Efficacy and safety of once-daily single-inhaler triple therapy (FF/UMEC/VI) versus FF/VI in patients with inadequately controlled asthma (CAPTAIN): a double-blind, randomised, phase 3A trial

Summary

Background

Despite inhaled corticosteroid plus long-acting β₂-agonist (ICS/LABA) therapy, 30–50% of patients with moderate or severe asthma remain inadequately controlled. We investigated the safety and efficacy of single-inhaler fluticasone furoate plus umeclidinium plus vilanterol (FF/UMEC/VI) compared with FF/VI.

Methods

In this double-blind, randomised, parallel-group, phase 3A study (Clinical Study in Asthma Patients Receiving Triple Therapy in a Single Inhaler [CAPTAIN]), participants were recruited from 416 hospitals and primary care centres across 15 countries. Participants were eligible if they were aged 18 years or older, with inadequately controlled asthma (Asthma Control Questionnaire [ACQ]-6 score of ≥1·5) despite ICS/LABA, a documented health-care contact or a documented temporary change in asthma therapy for treatment of acute asthma symptoms in the year before screening, pre-bronchodilator FEV₁ between 30% and less than 85% of predicted normal value, and reversibility (defined as an increase in FEV₁ of ≥12% and ≥200 mL in the 20–60 min after four inhalations of albuterol or salbutamol) at screening. Participants were randomly assigned (1:1:1:1:1:1), via central based randomisation stratified by pre-study ICS dose at study entry, to once-daily FF/VI (100/25 μg or 200/25 μg) or FF/UMEC/VI (100/31·25/25 μg, 100/62·5/25 μg, 200/31·25/25 μg, or 200/62·5/25 μg) administered via Ellipta dry powder inhaler (Glaxo Operations UK, Hertfordshire, UK). Patients, investigators, and the funder were masked to treatment allocation. Endpoints assessed in the intention-to-treat population were change from baseline in clinic trough FEV₁ at week 24 (primary) and annualised moderate and/or severe asthma exacerbation rate (key secondary). Other secondary endpoints were change from baseline in clinic FEV₁ at 3 h post-dose, St George's Respiratory Questionnaire (SGRQ) total score, and ACQ-7 total score, all at week 24. Change from baseline in Evaluating Respiratory Symptoms in Asthma total score at weeks 21–24 was also a secondary endpoint but is not reported here. Exploratory analyses of biomarkers of type 2 airway inflammation on treatment response were also done. This study is registered with ClinicalTrials.gov, NCT02924688, and is now complete.

Findings

Between Dec 16, 2016, and Aug 31, 2018, 5185 patients were screened and 2439 were recruited and randomly assigned to FF/VI (100/25 μg n=407; 200/25 μg n=406) or FF/UMEC/VI (100/31·25/25 μg n=405; 100/62·5/25 μg n=406; 200/31·25/25 μg n=404; 200/62·5/25 μg n=408), with three patients randomly assigned in error and not included in analyses. In the intention-to-treat population, 922 (38%) patients were men, the mean age was 53·2 years (SD 13·1) and body-mass index was 29·4 (6·6). Baseline demographics were generally similar across all treatment groups. The least squares mean improvement in FEV₁ change from baseline for FF/UMEC/VI 100/62·5/25 μg versus FF/VI 100/25 μg was 110 mL (95% CI 66–153; p<0·0001) and for 200/62·5/25 μg versus 200/25 μg was 92 mL (49–135; p<0·0001). Adding UMEC 31·25 μg to FF/VI produced similar improvements (FF/UMEC/VI 100/31·25/25 μg vs FF/VI 100/25 μg: 96 mL [52–139; p<0·0001]; and 200/31·25/25 μg vs 200/25 μg: 82 mL [39–125; p=0·0002]). These results were supported by the analysis of clinic FEV₁ at 3 h post-dose. Non-significant reductions in moderate and/or severe exacerbation rates were observed for FF/UMEC 62·5 μg/VI versus FF/VI (pooled analysis), with rates lower in FF 200 μg-containing versus FF 100 μg-containing treatment groups. All pooled treatment groups demonstrated mean improvements (decreases) in SGRQ total score at week 24 compared with baseline in excess of the minimal clinically important difference of 4 points; however, there were no differences between treatment groups. For mean change from baseline to week 24 in asthma control questionnaire-7 score, improvements (decreases) exceeding the minimal clinically important difference of 0·5 points were observed in all pooled treatment groups. Adding UMEC to FF/VI resulted in small, dose-related improvements compared with FF/VI (pooled analysis: FF/UMEC 31·25 μg/VI versus FF/VI, −0·06 (95% CI −0·12 to 0·01; p=0·094) FF/UMEC 62·5 μg/VI versus FF/VI, −0·09 (−0·16 to −0·02, p=0·0084). By contrast with adding UMEC, the effects of higher dose FF on clinic trough FEV₁ and annualised moderate and/or severe exacerbation rate were increased in patients with higher baseline blood eosinophil count and exhaled nitric oxide. Occurrence of adverse events was similar across treatment groups (patients with at least one event ranged from 210 [52%] to 258 [63%]), with the most commonly reported adverse events being nasopharyngitis (51 [13%]–63 [15%]), headache (19 [5%]–36 [9%]), and upper respiratory tract infection (13 [3%]–24 [6%]). The incidence of serious adverse events was similar across all groups (range 18 [4%]–25 [6%)). Three deaths occurred, of which one was considered to be related to study drug (pulmonary embolism in a patient in the FF/UMEC/VI 100/31·25/25 μg group).

