Characterization of Moderate and Severe Asthma Exacerbations in the CAPTAIN Study.

BACKGROUND: Limited data exist on the relative impact of moderate and severe exacerbations on asthma control and impairment. OBJECTIVE: To explore data from the CAPTAIN trial to evaluate the relationship between first moderate or severe exacerbation and changes in lung function, symptoms, physical activity limitation scores, and short-acting ß2-agonist (SABA) usage to determine the clinical relevance of moderate events. METHODS: CAPTAIN was a phase IIIA 24- to 52-week, multicenter, international, randomized controlled trial evaluating efficacy and safety of fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) versus FF/VI in patients with uncontrolled asthma on inhaled corticosteroid/long-acting ß2-agonist. Outcomes reported include first postrandomization exacerbation event by severity (wk 1-52), frequency and duration of moderate and severe exacerbations, and time course of changes over ± 14-day peri-exacerbation period for lung function, symptoms, limitations, and SABA use. RESULTS: Of the intent-to-treat population (n = 2,436), 550 patients (23%) continued to 52 weeks. There were 529 moderate and 546 severe exacerbations. Lung function changes were similar, but symptom, physical activity limitation scores, and SABA use were higher, for severe versus moderate exacerbations. Lung function decline preceded increases in symptom, physical activity limitation scores, and SABA use, irrespective of exacerbation severity. Lung function variables, limitation scores, and SABA use returned to pre-exacerbation baseline after approximately 8 to 12 days for both exacerbation severities. CONCLUSIONS: Whereas severe events were associated with greater impact on symptoms, physical activity limitations, and SABA use, onset and time to resolution were generally similar for moderate and severe events. Both exacerbation severities represent clinically important deteriorations comprising clinical and functional changes.

Clinic vs Home Spirometry for Monitoring Lung Function in Patients With Asthma.

BACKGROUND: Studies examining agreement between home and clinic spirometry in patients with asthma are limited, with conflicting results. Understanding the strengths and limitations of telehealth and home spirometry is particularly important considering the SARS-CoV-2 pandemic. RESEARCH QUESTION: How well do home and clinic measurements of trough FEV1 agree in patients with uncontrolled asthma? STUDY DESIGN AND METHODS: This post hoc analysis used trough FEV1 data from the randomized double-anonymized parallel-group phase 3A CAPTAIN (205715; NCT02924688) and phase 2B 205832 (NCT03012061) trials in patients with uncontrolled asthma. CAPTAIN evaluated the impact of adding umeclidinium to fluticasone furoate/vilanterol via a single inhaler; the 205832 trial investigated adding umeclidinium to fluticasone furoate vs placebo. Trough FEV1 measurements were collected via home spirometry and supervised in-person spirometry in the research clinic. To compare home and clinic spirometry, we examined the time-course analyses of home and clinic trough FEV1, and generated post hoc Bland-Altman plots to assess agreement between home and clinic spirometry. RESULTS: Data from 2,436 patients (CAPTAIN trial) and 421 patients (205832 trial) were analyzed. Treatment-related improvements in FEV1 were observed in both trials, using home and clinic spirometry. Improvements measured by home spirometry were of lower magnitude and less consistent than clinic measurements. Bland-Altman plots suggested poor agreement between home and clinic trough FEV1 at baseline and week 24. INTERPRETATION: This post hoc comparison of home and clinic spirometry is the largest conducted in asthma. Results showed that home spirometry was less consistent than and lacked agreement with clinic spirometry, suggesting that unsupervised home readings are not interchangeable with clinic measurements. However, these findings may only be applicable to home spirometry using the specific device and coaching methods employed in these studies. Postpandemic, further research to optimize home spirometry use is needed. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; Nos.: NCT03012061 and NCT02924688; URL: www. CLINICALTRIALS: gov.

Population Pharmacokinetic Modeling of Fluticasone Furoate, Umeclidinium Bromide, and Vilanterol in Patients with Asthma, Using Data from a Phase IIIA Study (CAPTAIN).

