Introduction
============

Recommendations for COPD treatment are primarily based on the burden of symptoms, categorized using the modified Medical Research Council and COPD assessment test questionnaires, and on risks, assessed based on severity of airflow limitation and history of exacerbations.[@b1-copd-10-1863] Studies have shown that coadministration of long-acting muscarinic antagonists (LAMAs) and long-acting β~2~-agonists (LABAs) is more effective than treatment with either drug class alone in stable COPD as the combination offers improvement in airflow obstruction, dynamic hyperinflation, reduction in rescue medication, and a safety profile that is similar to the components.[@b2-copd-10-1863]--[@b4-copd-10-1863]

LABA/LAMA combinations evaluated in clinical studies include open combinations of a LABA such as formoterol (FOR), salmeterol (SAL), or indacaterol (IND) and of a LAMA such as tiotropium (TIO), glycopyrronium (GLY), or aclidinium, and newer once-daily (OD), fixed-dose combinations such as umeclidinium and vilanterol (UMEC/VI, Anoro^®^ Ellipta^®^) and IND/GLY (QVA149, Ultibro^®^ Breezhaler^®^). Studies have shown that UMEC/VI is well tolerated and offers greater improvements in lung function, health status, and dyspnea scores compared with placebo and better lung function compared with its monotherapy components and TIO.[@b5-copd-10-1863]--[@b9-copd-10-1863] UMEC/VI administration in a single inhaler (Anoro^®^ Ellipta^®^) has been approved by the US Food and Drug Administration and the European Medicines Agency as a OD maintenance treatment for airflow obstruction in patients with COPD.[@b10-copd-10-1863] The nominal dose of UMEC/VI is 62.5/25 μg OD per the US label, whereas the actual dose delivered is 55/22 μg mentioned in the European Union label. Similarly, several studies have evaluated the safety and efficacy of other open-combination dual bronchodilators with a variety of dosing regimens, such as FOR + TIO (12 μg metered dose/10 μg delivered dose twice daily (bid) +18 μg OD), SAL + TIO (50 μg bid +18 μg OD), IND + TIO (150 μg +18 μg OD), and QVA149 (nominal dose, 110/50 μg OD; delivered dose, 85/43 μg OD) in patients with moderate-to-very severe COPD.[@b11-copd-10-1863]--[@b21-copd-10-1863]

With the recent introduction of a new class of fixed-dose combination bronchodilators (UMEC/VI and QVA149)[@b22-copd-10-1863],[@b23-copd-10-1863] and several others under development, assessing their efficacy relative to each other and with open dual combinations is desirable. Therefore, this study aimed to perform a systematic literature review (SLR) and to synthesize, by means of a Bayesian network meta-analysis (NMA), the published evidence on the efficacy of the fixed combination of UMEC/VI (55/22 μg OD) with that of all available dual-bronchodilator combinations in single or separate inhalers. The relative efficacy of the treatments was assessed at 12 weeks and 24 weeks by means of difference in change from baseline (CFB) on lung function (trough forced expiratory volume in 1 second \[FEV~1~\]), health status (St George's Respiratory Questionnaire \[SGRQ\] total score), difference in transitional dyspnea index (TDI) focal score, and difference in rescue medication use.

Methods
=======

Data sources
------------

The study protocol was approved by GSK internal protocol review committee. Since the study was based on data extracted from published literature, it was exempt from human subjects review.

An SLR was conducted to identify randomized controlled trials (RCTs) comparing UMEC/VI with alternative LABA/LAMA open and fixed combinations, using appropriate databases and registries from their inception up to April 16, 2014. RCTs in English language were included. A broad search strategy was employed to cover the entire range of available LABA, LAMA, or LABA/LAMA comparators. Details of the databases, selection criteria, and the search strategies are presented in Tables S1 and S2, respectively.

Inclusion criteria and study selection process
----------------------------------------------

Identified abstracts were independently assessed by two reviewers as per predefined selection criteria: patient population -- adult COPD patients (age ≥40 years of any race and sex); interventions -- UMEC/VI; comparators -- LABA/LAMA, placebo, TIO 18 μg (henceforth, TIO = TIO 18 μg); outcomes -- FEV~1~, SGRQ total scores, TDI focal scores, and rescue medication use; study design -- RCTs of ≥10-week duration.

Studies were included in the SLR if they compared interventions of interest in the analysis with each other or with placebo. During the SLR protocol development, it was known that three of UMEC/VI RCTs (clinical study reports provided by GlaxoSmithKline) had TIO as comparator. Due to this, we decided to include TIO as one of the comparators in the selection criteria. Because both TIO and placebo were selected as potential common comparators, studies comparing TIO with placebo were also of interest to strengthen the network.

Data abstraction and quality assessment
---------------------------------------

For studies that met the selection criteria, the following information was extracted: study design, patient characteristics, types of intervention and comparators, outcomes of interest, and patient withdrawals with reasons for withdrawal.

For each trial, the mean difference in CFB between the arms of interest (or least square mean) and the 95% confidence interval (95% CI), standard error (SE), or standard deviation (SD) were abstracted, where available. If not reported, the difference in CFB was calculated based on the CFB (or least square mean) per treatment arm. If not reported, the SE was imputed using the uncertainty of other trials in the network. A checklist for RCTs based on the guidance by the Institute for Quality and Efficiency in Health Care was used for risk of bias assessment.[@b24-copd-10-1863]

An effect modifier is a study or patient characteristic that influences the treatment effect. Because of the randomization process, potential effect modifiers are expectedly balanced between treatment arms within an RCT. However, an NMA involves different trials comparing different interventions. Therefore, the distribution of effect modifiers not only varies across studies for a particular comparison (heterogeneity) but also between comparisons (inconsistency). Although slight variations in patient characteristics across studies are always expected, an NMA is only valid when no imbalances exist in effect modifiers across comparisons. To reduce the risk of biased outcomes in the NMA, data from only studies that are similar with respect to patient populations and study designs should be compared.[@b25-copd-10-1863],[@b26-copd-10-1863]

The similarity of studies was assessed by evaluating the distribution of patient characteristics and study design across the direct comparisons in the network. If major imbalances in patient or study characteristics were detected that could influence the treatment effect, scenario analysis was used to explore the inhomogeneity. Meta-regression techniques could not be used to adjust for variations due to the limited number of studies available in the network.

Data synthesis
--------------

The identified trial evidence was used to perform an NMA within a Bayesian framework to simultaneously synthesize the results of the included studies and to obtain relative treatment effects. A linear model with normal likelihood distribution was used with flat (noninformative) prior distributions assumed for all outcomes. Prior distributions of the relative treatment effects were normal, with zero mean and a variance of 10,000. A uniform distribution ranging from zero to five was used as the prior of the interstudy SD.

For each outcome, fixed- and random-effects models were evaluated. The goodness of fit of each model to the data was assessed using the Deviance Information Criterion. The posterior densities for the outcomes of interest were estimated using the Markov Chain Monte Carlo simulations for each model. The results were based on 80,000 iterations on three chains, with a burn-in of 20,000 iterations. Convergence assessment was based on visual inspection of trace plots. Accuracy of the posterior estimates was assessed using the Monte Carlo error for each parameter (Monte Carlo error \<1% of the posterior SD). The models used in this study were based on those defined by Dias et al[@b27-copd-10-1863] and were implemented using WinBUGS version 1.4.3 (MRC Biostatistics Unit, Cambridge, UK).

The posterior distributions were summarized with the corresponding median values to reflect the most likely value of the estimate, and the 2.5 and 97.5 percentile to capture the 95% credible interval (95% CrI), which represents the range of true underlying effects with 95% probability. Pairwise comparisons for all treatments included in the network were calculated, including the relative effectiveness and the probability of each treatment being better than each of the rest. If studies reported mean values without any measure of uncertainty (SE, SD, 95% CI), scenario analyses were performed excluding this study because of the lack of data; however, such studies were included with the reported mean value and an imputation for the SE.

The feasibility of an NMA to compare LABA/LAMA treatments with each other or with placebo was assessed. Considering the lack of placebo-controlled LABA/LAMA studies, TIO was included in the network to allow indirect comparisons with more treatments of interest. Extending the network by including TIO does have potential advantages such as strengthening inference and producing a more robust analysis. Two sets of analyses were performed, one including only LABA/LAMA treatments and placebo in the network (data not shown) and the other including LABA/LAMA treatments, TIO, and placebo in the network. The second analysis (including TIO) allowed for indirect comparisons with more relevant open and closed dual comparators because many studies lacked a placebo arm.

Results
=======

Search and selection results
----------------------------

In total, 3,006 abstracts were identified, of which, 309 (10.3%) abstracts were of interest based on predefined selection criteria, and full-text articles were obtained ([Figure 1](#f1-copd-10-1863){ref-type="fig"}). Of the 4,720 identified registries, 159 were included. The registry screening results were merged with the abstracts and were screened against full-text selection criteria. The final NMA evidence base comprised 77 articles relating to 26 trials. These trials represented RCTs comparing LABA/LAMA combinations approved as of April 16, 2014 and TIO with each other or with placebo. The efficacy parameters shared between trials included lung function, defined as a difference in CFB in trough FEV~1~ and patient-reported outcomes, such as mean CFB in SGRQ total scores, difference in mean TDI focal scores, and change in rescue medication use estimated as mean number of puffs per day. Changes in efficacy parameters were compared at the 3-month (12-week) and 6-month time points (range, 24--26 weeks), to correspond to the duration of the UMEC/VI comparator trials ([Table 1](#t1-copd-10-1863){ref-type="table"}).