Interpretation

In patients with uncontrolled moderate or severe asthma on ICS/LABA, adding UMEC improved lung function but did not lead to a significant reduction in moderate and/or severe exacerbations. For such patients, single-inhaler FF/UMEC/VI is an effective treatment option with a favourable risk–benefit profile. Higher dose FF primarily reduced the rate of exacerbations, particularly in patients with raised biomarkers of type 2 airway inflammation. Further confirmatory studies into the differentiating effect of type 2 inflammatory biomarkers on treatment outcomes in asthma are required to build on these exploratory findings and further guide clinical practice.

Funding

GSK.

Introduction

Inhaled corticosteroid plus long-acting β₂-agonist (ICS/LABA) combination therapy is recommended for patients with asthma who are inadequately controlled with ICS monotherapy along with as-needed bronchodilation.¹ However, 30–50% of such patients remain symptomatic and poorly controlled on ICS/LABA, even when treatment adherence is optimal.2, 3, 4, 5 Additionally, between 10% and 25% of patients at step 3 or higher in the Global Initiative for Asthma guidelines¹ have an exacerbation within 1 year.6, 7 Therefore, effective step-up treatments after ICS/LABA in symptomatic patients both with and without an exacerbation history remain an unmet need. The use of tiotropium (a long-acting muscarinic antagonist; LAMA) as an add-on therapy to medium-dose or high-dose ICS/LABA is recommended by the Global Initiative for Asthma for severe asthma,¹ and the availability of a combined ICS/LABA/LAMA inhaler might be an advance for some patients. Furthermore, although biologics are effective for reducing severe exacerbations in patients with high type 2 inflammation, they are generally less consistent in improving lung function and symptoms.⁸ Studies comparing ICS with other treatments are needed for patients with low type 2 inflammation.

Research in context

Evidence before this study

Despite adherence to inhaled corticosteroid plus long-acting β₂-agonist (ICS/LABA) therapy, 30–50% of patients with asthma remain symptomatic and poorly controlled, indicating a clear unmet need in asthma management. Triple therapy—the combination of inhaled corticosteroid and long-acting muscarinic antagonist plus long-acting β₂-agonist (ICS/LAMA/LABA)—administered via multiple inhalers improves lung function and reduces exacerbation rates in patients with asthma. Two trials in which patients with asthma were given ICS/LAMA/LABA twice daily via a single inhaler resulted in positive effects on lung function and exacerbation rates. These studies all enrolled patients with uncontrolled asthma on ICS/LABA and a history of severe exacerbations in the preceding year, thus excluding patients whose main clinical problem is poor symptom control. Single-inhaler triple therapy (fluticasone furoate plus umeclidinium plus vilanterol [FF/UMEC/VI]) is widely approved as a once-daily treatment for chronic obstructive pulmonary disease; however, no studies have investigated its use in asthma. Asthma studies also need to better characterise patients who might respond to such therapy to precisely select their treatments based on the underlying problem.

Added value of this study

Relative to other studies investigating triple therapy in asthma, our inclusion criteria were intentionally broadened to capture the heterogeneity of uncontrolled asthma seen in real-world clinical practice, with no requirement for a history of exacerbations. Because we included both approved doses of FF/VI, direct comparisons of major treatment options for patients uncontrolled on ICS/LABA therapy can be made (ie, adding a LAMA or increasing the ICS dose, or both). UMEC improves lung function and symptom control when added to both FF/VI doses. Our study also shows a dose response for improvement in FEV₁ and exacerbation reduction by increasing the FF dose in either FF/VI or FF/UMEC/VI. Improved effects from increasing the FF dose were observed in patients with increased baseline blood eosinophils and fractional exhaled nitric oxide (FENO), which was not the case for the addition of UMEC.

Implications of all the available evidence

Results from this study suggest that adding a second long-acting bronchodilator, UMEC, to FF/VI dual therapy via a single inhaler, administered once daily, improves lung function in patients with poorly controlled asthma on ICS/LABA. Additionally, this is the first single-inhaler triple therapy asthma study (to our knowledge) to report treatment outcomes by underlying type 2 inflammatory markers. Adding UMEC appears to improve FEV₁ independently of blood eosinophils and FENO. By contrast, following an increase in FF dose, greater improvements in lung function and reductions in exacerbations are seen with increasing blood eosinophil counts and FENO. Findings from this study might aid clinicians' selection of the most appropriate inhaled treatment on the basis of patients' clinical problems being addressed, and the type and severity of the underlying airway inflammation. Further studies confirming this differentiating effect of biomarkers of type 2 inflammation on treatment outcomes in asthma, including in additional subgroups, are required.

To address these unmet needs, the Clinical Study in Asthma Patients Receiving Triple Therapy in a Single Inhaler (CAPTAIN) investigated the efficacy and safety of the single-inhaler triple combination of fluticasone furoate plus umeclidinium plus vilanterol (FF/UMEC/VI) in patients with uncontrolled asthma on medium-dose or high-dose ICS/LABA compared with FF/VI. To explore the potential for a treatable-traits approach to inhaled therapy, we also assessed whether the effects of increasing FF dose or adding UMEC on lung function and exacerbations were related to baseline type 2 airway inflammation biomarkers.