Lars Grönke

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 Georges 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. Lung function/symptomatic benefits of daily tiotropium+olodaterol fixed-dose combination in moderate-very severe COPD http://ow.ly/DIKiY

The 24-h lung-function profile of once-daily tiotropium and olodaterol fixed-dose combination in chronic obstructive pulmonary disease

BACKGROUND This study investigated the effects on 24-h lung function and lung volume of a once-daily fixed-dose combination (FDC) of the long-acting muscarinic antagonist tiotropium and the long-acting β2-agonist olodaterol in patients with chronic obstructive pulmonary disease. METHODS This was a randomised, double-blind, placebo-controlled, Phase III trial with an incomplete crossover design. Patients received four of the following six treatment options for 6 weeks each: placebo, olodaterol 5 μg, tiotropium 2.5 μg, tiotropium 5 μg, tiotropium + olodaterol FDC 2.5/5 μg and tiotropium + olodaterol FDC 5/5 μg, all delivered via the Respimat(®) inhaler. The primary end point was forced expiratory volume in 1 s (FEV1) area under the curve from 0 to 24 h (AUC0-24) response after 6 weeks of treatment; key secondary end points were FEV1 AUC from 0 to 12 h and AUC from 12 to 24 h, and further end points included lung-volume parameters measured using body plethysmography (subset of patients), measures of peak and trough FEV1, and incidence of adverse events. RESULTS A significant improvement in FEV1 AUC0-24 response was observed with tiotropium + olodaterol 5/5 μg and 2.5/5 μg versus placebo and monotherapies after 6 weeks of treatment; mean response with tiotropium + olodaterol 5/5 μg versus placebo was 0.280 L (p < 0.0001). Differences to monotherapies with tiotropium + olodaterol 5/5 μg were 0.115 L versus olodaterol 5 μg, 0.127 L versus tiotropium 2.5 μg and 0.110 L versus tiotropium 5 μg (p < 0.0001 for all comparisons). Secondary end points supported these data. No safety concerns were identified. CONCLUSIONS Overall, this study demonstrated improvements in lung function over 24 h with an FDC of tiotropium + olodaterol over tiotropium or olodaterol alone, with no observed difference in tolerability. ClinicalTrials.gov number: NCT01559116.

The lung function profile of once-daily tiotropium and olodaterol via Respimat(®) is superior to that of twice-daily salmeterol and fluticasone propionate via Accuhaler(®) (ENERGITO(®) study).

Background Tiotropium + olodaterol has demonstrated improvements beyond lung function benefits in a large Phase III clinical program as a once-daily maintenance treatment for COPD and may be a potential option for the initiation of maintenance treatment in COPD. Despite guideline recommendations that combined long-acting β2-agonists and inhaled corticosteroids should only be used in individuals at high risk of exacerbation, there is substantial use in individuals at lower risk. This raises the question of the comparative effectiveness of this combination as maintenance treatment in this group compared to other combination regimens. Objective The study aimed to assess the effect on lung function of once-daily tiotropium + olodaterol versus twice-daily salmeterol + fluticasone propionate in all participants with Global initiative for chronic Obstructive Lung Disease 2 or 3 (moderate to severe) COPD. Methods This was a randomized, double-blind, double-dummy, four-treatment, complete crossover study in which participants received once-daily tiotropium + olodaterol (5/5 µg and 2.5/5 µg) via Respimat® and twice-daily salmeterol + fluticasone propionate (50/500 µg and 50/250 µg) via Accuhaler® for 6 weeks. The primary end point was change in forced expiratory volume in 1 second (FEV1) area under the curve from 0 hour to 12 hours (AUC0–12) relative to the baseline after 6 weeks. Results Tiotropium + olodaterol 5/5 µg and 2.5/5 µg demonstrated statistically significant improvements in FEV1 AUC0–12 compared to salmeterol + fluticasone propionate (improvements from baseline were 317 mL and 295 mL with tiotropium + olodaterol 5/5 µg and 2.5/5 µg, and 188 mL and 192 mL with salmeterol + fluticasone propionate 50/500 µg and 50/250 µg, respectively). Tiotropium + olodaterol was superior to salmeterol + fluticasone propionate in lung function secondary end points, including FEV1 area under the curve from 0 hour to 24 hours (AUC0–24). Conclusion Once-daily tiotropium + olodaterol in participants with moderate-to-severe COPD provided superior lung function improvements to twice-daily salmeterol + fluticasone propionate. Dual bronchodilation can be considered to optimize lung function in individuals requiring maintenance treatment for COPD.

