Introduction

Bronchodilators, including long-acting muscarinic antagonists (LAMAs) and long-acting β2-agonists (LABAs), are central to the maintenance treatment of patients with moderate to very severe chronic obstructive pulmonary disease (COPD) [1]. The once-daily LAMA tiotropium is well established in the treatment of COPD and improves the main functional and patient-orientated outcomes of the disease [2–7]. Olodaterol is a novel once-daily LABA that provides 24-h bronchodilation [8–11], symptomatic benefit [12], and enhanced exercise capacity [13]. Tiotropium + olodaterol has recently been evaluated in a phase III program to determine its efficacy in the treatment of COPD [14, 15].

International guidelines indicate that combining bronchodilators of different pharmacologic classes may improve efficacy and reduce the risk of side effects, rather than increasing the dose of a single bronchodilator. The introduction of combination products raises questions regarding the timing of their initiation during the course of COPD, with recent data indicating the potential benefits of earlier pharmacologic intervention with combination bronchodilator medications [16–20].

The pivotal phase III trials TONADO-1 and -2 have demonstrated that once-daily tiotropium + olodaterol significantly improved lung function and health-related quality of life compared to the monocomponents over 1 year in patients with moderate to very severe COPD [14]. These studies were notable in that they included a higher proportion of patients with more severe disease (Global initiative for chronic Obstructive Lung Disease [GOLD] 3 and 4) compared to previously reported studies of other LAMA and LABA combinations such as indacaterol + glycopyrronium [21, 22], and thus studied a broader population with respect to disease severity.

While significant responses were observed in the overall population of TONADO, evaluating the effectiveness of tiotropium + olodaterol in specific subgroups of patients is of clear interest to help inform health care providers. This is particularly pertinent in light of the fact that in clinical practice the population of patients with COPD is heterogeneous with respect to factors such as severity of disease, age, and concurrent COPD medication usage. The large nature of the TONADO studies offers the opportunity to study such subgroups. This post hoc analysis of the efficacy data from TONADO-1 and -2 was conducted to help understand these points, considering the effectiveness of tiotropium + olodaterol across COPD disease severities, in patients with or without prior bronchodilator or inhaled corticosteroid (ICS) use, and according to patients’ age and sex. As this analysis is post hoc, all P values and confidence intervals are nominal.

Methods

Study Design

Two replicate, multinational, phase III, randomized, double-blind, active-controlled trials were conducted to evaluate the efficacy and safety of tiotropium + olodaterol in comparison to the monotherapy components (TONADO-1, Study 1237.5: NCT01431274; TONADO-2, Study 1237.6: NCT01431287) (Fig. 1).

Fig. 1
figure 1

Study design (Study 1237.5: NCT01431274; Study 1237.6: NCT01431287). R randomization, FDC fixed-dose combination, QD once daily

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After a screening visit and 2-week baseline period, patients were randomized to receive tiotropium + olodaterol (2.5/5 or 5/5 μg) or the individual components as monotherapy (tiotropium 2.5 or 5 μg, or olodaterol 5 μg) via the Respimat® Soft Mist™ inhaler (Boehringer Ingelheim, Ingelheim am Rhein, Germany) for 52 weeks. Due to the length of therapy and the severity of disease studied, placebo was not used as a treatment arm in these studies. Patients receiving ICS at the start of the study could continue with their medication and all patients were provided with salbutamol/albuterol metered-dose inhaler (100 μg per actuation) as rescue medication, as required during the trial. Patients receiving a LAMA or LABA prior to the study were required to discontinue these medications during screening. The studies included outpatients aged ≥40 years with a history of moderate to very severe COPD (GOLD 2–4). Key inclusion and exclusion criteria are detailed in Fig. 2.

Fig. 2
figure 2

Key inclusion and exclusion criteria. COPD chronic obstructive pulmonary disease, GOLD Global initiative for chronic Obstructive Lung Disease, FEV 1 forced expiratory volume in 1 s

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End Points

The primary spirometry end points were evaluated after 24 weeks of treatment as follows: 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 to 24 weeks). Details of all assessments performed, end points evaluated, statistical methodology, and primary results for these studies have been reported previously [14].

Statistical Methods

In this analysis, FEV1 AUC0–3 and trough FEV1 were evaluated according to the following subgroups: patients without prior LAMA or LABA treatment at baseline or patients with prior LAMA or LABA treatment at baseline. Within each category of prior LAMA/LABA use, analyses were split according to whether patients had GOLD 2 (predicted FEV1 50% to <80%) or GOLD 3 (30% to <50%)/4 (<30%) COPD at baseline.

