlled, multicenter, randomized studies, patients received tiotropium + olodaterol 2.5/5 μg or 5/5 μg, tiotropium 5 μg or 2.5 μg (TONADO only), olodaterol 5 μg (TONADO only), or placebo (OTEMTO only). This analysis used the approved doses of tiotropium + olodaterol 5/5 μg, tiotropium 5 μg, and olodaterol 5 μg. Primary end points at 12 weeks (OTEMTO) or 24 weeks (TONADO) included St George’s Respiratory Questionnaire (SGRQ) total score, forced expiratory volume in 1 second (FEV1) area under the curve from 0 hour to 3 hours (AUC0–3) response, and trough FEV1 response. Results A total of 1,621 patients were randomized (40 years to <65 years, n=749; 65 years to <75 years, n=674; 75 years to <85 years, n=186; ≥85 years, n=12) in OTEMTO and 5,162 patients (40 years to <65 years, n=2,654; 65 years to <75 years, n=1,967; 75 to <85 years, n=528; ≥85 years, n=13) in TONADO. FEV1 AUC0–3 and trough FEV1 responses improved with tiotropium + olodaterol 5/5 μg at 12 weeks and 24 weeks compared to monotherapies or placebo for all age groups. SGRQ scores generally improved with tiotropium + olodaterol 5/5 μg after 12 weeks in OTEMTO and improved after 24 weeks in all age groups in TONADO. In all age groups receiving tiotropium + olodaterol 5/5 μg compared to monotherapies or placebo, transition dyspnea index scores generally improved, while rescue medication usage improved. Conclusion No differences were noted in relative responses to treatment or safety when using tiotropium + olodaterol 5/5 μg compared to monotherapies or placebo across all age groups.

SESSION TITLE: Emerging Therapies in COPD SESSION TYPE: Original Investigation Slide PRESENTED ON: Tuesday, October 27, 2015 at 02:45 PM - 04:15 PM PURPOSE: To determine whether the response to tiotropium (T) + olodaterol (O) in patients (pts) with COPD differs across age groups. METHODS: Two sets of randomized, double-blind, parallel-group studies (52-week TONADO 1 & 2 [NCT01431274; NCT01431287] and 12-week OTEMTO 1 & 2 [NCT01964352; NCT02006732]) investigated the efficacy of T+O 2.5/5 μg or 5/5 μg once daily (QD) compared to T 2.5 or 5 μg QD, O 5 μg, or placebo, via Respimat®, in pts with moderate to very severe (only TONADO) COPD. Key end points were forced expiratory volume in 1 s (FEV1), area under the curve from 0-3 h post-dose (AUC0-3), and trough FEV1. This analysis evaluates the response to T+O in pts <65, 65-<75, 75-<85, and ≥85 years (y) old. RESULTS: 5162 pts were treated in the TONADO studies (2654 aged <65 y, 1967 aged 65-<75 y, 528 aged 75-<85 y, and 13 aged ≥85 y), and 1621 were treated in OTEMTO 1 & 2 (365 and 384 aged <65 y, 343 and 331 aged 65-<75 y, 99 and 87 aged 75-<85 y, and 5 and 7 aged ≥85 y, respectively). T+O 5/5 μg improved FEV1 AUC0-3 compared to monocomponents across all age groups after 24 weeks in TONADO 1 & 2. Treatment differences in adjusted mean FEV1 AUC0-3 responses for T+O 5/5 μg versus T 5 μg or O 5 μg (combined analysis of both studies) were 0.120 L and 0.151 L in pts aged <65 y, 0.104 L and 0.096 L in pts aged 65-<75 y, and 0.085 L and 0.126 L in pts aged 75-<85 y, respectively (all comparisons p<0.0001). In OTEMTO 1 & 2, treatment differences in adjusted mean FEV1 AUC0-3 responses for T+O versus T 5 μg or placebo after 12 weeks were 0.116 L (p=0.0003), 0.376 L (p<0.0001) and 0.094 L (p=0.004), 0.322 L (p<0.0001) in pts aged <65 y; 0.120 L, 0.292 L and 0.120 L, 0.303 L (all p<0.0001) in pts aged 65-<75 y; and 0.085 L (p=0.18), 0.301 (p<0.0001) and 0.092 L (p=0.21), 0.174 L (p=0.24) in pts aged 75-<85 y, respectively. T+O 5/5 μg generally improved trough FEV1 response compared to monocomponents or placebo across age groups in both sets of studies; there was a trend towards smaller improvement in pts aged 75-<85 y. T+O 2.5/5 μg gave similar results in both sets of studies. CONCLUSIONS: T+O showed generally greater improvements in lung function compared to monocomponents or placebo across all age groups, consistent between studies. CLINICAL IMPLICATIONS: Data from these studies demonstrate lung-function responses with T+O across age groups, including elderly pts with COPD. Funding: Boehringer Ingelheim. Editorial assistance: Complete HealthVizion. DISCLOSURE: Gary Ferguson: Grant monies (from industry related sources): Boehringer Ingelheim, Novartis, Pearl Therapeutics, AstraZeneca, Sunovian, Forest/Almirall, Consultant fee, speaker bureau, advisory committee, etc.: Boehringer Ingelheim, Novartis, Sunovian, AstraZeneca, Pearl Therapeutics, Fiduciary position (of any organization, association, society, etc, other than ACCP: GlaxoSmithKline Emmanuelle Clerisme-Beaty: Employee: Boehringer Ingelheim Lars Groenke: Employee: Boehringer Ingelheim Florian Voss: Employee: Boehringer Ingelheim Jill Karpel: Grant monies (from industry related sources): Boehringer Ingelheim Tiotripium+Olodaterol 5/5ug has been submitted to European and US regulatory authorities; currently awaiting approval decision