Tiotropium and olodaterol in the prevention of chronic obstructive pulmonary disease exacerbations (DYNAGITO): a double-blind, randomised, parallel-group, active-controlled trial

BACKGROUND Combinations of long-acting bronchodilators are recommended to reduce the rate of chronic obstructive pulmonary disease (COPD) exacerbations. It is unclear whether combining olodaterol, a long-acting beta-agonist, with tiotropium, a long-acting anti-muscarinic, reduces the rate of exacerbations compared with tiotropium alone. METHODS This 52-week, double-blind, randomised, parallel-group, active-controlled trial randomly assigned (1:1) patients with COPD with a history of exacerbations using a randomised block design to receive tiotropium-olodaterol 5 μg-5 μg or tiotropium 5 μg once daily. Patients using inhaled corticosteroids continued this therapy. Treatment was masked to patients, investigators, and those involved in analysing the data. The primary endpoint was the rate of moderate and severe COPD exacerbations from the first dose of medication until 1 day after last drug administration. The primary analysis included all randomly assigned patients who received any dose of study medication but were not from a site excluded due to on-site protocol violations. The trial is registered with ClinicalTrials.gov, number NCT02296138. FINDINGS Overall, 9009 patients were screened from 818 centres in 51 countries. We recruited 7880 patients between Jan 22, 2015 and March 7, 2016 (mean age 66·4 years [SD 8·5], 5626 [71%] were men, mean FEV1 percent predicted 44·5% [SD 27·7]): 3939 received tiotropium-olodaterol and 3941 tiotropium. The rate of moderate and severe exacerbations was lower with tiotropium-olodaterol than tiotropium (rate ratio [RR] 0·93, 99% CI 0·85-1·02; p=0·0498), not meeting the targeted 0·01 significance level. The proportion of patients reporting adverse events was similar between treatments. INTERPRETATION Combining tiotropium and olodaterol did not reduce exacerbation rate as much as expected compared with tiotropium alone. FUNDING Boehringer Ingelheim International GmbH.

The efficacy and safety of combined tiotropium and olodaterol via the Respimat(®) inhaler in patients with COPD: results from the Japanese sub-population of the Tonado(®) studies.

Background The efficacy and safety of once-daily tiotropium + olodaterol (T+O) maintenance treatment was demonstrated in the large, multinational, replicate, randomized, Phase III, Tonado® 1 (NCT01431274) and 2 (NCT01431287) studies in patients with moderate to very severe COPD. However, there may be racial differences in the effects of T+O on lung function in patients with COPD. Methods In this Tonado® subgroup analysis, we assessed efficacy and safety of T+O in Japanese participants. Results Versus the overall population, the 413 Japanese patients randomized and treated were slightly older, with more men, lower body mass index, lower baseline St George’s Respiratory Questionnaire (SGRQ) scores, fewer current smokers, but with higher pack-year smoking history. A lower proportion of Japanese patients used inhaled corticosteroids, short-acting muscarinic antagonists, or short- or long-acting β-adrenergic agonists at baseline, but use of long-acting muscarinic antagonists was higher. At Week 24, mean improvements with T+O 5/5 μg in forced expiratory volume in 1 second area under the curve from 0–3 hours response were 151 mL versus olodaterol and 134 mL versus tiotropium 5 μg; mean improvements with T+O 2.5/5 μg were 87 mL versus olodaterol and 70 mL versus tiotropium 2.5 μg. Mean improvements with T+O 5/5 μg in trough forced expiratory volume in 1 second were 131 mL versus olodaterol and 108 mL versus tiotropium 5 μg; mean improvements with T+O 2.5/5 μg were 60 mL versus olodaterol and 47 mL versus tiotropium 2.5 μg. SGRQ scores improved from baseline to a greater extent with both doses of T+O versus monotherapies. Responses were similar in the overall population. Adverse-event incidence was generally balanced across treatment groups. Conclusion Consistent with results from the overall population, T+O 5/5 μg was superior to each monotherapy for lung function and SGRQ in the Japanese sub-population of patients with COPD in Tonado®.

Efficacy and safety of tiotropium + olodaterol maintenance treatment in patients with COPD in the TONADO ® and OTEMTO ® studies: a subgroup analysis by age

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.

Effect of tiotropium and olodaterol on symptoms and patient-reported outcomes in patients with COPD: results from four randomised, double-blind studies

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.Chronic obstructive pulmonary disease: Combined inhaler proves effectiveResults from four in-depth studies show that a combined inhaler is very effective for treatment of moderate to severe chronic lung disease. Alleviating the symptoms of chronic obstructive pulmonary disease (COPD), particularly sleep disturbance, is crucial to enhancing patients’ quality of life. Gary Ferguson at the Pulmonary Research Institute of Southeast Michigan, together with other scientists across the USA and Germany, analysed data from four large-scale studies to evaluate the efficacy of STIOLTO Respimat, a combination of two bronchodilators—tiotropium, and olodaterol, which tackle airway obstruction and breathlessness, improving long-term lung function. They found that the new drug combination triggered significant improvements in patients’ quality of life and levels of breathlessness. Use of night-time rescue medication in patients on STIOLTO Respimat was considerably reduced. A greater number of patients responded positively to the combined inhaler than to monotherapy.