Pooled data from TONADO-1 and -2 were used in this analysis. Mean changes from baseline to 24 weeks were analyzed using a mixed-effect model repeated measures approach, including the fixed, categorical effects of treatment, test day, and treatment-by-test-day interaction, as well as the continuous, fixed covariates of baseline and baseline-by-test-day interaction. A spatial power covariance structure was used to model within-patient errors. The Kenward–Roger approximation was used to estimate denominator degrees of freedom.

In addition, pooled FEV1 AUC0–3 and trough FEV1 responses at 24 weeks were analyzed according to patients’ age (<65, 65 to <75, and 75 to <85 years), sex, and ICS usage using the model described above. These data are presented as forest plots, generated with SAS Version 9.2 (SAS Institute Inc., Cary, NC, USA).

Compliance with Ethics Guidelines

This article does not contain any new studies with human or animal subjects performed by any of the authors.

Results

Patient Disposition and Baseline Characteristics

A total of 5163 patients were randomized, of whom 5162 received study treatment (2624 Study 1237.5; 2538 Study 1237.6). The baseline characteristics of patients are presented in Tables 1 and 2 based on prior LAMA or LABA maintenance treatment for COPD and GOLD stage.

Table 1 Demographic and baseline patient characteristics (treated population): combined data for patients without prior LAMA or LABA treatment at baseline, stratified by initial GOLD stagea
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Table 2 Demographic and baseline patient characteristics (treated population): combined data for patients with prior LAMA or LABA at baseline, stratified by initial GOLD stagea
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Overall baseline characteristics were similar across maintenance-treatment subgroups. Lung function in patients with GOLD 2 disease did tend to be slightly better in those who did not receive prior LAMA or LABA maintenance treatment than in those who received maintenance therapies before the study. In addition, more patients who received prior LAMA or LABA maintenance treatment were also taking ICS than those without prior maintenance treatment.

Efficacy

Patients Without Prior LAMA or LABA Maintenance Treatment

In each treatment group, FEV1 AUC0–3 responses (i.e., change from baseline) were greater in patients with GOLD 2 disease than GOLD 3–4 disease (Fig. 3a; Table S1 in the electronic supplementary material). In both of the GOLD subgroups, FEV1 AUC0–3 responses were greater with both doses of tiotropium + olodaterol than the monotherapy components at Week 24, and differences were statistically significant for all comparisons analyzed (Table 3).

Fig. 3
figure 3

Adjusted mean FEV1 AUC0–3 responses at 24 weeks; pooled data from TONADO-1 and -2. a Patients without prior LAMA or LABA use; b patients with prior LAMA or LABA use. FEV 1 forced expiratory volume in 1 s, AUC 0–3 area under the curve from 0 to 3 h, LAMA long-acting muscarinic antagonist, LABA long-acting β2-agonist, SE standard error, O olodaterol, T tiotropium, GOLD Global initiative for chronic Obstructive Lung Disease

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Table 3 Adjusted mean (SE) FEV1 AUC0–3 and trough FEV1 responses (i.e., change from baseline) after 24 weeks of treatment (full analysis set): combined data for patients without prior LAMA or LABA treatment at baseline: treatment differences
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Trough FEV1 responses were consistently greater with both doses of tiotropium + olodaterol than the monotherapy components; no obvious trend was apparent between patients with GOLD 2 and GOLD 3–4 COPD (Fig. 4a). While all differences between the various monotherapies and tiotropium + olodaterol 5/5 µg were statistically significant in patients with GOLD 2 COPD, in GOLD 3–4 COPD patients receiving tiotropium + olodaterol 2.5/5 µg the differences were not as robust, such that changes in trough FEV1 with tiotropium 5 µg were not significantly different from tiotropium + olodaterol 2.5/5 µg (Table 3).

Fig. 4
figure 4

Adjusted mean trough FEV1 responses at 24 weeks; pooled data from TONADO-1 and -2. a Patients without prior LAMA or LABA use; b patients with prior LAMA or LABA use. FEV 1 forced expiratory volume in 1 s, LAMA long-acting muscarinic antagonist, LABA long-acting β2-agonist, SE standard error, O olodaterol, T tiotropium, GOLD Global initiative for chronic Obstructive Lung Disease

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Patients Receiving Prior LAMA or LABA Maintenance Treatment

In patients who received prior maintenance treatment, as in patients without prior LAMA or LABA maintenance bronchodilator therapy, the FEV1 AUC0–3 responses for the individual treatments were greater in those with less severe COPD (Fig. 3b; Table S2 in the electronic supplementary material). Again, FEV1 AUC0–3 responses were greater with both doses of tiotropium + olodaterol than the monotherapy components and all comparisons were statistically significant (P < 0.001).

