The effects of benralizumab on airway geometry and dynamics in severe eosinophilic asthma: a single-arm study design exploring a functional respiratory imaging approach.

BACKGROUND: Severe eosinophilic asthma (SEA) is characterised by elevated blood/sputum eosinophil counts and airway inflammation, which can lead to mucus plug-mediated airway obstruction, increased exacerbation frequency, declines in lung function, and death. Benralizumab targets the alpha-subunit of the interleukin-5 receptor found on eosinophils, leading to rapid and near complete eosinophil depletion. This is expected to result in reduced eosinophilic inflammation, reduced mucus plugging and improved airway patency and airflow distribution. METHODS: BURAN is an interventional, single-arm, open-label, uncontrolled, prospective, multicentre study during which participants will receive three 30 mg subcutaneous doses of benralizumab at 4-week intervals. This study will use functional respiratory imaging (FRI), a novel, quantitative method of assessing patients' lung structure and function based on detailed, three-dimensional models of the airways, with direct comparison of images taken at Weeks 0 and 13. Patients aged ≥ 18 years with established SEA who may be receiving oral corticosteroids and/or other asthma controller medications, who are inadequately controlled on inhaled corticosteroid-long-acting ß2-agonist therapies and who have had ≥ 2 asthma exacerbations in the previous 12 months will be included. The objectives of BURAN are to describe changes in airway geometry and dynamics, measured by specific image-based airway volume and other FRI endpoints, following benralizumab therapy. Outcomes will be evaluated using descriptive statistics. Changes in FRI parameters, mucus plugging scores and central/peripheral ratio will be quantified as mean percent change from baseline (Week 0) to Week 13 (± 5 days) and statistical significance will be evaluated using paired t-tests. Relationships between FRI parameters/mucus plugging scores and conventional lung function measurements at baseline will be assessed with linear regression analyses for associations between outcomes, scatterplots to visualise the relationship, and correlation coefficients (Spearman's rank and Pearson's) to quantify the strength of these associations. CONCLUSIONS: The BURAN study will represent one of the first applications of FRI-a novel, non-invasive, highly sensitive method of assessing lung structure, function and health-in the field of biologic respiratory therapies. Findings from this study will increase understanding of cellular-level eosinophil depletion mechanisms and improvements in lung function and asthma control following benralizumab treatment. Trial registration EudraCT: 2022-000152-11 and NCT05552508.

Biologic use and outcomes among adults with severe asthma treated by US subspecialists.

BACKGROUND: Multiple biologics are now available for severe asthma (SA) treatment and can improve outcomes for patients. However, few available data describe the real-world use and effectiveness of multiple approved biologics, including biologic switching, among subspecialists in the United States. OBJECTIVE: To evaluate biologic use and associated exacerbation outcomes in a large cohort of subspecialist-treated US adults with SA. METHODS: CHRONICLE is an ongoing, noninterventional study of subspecialist-treated US adults with SA receiving biologics, maintenance systemic corticosteroids, or those persistently uncontrolled by high-dose inhaled corticosteroids with additional controllers. For enrolled patients, sites report asthma exacerbations and medication use starting 12 months before enrollment. For patients enrolled between February 2018 and February 2021, biologic use and exacerbation outcomes before and after biologic initiation are described. RESULTS: Among 2793 enrolled patients, 66% (n = 1832) were receiving biologics. The most used biologic (> 1 biologic use per patient allowed) was omalizumab (47%), followed by benralizumab (27%), mepolizumab (26%), dupilumab (18%), and reslizumab (3%). Overall, 16% of patients had biologic switches, 13% had stops, and 89% had ongoing biologic use. Patients starting and switching biologics experienced a 58% (1.80 vs 0.76 per patient-year) and 49% (1.47 vs 0.75 per patient-year) reduction in exacerbations, respectively (both P < .001), with a numerically greater reduction observed among those starting non-anti-immunoglobulin E biologics compared with anti-immunoglobulin E. CONCLUSION: Real-world starting and switching of biologic therapies for SA were associated with meaningful reductions in exacerbations. With increasing biologic options available, individualized approaches to therapy may improve patient outcomes. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03373045.

Severe asthma exacerbation rates are increased among female, Black, Hispanic, and younger adult patients: results from the US CHRONICLE study.