An overview of the study design, inclusion criteria, and background treatments of these trials is presented in [Table 1](#t1-copd-10-1863){ref-type="table"}. Study participants included individuals aged ≥40 years with an established diagnosis of COPD and a smoking history of ≥10 pack-years. Patients with moderate-to-very severe (GOLD stages II--IV) COPD, with an FEV~1~ of ≤70% of predicted normal value, and no inclusion criterion related to the number of exacerbations in the previous year were considered[@b21-copd-10-1863]; potential exceptions were the SPARK study, which included no patients with moderate COPD, but only patients with a history of \>1 moderate or severe exacerbation during the past year,[@b16-copd-10-1863] and the UMEC/VI studies, all of which included patients who had breathlessness (modified Medical Research Council scale ≥2).[@b6-copd-10-1863],[@b9-copd-10-1863],[@b28-copd-10-1863] Regarding the background treatments, most of the studies allowed the use of inhaled corticosteroids (ICSs), while the use of LAMAs, LABAs, or LABA/ICS was not allowed.

[Table 2](#t2-copd-10-1863){ref-type="table"} presents an overview of the primary patient characteristics (and potential treatment effect modifiers in COPD), including age, sex, smoking status, ICS use, COPD duration, number of pack-years, predicted FEV~1~, and proportion of patients with severe or very severe disease. The patients were primarily male (49%--99%), with a mean age above 60 years (60--68 years) and heavy smokers (36--69.2 pack-years). Some variation in ICS use was detected (25%--76%), with Aaron et al[@b20-copd-10-1863] and Tashkin et al[@b18-copd-10-1863] reporting that \<30% of patients used ICS at baseline in at least one of the treatment arms.

Overall, patient characteristics were comparable between UMEC/VI and other dual-bronchodilator trials. No major imbalances in the study and patient characteristics were observed between direct comparisons in the network that could act as effect modifiers of the relative treatment effects; therefore, an NMA was deemed to be feasible.[@b26-copd-10-1863] The results of the risk of bias assessment at study level for all studies included in the NMA are summarized in Table S3.

Bayesian NMA
------------

[Figure 2](#f2-copd-10-1863){ref-type="fig"} presents the overall network of studies in the analysis. These studies were identified in the SLR comparing QVA149, FOR + TIO, SAL + TIO, IND + TIO, or UMEC/VI with TIO OD or placebo as common comparators. The common endpoints in the identified studies were trough FEV~1~, SGRQ total scores, TDI focal scores, and rescue medication use at 24 weeks and within the time margins around these time points.

Trough FEV~1~
-------------

In total, 14 studies were included for the FEV~1~ endpoint ([Figure 2](#f2-copd-10-1863){ref-type="fig"} and [Table 3](#t3-copd-10-1863){ref-type="table"}). Combination therapies of UMEC/VI, QVA149, and TIO + SAL were more efficacious than placebo, and UMEC/VI and QVA149 were more efficacious than TIO monotherapy as indicated by CFB in mean trough FEV~1~ at 24 weeks. The difference in CFB in mean trough FEV~1~ numerically favored UMEC/VI in comparison to both QVA149 (estimated difference \[ED\], 14.14 mL; 95% CrI: −14.18, 42.25) and TIO + SAL (ED, 67.40 mL; 95% CrI: −25.25, 159.40), although no statistically or clinically significant differences were observed between the LABA/LAMA combinations ([Figure 3A](#f3-copd-10-1863){ref-type="fig"} and [Table 4](#t4-copd-10-1863){ref-type="table"}).

SGRQ total scores
-----------------

Fourteen studies were included in the analysis of SGRQ total scores ([Figure 2](#f2-copd-10-1863){ref-type="fig"} and [Table 3](#t3-copd-10-1863){ref-type="table"}). All the combination therapies, including UMEC/VI, QVA149, TIO + SAL, and TIO + FOR, demonstrated significantly higher efficacy in CFB in SGRQ total scores compared with placebo and TIO at 24 weeks. UMEC/VI was not significantly different from QVA149 (ED, 0.18; 95% CrI: −1.28, 1.63), TIO + SAL (ED, −0.11; 95% CrI: −1.84, 1.61), and TIO + FOR (ED, −0.68; 95% CrI: −1.77, 0.40) ([Figure 3B](#f3-copd-10-1863){ref-type="fig"} and [Table 4](#t4-copd-10-1863){ref-type="table"}). As a scenario analysis, SE was imputed for the study by Donohue et al (TIO vs placebo),[@b29-copd-10-1863] and this study was included in the network, having marginal impact on the results.

TDI focal scores
----------------

In total, ten studies were included in the TDI analysis ([Figure 2](#f2-copd-10-1863){ref-type="fig"} and [Table 3](#t3-copd-10-1863){ref-type="table"}). Combination therapies of UMEC/VI and QVA149 were more efficacious than placebo, and QVA149 was more efficacious than TIO monotherapy in TDI focal score at 24 weeks. UMEC/VI was not significantly different from QVA149 (ED, −0.30; 95% CrI: −0.73, 0.13) and TIO + SAL (ED, 0.58; 95% CrI: −0.33, 1.50) ([Figure 3C](#f3-copd-10-1863){ref-type="fig"} and [Table 4](#t4-copd-10-1863){ref-type="table"}). The addition of imputed evidence from the Donohue et al study[@b29-copd-10-1863] had marginal impact on the results.

Rescue medication use
---------------------

In total, seven studies were included in the rescue medication use network ([Figure 2](#f2-copd-10-1863){ref-type="fig"} and [Table 3](#t3-copd-10-1863){ref-type="table"}). For rescue medication use at 24 weeks, the combination therapies of UMEC/VI and QVA149 were more efficacious than placebo and TIO. No significant difference was observed between UMEC/VI and QVA149 (ED, 0.02; 95% CrI: −0.27, 0.32) ([Figure 3D](#f3-copd-10-1863){ref-type="fig"} and [Table 4](#t4-copd-10-1863){ref-type="table"}) with imputed evidence from the Donohue et al[@b29-copd-10-1863] study having marginal impact.

Discussion
==========

This study evaluated the comparative efficacy of UMEC/VI 55/22 μg with all the available open and closed dual-combination bronchodilators in patients with moderate-to-very severe COPD who were eligible to receive maintenance bronchodilator therapy. Four endpoints, including mean CFB in trough FEV~1~, CFB in SGRQ total scores, TDI focal scores, and CFB in rescue medication use, were selected and analyzed because they were consistently reported across all the studies and deemed as important endpoints in clinical practice. The Bayesian NMA showed that for each endpoint, UMEC/VI was similar to all the other dual fixed or open LABA/LAMA combination bronchodilators (IND + TIO, TIO + SAL, TIO + FOR, and QVA149) available at the time of this analysis. Indirect treatment comparison within a frequentist framework by using Bucher's method also showed consistent results for all the aforementioned efficacy parameters (data not shown).[@b30-copd-10-1863] This suggests that combination therapies of LABA/LAMA are broadly comparable across the most common endpoints evaluated in RCT settings. These aforementioned observations are consistent with two other recent NMAs, which suggested that bronchodilator monotherapies are broadly similar across a range of clinical endpoints.[@b31-copd-10-1863] One NMA, however, showed that newer OD LABAs were likely to be more effective compared with bid LABAs at improving FEV~1~ and SGRQ scores.[@b32-copd-10-1863] The NMA focused on four most commonly reported endpoints in RCTs of bronchodilators. Endpoints such as adverse events, exercise tolerance, and exacerbations were excluded. Our feasibility assessment suggested that the definitions of adverse events, exacerbations, and exercise tolerance tests used in manufacturer-conducted trials differed significantly across various LABA and/or LAMA treatments, preventing robust comparison. The patients assessed in most trials reported a limited history of exacerbations and in those trials enriched for patients with exacerbations; no placebo comparisons were included. Moreover, exacerbation was not a key endpoint in most selected studies, including the UMEC/VI studies. Patients with exacerbations were withdrawn from UMEC/VI studies at the first event,[@b6-copd-10-1863],[@b9-copd-10-1863],[@b28-copd-10-1863] thereby limiting the available evidence to the risk of a first event but providing no data on exacerbation rates. Other trials designed to examine exacerbations included the SPARK study,[@b16-copd-10-1863] in which the LABA/LAMA combination (QVA149) was compared with two LAMAs and was reported to provide superior reductions in the rate of moderate or severe exacerbations versus GLY but not versus TIO. This benefit of QVA149 was also entirely confined to patients using concurrent corticosteroids.[@b16-copd-10-1863] Similarly, Aaron et al[@b20-copd-10-1863] reported no exacerbation benefit with TIO + SAL versus TIO in patients not using corticosteroids. In the UMEC/VI studies, approximately 50% of patients used corticosteroids and a superior exacerbation benefit was observed on the time to the first exacerbation with UMEC/VI versus placebo[@b6-copd-10-1863] and versus TIO but only in the largest of three similar 6-month trials.[@b28-copd-10-1863] Consequently, uncertainty still exists on this endpoint, which is out of scope for this NMA.

