Composite endpoints in COPD: clinically important deterioration in the UPLIFT trial.

BACKGROUND: Assessments of lung function, exacerbations and health status are common measures of chronic obstructive pulmonary disease (COPD) progression and treatment response in clinical trials. We hypothesised that a composite endpoint could more holistically assess clinically important deterioration (CID) in a COPD clinical trial setting. METHODS: A composite endpoint was tested in a post hoc analysis of 5652 patients with Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2-4 COPD from the 4-year UPLIFT study. Patients received tiotropium 18 µg or placebo. RESULTS: The composite endpoint included time to first confirmed decrease in trough forced expiratory volume in 1 s (FEV1) ≥100 mL, confirmed increase in St. George's Respiratory Questionnaire (SGRQ) total score ≥ 4 units, or moderate/severe exacerbation. Most patients (> 80%) experienced CID, with similar incidence among GOLD subgroups. Most confirmed trough FEV1 (74.6-81.6%) and SGRQ (72.3-78.1%) deteriorations were sustained across the study and in all GOLD subgroups. Patients with CID more frequently experienced subsequent exacerbation (hazard ratio [HR] 1.79; 95% confidence interval [CI] 1.67, 1.92) or death (HR 1.21; 95% CI 1.06, 1.39) by Month 6. CID was responsive to bronchodilator treatment. CONCLUSIONS: Composite endpoints provide additional information on COPD progression and treatment effects in clinical trials. TRIAL REGISTRATION: ClinicalTrials.gov NCT00144339 .

Effects of baseline symptom burden on treatment response in COPD.

RATIONALE: In symptomatic patients with COPD, the decision whether to initiate maintenance treatment with a single agent or a combination of long-acting bronchodilators remains unclear. OBJECTIVE: To investigate whether baseline symptomatic status influences response to tiotropium/olodaterol treatment. MATERIALS AND METHODS: Post hoc analysis of the randomized OTEMTO® studies (NCT01964352; NCT02006732), in which patients with moderate-to-severe COPD received placebo, tiotropium 5 µg, tiotropium/olodaterol 2.5/5 µg, or tiotropium/olodaterol 5/5 µg once daily for 12 weeks via the Respimat® inhaler (Boehringer Ingelheim, Ingelheim am Rhein, Germany). Impact of baseline symptomatic status (modified Medical Research Council [mMRC] score) on response to treatment with tiotropium/olodaterol 5/5 µg, tiotropium 5 µg, or placebo at Week 12 was assessed by St George's Respiratory Questionnaire (SGRQ) total score and response rate, transition dyspnea index (TDI) focal score and response rate, and trough forced expiratory volume in 1 second response. RESULTS: Tiotropium/olodaterol improved SGRQ total scores and response rates compared with placebo and tiotropium for patients with baseline mMRC scores 0-1 and ≥2. For tiotropium/olodaterol vs tiotropium, greater improvements were observed for patients with mMRC ≥2 (SGRQ score adjusted mean treatment difference -3.44 [95% CI: -5.43, -1.46]; P=0.0007; SGRQ response rate ORs 2.09 [95% CI: 1.41, 3.10]; P=0.0002). Dyspnea, measured by TDI score, was consistently improved with tiotropium/olodaterol vs placebo for patients with mMRC scores 0-1 and ≥2 (adjusted mean treatment difference 1.63 [95% CI: 1.06, 2.20]; P<0.0001 and 1.60 [95% CI: 1.09, 2.10]; P<0.0001, respectively). In patients with mMRC scores 0-1 and ≥2, tiotropium/olodaterol consistently improved TDI response rate and lung function vs placebo and tiotropium. CONCLUSIONS: Patients with COPD with more severe baseline dyspnea appear to derive greater health status benefit with tiotropium/olodaterol compared with tiotropium alone.

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.

ß-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 ß-adrenoceptor blocking agents (ß-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 ß-blockers in the studies. RESULTS: In total, 557 of 5,162 patients (11%) received ß-blockers at baseline. Postbronchodilator FEV1 at baseline was higher in the ß-blocker group (1.470 L) compared with that in the no ß-blocker group (1.362 L). As expected, patients receiving ß-blockers had a more frequent history of cardiovascular comorbidities and medications. Lung function improved from baseline in patients with or those without ß-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. George's Respiratory Questionnaire results and Transition Dyspnea Index in patients with ß-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 ß-blocker treatment in patients with moderate to very severe COPD. Results from this large patient cohort support the cautious and appropriate use of ß-blockers in patients with COPD and cardiovascular comorbidity. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01431274 and No. NCT01431287; URL: www.clinicaltrials.gov.