OBJECTIVE: To describe clinical outcomes in patients with severe asthma (SA) by common sociodemographic determinants of health: sex, race, ethnicity, and age. METHODS: CHRONICLE is an observational study of subspecialist-treated, United States adults with SA receiving biologic therapy, maintenance systemic corticosteroids, or uncontrolled by high-dosage inhaled corticosteroids with additional controllers. For patients enrolled between February 2018 and February 2020, clinical characteristics and asthma outcomes were assessed by sex, race, ethnicity, age at enrollment, and age at diagnosis. Treating subspecialists reported exacerbations, exacerbation-related emergency department visits, and asthma hospitalizations from 12 months before enrollment through the latest data collection. Patients completed the St. George's Respiratory Questionnaire and the Asthma Control Test at enrollment. RESULTS: Among 1884 enrolled patients, the majority were female (69%), reported White race (75%), non-Hispanic ethnicity (69%), and were diagnosed with asthma as adults (60%). Female, Black, Hispanic, and younger patients experienced higher annualized rates of exacerbations that were statistically significant compared with male, White, non-Hispanic, and older patients, respectively. Black, Hispanic, and younger patients also experienced higher rates of asthma hospitalizations. Female and Black patients exhibited poorer symptom control and poorer health-related quality of life. CONCLUSIONS: In this contemporary, real-world cohort of subspecialist-treated adults with SA, female sex, Black race, Hispanic ethnicity, and younger age were important determinants of health, potentially attributable to physiologic and social factors. Knowledge of these disparities in SA disease burden among subspecialist-treated patients may help optimize care for all patients.Supplemental data for this article is available online at at www.tandfonline.com/ijas .

Differing perceptions of asthma control and treatment effectiveness by patients with severe asthma and treating subspecialists in the United States.

OBJECTIVE: For patients with severe asthma (SA), overestimation of asthma control may lead to poorer outcomes. The objective of this study was to assess concurrent patient and specialist assessments of asthma control and treatment effectiveness among a large US cohort of SA patients. METHODS: CHRONICLE is an ongoing observational study of patients with SA treated by US subspecialists. Asthma control was assessed using the patient-completed Asthma Control Test™ (ACT™) and specialist clinical assessment of control. Treatment effectiveness was measured using the Global Evaluation of Treatment Effectiveness (GETE) completed by patients and specialists. RESULTS: 1109 patients who completed online surveys at enrollment were included. 14%, 28%, 25%, and 33% of patients had ACT™ scores of 5-9, 10-15, 16-19, and 20-25, respectively. Compared with 67% of patients with uncontrolled asthma by ACT™, 44% were uncontrolled by specialist assessment. 54% of patients who were uncontrolled according to the ACT™ were rated as controlled by specialists, demonstrating overestimation of asthma control. Based on ACT™ score, asthma control was more frequent among patients treated with biologics compared to other treatments. Using the GETE, 90% of patients reported treatment effectiveness compared with 71% of specialists. Patient and specialist treatment effectiveness categorizations agreed 73% of the time. CONCLUSION: Specialists commonly overestimated asthma control relative to ACT™ scores. Patients reported treatment effectiveness more frequently than specialists. These findings emphasize the importance of validated instruments to assess asthma control and reduce potential treatment gaps associated with patient-specialist discordance. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03373045.

Severe asthma exacerbations in the United States:: Incidence, characteristics, predictors, and effects of biologic treatments.

BACKGROUND: Patients with severe asthma (SA) have a heightened risk of exacerbations including hospitalization. The real-world, specialist-verified incidence and characteristics of exacerbations among patients with SA in the United States have not been described. OBJECTIVE: To describe the real-world incidence, characteristics, and predictors of exacerbations among patients with SA in the United States. METHODS: The CHRONICLE study is an ongoing observational study of specialist-treated adults with SA in the United States receiving biologic treatment or maintenance systemic corticosteroids or uncontrolled by high-dosage inhaled corticosteroids with additional controllers. For patients enrolled from February 2018 to February 2020, annualized rates and characteristics of exacerbation-related events were summarized by treatment category for 12 months before enrollment and after enrollment through the latest data collection. Results were further analyzed for subgroups of interest. RESULTS: Among 1884 enrolled patients, 53.5% and 12.3% experienced an exacerbation and asthma hospitalization, respectively (0.81 and 0.14 per person-year). Of all exacerbations, 36%, 9%, and 15% required an unscheduled health care provider visit, emergency department visit without hospitalization, and hospitalization, respectively. Among patients not receiving biologics or systemic corticosteroids, higher blood eosinophil count, higher fractional exhaled nitric oxide, and lower total immunoglobulin E level were associated with higher exacerbation rates. Exacerbation rates decreased after starting or switching biologics (n = 1299). Multivariate analyses of enrolled patients revealed previous-year exacerbations or hospitalizations, lack of asthma control, and the geographic region also predicted event risk. CONCLUSION: In this real-world cohort of specialist-treated adults with SA in the United States, there was a substantial burden of exacerbations and associated health care resource utilization. Patients receiving biologics had a lower exacerbation burden. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03373045.

An expert consensus framework for asthma remission as a treatment goal.