These meta-analyses also demonstrated that monobronchodilators when compared with placebo generally failed to improve total SGRQ scores by ≥4 units and TDI focal scores by ≥1 unit at 6 months, which are the minimal clinically important differences for each of these commonly used patient-reported outcomes, even when the trough FEV~1~ improved by at least 100 mL compared with placebo.[@b32-copd-10-1863] In the current analysis, we observed that UMEC/VI consistently demonstrated clinically important benefits versus placebo and statistically significant benefits versus TIO at 6 months, which were broadly comparable to any alternative dual-bronchodilator combinations. These findings highlight that LAMA or LABA monotherapy alone may not always provide all patients with sustained benefits enabling freedom from recurrence of COPD symptoms.[@b33-copd-10-1863] Dual bronchodilators, which are sparingly used in current clinical practice, may provide optimal symptom control in addition to maximum bronchodilation to appropriate COPD patients.[@b34-copd-10-1863] Overall, both QVA149 and UMEC/VI demonstrated beneficial effects compared with monotherapy at 24 weeks, and these findings were further corroborated by the supplementary analysis performed at 12 weeks. This NMA also revealed comparable efficacy of UMEC/VI to open dual-combination bronchodilators. However, caution is needed in this regard, as the advantage of combining two long-acting bronchodilators in a single inhaler in terms of improved medication adherence leading to potentially better outcomes may become evident only in studies of a less controlled nature.

Limitations
===========

A potential limitation of this analysis is the low number of studies for some of the treatments (eg, TIO18 + SAL50) and the absence of direct evidence with other active treatments of interest. The fact that for these treatments only indirect comparison (via TIO or placebo) was available is reflected in the uncertainty of the relative efficacy results (ie, wide CIs).

An additional limitation is that studies reporting data for aclidinium/FOR were not identified.

A further limitation of the analysis, as with all meta-analyses, is the potential influence of confounders. A meta-regression to adjust for possible confounders was not feasible because of the limited number of studies included in each analysis. Although two studies[@b18-copd-10-1863],[@b20-copd-10-1863] reported lower ICS use at baseline, it was not possible to design scenario analyses excluding these studies. In both cases, it would result in the loss of a comparator in the network and would not affect the other relative efficacy estimates due to the shape of the network. Because recent NMAs[@b31-copd-10-1863],[@b32-copd-10-1863],[@b35-copd-10-1863] evaluating long-acting bronchodilators in COPD did not suggest the relative efficacy estimates to be greatly affected by this and other potential effect modifiers, the impact of this imbalance was not believed to be a likely source of bias. Although the studies were similar enough to be included in an NMA, residual confounding may exist in these aggregated data.

Conclusion
==========

Based on the results of this 6-month NMA of the available RCTs reporting on efficacy outcomes in terms of trough FEV~1~, SGRQ total scores, TDI focal scores, and rescue medication use, UMEC/VI is comparable to QVA149 and is expected to be at least comparable to the remaining dual-bronchodilator combinations.

Statement of originality/clinical relevance
===========================================

With the recent introduction of a new class of fixed-dose combination bronchodilators (UMEC/VI and QVA149) and several others under development, assessing their efficacy relative to each other and with open dual combinations is desirable. Therefore, this study aimed to perform an SLR and to synthesize, by means of a Bayesian NMA, the published evidence on the efficacy of the fixed combination of UMEC/VI (55/22 μg OD) with that of all available dual-bronchodilator combinations in single or separate inhalers. The analysis was conducted with TIO and placebo as common comparators. The relative efficacy of the treatments was assessed at 12 weeks and 24 weeks in terms of lung function (trough FEV~1~), health status (SGRQ total scores), TDI focal scores, and rescue medication use. To our knowledge, this is the first study to compare fixed-dose combination bronchodilators with other such fixed-dose and open combinations and to provide valuable evidence for clinicians and payers to choose the most optimal medication for their patients.

This study was funded by GlaxoSmithKline. Medical writing services were provided by Dr Annirudha Chillar of Cactus Communications and funded by GlaxoSmithKline.

**Author contributions**

All authors contributed to the conception and design of the study. AK and ELH contributed to data acquisition, and all five authors contributed to data analysis and interpretation, drafting and critically revising the paper, and agree to be accountable for all aspects of the work.

**Disclosure**

SMC, ASI, and YSP are employees of GlaxoSmithKline and hold stocks at GlaxoSmithKline. AK and ELH are employees of Mapi Group and were consultants to GlaxoSmithKline on this study. The authors report no conflicts of interest in this work.

![Summary of study-flow (**A**) registries (**B**) study selection.\
**Abbreviations:** CDSR, Cochrane Database of Systematic Review; CSR, clinical study report; DARE, Database of Abstracts of Reviews of Effects; EMBASE, Excerpta Medica dataBASE; EU-CTR, European Union Clinical Trials Register; HTA, Health Technology Assessment Database; GSK, GlaxoSmithKline; MEDLINE, Medical Literature Analysis and Retrieval System Online; NMA, network meta-analysis; PROSPERO, international prospective register of systematic review; WHO ICTRP, World Health Organization International Clinical Trials Registry Platform.](copd-10-1863Fig1){#f1-copd-10-1863}

![Overall network of studies in the NMA analysis of UMEC/VI versus LABA/LAMA combination therapies evaluated at 24 weeks for (**A**) trough FEV~1~, (**B**) SGRQ total score, (**C**) TDI focal score, and (**D**) rescue medication use.\
**Notes:** Studies in bold represent those that report only mean values without reporting SE, SD, and 95% CI. Studies DB2113360 and DB2113374 from Decramer et al.[@b9-copd-10-1863] Study DB2113373 from Donohue et al.[@b6-copd-10-1863] Study ZEP117115 from Maleki-Yazdi et al.[@b28-copd-10-1863]\
**Abbreviations:** CI, confidence interval; FEV~1~, forced expiratory volume in 1 second; FOR, formoterol; LABA, long-acting β2-agonist; LAMA, long-acting muscarinic antagonist; NMA, network meta-analysis; PBO, placebo; QVA149, indacaterol/glycopyrronium; SAL, salmeterol; SD, standard deviation; SE, standard error; SGRQ, St George's Respiratory Questionnaire; TDI, transitional dyspnoea index; TIO, tiotropium; UMEC, umeclidinium; VI, vilanterol.](copd-10-1863Fig2){#f2-copd-10-1863}

![Forest plot for (**A**) mean trough FEV~1~, (**B**) mean SGRQ total scores, (**C**) mean TDI focal scores, and (**D**) mean rescue medication use of UMEC 55 μg/VI 22 μg versus comparators at 24 weeks.\
**Notes:** Dotted lines included in panels (**A**--**C**) indicate the MCIDs versus placebo if these have been defined: these have been included in the graph for reference purpose only. The values shown on the right of each figure represent mean (95% CI).\
**Abbreviations:** CFB, change from baseline; FEV~1~, forced expiratory volume in 1 second; FOR, formoterol; MCID, minimal clinically important difference; PBO, placebo; QVA149, indacaterol/glycopyrronium; SAL, salmeterol; SGRQ, St George's Respiratory Questionnaire; TDI, transitional dyspnea index; TIO, tiotropium; UMEC, umeclidinium; VI, vilanterol.](copd-10-1863Fig3){#f3-copd-10-1863}

###### 

Key study characteristics for all studies included in the NMA (only arms of interest)

  -----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
  Study                                                                          Study design                                                                                               Treatment                                                                 Trial duration   Inclusion criteria                                                                                                                                                                                                                                                                              Background treatment
  ------------------------------------------------------------------------------ ---------------------------------------------------------------------------------------------------------- ------------------------------------------------------------------------- ---------------- ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
  Decramer et al[@b9-copd-10-1863] (DB2113360)                                   Phase III multicenter, randomized, double-blind, double-dummy, parallel-group study                        Tiotropium 18 μg OD\                                                      24 weeks         Outpatient; age ≥40 years; diagnosed with COPD; post-salbutamol FEV~1~ ≤70% and post-salbutamol FEV~1~/FVC ratio \<0.7; smoking history a ≥10 pack-years                                                                                                                                        Allowed: ICS at a dose of up to 1,000 μg/day of FP or equivalent, salbutamol/albuterol as rescue medication\
                                                                                                                                                                                            Vilanterol 22 μg/umeclidinium 55 μg OD                                                                                                                                                                                                                                                                                                                                                     Not allowed: LABAs, SABAs, short-acting anticholinergics, and SABA/ICS combination products

  Decramer et al[@b9-copd-10-1863] (DB2113374)                                   Phase III multicenter, randomized, double-blind, double-dummy, parallel-group study                        Tiotropium 18 μg OD\                                                      24 weeks         Outpatient; age ≥40 years; diagnosed with COPD; post-salbutamol FEV~1~/FVC ratio \<0.70 and post-salbutamol FEV~1~ ≤70%; smoking history ≥ 10 pack-years                                                                                                                                        Allowed: ICS at a dose of up to 1,000 μg/day of FP or equivalent, salbutamol/albuterol as rescue medication\
                                                                                                                                                                                            Vilanterol 22 μg/umeclidinium 55 μg OD                                                                                                                                                                                                                                                                                                                                                     Not allowed: LABAs, oral SABAs and LABAs, inhaled SABAs, inhaled short-acting anticholinergics, and SABA/ICS combination products

  Donohue et al[@b6-copd-10-1863] (DB2113373)                                    Phase III multicenter, randomized, double-blind, placebo-controlled, parallel-group study                  Placebo\                                                                  24 weeks         Outpatient; age ≥40 years; diagnosed with COPD; post-salbutamol FEV~1~/FVC ratio \<0.70 and post-salbutamol FEV~1~ ≤70%; smoking history ≥ 10 pack-years                                                                                                                                        Allowed: ICS at a dose of up to 1,000 μg/day of FP or equivalent, salbutamol/albuterol as rescue medication\
                                                                                                                                                                                            Vilanterol 22 μg/umeclidinium 55 μg OD                                                                                                                                                                                                                                                                                                                                                     Not allowed: LABAs, LABA/ICS combination products, SABAs, short-acting anticholinergics, and SABA/ICS combination products

