BACKGROUND:Chronic rhinosinusitis with nasal polyps (CRSwNP) symptoms are frequently driven by type 2 inflammation. Depemokimab is the first ultra-long-acting biological drug engineered with enhanced interleukin-5 binding affinity, high potency, and an extended half-life, enabling twice per year dosing and sustained type 2 inflammation inhibition. The ANCHOR-1 and ANCHOR-2 trials investigated the efficacy and safety of depemokimab in people with CRSwNP. METHODS:ANCHOR-1 and ANCHOR-2 were randomised, double-blind, placebo-controlled, parallel-group, replicate phase 3 trials conducted concurrently at 190 centres (hospitals, specialised clinics, and clinical trial sites) in 16 countries (Argentina, Belgium, Canada, China, France, Germany, Italy, Japan, the Netherlands, Poland, Romania, Spain, Sweden, Türkiye, the UK, and the USA). Individuals aged 18 years or older at the time of consent, with inadequately controlled CRSwNP, an endoscopic bilateral nasal polyps score of 5 or more, previous surgery for CRSwNP or previous treatment with or intolerance to systemic corticosteroids, and severe symptoms were stratified by previous CRSwNP surgery and randomly assigned 1:1 to receive either depemokimab (100 mg subcutaneously) or placebo every 26 weeks (with standard of care). Allocation was computer generated. The trial sponsor, site staff, and participants were masked. The coprimary endpoints were change from baseline in total endoscopic nasal polyps score (0-8) at week 52 and mean nasal obstruction score (verbal response scale [0-3]) over weeks 49-52, assessed in the full analysis set. Integrated analyses were conducted. Adverse events on treatment and after treatment were monitored. The trials are complete and are registered with ClinicalTrials.gov (NCT05274750 and NCT05281523). FINDINGS:Between April 18, 2022, and Aug 7, 2023, 540 individuals were randomly assigned across ANCHOR-1 and ANCHOR-2; 528 participants comprised the full analysis set (depemokimab, n=272; placebo, n=256). Depemokimab had statistically significant improvements from baseline versus placebo in the coprimary endpoints of total nasal polyps score (treatment difference: ANCHOR-1, -0·7, 95% CI -1·1 to -0·3; p<0·001; ANCHOR-2, -0·6, -1·0 to -0·2; p=0·004; integrated, -0·7, -0·9 to -0·4) and mean nasal obstruction verbal response scale score (ANCHOR-1, -0·23, -0·46 to 0·00; p=0·047; ANCHOR-2, -0·25, -0·46 to -0·03; p=0·025; integrated, -0·24, -0·39 to -0·08). Adverse events were similar between depemokimab and placebo in ANCHOR-1 (74% [n=106] vs 79% [n=101]) and ANCHOR-2 (76% [n=98] vs 80% [n=102]). INTERPRETATION:Depemokimab significantly improved clinically relevant coprimary endpoints versus placebo and was well tolerated, supporting its use as a twice per year treatment option, with the potential to reduce treatment burden for people with CRSwNP. FUNDING:GSK.

BackgroundFindings from CAPTAIN (NCT02924688) suggest treatment response to fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) differs according to baseline type 2 (T2) inflammation markers in patients with moderate-to-severe asthma. Understanding how other patient physiologic and clinical characteristics affect response to inhaled therapies may guide physicians toward a personalized approach for asthma management.ObjectiveTo investigate, using CAPTAIN data, the predictive value of key demographic and baseline physiologic variables in patients with asthma (lung function, bronchodilator reversibility, age, age at asthma onset) on response to addition of the long-acting muscarinic antagonist UMEC to inhaled corticosteroid/long-acting β2-agonist combination FF/VI, or doubling FF dose.MethodsPrespecified and post hoc analyses of CAPTAIN data were performed using categorical and continuous variables of key baseline characteristics to understand their influence on treatment outcomes (lung function [trough forced expiratory volume in 1 second, FEV1], annualized rate of moderate/severe exacerbations, and asthma control [Asthma Control Questionnaire, ACQ]) following addition of UMEC to FF/VI or doubling FF dose in FF/VI or FF/UMEC/VI.ResultsAdding UMEC to FF/VI led to greater improvements in trough FEV1 versus doubling FF dose across all baseline characteristics assessed. Doubling FF dose was generally associated with numerically greater reductions in the annualized rate of moderate/severe exacerbations compared with adding UMEC, independent of baseline characteristics. Adding UMEC and/or doubling FF dose generally led to improvements in ACQ scores irrespective of baseline characteristics.ConclusionUnlike previous findings with T2 biomarkers, lung function, bronchodilator reversibility, age and age at asthma onset do not appear to predict response to inhaled therapy.