BACKGROUND: This analysis aimed to characterize the pharmacokinetics (PK) of the inhaled corticosteroid (ICS) fluticasone furoate (FF), the long-acting muscarinic antagonist umeclidinium (UMEC), and the long-acting ß2-agonist (LABA) vilanterol (VI), administered as dual (FF/VI) or triple (FF/UMEC/VI) single-inhaler therapy to patients with asthma, and to identify covariates that may influence the PK of each analyte. METHODS: Blood samples were obtained from the phase IIIA CAPTAIN study (ClinicalTrials.gov: NCT02924688), which evaluated the efficacy and safety of once-daily FF/UMEC/VI versus FF/VI in patients with uncontrolled asthma taking ICS/LABA. Samples were collected at trough (defined as ≥ 20 h after the last dose) from all subjects randomized to the six treatment groups (FF/UMEC/VI 100/31.25/25 µg, 100/62.5/25 µg, 200/31.25/25 µg, 200/62.5/25 µg; FF/VI 100/25 µg, 200/25 µg) at week 24 or the early withdrawal visit. In a subset of patients, PK samples were obtained predose at week 12, and at 5-30 min, 45-90 min, and 2-3 h postdose. For each analyte, a population PK model was developed using non-linear mixed-effects modeling. The maximum likelihood method was utilized to incorporate data below the quantifiable limit (BQL). Final models were used to derive the area under the plasma concentration-time curve and maximum observed concentration at steady-state for each analyte. RESULTS: We obtained 4018, 2695, and 4032 samples from 1891, 1258, and 1891 patients, for FF, UMEC, and VI, respectively; 48%, 49%, and 50% of samples were reported as BQL for each analyte, respectively. The PK were adequately described by a two-compartment model with first-order absorption and elimination for FF, a two-compartment model with intravenous bolus input and first-order elimination for UMEC, and a three-compartment model with zero-order input and first-order elimination for VI. Statistically significant covariates were body weight on apparent inhaled clearance of FF, creatinine clearance on apparent clearance and body weight on apparent inhaled volume of distribution of the central compartment for UMEC, and race (East Asian, Japanese, and South East Asian heritage) on inhaled apparent volume of distribution of the central compartment for VI. However, the overall effects of covariates were marginal and thus do not warrant dose adjustment. Systemic exposures of FF or VI did not differ when administered as a single-inhaler triple (FF/UMEC/VI) or dual combination (FF/VI), and were similar to those reported for patients with chronic obstructive pulmonary disease. CONCLUSION: Only marginal covariate effects were observed, and thus no dose adjustments are deemed necessary for FF, UMEC, or VI. There was no difference in FF or VI systemic exposure in patients with asthma when administered as either triple (FF/UMEC/VI) or dual therapy (FF/VI). Together with efficacy findings from the CAPTAIN study, our data support the use of single-inhaler FF/UMEC/VI triple therapy for patients with uncontrolled asthma currently receiving ICS/LABA.

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.

BACKGROUND: Despite inhaled corticosteroid plus long-acting ß2-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.

Healthcare Resource Utilization in Patients Receiving Omalizumab for Allergic Asthma in a Real-World Setting.