  Maleki-Yazdi et al[@b28-copd-10-1863] (ZEP117115)                              Phase III multicenter, randomized, double-blind, double-dummy, parallel-group study                        Tiotropium 18 μg OD\                                                      24 weeks         Outpatient; age ≥40 years; diagnosed with COPD; post-salbutamol FEV~1~/FVC ratio \<0.70 and post-salbutamol FEV~1~ ≤70%; smoking history ≥ 10 pack-years                                                                                                                                        Allowed: ICS at a dose of up to 1,000 μg/day of FP or equivalent, salbutamol/albuterol as rescue medication\
                                                                                                                                                                                            Vilanterol 22 μg/umeclidinium 55 μg OD                                                                                                                                                                                                                                                                                                                                                     Not allowed: LABAs, LABA/ICS combination products, oral SABAs and LABAs, inhaled SABAs, inhaled short-acting anticholinergics, and SABA/ICS combination products

  INTRUST 1 (Mahler et al[@b17-copd-10-1863])                                    Randomized, double-blind, controlled, parallel-group study                                                 Tiotropium 18 μg OD\                                                      12 weeks         Age ≥40 years; post-bronchodilator FEV~1~ ≤65% and ≥30%; post-bronchodilator FEV~1~/FVC \<70%; smoking history ≥ 10 pack-years                                                                                                                                                                  Allowed: ICS monotherapy, salbutamol/albuterol as rescue medication\
                                                                                                                                                                                            Indacaterol 150 μg + tiotropium 18 μg OD                                                                                                                                                                                                                                                                                                                                                   Not allowed: LABAs, SABAs (except those prescribed in the study), theophylline, and anticholinergics

  INTRUST 2 (Mahler et al[@b17-copd-10-1863])                                    Randomized, double-blind, controlled, parallel-group study                                                 Tiotropium 18 μg OD\                                                      12 weeks         Age ≥40 years; post-bronchodilator FEV~1~ ≤65% and ≥30%; post-bronchodilator FEV~1~/FVC \<70%; smoking history ≥ 10 pack-years                                                                                                                                                                  Allowed: ICS monotherapy, salbutamol/albuterol as rescue medication\
                                                                                                                                                                                            Indacaterol 150 μg + tiotropium 18 μg OD                                                                                                                                                                                                                                                                                                                                                   Not allowed: LABAs, SABA (except those prescribed in the study), theophylline, and anticholinergics

  Aaron et al[@b20-copd-10-1863]                                                 Randomized, double-blind, placebo-controlled study                                                         Tiotropium 18 μg OD + salmeterol 25 μg 2 puffs bid\                       52 weeks         Age ≥35 years; diagnosed with moderate or severe COPD; ≥ 1 exacerbation of COPD requiring systemic steroids or antibiotics in previous 12 months; smoking history ≥ 10 pack-years; post-bronchodilator FEV~1~ ≤65%; FEV~1~/FVC \<70%.                                                           Allowed: albuterol for relief of symptoms\
                                                                                                                                                                                            Tiotropium l8 μg OD + placebo 2 puffs bid\                                                                                                                                                                                                                                                                                                                                                 Not allowed: ICS, LABAs, and anticholinergics
                                                                                                                                                                                            Tiotropium 18 ug OD + fluticasone 250 ug/salmeterol 25 ug 2 puffs bid                                                                                                                                                                                                                                                                                                                      

  ENLIGHTEN (Dahl et al[@b13-copd-10-1863])                                      Multicenter, randomized, double-blind, parallel-group, placebo-controlled study                            Placebo\                                                                  52 weeks         Age ≥40 years; diagnosed with moderate or severe COPD (stage II or III according to GOLD 2008 criteria); post-bronchodilator FEV~1~ \<80% and ≥30%; post-bronchodilator FEV~1~/FVC \<0.70; smoking history ≥ 10 pack-years                                                                      Allowed: albuterol as rescue medication, ICS monotherapy\
                                                                                                                                                                                            QVA149 (indacaterol 110 ug/glycopyrronium 50 ug) OD                                                                                                                                                                                                                                                                                                                                        Not allowed: long-acting bronchodilators (LABAs, LAMAs, theophylline) and short-acting muscarinic antagonists

  SPARK (Wedzicha et al[@b16-copd-10-1863])                                      Multicenter, randomized, double-blind, parallel-group, active-controlled study                             Tiotropium 18 μg OD QVA149 (indacaterol 110 ug/glycopyrronium 50 ug) OD   64 weeks         Age ≥40 years; diagnosed with severe or very severe COPD (stage III or IV according to GOLD 2008 criteria); post-bronchodilator FEV~1~ \<50%; FEV~1~/FVC \<0.70; ≥1 exacerbation in the previous 12 months requiring systemic corticosteroids or antibiotics; smoking history ≥ 10 pack-years   Allowed: salbutamol, stable dose of ICS\
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       Not allowed: long-acting bronchodilators

  SHINE (Bateman et al[@b11-copd-10-1863])                                       Multicenter, randomized, double-blind, parallel-group, placebo- and active-controlled (open-label) study   Placebo\                                                                  26 weeks         Age ≥40 years; diagnosed with moderate or severe COPD (stage II or III according to GOLD 2008 criteria); post-bronchodilator FEV~1~ \<80% and ≥30%; post-bronchodilator FEV~1~/FVC \<0.70; smoking history ≥ 10 pack-years                                                                      Allowed: salbutamol/albuterol as rescue medication, inhaled or intranasal corticosteroids in constant doses\
                                                                                                                                                                                            Tiotropium 18 μg OD QVA149 (indacaterol 110 ug/glycopyrronium 50 ug) OD                                                                                                                                                                                                                                                                                                                    Not allowed: LABAs, LAMAs, and LABA/ICS

  Vogelmeier et al[@b19-copd-10-1863]                                            Randomized, partially blinded, placebo-controlled study                                                    Formoterol 10 μg bid + tiotropium 18 μg OD\                               24 weeks         Diagnosed with stable COPD; age ≥40 years at COPD onset; smoking history ≥ 10 pack-years; FEV~1~ \<70% of patient's predicted normal value (and ≥ 1.00 L); FEV~1~/FVC \<70%                                                                                                                     Allowed: salbutamol, ICS monotherapy
                                                                                                                                                                                            Tiotropium 18 μg OD Placebo                                                                                                                                                                                                                                                                                                                                                                

  Tashkin et al[@b18-copd-10-1863]                                               Active-control led, double-blind, multicenter study                                                        Tiotropium l8 μg OD + formoterol 12 μg bid\                               12 weeks         Age ≥40 years; post-bronchodilator FEV~1~ \<70% and \>30% of the predicted normal value or \>0.75 L, whichever was lesser at run-in; FEV~1~/FVC \<0.70                                                                                                                                          Continued use of prior stable ICS regimens and systemic corticosteroids for the treatment of exacerbations was permitted throughout the study. All patients were provided with albuterol inhalers for use as rescue medication.
                                                                                                                                                                                            Tiotropium l8 μg OD + placebo bid                                                                                                                                                                                                                                                                                                                                                          

  Chan et al[@b36-copd-10-1863] Bl trial: 205.259                                Randomized, double-blind, parallel-group study                                                             Tiotropium 18 μg OD\                                                      48 weeks         Age ≥40 years; smoking history ≥ 10 pack-years; FEV~1~ ≤65%; FEV~1~/FVC ≤70%; included if ≥ 1 exacerbation noted during the previous year, but not within 6 weeks prior to treatment (later amended to include 1 exacerbation in past 2 years)                                                  Allowed: stable dose of oral corticosteroids, ICS, theophylline preparations, mucolytic preparations (not containing bronchodilators), LABAs
                                                                                                                                                                                            Placebo                                                                                                                                                                                                                                                                                                                                                                                    

  TIPHON (Tonnel et al[@b37-copd-10-1863])                                       Randomized, double-blind, multicenter study                                                                Tiotropium 18 μg OD\                                                      36 weeks         Age ≥40 years; smoking history \> 10 pack-years; FEV~1~, 20%--70%; FEV~1~/FVC ≤70%;                                                                                                                                                                                                             Allowed: stable doses of theophylline preparations (excluding 24-hour preparations), mucolytics, ICS, and oral steroids
                                                                                                                                                                                            Placebo                                                                                                                                                                                                                                                                                                                                                                                    

  UPLIFT (Tashkin et al[@b38-copd-10-1863] and Celli et al[@b35-copd-10-1863])   Placebo-controlled study and randomized, double-blind study                                                Tiotropium 18 μg OD\                                                      4 years          Age ≥40 years; smoking history \> 10 pack-years; FEV~1~, ≤70%; FEV~1~/FVC ≤70%; excluded if exacerbation observed 4 weeks prior                                                                                                                                                                 Allowed: all respiratory medications, except other inhaled anticholinergic drugs
                                                                                                                                                                                            Placebo                                                                                                                                                                                                                                                                                                                                                                                    

  Niewoehner et al[@b40-copd-10-1863]                                            Randomized, double-blind study                                                                             Tiotropium 18 μg OD\                                                      6 months         Age ≥40 years; smoking history ≥ 10 pack-years; FEV~1~ ≤60%; FEV~1~/FVC ≤70%; excluded if no recovery from exacerbation ≥30 days prior                                                                                                                                                          Allowed: all other respiratory medications (including ICS and LABAs)\
                                                                                                                                                                                            Placebo                                                                                                                                                                                                                                                                                                                                                                                    Not allowed: open-label anticholinergic bronchodilators