Study Design of VESUTO®: Efficacy of Tiotropium/Olodaterol on Lung Hyperinflation, Exercise Capacity, and Physical Activity in Japanese Patients with Chronic Obstructive Pulmonary Disease.

INTRODUCTION: The superiority of tiotropium/olodaterol is demonstrated in improvement of lung function, dyspnea, lung hyperinflation, and quality of life compared with either monotherapy in patients with chronic obstructive pulmonary disease (COPD). Japanese Respiratory Society Guidelines for COPD management include improvement of exercise tolerance and daily physical activity as the treatment goals; however, there is limited evidence in Japanese patients with COPD. METHODS: A protocol is developed for the VESUTO® study that investigates the efficacy of tiotropium/olodaterol fixed-dose combination (FDC) compared with tiotropium alone on inspiratory capacity (IC, volume from functional residual capacity to total lung capacity), exercise capacity, and daily physical activity in Japanese patients with COPD. RESULTS: A total of 180 Japanese patients with COPD, aged ≥40 years will be enrolled into the double-blind, multicenter, active-controlled, crossover study (NCT02629965) and will be randomized to receive either tiotropium/olodaterol FDC or tiotropium for 6 weeks each [two puffs via RESPIMAT® (Boehringer Ingelheim, Ingelheim, Germany) inhaler in the morning]. The primary endpoint is IC at rest measured at 60 min post-dose after 6 weeks treatment. The secondary endpoints include the 6-min walk distance (6MWD) at 90 min post-dose and physical activity measured by the activity monitor in the last 2 weeks of the 6-week treatment periods. Lung function tests will also be assessed after 6 weeks treatment. A mixed-effects model repeated measures approach will be used for the primary and secondary endpoints. CONCLUSION: The VESUTO® study is the first randomized interventional study to investigate exercise capacity (6MWD) and physical activity measured by a 3-axis accelerometer in Japanese patients with COPD. The study could provide additional evidence of long-acting muscarinic antagonist (LAMA) + long-acting ß2-agonist (LABA) combination therapy on patients' physical activities as well as lung function. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02629965 (registered on December 1, 2015). FUNDING: The VESUTO study was funded by Nippon Boehringer Ingelheim Co., Ltd., Tokyo, Japan.

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.

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 EFFECTIVE: Results 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.

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 ß2-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.

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 ß-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(®).

Effects of tiotropium + olodaterol versus tiotropium or placebo by COPD disease severity and previous treatment history in the OTEMTO® studies.

BACKGROUND: As lung function declines rapidly in the early stages of chronic obstructive pulmonary disease (COPD), the effects of bronchodilators in patients with moderate disease and those who have not previously received maintenance therapy are of interest. OTEMTO® 1 and 2 were two replicate, 12-week, Phase III studies investigating the benefit of tiotropium + olodaterol on lung function and quality of life in patients with moderate to severe disease. Post hoc analyses were performed to assess the benefits for patients according to disease severity and treatment history. METHODS: Four subgroup analyses were performed: Global initiative for chronic Obstructive Lung Disease (GOLD) 2/3, GOLD A/B/C/D, treatment naive/not treatment naive and receiving inhaled corticosteroids (ICS) at baseline/not receiving ICS at baseline. Primary end points were change in forced expiratory volume in 1 s (FEV1) area under the curve from 0 to 3 h response, change in trough FEV1 and St George's Respiratory Questionnaire (SGRQ) total score. Transition Dyspnoea Index (TDI) focal score was a secondary end point, and SGRQ and TDI responder analyses were further end points; all were assessed at 12 weeks. RESULTS: In all subgroups, patients receiving tiotropium + olodaterol responded better overall than those receiving tiotropium monotherapy. Improvements with tiotropium + olodaterol over placebo or tiotropium monotherapy were noted across GOLD 2/3 and GOLD A/B/C/D; however, improvements in SGRQ total score were most evident in the GOLD B subgroup. Moreover, lung-function outcomes were generally greater in those patients who had been receiving previous long-acting bronchodilator and/or ICS maintenance treatment. CONCLUSIONS: These data suggest that tiotropium + olodaterol should be considered as a treatment option in patients with moderate COPD who are initiating maintenance therapy, as well as those with more severe disease. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01964352 and NCT02006732 .

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 ß2-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 + olodaterol shows clinically meaningful improvements in quality of life.