With novel therapies in development, there is an opportunity to consider asthma remission as a treatment goal. In this Rostrum, we present a generalized framework for clinical and complete remission in asthma, on and off treatment, developed on the basis of medical literature and expert consensus. A modified Delphi survey approach was used to ascertain expert consensus on core components of asthma remission as a treatment target. Phase 1 identified other chronic inflammatory diseases with remission definitions. Phase 2 evaluated components of those definitions as well as published definitions of spontaneous asthma remission. Phase 3 evaluated a remission framework created using consensus findings. Clinical remission comprised 12 or more months with (1) absence of significant symptoms by validated instrument, (2) lung function optimization/stabilization, (3) patient/provider agreement regarding remission, and (4) no use of systemic corticosteroids. Complete remission was defined as clinical remission plus objective resolution of asthma-related inflammation and, if appropriate, negative bronchial hyperresponsiveness. Remission off treatment required no asthma treatment for 12 or more months. The proposed framework is a first step toward developing asthma remission as a treatment target and should be refined through future research, patient input, and clinical study.

Benralizumab efficacy for patients with fixed airflow obstruction and severe, uncontrolled eosinophilic asthma.

BACKGROUND: Fixed airflow obstruction (FAO) is associated with severe eosinophilic asthma. Benralizumab is an interleukin-5 receptor alpha-directed cytolytic monoclonal antibody for patients with severe, uncontrolled eosinophilic asthma. OBJECTIVE: We evaluated FAO influence on benralizumab treatment response. METHODS: We performed a post hoc analysis of pooled phase III SIROCCO (NCT01928771) and CALIMA (NCT01914757) data for patients with severe, uncontrolled asthma with baseline blood eosinophil counts of 300 or more cells/µL who received benralizumab 30 mg every 8 weeks or placebo. Demographics, baseline clinical characteristics, and treatment responses were evaluated by FAO status. FAO+ and FAO- were defined as ratios of postbronchodilator forced expiratory volume in 1 second (FEV1) to forced vital capacity of less than 70% and 70% or more, respectively, at baseline. RESULTS: FAO+ prevalence was 63% (935/1493). With benralizumab, similar annual asthma exacerbation rate (AER) reductions vs placebo were achieved for FAO+ and FAO- patients (rate ratio [95% confidence interval (CI)] = 0.56 [0.44-0.71] and 0.58 [0.41-0.83], respectively), whereas annual AER reductions associated with emergency department visits or hospitalizations were greater for FAO+ vs FAO- patients (rate ratio [95% CI] = 0.55 [0.33-0.91] and 0.70 [0.33-1.48], respectively). Prebronchodilator FEV1 (95% CI) increase from baseline to end of treatment was greater for FAO+ vs FAO- patients receiving benralizumab compared with placebo (0.159 L [0.082-0.236] vs 0.103 L [-0.008 to 0.215]). Other lung function measures, patient-reported outcomes, and symptom improvements were also numerically greater for FAO+ vs FAO- patients. CONCLUSION: Benralizumab improved asthma control across several measures for patients with severe, uncontrolled eosinophilic asthma and FAO. TRIAL REGISTRATION: SIROCCO trial: NCT01928771 (URL: https://clinicaltrials.gov/ct2/show/NCT01928771) CALIMA trial: NCT01914757 (URL: https://clinicaltrials.gov/ct2/show/NCT01914757).

Blood eosinophil count group shifts and kinetics in severe eosinophilic asthma.

BACKGROUND: Blood eosinophil count (BEC) measurements are a noninvasive, relatively reliable surrogate marker for eosinophilic airway inflammation. Single measurements of peripheral BEC greater than or equal to 150 cells/µL predict the response to anti-eosinophil therapies for patients with characteristics of severe eosinophilic asthma. OBJECTIVE: To describe how BECs shift over time for patients with severe, uncontrolled asthma receiving placebo in 2 large, randomized, placebo-controlled clinical trials of benralizumab (SIROCCO and CALIMA). METHODS: Our analysis included all adult patients who were randomized to placebo in the SIROCCO and CALIMA phase III benralizumab studies. Patients were categorized into baseline BEC groups of less than 150 cells/µL, greater than or equal to 150 cells/µL but less than 300 cells/µL, and greater than or equal to 300 cells/µL. The timing of the initial shift from baseline to a different group was evaluated at weeks 4, 8, 24, and 40 and at the end of treatment. Baseline characteristics, including oral corticosteroid use, were described based on the presence or absence of a BEC group shift. RESULTS: Of the 734 evaluable patients, 65% (n = 474) shifted BEC groups during the study, and most patients (86% [n = 410]) shifted by week 24. Patients who started in the less than 150 cells/µL group tended to shift groups earlier, with 59% shifting by week 4 compared with 38% to 55% for other groups in the same time frame. Patients who shifted BEC groups vs those who did not tend to have lower BECs, more oral corticosteroid use, and less incidence of nasal polyps or past polypectomy. CONCLUSION: A single BEC measurement, particularly when low, may be inadequate to help establish a phenotype of severe eosinophilic asthma. TRIAL REGISTRATION: ClinicalTrials.gov Identifiers NCT01928771 (SIROCCO trial) and NCT01914757 (CALIMA trial).