  Brusasco et al[@b41-copd-10-1863]                                              Randomized, placebo-controlled, double-blind, double-dummy study                                           Tiotropium 18 μg OD\                                                      24 weeks         Age \>40 years; smoking history \> 10 pack-years; FEV~1~ ≤65%; FEV~1~/FVC ≤70%                                                                                                                                                                                                                  NR
                                                                                                                                                                                            Placebo                                                                                                                                                                                                                                                                                                                                                                                    

  Donohue et al[@b25-copd-10-1863]                                               Randomized, placebo-controlled, double-blind, double-dummy, parallel-group study                           Tiotropium 18 μg OD\                                                      24 weeks         Age ≥40 years; smoking history \> 10 pack-years; FEV~1~ ≤60%; FEV~1~/FVC ≤70%                                                                                                                                                                                                                   Allowed: regular ICS and oral steroids\
                                                                                                                                                                                            Placebo                                                                                                                                                                                                                                                                                                                                                                                    Not allowed: inhaled anticholinergic LABAs

  Casaburi et al[@b42-copd-10-1863]                                              Randomized, double-blind placebo-controlled study                                                          Tiotropium 18 μg OD\                                                      56 weeks         Age ≥40 years; smoking history ≥ 10 pack-years; FEV~1~ ≤65%; FEV~1~/FVC ≤70%                                                                                                                                                                                                                    Allowed: stable doses of theophylline, ICS, and oral prednisone
                                                                                                                                                                                            Placebo                                                                                                                                                                                                                                                                                                                                                                                    

  Donohue et al[@b43-copd-10-1863]                                               Randomized, double-blind study                                                                             Tiotropium 18 μg OD\                                                      26 weeks         Patients aged ≥40 years; smoking history ≥20 pack-years; diagnosed with moderate-to-severe COPD (GOLD criteria) were enrolled. Post-bronchodilator (within 30 minutes of inhaling albuterol 360 ug) FEV~1~ \<80% and ≥30% of the predicted normal value; FEV~1~/FVC \<70%                       Patients could continue ICS monotherapy if stable for 1 month before screening; dose and regimen were kept stable throughout the study. Before the start of the run-in period, treatment with anticholinergic bronchodilators or with β2-agonists was discontinued with appropriate washout, and patients receiving fixed-combination P2-agonists/ICS were switched to ICS monotherapy at an equivalent dose. All patients were provided albuterol for use as needed
                                                                                                                                                                                            Placebo                                                                                                                                                                                                                                                                                                                                                                                    

  GLOW 2 (Kerwin et al[@b44-copd-10-1863])                                       Randomized, placebo-controlled study                                                                       Tiotropium 18 μg OD\                                                      52 weeks         Patients aged ≥40 years; any sex; smoking history ≥ 10 pack-years; diagnosed with moderate-to-severe stable COPD; post-bronchodilator FEV~1~ ≥30% and \<80% of the predicted normal value; post-bronchodilator FEV~1~/FVC \<0.70 were enrolled                                                  Allowed: inhaled or intranasal corticosteroids and HI antagonists, salbutamol/albuterol as rescue medication\
                                                                                                                                                                                            Placebo                                                                                                                                                                                                                                                                                                                                                                                    Not allowed: LAMAs (at least 7 days before run-in), LABAs or LABA/ICS combinations (at least 48 hours before run-in)

  Verkindre et al[@b45-copd-10-1863]                                             Randomized, placebo-controlled study                                                                       Tiotropium 18 μg OD\                                                      12 weeks         FEV~1~ ≤50%; FEV~1~/FVC ≤70%; residual volume ≥ 125%; excluded if unstable doses of oral corticosteroids received 6 weeks prior                                                                                                                                                                 Allowed: stable-dose oral corticosteroids, ICS, theophylline preparations, mucolytic agents\
                                                                                                                                                                                            Placebo                                                                                                                                                                                                                                                                                                                                                                                    Not allowed: SABAs, oral β2-agonists, or LABAs

  Casaburi et al[@b46-copd-10-1863]                                              Randomized, double-blind, placebo-controlled, multicenter study                                            Tiotropium 18 μg OD\                                                      13 weeks         Age ≥40 years; diagnosed with COPD defined by ATS; smoking history \> 10 pack-years; FEV~1~ ≤65%; FEV~1~/FVC ≤70%                                                                                                                                                                               Allowed: stable doses of theophylline, ICS, oral prednisone\
                                                                                                                                                                                            Placebo                                                                                                                                                                                                                                                                                                                                                                                    Not allowed: other inhaled or oral bronchodilators

  Covelli et al[@b47-copd-10-1863]                                               Randomized, double-blind, placebo-controlled, parallel-group study                                         Tiotropium 18 μg OD\                                                      12 weeks         FEV~1~ ≤60%; FEV~1~/FVC ≤70%; excluded if exacerbation during 6 weeks prior                                                                                                                                                                                                                     Allowed: ICS, LABAs, and theophyllines\
                                                                                                                                                                                            Placebo                                                                                                                                                                                                                                                                                                                                                                                    Not allowed: cromones, leukotriene antagonists, and inhaled anticholinergics

  Garcia et al[@b48-copd-10-1863]                                                Randomized, double-blind, placebo-controlled study                                                         Tiotropium 18 μg OD\                                                      12 weeks         Ambulatory patients of either sex; age \>40 years; diagnosed with COPD (FEV~1~ \<60% of the predicted value and FEV~1~/FVC \<70%); smokers or                                                                                                                                                   NR
                                                                                                                                                                                            Placebo                                                                                                                                                                                                                                                                                                                                                                                    

  Moita et al[@b49-copd-10-1863]                                                 Randomized, double-blind, placebo-controlled study                                                         Tiotropium 18 μg OD\                                                      12 weeks         ex-smokers with smoking history ≥ 10 pack-years FEV~1~ ≤70%; FEV~1~/FVC ≤70%; excluded if ≥3 exacerbations during the previous year or an exacerbation 6 weeks prior                                                                                                                            Allowed: LABAs, theophylline, mucolytics, ICS, stable-dose oral corticosteroids; temporary increases in theophylline or oral steroids for exacerbations\
                                                                                                                                                                                            Placebo                                                                                                                                                                                                                                                                                                                                                                                    Not allowed: 24-hour preparations of theophylline
  -----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------

**Abbreviations:** ATS, American Thoracic Society; COPD, chronic obstructive pulmonary disease; FEV~1~, forced expiratory volume in 1 second; FVC, forced expiratory vital capacity; GOLD, Global initiative for chronic Obstructive Lung Disease; ICS, inhaled corticosteroid; LABA, long-acting β2-agonist; LAMA, long-acting muscarinic antagonist; NMA, network meta-analysis; OD, once daily; QVA149, indacaterol/glycopyrronium; NR, not reported; SABA, short-acting β2-agonist.

###### 

Key patient characteristics at baseline for all studies included in the NMA (only arms of interest)

  ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
  Studies included in the NMA                                                    Treatment                                         ITT (n)                                           Male (%)      Age (SD) in years   Current smokers (%)   Severe or very severe (%)   ICS usage (%)   COPD duration mean (SD) in years                         Pack-years (SD)   FEV~1~% predicted (SD)
  ------------------------------------------------------------------------------ ------------------------------------------------- ------------------------------------------------- ------------- ------------------- --------------------- --------------------------- --------------- -------------------------------------------------------- ----------------- ------------------------
  Decramer et al[@b9-copd-10-1863] (DB2113360)                                   Tiotropium 18 μg OD                               208                                               67            62.6 (9.39)         48                    53                          45              NR                                                       41.9 (24.44)      47.8 (13.36)

  Vilanterol 22 μg/umeclidinium 55 μg OD                                         212                                               70                                                63 (8.67)     46                  50                    44                          NR              44.8 (27.65)                                             48.0 (12.94)      

  Decramer et al[@b9-copd-10-1863] (DB2113374)                                   Tiotropium 18 μg OD                               215                                               71            65.2 (8.3)          47                    52                          53              NR                                                       54.0 (31.59)      47.4 (13.10)

  Vilanterol 22 μg/umeclidinium 55 μg OD                                         217                                               65                                                65 (8.62)     42                  51                    47                          NR              47.8 (26.13)                                             47.7 (13.55)      

  Donohue et al[@b6-copd-10-1863] (DB2113373)                                    Placebo                                           280                                               70            62.2 (9.04)         54                    58                          49              NR                                                       47.2 (27.21)      46.7 (12.71)

  Vilanterol 22 μg/umeclidinium 55 μg OD                                         413                                               74                                                63.1 (8.71)   49                  51                    51                          NR              46.5 (25.80)                                             47.8 (13.19)      

  Maleki-Yazdi et al[@b28-copd-10-1863] (ZEP117115)                              Tiotropium 18 μg OD                               451                                               67            62.7 (8.50)         54                    58                          53              NR                                                       44.4 (25.03)      46.5 (12.76)

  Vilanterol 22 μg/umeclidinium 55 μg OD                                         454                                               68                                                61.9 (8.41)   59                  60                    54                          NR              44.1 (24.44)                                             46.2 (13.02)      

  INTRUST 1 (Mahler et al[@b17-copd-10-1863])                                    Tiotropium 18 μg OD                               564                                               67            63.4 (9.22)         36                    53                          52              6.6 (6.45)                                               47.2 (26.58)      48.9 (11.46)