INTRODUCTION: Inadequately controlled asthma is associated with increased healthcare resource utilization. The eXpeRience registry was initiated to evaluate real-world outcomes in patients receiving omalizumab for uncontrolled persistent allergic asthma. The current analysis of data from the eXpeRience registry focuses on healthcare resource utilization and on absences from work or school. METHODS: The eXpeRience was a 2-year, multinational, non-interventional, observational registry conducted to investigate real-world outcomes among patients receiving omalizumab in accordance with country-specific prescribing criteria for the treatment of uncontrolled persistent allergic asthma. Asthma-related healthcare resource utilization (hospitalizations, emergency room visits or unscheduled-asthma-related doctor visits or interventions) and absences from work or school were assessed pre-treatment (12-month data were collected retrospectively at baseline) and at months 12 and 24 after the initiation of omalizumab treatment. Serious adverse event (SAE) data were also assessed. RESULTS: A total of 943 patients (mean age 45 years; female 65%) were enrolled in the registry. Overall, the mean (standard deviation [SD]) number of asthma-related medical healthcare uses per patient decreased from 6.2 (6.97) during the pre-treatment period to 1.0 (1.96) and 0.5 (1.28) at months 12 and 24, respectively. The mean (SD) number of work or school days missed due to asthma was also lower at months 12 (3.5 [17.28] and 1.6 [4.28], respectively) and 24 (1.0 [4.66] and 1.9 [5.46], respectively) compared with the pre-treatment period (26.4 [49.61] and 20.7 [27.49], respectively). The nature and frequency of SAEs in the eXpeRience registry were comparable to that seen in interventional clinical trials with omalizumab. CONCLUSION: The results of the eXpeRience registry indicate that omalizumab is associated with reductions in healthcare utilization, and in the number of days of absence from work or school, in patients with uncontrolled persistent allergic asthma in the real-world setting. FUNDING: Novartis Pharma AG, Basel, Switzerland.

Immunogenicity and safety of omalizumab in pre-filled syringes in patients with allergic (IgE-mediated) asthma.

BACKGROUND: Omalizumab, a humanised anti-immunoglobulin E monoclonal antibody for treatment of uncontrolled moderate-to-severe or severe persistent allergic asthma, was developed as a lyophilised powder for reconstitution. A liquid formulation in pre-filled syringes has now been developed. The purpose of this study was to assess the immunogenicity and safety of this liquid formulation. METHODS: In this multinational, open-label, single-arm study, patients (≥12 years) with moderate-to-severe allergic asthma were treated for 24 weeks with the liquid formulation of omalizumab (75 or 150 mg in a pre-filled syringe) at 2 or 4 week intervals. Immunogenicity was assessed by measurement of human anti-therapeutic antibody (ATA) levels. Safety was assessed by monitoring adverse events (AEs), haematology, blood chemistry, urine analysis and vital signs. RESULTS: A total of 155 patients were enrolled in the study. No patient had a confirmed positive ATA test result. Most frequent individual AEs were asthma (17.4%), sinusitis (17.4%) and upper respiratory tract infection (11.6%). Fourteen patients (9.0%) had serious AEs and there was one death (not treatment related). There were no cases of anaphylaxis according to Sampson criteria. Most patients remained within normal ranges for haematology and biochemistry laboratory variables. CONCLUSIONS: Omalizumab in pre-filled syringes was not associated with immunogenicity. This novel formulation, which does not require reconstitution, had a safety profile consistent with the lyophilised formulation. A limitation of this study is that efficacy of omalizumab in the treatment of asthma was not specifically addressed herein. Clinicaltrials.gov identifier: NCT00500539.

Reduction in oral corticosteroid use in patients receiving omalizumab for allergic asthma in the real-world setting.

BACKGROUND: Oral corticosteroids (OCS) are commonly administered in patients with severe persistent allergic asthma. Despite their efficacy, they are associated with a wide variety of adverse events. The eXpeRience registry was set up to investigate real-world outcomes among patients receiving omalizumab for the treatment of uncontrolled allergic asthma. Here, we present the effect of omalizumab treatment on OCS use. METHODS: eXpeRience was a 2-year, multinational, non-interventional, observational registry of patients receiving omalizumab for uncontrolled allergic asthma. OCS use (proportion of patients on maintenance OCS, mean total daily OCS dose and change in status of OCS therapy) was assessed at baseline, 16 weeks, and 8, 12, 18, and 24 months after the initiation of omalizumab. Response to omalizumab was assessed using the physician's Global Evaluation of Treatment Effectiveness (GETE) at approximately Week 16. Safety data were also recorded. RESULTS: A total of 943 patients (mean age, 45 years; female, 64.9%) were enrolled in the registry, 263 of whom were receiving maintenance OCS at baseline. The proportion of patients taking maintenance OCS was markedly lower at Months 12 (16.1%) and 24 (14.2%) than at baseline (28.6%; intent-to-treat population). GETE status was determined in 915 patients receiving omalizumab: 64.2% were responders (excellent or good response), 30.7% were non-responders (moderate, poor or worsening response); 5.1% had no assessment. The frequency of serious adverse events was comparable to that seen in controlled trials of omalizumab. CONCLUSIONS: Omalizumab use is associated with an OCS-sparing effect in patients with uncontrolled persistent allergic asthma in the real-world setting.