β-Blockers in COPD: A Cohort Study From the TONADO Research Program

Background: Cardiovascular disease is a frequent comorbidity in patients with COPD. Many physicians, particularly pulmonologists, are reluctant to use &bgr;‐adrenoceptor blocking agents (&bgr;‐blockers) in patients with COPD, despite their proven effectiveness in preventing cardiovascular events. Methods: The large (5,162 patients) phase III TONADO 1 and 2 studies assessed lung function and patient‐reported outcomes in patients with moderate to very severe COPD receiving long‐acting bronchodilator treatment across 1 year. This post hoc analysis characterized lung‐function changes, patient‐reported outcomes, and safety in the subgroup of patients receiving &bgr;‐blockers in the studies. Results: In total, 557 of 5,162 patients (11%) received &bgr;‐blockers at baseline. Postbronchodilator FEV1 at baseline was higher in the &bgr;‐blocker group (1.470 L) compared with that in the no &bgr;‐blocker group (1.362 L). As expected, patients receiving &bgr;‐blockers had a more frequent history of cardiovascular comorbidities and medications. Lung function improved from baseline in patients with or those without &bgr;‐blocker treatment, and no relevant between‐group differences were observed in trough FEV1 or trough FVC at 24 or 52 weeks. No relevant differences were observed for St. Georges Respiratory Questionnaire results and Transition Dyspnea Index in patients with &bgr;‐blockers compared with those in patients without. Safety findings were comparable between groups. Conclusions: Lung function, overall respiratory status, and safety of tiotropium/olodaterol were not influenced by baseline &bgr;‐blocker treatment in patients with moderate to very severe COPD. Results from this large patient cohort support the cautious and appropriate use of &bgr;‐blockers in patients with COPD and cardiovascular comorbidity. Trial Registry: ClinicalTrials.gov; No.: NCT01431274 and No. NCT01431287; URL: www.clinicaltrials.gov

β-Blockers in COPD

Background: Cardiovascular disease is a frequent comorbidity in patients with COPD. Many physicians, particularly pulmonologists, are reluctant to use &bgr;‐adrenoceptor blocking agents (&bgr;‐blockers) in patients with COPD, despite their proven effectiveness in preventing cardiovascular events. Methods: The large (5,162 patients) phase III TONADO 1 and 2 studies assessed lung function and patient‐reported outcomes in patients with moderate to very severe COPD receiving long‐acting bronchodilator treatment across 1 year. This post hoc analysis characterized lung‐function changes, patient‐reported outcomes, and safety in the subgroup of patients receiving &bgr;‐blockers in the studies. Results: In total, 557 of 5,162 patients (11%) received &bgr;‐blockers at baseline. Postbronchodilator FEV1 at baseline was higher in the &bgr;‐blocker group (1.470 L) compared with that in the no &bgr;‐blocker group (1.362 L). As expected, patients receiving &bgr;‐blockers had a more frequent history of cardiovascular comorbidities and medications. Lung function improved from baseline in patients with or those without &bgr;‐blocker treatment, and no relevant between‐group differences were observed in trough FEV1 or trough FVC at 24 or 52 weeks. No relevant differences were observed for St. Georges Respiratory Questionnaire results and Transition Dyspnea Index in patients with &bgr;‐blockers compared with those in patients without. Safety findings were comparable between groups. Conclusions: Lung function, overall respiratory status, and safety of tiotropium/olodaterol were not influenced by baseline &bgr;‐blocker treatment in patients with moderate to very severe COPD. Results from this large patient cohort support the cautious and appropriate use of &bgr;‐blockers in patients with COPD and cardiovascular comorbidity. Trial Registry: ClinicalTrials.gov; No.: NCT01431274 and No. NCT01431287; URL: www.clinicaltrials.gov

Long-term safety and efficacy of combined tiotropium and olodaterol in Japanese patients with chronic obstructive pulmonary disease

BACKGROUND The efficacy and safety of once-daily tiotropium+olodaterol (T+O) (2.5/5µg or 5/5µg) for treating chronic obstructive pulmonary disease (COPD) have been demonstrated in the large, multinational, randomized, Phase III studies TONADO® 1 and 2, which included 413 Japanese patients (~80 in each group). This study was conducted to supplement the TONADO® study data to assess long-term safety in ≥100 Japanese patients treated for 1 year in compliance with International Conference on Harmonisation guidelines. Efficacy was evaluated descriptively as a secondary end point. METHODS Patients were randomized to 52 weeks of double-blind treatment with once-daily T+O (2.5/5 or 5/5µg) or O (5µg) monotherapy via the Respimat® inhaler. We report the safety and efficacy data descriptively. RESULTS The incidence of adverse events (AEs) was comparable in the T+O 2.5/5µg (75.0%), T+O 5/5µg (85.4%), and O 5µg (80.5%) groups, with drug-related AEs being reported in 5.0%, 7.3%, and 4.9% of patients, respectively. Serious AEs were reported in 14 patients (11.5%). The change from baseline in forced expiratory volume in 1s (FEV1) area under the curve from 0 to 3h and trough FEV1 were numerically higher in the T+O treatment groups than in the O monotherapy group throughout the study period. Overall safety of T+O was comparable to that in the TONADO® studies. CONCLUSIONS No safety concerns for long-term T+O treatment were identified in Japanese patients with COPD. A numerical improvement in lung function was observed with T+O treatment compared to O monotherapy.