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: This post-hoc analysis examined the impact of roflumilast on chronic obstructive pulmonary disease (COPD) exacerbations and lung function in patients with COPD who received concomitant long-acting beta(2)-agonists (LABA) with or without prior inhaled corticosteroid (ICS) and the influence of various demographic and clinical characteristics on these outcomes.Methods: Data were pooled from 2 double-blind, placebo-controlled, 52-week studies of once-daily roflumilast 500 mu g in patients with COPD. Endpoints were mean rate of exacerbations and change from baseline in pre- and postbronchodilator FEV1.Results: In this pooled analysis (N = 3091), addition of roflumilast to LABAs for 1 year in patients who discontinued ICS prior to study entry (n = 945) significantly reduced the risk of COPD exacerbations vs. placebo by 19.2% (p < 0.05) and significantly improved pre- and postbronchodilator FEV1 by 40 mL and 34 mL, respectively (both, p < 0.01). Similar improvements were observed in patients who received concomitant LABAs but were not taking ICS prior to study entry (n = 597). A significant reduction in COPD exacerbation risk with roflumilast vs. placebo was observed regardless of age or smoking status, and in patients who had severe or very severe COPD. Significantly improved lung function was observed with roflumilast in all the subgroups (p < 0.05), with the exception of patients with moderate COPD.Conclusions: Roflumilast reduced exacerbation rates and improved lung function in patients with COPD who received concomitant LABA, regardless of. prior ICS use, and across various patient subgroups regardless of age and smoking status.ClinicalTrials.gov registration numbers: NCT00297102 (M2-124) and NCT00297115 (M2-125). (C) 2013 Published by Elsevier Ltd.

Background: To determine the safety and efficacy of BEA2180, an anticholinergic agent in patients with chronic obstructive pulmonary disease (COPD).Methods: Smokers or ex-smokers >= 40 years with COPD and a postbronchodilator forced expiratory volume in 1 s (FEV1) <80% predicted and FEV1/forced vital capacity <= 70% participated in this multinational, randomised, double-blind, parallel study. Patients received BEA2180 (50, 100 or 200 mu g), tiotropium (5 mu g) or placebo once daily via Respimat (R) Soft Mist (TM). The primary endpoint was trough FEV1 after 24 weeks. Secondary endpoints included Transition Dyspnoea Index (TDI) focal score, St. George's Respiratory Questionnaire (SGRQ) total score, exacerbations and adverse events.Results: Patients (n = 2080, 64.5% male) had a mean age of 64.2 years and a baseline FEV1 of 1.2 L. Trough FEV1 at 24 weeks with all BEA2180 doses (0.044-0.087 L) and tiotropium 5 mu g (0.092 L) was significantly higher (p < 0.0001) than placebo (-0.034 L) and BEA2180 (200 mu g) was noninferior to tiotropium. Mean TDI focal scores were higher with BEA2180 (1.43-1.48) or tiotropium (1.46) versus placebo (0.94; p <= 0.01 for all). Mean SGRQ total scores also improved with BEA2180 (40.1-40.7) or tiotropium (39.5) compared with placebo (43.0, p < 0.01 for all). COPD exacerbation rates were reduced for all active treatments, reaching statistical significance for BEA2180 (50 and 200 mu g) (p < 0.05, for both).Conclusion: All study doses of BEA2180 improved lung function, reduced symptoms and exacerbations, and improved health status in COPD; all treatments were well tolerated. (c) 2013 Elsevier Ltd. All rights reserved.