Trough FEV1 responses were consistently greater with both doses of tiotropium + olodaterol than the monotherapy components and were generally greater in patients with less severe COPD (with the exception of tiotropium + olodaterol 2.5/5 µg) (Fig. 4b). All comparisons between tiotropium + olodaterol and the monotherapies were statistically significant in patients with GOLD 3–4 COPD; however, the comparisons between tiotropium + olodaterol 2.5/5 µg and tiotropium 2.5 or 5 µg in patients with GOLD 2 COPD did not achieve statistical significance (Table 4).

Table 4 Adjusted mean (SE) FEV1 AUC0–3 and trough FEV1 responses (i.e., change from baseline) after 24 weeks of treatment (full analysis set): combined data for patients with prior LAMA or LABA treatment at baseline: treatment differences
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Other Patient Subgroups

FEV1 AUC0–3 and trough FEV1 responses at 24 weeks are presented by age, sex, and prior ICS usage in Figs. 5 and 6. These show that tiotropium + olodaterol was more effective than the monotherapy components across all of the subgroups analyzed, with the exception of trough FEV1 (tiotropium + olodaterol 5/5 µg versus tiotropium 5 µg) in patients aged 75–85 years.

Fig. 5
figure 5

Forest plots for FEV1 AUC0–3 responses at 24 weeks. a Tiotropium + olodaterol 5/5 µg versus olodaterol 5 µg; b tiotropium + olodaterol 5/5 µg versus tiotropium 5 µg. FEV 1 forced expiratory volume in 1 s, AUC 0–3 area under the curve from 0 to 3 h, ICS inhaled corticosteroid

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Fig. 6
figure 6

Forest plots for trough FEV1 responses at 24 weeks. a Tiotropium + olodaterol 5/5 µg versus olodaterol 5 µg; b tiotropium + olodaterol 5/5 µg versus tiotropium 5 µg. FEV 1 forced expiratory volume in 1 s, ICS inhaled corticosteroid

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Discussion

In all the patient subgroups included in this analysis of pooled data from the TONADO-1 and -2 studies, tiotropium + olodaterol consistently resulted in greater improvements in lung function than the monotherapy components, as determined by FEV1 AUC0–3 and trough FEV1 responses at 24 weeks. These results are in line with data from other studies using a LAMA and a LABA, and further highlight the benefits of combined bronchodilation over monotherapy treatment [23–25]. Of particular note, tiotropium + olodaterol 5/5 µg once daily improved lung function in patients with GOLD 2 and 3–4 disease, and there were no apparently relevant differences in lung-function responses according to whether these patients had or had not received prior maintenance therapy with a LAMA or a LABA.

While no statistical comparisons were made between subgroups, it was apparent that both FEV1 AUC0–3 and trough FEV1 responses for the individual treatments were, in general, greater in patients with less severe disease. The greater lung-function responses observed in patients with GOLD 2 COPD in our studies are in line with other clinical trials, including the 4-year study of tiotropium (UPLIFT; NCT00144339) [18]. While patients are less symptomatic earlier in their disease course, recent data have suggested that the progression of early COPD occurs at a faster rate than during the later stages of disease [16, 17]. In addition, the UPLIFT study suggested a possible reduction in the rate of decline of post-bronchodilator FEV1 in patients with GOLD 2 COPD using tiotropium [18]. As more information becomes available related to the response of symptoms, lung function, and exacerbations to good maintenance bronchodilator therapy in COPD patients with less severe disease, opinion is moving towards using effective bronchodilation in the earlier stages of COPD [18, 26].

Our data support the use of dual-action maintenance bronchodilator therapy with LAMA + LABA for treatment-naive and less severe COPD, as well as those more severe patients already receiving maintenance therapies. Both doses of tiotropium + olodaterol were more effective than the monotherapy components in all subgroups analyzed, although the lower dose of the combination (2.5/5 µg) may have been slightly less effective in providing trough bronchodilation in less severe, treatment-naive patients. In addition, it appeared that the FEV1 AUC0–3 responses were somewhat greater in younger patients than older patients, a finding that may reflect more the greater response in the less severe patients rather than a primary age effect. Otherwise, no major differences in responses were observed between treatment groups.

Our analysis does have some limitations in so far as it was post hoc and no direct statistical comparisons could be made between subgroups. However, based on the fact that data were pooled from two large phase III studies, the subgroups were all sizeable (each comprising >900 patients), allowing a clear evaluation of the effects of tiotropium + olodaterol in comparison to the monotherapy components.

Conclusions

Tiotropium + olodaterol 5/5 µg resulted in improved lung-function responses compared to the monotherapy components across all subgroups analyzed. These data show that tiotropium + olodaterol is effective in patients irrespective of age, disease severity, and prior treatment with bronchodilators and/or ICS.

The improvements from baseline in lung function were greater in patients with less severe disease, adding support for the use of combination bronchodilation earlier in the course of COPD.