Background The run-in period is an important element of randomized controlled trials, and is often used in respiratory disease trials. The design of the run-in period can greatly impact results and data interpretation, and as such should be designed carefully. Methods In this review, we describe the design of run-in periods across six phase 3A trials of triple therapy in asthma, and discuss how differences in run-in period design (specifically the duration, treatment, and reporting of run-in results) may have the potential to alter the interpretation of study outcomes. Results We found that the duration of run-in periods ranged between 2 and 7 weeks, with some studies including a combination of screening, run-in and stabilization periods, and others including a run-in period only. Run-in treatment also varied, with some studies running in patients on their previous inhaled corticosteroid/long-acting β2-agonist (ICS/LABA) therapy, and others harmonizing treatment by switching to the same ICS/LABA combination used in the on-treatment phase, or a different ICS/LABA combination entirely. Most of the studies included did not report any changes to study outcomes seen prior to randomization. Conclusion We discuss the potential implications associated with the various trial designs, and propose that run-in periods should be consciously designed to meet the goals of the specific study. We also propose that standardized reporting of run-in changes would further allow for differentiation between improvements due to improved adherence and true treatment benefits, and aid with comparing data from different clinical trials.

Bayesian Dynamic Borrowing (BDB) designs are being increasingly used in clinical drug development. These methods offer a mathematically rigorous and robust approach to increase efficiency and strengthen evidence by integrating existing trial data into a new clinical trial. The regulatory acceptability of BDB is evolving and varies between and within regulatory agencies. This paper describes how BDB can be used to design a new randomised clinical trial including external data to supplement the planned sample size and discusses key considerations related to data re-use and BDB in drug development programs. A case-study illustrating the planning and evaluation of a BDB approach to support registration of a new medicine with the Center for Drug Evaluation in China will be presented. Key steps and considerations for the use of BDB will be discussed and evaluated, including how to decide whether it is appropriate to borrow external data, which external data can be re-used, the weight to put on the external data and how to decide if the new study has successfully demonstrated treatment benefit.

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.

Approximately 50% of asthma patients have inadequately controlled symptoms despite inhaled corticosteroid/long-acting β2-agonist therapy. Phase III, randomized, double-blind, 24-52 week, parallel-group study in adults with asthma with pre-bronchodilator FEV1 <85% and Asthma Control Questionnaire (ACQ-6) score ≥1.5. Treatment: once-daily fluticasone furoate/vilanterol (FF/VI, 100/25, 200/25mcg) or FF/umeclidinium (UMEC)/VI (100/31.25/25, 100/62.5/25, 200/31.25/25, 200/62.5/25mcg) via Ellipta inhaler. Endpoints: mean change from baseline in trough FEV1 at Week 24 (primary), annualized moderate/severe asthma exacerbation rates, proportion of ACQ-7 and St George’s Respiratory Questionnaire (SGRQ) responders (Week 24). Safety was assessed. FF doses were pooled for non-lung function endpoints for each UMEC dose. In the intent-to-treat population (n=2436), FF/UMEC 62.5mcg/VI statistically significantly improved trough FEV1 versus FF/VI for each corresponding FF dose (100/62.5/25mcg vs FF/VI 100/25mcg: 110mL [95%CI 66-153], 200/62.5/25mcg vs FF/VI 200/25mcg: 92mL [95%CI: 49-135]; all p<0.001). FF/UMEC 31.25mcg/VI showed nominally statistically significant improvements in trough FEV1 (100/31.25/25mcg vs FF/VI 100/25mcg: 96mL [95%CI: 52-139]; 200/31.25/25mcg vs FF/VI 200/25mcg: 82mL [95%CI 39-125]). Numerical reduction in exacerbation rate observed for FF/UMEC 62.5mcg/VI versus FF/VI (rate ratio [95%CI]: 0.87 [0.72-1.05]). ACQ-7 responder rates were greater for FF/UMEC 62.5mcg/VI versus FF/VI (63% vs 55%; OR 1.43; 95%CI: 1.16-1.76); there were no differences in SGRQ responder rates (69%, vs 66%; OR 1.14; 95%CI: 0.92-1.42). FF/UMEC/VI safety profile was similar to FF/VI. Dual bronchodilation effects are additive in asthma. FF/UMEC 31.25 and 62.5mcg/VI provided statistically significant increases in lung function versus FF/VI. FF/UMEC 62.5mcg/VI improved asthma control versus FF/VI in asthma patients inadequately controlled on ICS/LABA.