  Indacaterol 150 μg OD + tiotropium 18 μg OD                                    570                                               70                                                64.0 (9.07)   40                  53                    52                          7.1 (6.12)      47.2 (25.86)                                             48.3 (9.70)       

  INTRUST 2 (Mahler et al[@b17-copd-10-1863])                                    Tiotropium 18 μg OD                               570                                               68            62.8 (8.98)         43                    54                          51              7.1 (6.26)                                               46.3 (24.64)      48.6 (9.76)

  Indacaterol 150 μg OD + tiotropium 18 μg OD                                    572                                               63                                                63.1 (8.83)   38                  54                    57                          7.3 (6.48)      46.2 (25.52)                                             48.6 (9.74)       

  Aaron et al[@b20-copd-10-1863]                                                 Tiotropium 18 μg OD                               156                                               53.8          68.1 (8.9)          27                    NR                          25              11.3 (8.8)[a](#tfn2-copd-10-1863){ref-type="table-fn"}   51.8 (28.0)       42.1 (13.5)

  Tiotropium 18 μg OD + salmeterol 25 μg\                                        148                                               57.4                                              67.6 (8.2)    24.3                NR                    34.9                        NR              48.7 (27.1)                                              41.2 (13.0)       
  2 puffs bid                                                                                                                                                                                                                                                                                                                                                       

  ENLIGHTEN (Dahl et al[@b13-copd-10-1863])                                      Placebo                                           113[b](#tfn3-copd-10-1863){ref-type="table-fn"}   76.1          62.9 (8.14)         45                    19                          39              5.46 (5.1)                                               38.1 (15.93)      59.43 (12.5)

  QVA149 (indacaterol 110 μg/glycopyrronium 50 μg) OD                            226[b](#tfn3-copd-10-1863){ref-type="table-fn"}   77.3                                              62.5 (8.81)   45                  31                    46                          5.82 (5.74)     36.3 (16.01)                                             56.39 (13.27)     

  SPARK (Wedzicha et al[@b16-copd-10-1863])                                      Tiotropium 18 μg OD                               742[b](#tfn3-copd-10-1863){ref-type="table-fn"}   75            63.6 (7.8)          37                    100                         76              7.2 (5.5)                                                47 (28)           37.4 (8.1)

  QVA149 (indacaterol 110 μg/glycopyrronium 50 μg) OD                            741[b](#tfn3-copd-10-1863){ref-type="table-fn"}   76                                                63.1 (8.1)    38                  100                   75                          7.2 (5.8)       45 (23)                                                  37.0 (8.1)        

  SHINE (Bateman et al[@b11-copd-10-1863])                                       Placebo                                           234[b](#tfn3-copd-10-1863){ref-type="table-fn"}   72.8          64.4 (8.6)          40                    32                          58              6.4 (5.7)                                                NR                55.2 (12.7)

  Tiotropium 18 μg OD                                                            483[b](#tfn3-copd-10-1863){ref-type="table-fn"}   75.0                                              63.5 (8.7)    39                  38                    59                          6.1 (5.5)       NR                                                       55.1 (13.5)       

  QVA149 (indacaterol 110 μg/glycopyrronium 50 μg) OD                            475[b](#tfn3-copd-10-1863){ref-type="table-fn"}   76.4                                              64.0 (8.9)    40                  34                    56                          6.0 (5.5)       NR                                                       55.7 (13.2)       

  Vogelmeier et al[@b19-copd-10-1863]                                            Tiotropium 18 μg OD                               221                                               79.2          63.4 (9.5)          NR                    NR                          NR              6.9 (6.3)                                                38.6 (19.3)       51.6 (11.2)

  Formoterol 10 μg bid + tiotropium 18 μg OD                                     207                                               79.2                                              62.6 (8.8)    NR                  NR                    NR                          7.2 (7.0)       37.9 (18.2)                                              50.4 (10.5)       

  Placebo                                                                        209                                               77.5                                              62.5 (8.6)    NR                  NR                    NR                          6.7 (6.1)       40.1 (22.8)                                              51.1 (11)         

  Tashkin et al[@b18-copd-10-1863]                                               Tiotropium 18 μg OD + formoterol 12 μg bid        124                                               65            63.8 (8.7)          49                    NR                          27              NR                                                       NR                NR

  Tiotropium 18 μg OD + placebo bid                                              131                                               68                                                63.9 (8.5)    46                  NR                    27                          NR              NR                                                       NR                

  Chan et al[@b36-copd-10-1863]\                                                 Tiotropium 18 μg OD                               608                                               59            67.0 (8.7)          32                    NR                          66              9.9 (8.1)                                                50.2 (22.6)       39 (13)
  BI trial: 205.259                                                                                                                                                                                                                                                                                                                                                 

  Placebo                                                                        305                                               61                                                67.0 (9.1)    30                  NR                    71                          9.9 (7.9)       51.0 (26.3)                                              39 (14)           

  TIPHON (Tonnel et al[@b37-copd-10-1863])                                       Tiotropium 18 μg OD                               266                                               87            65.0 (9.7)          24                    57                          38              7.9 (7.6)                                                44.4 (21.3)       47 (13)

  Placebo                                                                        288                                               85                                                64.0 (10.1)   30                  62                    36                          8.0 (7.9)       43.0 (22.5)                                              46 (12)           

  UPLIFT (Tashkin et al[@b38-copd-10-1863] and Celli et al[@b39-copd-10-1863])   Tiotropium 18 μg OD                               2,987                                             75            65.0 (8.4)          29                    52                          62              9.9 (7.6)                                                49.0 (28.0)       40 (12)

  Placebo                                                                        3,006                                             74                                                65.0 (8.5)    30                  53                    62                          9.7 (7.4)       48.4 (27.9)                                              39 (12)           

  Niewoehner et al[@b40-copd-10-1863]                                            Tiotropium 18 μg OD                               914                                               98            67.6 (8.7)          29                    NR                          61              12.2 (10.4)                                              67.4 (35.4)       36 (13)

  Placebo                                                                        915                                               99                                                68.1 (8.5)    30                  NR                    58                          11.9 (10.5)     69.4 (36.6)                                              36 (13)           

  Brusasco et al[@b41-copd-10-1863]                                              Tiotropium 18 μg OD                               402                                               77            63.8 (8.0)          NR                    NR                          NR              9.0 (7.3)                                                44.1 (22.9)       39 (12)

  Placebo                                                                        400                                               76                                                64.6 (8.6)    NR                  NR                    NR                          9.8 (7.4)       42.4 (22.7)                                              39 (12)           

  Donohue et al[@b29-copd-10-1863]                                               Tiotropium 18 μg OD                               209                                               74            64.5 (7.9)          NR                    NR                          66              9.2 (7.8)                                                47.0 (25.0)       41 (NR)

  Placebo                                                                        201                                               75                                                65.6 (7.8)    NR                  NR                    66                          9.7 (7.9)       46.0 (24.0)                                              41 (NR)           

  Casaburi et al[@b42-copd-10-1863]                                              Tiotropium 18 μg OD                               550                                               67            65.0 (9.0)          NR                    NR                          44              8.6 (7.4)                                                63.0 (31.0)       39 (14)

  Placebo                                                                        371                                               63                                                65.0 (9.0)    NR                  NR                    40                          8.1 (6.8)       59.0 (30.0)                                              38 (14)           

  Donohue et al[@b43-copd-10-1863]                                               Tiotropium 18 μg OD                               420                                               65            64 (8.8)            NR                    NR                          35              NR                                                       50.0 (25.1)       54 (16)

  Placebo                                                                        425                                               61                                                63.6 (8.9)    NR                  NR                    40                          NR              49.7 (23.9)                                              56 (14)           

  GLOW 2 (Kerwin et al[@b44-copd-10-1863])                                       Tiotropium 18 μg OD                               267                                               63            63.9 (8.2)          44                    NR                          52              7.5 (6.6)                                                50.2 (28.0)       56 (13)

  Placebo                                                                        268                                               65                                                63.6 (9.1)    46                  NR                    51                          7.4 (6.6)       48.0 (24.0)                                              56 (14)           

  Verkindre et al[@b45-copd-10-1863]                                             Tiotropium 18 μg OD                               46                                                94            61.0 (9.5)          24                    NR                          NR              9.7 (6.9)                                                45.6 (23.1)       35 (9)

  Placebo                                                                        54                                                94                                                60.0 (10.2)   33                  NR                    NR                          8.8 (6.6)       41.8 (18.0)                                              36 (9)            

  Casaburi et al[@b46-copd-10-1863]                                              Tiotropium 18 μg OD                               276                                               67            65.0 (8.6)          NR                    NR                          NR              9.3 (8.0)                                                64.5 (33.1)       39 (14)

  Placebo                                                                        188                                               63                                                65.0 (9.0)    NR                  NR                    NR                          8.6 (6.9)       60.5 (30.2)                                              38 (14)           

  Covelli et al[@b47-copd-10-1863]                                               Tiotropium 18 μg OD                               94                                                66            66.0 (8.9)          40                    NR                          54              10.1 (8.1)                                               66 (35.6)         40 (13)

  Placebo                                                                        84                                                49                                                63.0 (9.2)    37                  NR                    58                          10.4 (7.7)      65 (31.2)                                                39 (14)           

  Garcia et al[@b48-copd-10-1863]                                                Tiotropium 18 μg OD                               123                                               NR            NR                  NR                    NR                          NR              NR                                                       NR                NR

  Placebo                                                                        125                                               NR                                                NR            NR                  NR                    NR                          NR              NR                                                       NR                

  Moita et al[@b49-copd-10-1863]                                                 Tiotropium 18 μg OD                               147                                               NR            NR                  28                    NR                          NR              NR                                                       NR                NR

  Placebo                                                                        164                                               NR                                                NR            25                  NR                    NR                          NR              NR                                                       NR                
  ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------

**Notes:**

Duration of reported dyspnea.