BACKGROUND: Tiotropium + olodaterol improves lung function and symptoms compared to monotherapies in chronic obstructive pulmonary disease (COPD). The OTEMTO 1 and 2 studies investigated the effects of tiotropium + olodaterol on lung function and health-related quality of life compared to placebo in patients with moderate to severe COPD. METHODS: In these two replicate, double-blind, parallel-group, placebo-controlled trials, patients were randomised to receive tiotropium + olodaterol 5/5 µg, 2.5/5 µg, tiotropium 5 µg or placebo for 12 weeks, via the Respimat(®) inhaler. Primary end points were St George's Respiratory Questionnaire (SGRQ) total score, forced expiratory volume in 1 s (FEV1) area under the curve from 0 to 3 h (AUC0-3) response and trough FEV1 response. RESULTS: In OTEMTO 1 and 2, tiotropium + olodaterol 5/5 µg improved SGRQ total score by 4.89 (95% confidence interval [CI] -6.90, -2.88) and 4.56 (95% CI -6.50, -2.63) units versus placebo (both p < 0.0001), and 2.49 (95% CI -4.47, -0.51; p < 0.05) and 1.72 (95% CI -3.63, 0.19) units versus tiotropium 5 µg. Tiotropium + olodaterol 2.5/5 µg significantly improved SGRQ score compared to placebo. Both doses significantly improved FEV1 AUC0-3 response compared to placebo and tiotropium 5 µg. Tiotropium + olodaterol 5/5 and 2.5/5 µg also significantly improved trough FEV1 response compared to placebo (both studies) and separated from tiotropium 5 µg in OTEMTO 2. Adverse-event incidence was similar between treatment groups. CONCLUSION: Tiotropium + olodaterol improved lung function and quality of life compared to placebo and tiotropium 5 µg. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01964352 and NCT02006732.

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.

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 ß2-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.

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.

Effect of azelastine, montelukast, and their combination on allergen-induced bronchoconstriction in asthma.

OBJECTIVES: Histamine and cysteinyl leukotrienes play an important role in early (EAR) and late (LAR) allergen reactions. Although protection by anti-histamines and anti-leukotrienes has been studied extensively, little is known about the effect of their combination. We, therefore, assessed the effect of clinically recommended doses of azelastine and montelukast alone and in combination on EAR and LAR. METHODS: Seventeen patients (mean age 31 years, 14 m/3 f) with asthma and proven EAR and LAR received an oral dose of 4 mg azelastine twice daily, or 10mg montelukast once daily, or both for 1 week, in a double-blind, double-dummy, cross-over fashion. FEV(1) was measured after single-dose allergen challenges during EAR (0-2h) and LAR (2-9h). RESULTS: Azelastine, montelukast and their combination protected against both EAR and LAR (p<0.004, each) by 46% and 43%, 76% and 59%, and 89% and 78%, respectively. Azelastine was not as effective during EAR but equally effective to montelukast during LAR. The combination was superior to each drug alone during both EAR and LAR (p<0.05, each). CONCLUSION: The combination of azelastine and montelukast in clinically recommended doses has a greater effect in suppressing early and late allergen reactions than each drug alone.

Effect of cetirizine dihydrochloride on the airway response to hypertonic saline aerosol in patients with chronic obstructive pulmonary disease (COPD).

Hypertonic saline aerosol can elicit airway obstruction in patients with moderate or severe COPD. In the present study we assessed whether cetirizine dihydrochloride is capable of modulating this response. After a screening visit, 20 patients with COPD (mean FEV(1) 49% pred) were treated with cetirizine 10mg daily or placebo over 1 week in a randomized, double-blind, cross-over fashion and measurements performed at the end of treatment periods. At each visit, patients were challenged by 3% saline aerosol (screening: 0.9%) over 5 min after prior inhalation of salbutamol, and 45 min later sputum was obtained after inhalation of 0.9% saline. Lung function was quantified in terms of forced expiratory (FEV(1)) and inspiratory (FIV(1)) volumes. Spirometric values did not differ between visits and salbutamol-induced bronchodilation was not altered by cetirizine. Compared to baseline or post-salbutamol values, the saline-induced fall in FEV(1) was smallest at screening (P<0.01), without a significant difference between treatments. Regarding FIV(1), however, the percent fall from baseline was higher after placebo (Delta=-10.1%; P<0.05) compared to screening (0.4%) or cetirizine (-4.3%). Sputum composition showed no significant differences except for a tendency towards reduced concentrations of alpha(2)-macroglobulin after cetirizine compared to placebo (P=0.045). The present data indicate some, though small, effects of the H1 receptor antagonist cetirizine on hypertonic saline-induced airway obstruction in patients with moderate-to-severe COPD. In view of the mechanisms involved, it is an open question whether stronger effects can be elicited with higher doses and whether such effects would translate into clinical benefits, e.g. during exacerbations.