SESSION TYPE: COPD: Safety and Effectiveness of Newer Therapies

Ciclesonide is a nonhalogenated synthetic inhaled corticosteroid (ICS) that has been approved by the US Food and Drug Administration for the treatment of all severities of persistent asthma. It is available as a hydrofluroalkane pressurized metered-dose inhaler in two strengths, 80 mcg/activation and 160 mcg/activation, with the recommenced dosage being two inhalations twice-daily. It is a prodrug that is converted in the lung to its active form, which possesses 100-fold greater glucocorticoid-receptor-binding affinity than the parent compound. Its relative receptor affinity is similar to budesonide. In clinical studies, ciclesonide was effective in improving pulmonary function, reducing asthma symptoms, and reducing or eliminating the need for oral corticosteroids (OCSs). Patients with severe asthma dependent on OCSs and high doses of ICSs were able to achieve greater asthma control and reduce or even eliminate the use of OCSs when switched to ciclesonide. In comparison with fluticasone propionate and budesonide, ciclesonide was demonstrated to be at least as effective in maintaining pulmonary function and asthma control. In clinical trials, ciclesonide was well tolerated, with the majority of adverse events considered mild or moderate in intensity. It had low systemic bioavailability and no clinically significant hypothalamic-pituitary-adrenal axis suppression at therapeutic doses. Its safety profile establishes ciclesonide as an important addition to the currently available ICSs.

PURPOSE: Exacerbations of COPD result in worsening lung function and mortality. In the roflumilast pivotal trials, moderate or severe exacerbations were assessed by medical intervention (moderate=oral/parenteral corticosteroid use; severe=hospitalization/death). However, assessments of exacerbations across studies can be affected by the different definitions used. In this post hoc analysis, we examined primary outcome measure exacerbation events from the two roflumilast pivotal trials using two alternative exacerbation definitions based either on symptoms or rescue medication use.

BACKGROUND:Asthma guidelines advocate maintaining asthma control while minimizing corticosteroid exposure. OBJECTIVE:To assess the reduction in corticosteroid burden during long-term treatment and the corresponding impact of this reduction on asthma control, lung function, and inflammation in patients with moderate to severe allergic asthma. METHODS:We conducted a pooled analysis (N = 1,071) of 2 similarly designed, randomized, double-blind, placebo-controlled omalizumab trials and their extension phases. Each study included a 16-week steroid-stable phase, a 12-week steroid-reduction phase, and a 24-week extension phase. Patients received subcutaneous omalizumab (minimum, 0.016 mg/kg/IU (IgE/mL) every 4 weeks) or placebo every 2 or 4 weeks. Outcomes included change from baseline in inhaled corticosteroid dose, number of oral corticosteroid bursts, and other clinical measures, including asthma exacerbations and change in asthma quality-of-life score (questionnaire), lung function, and eosinophil count. RESULTS:The median reduction from baseline in inhaled corticosteroid dose (beclomethasone dipropionate equivalent dose) by the completion of the extension phase was greater for the omalizumab group than for the placebo group (-420.0 vs -252.0 μg/d; P < .001). During that time, omalizumab-treated patients required fewer oral corticosteroid bursts overall for treatment of acute exacerbations (mean, 0.2 vs 0.3; relative risk, 0.56; 95% confidence interval, 0.41 to 0.76; P < .001) and demonstrated greater improvements in measures of asthma control. CONCLUSION:The addition of omalizumab to baseline therapy in patients 12 years or older with moderate to severe persistent allergic asthma resulted in a durable reduction in the overall steroid burden and improvement in other clinical measures of asthma control.

Background: Inhaled corticosteroids and long-acting beta-agonists (LABAs) are recommended for treating moderate to severe persistent asthma. The Food and Drug Administration has issued a black box warning (BBW) for LABAs.Objective: To investigate physician knowledge of the BBW and its effect on the practice of specialists (pulmonologists and allergists) and primary care physicians (PCPs) (internists and family physicians).Methods: A total of 1,107 physicians responded to a questionnaire to determine their awareness of the BBW and whether it changed their practice.Results: The group comprised 429 pulmonologists (38.8%), 395 allergists (35.7%), 141 internists (12.7%), 132 family physicians (11.9%), and 10 pediatricians (0.9%). Comparing specialists with PCPs, there was approximately a 10% difference in the rate of knowledge concerning the BBW (99.0% vs 90.8%, P < .001). Approximately a quarter of specialists agreed with the BBW compared with 52.9% of family physicians and 40.3% of internists. Twice as many PCPs vs specialists agreed with the warning (45.6% vs 24.2%, P < .001). The PCPs were more likely to alter their prescribing habits than were specialists (40.1% vs 34.6%, P < .005). Specialists were more likely to discuss the warning with patients than were PCPs (87.4% vs 64.8%, P < .001). For mild persistent asthma, most respondents chose inhaled corticosteroids as the preferred first-line therapy, but 11.4% of PCPs and 2.1% of specialists identified LABA monotherapy as their first choice. For moderate to severe asthma, the pattern of response was similar.Conclusion: Although most physicians were aware of the BBW for LABAs, there was a difference in how specialists and PCPs approached it and altered their prescribing habits. Am? Allergy Asthma Immunol. 2009; 103:304-310.