Randomized population.

**Abbreviations:** bid, twice daily; COPD, chronic obstructive pulmonary disease; FEV~1~, forced expiratory volume in 1 second; FP, fluticasone propionate; ICS, inhaled corticosteroid; ITT, intent-to-treat; NMA, network meta-analysis; NR, not reported; OD, once daily; QVA149, indacaterol/glycopyrronium; SD, standard deviation.

###### 

Individual study results at 12 weeks and 24 weeks for trough FEV~1~, SGRQ total scores, TDI focal scores, and rescue medication use (puffs/day)

  Study                                               Treatment                                                                    Weeks   Trough FEV~1~ in mL (difference in CFB), mean (SE)   SGRQ total score (difference in CFB), mean (SE)             TDI focal score (difference in TDI), mean (SE)             Rescue medication use (difference in puffs/day vs placebo), mean (SE)
  --------------------------------------------------- ---------------------------------------------------------------------------- ------- ---------------------------------------------------- ----------------------------------------------------------- ---------------------------------------------------------- -----------------------------------------------------------------------
  Donohue et al[@b6-copd-10-1863] (DB2113373)         Vilanterol 22 μg/umeclidinium 55 μg OD vs placebo                            12      195.00 (17.86)                                       −4.72 (1.06)                                                1.30 (0.23)                                                −1.00 (0.24)
                                                                                                                                   24      167.00 (20.15)                                       −5.51 (1.21)                                                1.20 (0.26)                                                −0.80 (0.26)
  Decramer et al[@b9-copd-10-1863] (DB2113360)        Vilanterol 22 μg/umeclidinium 55 μg OD vs tiotropium 18 μg OD                12      95.00 (21.94)                                        −2.01 (1.26)                                                0.70 (0.31)                                                −0.51 (0.32)
                                                                                                                                   24      60.00 (25.26)                                        −0.17 (1.37)                                                0.20 (0.36)                                                −0.60 (0.31)
  Decramer et al[@b9-copd-10-1863] (DB2113374)        Vilanterol 22 μg/umeclidinium 55 μg OD vs tiotropium 18 μg OD                12      80.00 (24.49)                                        −0.23 (1.29)                                                0.20 (0.26)                                                −0.78 (0.30)
                                                                                                                                   24      90.00 (26.02)                                        0.75 (1.47)                                                 −0.10 (0.31)                                               −0.70 (0.28)
  Maleki-Yazdi et al[@b28-copd-10-1863] (ZEP117115)   Vilanterol 22 μg/umeclidinium 55 μg OD vs tiotropium 18 μg OD                12      109.00 (15.82)                                       −2.08 (0.70)                                                                                                           −0.50 (0.10)
                                                                                                                                   24      112.00(16.07)                                        −2.10(0.77)                                                                                                            −0.50 (0.13)
  SHINE[@b11-copd-10-1863]                            QVA149 (indacaterol 110 μg/glycopyrronium 50 μg) OD vs placebo               12      230.00 (17.86)                                       −3.99 (0.87[\*](#tfn5-copd-10-1863){ref-type="table-fn"})   1.22(0.26)                                                 
                                                                                                                                   24      200.00 (17.86)                                       −3.01 (1.04)                                                1.09(0.24)                                                 −0.96 (0.17)
  SHINE[@b11-copd-10-1863]                            Tiotropium 18 μg OD vs placebo                                               12      130.00 (17.86)                                       −2.37 (0.87[\*](#tfn5-copd-10-1863){ref-type="table-fn"})   0.59 (0.27)                                                
                                                                                                                                   24      130.00 (17.86)                                       −0.88 (1.04)                                                0.58 (0.24)                                                −0.41 (0.17)
  SPARK[@b16-copd-10-1863]                            QVA149 (indacaterol 110 μg/glycopyrronium 50 μg) OD vs tiotropium 18 μg OD   12      70.00 (13.79)                                        −3.00 (0.88)                                                                                                           
                                                                                                                                   24      70.00 (13.79)                                        −1.60 (0.92)                                                                                                           
  ENLIGHTEN[@b13-copd-10-1863]                        QVA149 (indacaterol 110 μg/glycopyrronium 50 μg) OD vs placebo               12      163.00 (32.02)                                                                                                                                                              
                                                                                                                                   24      152.00 (35.36)                                                                                                                                                              
  Niewoehner et al[@b40-copd-10-1863]                 Tiotropium 18 μg OD vs placebo                                               12      100.00 (10.00)                                                                                                                                                              
                                                                                                                                   24      100.00 (13.00)                                                                                                                                                              
  Donohue et al[@b43-copd-10-1863]                    Tiotropium 18 μg OD vs placebo                                               12      140.00 (20.41)                                       −1.10 (0.87)                                                0.75 (0.22)                                                
                                                                                                                                   24      140.00 (20.41)                                       −1.00 (0.92)                                                0.87 (0.23)                                                −0.60 (0.19)
  GLOW 2[@b44-copd-10-1863]                           Tiotropium 18 μg OD vs placebo                                               12      83.00 (19.00)                                        −2.84 (0.97)                                                0.26 (0.30)                                                
                                                                                                                                   24      84.00 (21.60)                                        −2.52 (1.11)                                                0.94 (0.30)                                                
  TIPHON[@b37-copd-10-1863]                           Tiotropium 18 μg OD vs placebo                                               12                                                           −3.59 (1.22)                                                                                                           
                                                                                                                                   24                                                           −3.51 (0.65)                                                                                                           
  Casaburi et al[@b42-copd-10-1863]                   Tiotropium 18 μg OD vs placebo                                               12                                                                                                                       0.95 (0.18)                                                
                                                                                                                                   24                                                                                                                       0.85 (0.19)                                                
  INTRUST 1[@b17-copd-10-1863]                        Indacaterol 150 μg OD + tiotropium 18 μg OD vs tiotropium 18 μg OD           12      80.00 (12.76)                                                                                                                                                               −1.10 (0.18)
  INTRUST 2[@b17-copd-10-1863]                        Indacaterol 150 μg OD + tiotropium 18 μg OD vs tiotropium 18 μg OD           12      70.00 (10.20)                                                                                                                                                               −0.70(0.15)
  Tashkin et al[@b18-copd-10-1863]                    Tiotropium 18 μg OD + formoterol 12 μg bid vs tiotropium 18 μg OD            12      90.00 (28.06)                                        −1.01 (1.68[\*](#tfn5-copd-10-1863){ref-type="table-fn"})   0.07 (0.39)                                                −0.25 (0.35[\*](#tfn5-copd-10-1863){ref-type="table-fn"})
  Chan et al[@b36-copd-10-1863]                       Tiotropium 18 μg OD vs placebo                                               12      100.00 (15.00)                                                                                                                                                              
  Niewoehner et al[@b40-copd-10-1863]                 Tiotropium 18 μg OD vs placebo                                               12      100.00 (10.00)                                                                                                                                                              
  Verkindre et al[@b45-copd-10-1863]                  Tiotropium 18 μg OD vs placebo                                               12      110.00 (40.00)                                       −6.50 (2.90)                                                1.28 (0.89)                                                −0.13 (0.25)
  Casaburi et al[@b46-copd-10-1863]                   Tiotropium 18 μg OD vs placebo                                               12      150.00 (14.00)                                                                                                                                                              
  Covelli et al[@b47-copd-10-1863]                    Tiotropium 18 μg OD vs placebo                                               12      184.00 (37.00)                                                                                                                                                              
  Moita et al[@b45-copd-10-1863]                      Tiotropium 18 μg OD vs placebo                                               12      102.00 (31.38)                                                                                                                                                              
  Aaron et al[@b20-copd-10-1863]                      Tiotropium 18 μg OD + salmeterol 50 μg vs tiotropium 18 μg OD                24      18.49 (45.46)                                        −1.47 (0.69)                                                −0.42 (0.43)                                               
  UPLIFT[@b38-copd-10-1863],[@b35-copd-10-1863]       Tiotropium 18 μg OD vs placebo                                               24      100.00 (7.00)                                        −2.5 (0.36)                                                                                                            
  Brusasco et al[@b41-copd-10-1863]                   Tiotropium 18 μg OD vs placebo                                               24      120.00 (100.00)                                      −2.7 (0.99)                                                 1.10 (0.30)                                                
  Donohue et al[@b29-copd-10-1863]                    Tiotropium 18 μg OD vs placebo                                               24      137.00 (20.00)                                       −2.71 (0.99[\*](#tfn5-copd-10-1863){ref-type="table-fn"})   1.02 (0.25[\*](#tfn5-copd-10-1863){ref-type="table-fn"})   −1.45 (0.26[\*](#tfn5-copd-10-1863){ref-type="table-fn"})
  Vogelmeier et al[@b19-copd-10-1863]                 Tiotropium 18 μg OD + formoterol 10 μg bid vs placebo                        24                                                           −2.93 (1.33)                                                                                                           
  Vogelmeier et al[@b19-copd-10-1863]                 Tiotropium 18 μg OD + formoterol 10 μg bid vs tiotropium 18 μg OD            24                                                           −0.88(1.84)                                                                                                            
  Vogelmeier et al[@b19-copd-10-1863]                 Tiotropium 18 μg OD vs placebo                                               24                                                           −2.05(1.27)                                                                                                            

**Notes:**

Imputed value. Blank spaces in the table indicate not applicable.