Oral corticosteroid sparing with omalizumab in severe allergic (IgE-mediated) asthma patients.

BACKGROUND: Long-term oral corticosteroid (OCS) therapy and related adverse events are associated with a significant burden on patients and healthcare resources. METHODS: This subgroup analysis of a randomized, open-label, parallel-group study evaluated the OCS-sparing effect of omalizumab (OMA) added to optimized asthma therapy (OAT), compared with OAT alone. Patients (12-75 years) with severe allergic asthma, uncontrolled despite GINA 2004 Step 4 therapy, received OMA or OAT for 32 weeks. The change from baseline in OCS use by Week 32 in patients requiring maintenance OCS at baseline was assessed in terms of percent OCS dose change and numbers of patients with reduced/stopped or maintained/increased OCS. RESULTS: Eighty-two patients were receiving maintenance OCS at baseline (OMA/OAT n = 59, OAT n = 23). Change from baseline in mean maintenance OCS dose at Week 32 was significantly greater in the OMA/OAT group compared with the OAT group (-45% vs. + 18.3%, p = 0.002). In the OMA/OAT group, 37 patients (62.7%) reduced/stopped OCS use at Week 32, compared with seven patients (30.4%) receiving OAT (p = 0.013). Improvements in other efficacy outcomes were seen at Week 32 in the OMA/OAT group, irrespective of OCS use. An investigator global evaluation of treatment effectiveness at Week 16 was an effective predictor of persistent treatment response at 32 weeks for the majority of OMA/OAT patients (93%), also irrespective of OCS use. CONCLUSION: In this open-label study of patients with severe allergic asthma, OMA/OAT therapy reduced maintenance OCS use, compared with OAT alone. Improvements in efficacy measures were observed in the OMA/OAT group, irrespective of OCS change. CLINICALTRIALS.GOV IDENTIFIER: NCT00264849.

Uncontrolled persistent allergic asthma in practice: eXpeRience registry baseline characteristics.

BACKGROUND: Medical registries can be used to assess and monitor the effectiveness and safety of approved therapy, and provide insights into how quality of care can be optimized. METHODS: The post-marketing, non-interventional, observational registry (eXpeRience) aims to collect data on the treatment effectiveness and safety of omalizumab in 'real-world' practice. The baseline characteristics of patients with uncontrolled allergic asthma receiving omalizumab therapy and included in the first interim analysis of this observational registry are reported. RESULTS: A total of 294 patients were included in the first interim analysis. Of these patients, 271 (92.2%) were active in the registry at the time of reporting. At baseline, the mean duration of allergic asthma was approximately 19 years, with over 87% of patients testing positive for a perennial allergen. Mean % predicted FEV(1) and serum total IgE levels were 62.4% and 316.7 IU/mL, respectively. Asthma was uncontrolled for approximately 62% of patients, while around 23% were partly controlled. The majority of patients were being treated with multiple asthma controller medications, including inhaled-corticosteroids, long-acting ß(2)-agonists and leukotriene receptor antagonists, and 28% of patients were also receiving maintenance oral corticosteroids. Concomitant diseases were present in many patients, the most common being perennial allergic rhinitis (42.5%). CONCLUSIONS: Demographic and disease characteristics highlight the unmet clinical need in patients with uncontrolled allergic asthma. Future analyses from this study will further determine the real-life effectiveness and safety of omalizumab.