Little evidence exists that doubling inhaled corticosteroid (ICS) dose improves clinical outcomes. We evaluated this in inadequately controlled asthma patients receiving ICS/long-acting β2-agonist (LABA) therapy. Phase III, randomized, double-blind, 24-52 week, parallel-group study in adults with asthma with pre-bronchodilator FEV1 <85% and Asthma Control Questionnaire (ACQ-6) score ≥1.5, receiving ICS/LABA with daily >250mcg fluticasone propionate/equivalent. Following 3-week run-in and 2-week stabilization on open-label low-medium dose ICS/LABA, patients were randomized to once-daily FF/VI (100/25, 200/25mcg) or FF/umeclidinium/VI (100/31.25/25, 100/62.5/25, 200/31.25/25, 200/62.5/25mcg) via Ellipta inhaler. Endpoints for FF/VI 200/25mcg versus 100/25mcg are reported here: mean change from baseline in trough FEV1 at Week 24 (primary), annualized moderate/severe asthma exacerbation rates, proportion of ACQ-7 and St George’s Respiratory Questionnaire (SGRQ) responders (Week 24). During run-in and stabilization, ICS/LABA therapy provided clinically meaningful improvements from baseline in mean [SD] trough FEV1 (287 [356] mL) and ACQ-6 score (0.632 [0.762]) in the intent-to-treat population (n=2436). Post randomization, FF/VI 200/25mcg improved mean trough FEV1 versus FF/VI 100/25mcg by 51mL (95%CI: 8-95) and reduced exacerbation rate versus 100/25mcg (rate ratio [95%CI]: 0.65 [0.50-0.85]). Responder rates for FF/VI 200/25mcg versus 100/25mcg were 58% versus 52% for ACQ-7 (OR 1.34; 95%CI: 1.00-1.79), and 68% versus 64% for SGRQ (OR 1.21; 95%CI: 0.89-1.63). There was no increase in adverse events for FF/VI 200/25mcg versus 100/25mcg. Doubling FF dose in inadequately controlled asthma patients on FF/VI reduces exacerbations by 35% and provides modest improvements in FEV1 and ACQ-7, demonstrating an ICS dose response on outcomes.

Background Despite inhaled corticosteroid plus long-acting beta(2)-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 FEV 1 between 30% and less than 85% of predicted normal value, and reversibility (defined as an increase in FEV 1 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 mu g or 200/25 mu g) or FF/UMEC/VI (100/31.25/25 mu g, 100/62.5/25 mu g, 200/31.25/25 mu g, or 200/62.5/25 mu g) 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 FEV 1 at week 24 (primary) and annualised moderate and/or severe asthma exacerbation rate (key secondary). Other secondary endpoints were change from baseline in clinic FEV 1 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 mu g n=407; 200/25 mu g n=406) or FF/UMEC/VI (100/31.25/25 mu g n=405; 100/62.5/25 mu g n=406; 200/31.25/25 mu g n=404; 200/62.5/25 mu g 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 FEV 1 change from baseline for FF/UMEC/VI 100/62.5/25 mu g versus FF/VI 100/25 mu g was 110 mL (95% CI 66-153; p<0.0001) and for 200/62.5/25 mu g versus 200/25 mu g was 92 mL (49-135; p<0.0001). Adding UMEC 31.25 mu g to FF/VI produced similar improvements (FF/UMEC/VI 100/31.25/25 mu g vs FF/VI 100/25 mu g: 96 mL [52-139; p<0.0001]; and 200/31.25/25 mu g vs 200/25 mu g: 82 mL [39-125; p=0.0002]). These results were supported by the analysis of clinic FEV 1 at 3 h post-dose. Non-significant reductions in moderate and/or severe exacerbation rates were observed for FF/UMEC 62.5 mu g/VI versus FF/VI (pooled analysis), with rates lower in FF 200 mu g-containing versus FF 100 mu g-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 mu g/VI versus FF/VI, -0.06 (95% CI -0.12 to 0.01; p=0.094) FF/UMEC 62.5 mu g/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 FEV 1 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 mu g 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, singleinhaler 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. Copyright (C) 2020 Elsevier Ltd. All rights reserved.