**Abbreviations:** bid, twice daily; CFB, change from baseline; FEV~1~, forced expiratory volume in 1 second; OD, once daily; QVA149, indacaterol/glycopyrronium; SE, standard error; SGRQ, St George's Respiratory Questionnaire; TDI, transitional dyspnea index.

###### 

Results of the NMA

  Intervention                                       Weeks                  Comparator                                                                                        
  -------------------------------------------------- ------- -------------- ---------------- ---------------- ---------------- ---------------- ------------- --------------- --------------
  **CFB in trough FEV~1~**                                                                                                                                                    
  Tiotropium 18 μg                                   12      Estimate       114.50                                                                                            
                                                             95% Crl        103.60, 125.30                                                                                    
                                                             *P* (better)   \>99%                                                                                             
                                                     24      Estimate       105.40                                                                                            
                                                             95% Crl        95.10, 115.90                                                                                     
                                                             *P* (better)   \>99%                                                                                             
  QVA149 (indacaterol 110 μg/glycopyrronium 50 μg)   12      Estimate       198.70           84.20                                                                            
                                                             95% Crl        178.50, 218.70   65.58, 102.90                                                                    
                                                             *P* (better)   \>99%            \>99%                                                                            
                                                     24      Estimate       177.50           72.01                                                                            
                                                             95% Crl        157.30, 197.80   53.74, 90.75                                                                     
                                                             *P* (better)   \>99%            \>99%                                                                            
  Vilanterol 22 μg/umeclidinium 55 μg                12      Estimate       208.10           93.65            9.41                                            3.86            19.80
                                                             95% Crl        187.90, 228.40   74.53, 112.60    −16.96, 35.77                                   −54.14,62.18    −4.90, 44.40
                                                             *P* (better)   \>99%            \>99%            76%                                             55%             94%
                                                     24      Estimate       191.50           86.16            14.14            67.40                                          
                                                             95%Crl         169.70, 213.40   65.74, 106.50    −14.18, 42.25    −25.25, 159.40                                 
                                                             *P* (better)   \>99%            \>99%            84%              92%                                            
  Formoterol 12 μg + tiotropium 18 μg                12      Estimate       204.30           89.78            5.56                                                            
                                                             95%Crl         148.30, 260.00   34.82, 144.50    −52.53, 63.42                                                   
                                                             *P* (better)   \>99%            \>99%            57%                                                             
  Indacaterol 150 μg + tiotropium 18 μg              12      Estimate       188.30           73.85            −10.32                                          −15.94          
                                                             95%Crl         169.30, 207.40   58.21, 89.46     −34.82, 13.93                                   −72.84, 41.26   
                                                             *P* (better)   \>99%            \>99%            20%                                             29%             
  Tiotropium 18 μg + salmeterol 50 μg                24      Estimate       124.50           19.18            −53.00                                                          
                                                             95%Crl         33.98, 214.20    −71.35, 108.70   −146.80, 38.38                                                  
                                                             *P* (better)   \>99%            65%              13%                                                             
  **SGRQ total score**                                                                                                                                                        
  Tiotropium 18 μg                                   12      Estimate       −2.52                                                                                             
                                                             95%Crl         −3.51, −1.53                                                                                      
                                                             *P* (better)   \>99%                                                                                             
                                                     24      Estimate       −2.50                                                                                             
                                                             95%Crl         −3.01, −2.01                                                                                      
                                                             *P* (better)   \>99%                                                                                             
  QVA149 (indacaterol 110 μg/glycopyrronium 50 μg)   12      Estimate       −5.52            −3.00                                                                            
                                                             95%Crl         −7.50, −3.52     −4.72, −1.28                                                                     
                                                             *P* (better)   \>99%            \>99%                                                                            
                                                     24      Estimate       −*A.*27          −1.77                                                                            
                                                             95%Crl         −5.34, −3.20     −2.75, −0.78                                                                     
                                                             *P* (better)   \>99%            \>99%                                                                            
  Vilanterol 22 μg/umeclidinium 55 μg                12      Estimate       −4.35            −1.83            1.17                                                            
                                                             95%Crl         −5.58, −3.11     −2.81, −0.84     −0.81, 3.15                                                     
                                                             *P* (better)   \>99%            \>99%            12%                                                             
                                                     24      Estimate       −4.09            −1.58            0.18             −0.11            −0.68                         
                                                             95%Crl         −5.23, −2.95     −2.66, −0.52     −1.28, 1.63      −1.84, 1.61      −1.77, 0.39                   
                                                             *P* (better)   \>99%            \>99%            41%              55%              89%                           
  Tiotropium 18 μg + formoterol 10 μg                24      Estimate       −3.41            −0.90            0.86                                                            
                                                             95%Crl         −3.95, −2.86     −1.06, −0.74     −0.13, 1.86                                                     
                                                             *P* (better)   \>99%            \>99%            4%                                                              
  Tiotropium 18 μg + salmeterol 50 μg                24      Estimate       −3.98            −1.47            0.29                              −0.57                         
                                                             95%Crl         −5.42, −2.53     −2.83, −0.12     −1.38, 1.96                       −1.93, 0.79                   
                                                             *P* (better)   \>99%            98%              37%                               80%                           
  **TDI focal score**                                                                                                                                                         
  Tiotropium 18 μg                                   12      Estimate       0.76                                                                                              
                                                             95% Crl        0.55, 0.97                                                                                        
                                                             *P* (better)   \>99%                                                                                             
                                                     24      Estimate       0.87                                                                                              
                                                             95% Crl        0.67, 1.07                                                                                        
                                                             *P* (better)   \>99%                                                                                             
  QVA149 (indacaterol 110 μg/glycopyrronium 50 μg)   12      Estimate       1.33             0.57                                                                             
                                                             95% Crl        0.92, 1.73       0.18, 0.96                                                                       
                                                             *P* (better)   \>99%            \>99%                                                                            
                                                     24      Estimate       1.34             0.46                                                                             
                                                             95% Crl        1.03, 1.64       0.21,0.72                                                                        
                                                             *P* (better)   \>99%            \>99%                                                                            
  Vilanterol 22 μg/umeclidinium 55 μg                12      Estimate       1.22             0.46             −0.10                                           0.39            
                                                             95% Crl        0.90, 1.54       0.16, 0.77       −0.59, 0.38                                     −0.43, 1.22     
                                                             *P* (better)   \>99%            \>99%            34%                                             83%             
                                                     24      Estimate       1.04             0.16             −0.30            0.58                                           
                                                             95% Crl        0.68, 1.39       −0.19, 0.52      −0.73, 0.13      −0.33, 1.50                                    
                                                             *P* (better)   \>99%            82%              9%               90%                                            
  Tiotropium 18 μg + formoterol 12 μg                12      Estimate       0.83             0.07             −0.50                                                           
                                                             95%Crl         0.03, 1.62       −0.70, 0.83      −1.36, 0.36                                                     
                                                             *P* (better)   0.98             57%              13%                                                             
  Tiotropium 18 μg + salmeterol 50 μg                24      Estimate       0.45             −0.42            −0.89                                                           
                                                             95% Crl        −0.42, 1.31      −1.26, 0.42      −1.77, −0.01                                                    
                                                             *P* (better)   0.85             16%              2%                                                              
  **Rescue medication use**                                                                                                                                                   
  Tiotropium 18 μg                                   12      Estimate       −0.21                                                                                             
                                                             95% Crl        −0.60, 0.18                                                                                       
                                                             *P* (better)   0.86                                                                                              
                                                     24      Estimate       −0.46                                                                                             
                                                             95% Crl        −0.68, −0.23                                                                                      
                                                             *P* (better)   \>99%                                                                                             
  Vilanterol 22 μg/umeclidinium 55 μg                12      Estimate       −0.93            −0.71                                                                            0.15
                                                             95% Crl        −1.31, −0.55     −1.08, −0.35                                                                     −0.28, 0.58
                                                             *P* (better)   \>99%            \>99%                                                                            25%
                                                     24      Estimate       −0.97            −0.51            0.02                                                            
                                                             95% Crl        −1.25, −0.69     −0.71, −0.31     −0.27, 0.32                                                     
                                                             *P* (better)   \>99%            \>99%            43%                                                             
  Indacaterol 150 μg + tiotropium 18 μg              12      Estimate       −1.08            −0.86                                                                            
                                                             95% Crl        −1.53, −0.63     −1.09, −0.64                                                                     
                                                             *P* (better)   \>99%            \>99%                                                                            
  QVA149 (indacaterol 110 μg/glycopyrronium 50 μg)   24      Estimate       −0.99            −0.54                                                                            
                                                             95% Crl        −1.27, −0.72     −0.77, −0.31                                                                     
                                                             *P* (better)   \>99%            \>99%                                                                            

**Notes:** Differences in intervention versus the comparator for CFB in trough FEV~1~ (mL), SGRQ total scores, TDI focal scores, and rescue medication use at 12 weeks and 24 weeks, 95% CrI, and probability (*P*) that the intervention is better than the comparator. Blank spaces in the table indicate not applicable.

**Abbreviations:** CFB, change from baseline; CrI, credible interval; FEV~1~, forced expiratory volume in 1 second; NMA, network meta-analysis; OD, once daily; QVA149, indacaterol/glycopyrronium; SGRQ, St George's Respiratory Questionnaire; TDI, transitional dyspnea index.