Results from two clinical trials of mometasone furoate administered via a dry powder inhaler (MF-DPI) were reviewed to evaluate the consistency of effects of MF-DPI administered once-daily in the evening (QD PM) or twice-daily (BID) on health-related quality of life (HRQOL) in adults with persistent asthma previously treated with inhaled corticosteroids. HRQOL data were collected from two 12-week, randomized, double-blind trials: in study 1 (n = 268), patients received MF-DPI 400 g QD PM (1 inhalation), MF-DPI 200 g BID, or placebo; in study 2 (n = 400), patients received MF-DPI 200 g QD PM, MF-DPI 400 g QD PM (1 inhalation), MF-DPI 200 g BID, MF-DPI 400 g QD PM (2 inhalations of 200 g), or placebo. In both studies, HRQOL was assessed using the Medical Outcomes Survey 36-item Short Form (SF-36) and an asthma-specific module. MF-DPI was associated with consistent, statistically significant improvements in asthma-specific total scores, breathlessness, asthma concerns, and physical symptoms compared with placebo in both trials (p 0.05 vs. placebo). MF-DPI improved SF-36 Physical Component Summary scores at all doses except 200 g QD PM. In conclusion, the results from two placebo-controlled trials suggest that MF-DPI 400 g/d, administered once or twice-daily, produces consistent, statistically, and clinically significant improvement in HRQOL measures in patients with persistent asthma.

Many patients with chronic obstructive pulmonary disease (COPD) are treated with twice daily (BID) inhaled corticosteroids (ICS). This study evaluated whether daily PM mometasone furoate administered via a dry powder inhaler (MF-DPI) was equally effective compared to twice daily dosing. In a 52-week, randomized, double-blind, placebo-controlled study, 911 subjects with moderate-to-severe COPD managed without ICS received MF-DPI 800 μg QD PM, MF-DPI 400 μg BID, or placebo. The change from baseline in postbronchodilator forced expiratory volume in 1 second (FEV 1 ), total COPD symptom scores, and health status as well as the percentage of subjects with a COPD exacerbation were assessed. Adverse events were recorded. Mometasone furoate administered via a dry powder inhaler 800 μg QD PM and 400 μg BID significantly increased postbronchodilator FEV 1 from baseline (50 mL and 53 mL, respectively, versus a 19 mL decrease for placebo; P < 0.001). The percentage of subjects exacerbating was significantly lower in the pooled MF-DPI groups than in the placebo group ( P = 0.043). Subjects receiving MF-DPI 400 μg BID reported a statistically significant (19%) reduction in COPD symptom scores compared with placebo ( P < 0.001). Health status as measured with St. George's Respiratory Questionnaire (SGRQ) improved significantly in all domains (Total, Activity, Impacts, and Symptoms) in the pooled MF-DPI groups versus placebo ( P ≤ 0.031). MF-DPI treatment was well tolerated. Once-daily MF-DPI improved lung function and health status in subjects with moderate-to-severe COPD and was comparable to BID MF-DPI.

PURPOSE: To evaluate documentation of compliance with national asthma guidelines in two different clinical environments and correlate documentation of compliance with asthma control.

Background: The potential of anticholinergics to provide bronchodilatory benefits over short-acting beta(2)-agonists (SABA) alone in patients with moderate-to-severe persistent asthma has not been well defined.Methods: An outpatient, randomized, double-blind, single-dose, crossover study in adult asthmatics with moderate-to-severe obstruction despite treatment with inhaled corticosteroids (ICS) was conducted comparing the fixed combination of ipratropium and albuterol (IB + ALB) to albuterol alone (ALB). Serial spirometry was performed over 6 h. SABA were withheld for 8 h, ICS and LABA for 24 h.Results: A total of 113 patients were randomized, 106 completed the study (males n = 47; mean +/- SD age = 51 +/- 13 years). Mean +/- SD baseline FEV1 = 1.4 +/- 0.5 L (49 +/- 12% predicted). IB + ALB resulted in significantly greater improvements over ALB in the average improvement over baseline in FEV1 as approximated from the area under the curve from 0 to 6 h after drug administration (72 ml, p<0.01) and mean peak FEV1 response (55 ml, p<0.01) as well as higher FEV1 responses at individual time points from 0.5 to 6 h postdose (p<0.01 for all). Time to onset of response was similar between groups but time to peak and duration of response were longer with IB + ALB versus ALB (120 versus 60 min and 245 versus 106 min, respectively).Conclusion: IB + ALB resulted in significantly greater improvement in FEV1 and longer duration of response compared to ALB alone in patients with moderate-to-severe persistent asthma (Trial number: 1012.50; ClinicalTrial.gov NCT00096616). (C) 2008 Elsevier Ltd. All rights reserved.