Biologic and maintenance systemic corticosteroid therapy among US subspecialist-treated patients with severe asthma.

BACKGROUND: Severe asthma (SA) often requires subspecialist management and treatment with biologic therapies or maintenance systemic corticosteroids (mSCS). OBJECTIVE: To describe contemporary, real-world biologic and mSCS use among US subspecialist-treated patients with SA. METHODS: CHRONICLE is an ongoing, noninterventional study of US adults with SA treated by allergists/immunologists or pulmonologists. Eligible patients are receiving biologics or mSCS or are uncontrolled on high-dosage inhaled corticosteroids with additional controllers. Biologic and mSCS use patterns and patient characteristics were summarized for patients enrolled between February 2018 and February 2019. RESULTS: Among protocol-eligible patients, 58% and 12% were receiving biologics and mSCS, respectively, with 7% receiving both. Among 796 enrolled, most were women (67%), non-Hispanic white (71%), of suburban residence (50%), and had elevated body mass index (median: 31). Respiratory and nonrespiratory comorbidities were highly prevalent. With biologics (n = 557), 51% were anti-immunoglobulin E and 48% were anti-interleukin (IL)-5/IL-5Rα; from May 2018, 76% of initiations were anti-IL-5/IL-5Rα. In patients receiving mSCS, median prednisone-equivalent daily dose was 10 mg. Multivariate logistic regression found that patients of hospital clinics, sites with fewer nonphysician staff, and with a recorded concurrent chronic obstructive pulmonary disease diagnosis were less likely to receive biologics and more likely to receive mSCS. CONCLUSION: In this real-world sample of US subspecialist-treated patients with SA not controlled by high-dosage inhaled corticosteroids with additional controllers, mSCS use was infrequent and biologic use was common, with similar prevalence of anti-immunoglobulin E and anti-IL-5/IL-5Rα biologics. Treatment differences associated with patient and site characteristics should be investigated to ensure equitable access to biologics and minimize mSCS use. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03373045.

Rapid onset of effect of benralizumab on morning peak expiratory flow in severe, uncontrolled asthma.

BACKGROUND: Benralizumab is a unique eosinophil-depleting monoclonal antibody that significantly reduces asthma exacerbations, improves lung function and asthma symptoms, and permits the reduction of maintenance oral corticosteroid dosage for patients with severe, uncontrolled eosinophilic asthma. OBJECTIVE: To assess benralizumab's onset of action and efficacy by examining change in morning peak expiratory flow (PEF) after initiation of treatment in the phase 3 clinical trials SIROCCO, CALIMA, and ZONDA. METHODS: Mixed-model repeated-measures analysis was used to calculate PEF using daily least squares mean changes from baseline in morning PEF as well as differences between the benralizumab every 8 weeks (first 3 doses every 4 weeks) and placebo groups. A Bayesian nonlinear mixed-effects approach with an exponential relationship was used to model trial data to determine time to clinically meaningful improvement in morning PEF (defined as ≥25 L/min). RESULTS: Least squares mean morning PEF improvement from baseline was numerically greater by Day 2 after initiation of benralizumab therapy in all 3 trials. The Bayesian nonlinear mixed-effects model indicated that PEF improvement reached the clinically meaningful threshold within 3 weeks in SIROCCO and CALIMA and 2 weeks in ZONDA. CONCLUSION: In 3 phase 3 randomized clinical trials, benralizumab provided notable improvement in morning PEF 2 days after initiation and clinically meaningful improvements within 3 weeks for patients with severe, uncontrolled eosinophilic asthma. The rapid improvement in PEF demonstrated in these trials suggests that benralizumab's unique mechanism of action rapidly improves lung function for patients with severe, eosinophilic asthma. TRIAL REGISTRATION: ClinicalTrials.gov Identifiers: NCT01928771 (SIROCCO), NCT01914757 (CALIMA), and NCT02075255 (ZONDA).

Burden of asthma among patients adherent to ICS/LABA: A real-world study.

OBJECTIVES: Asthma is a chronic respiratory condition with a U.S. prevalence of 7.4%. Despite numerous treatment options, asthma remains poorly controlled in some patients. Uncontrolled asthma is associated with high healthcare resource utilization (HCRU) and reduced productivity. This study assessed symptoms, productivity, and HCRU of patients adherent to medium/high-dosage inhaled corticosteroid/long-acting beta2-agonist (ICS/LABA) treatment, and the relationship of asthma control with these parameters. METHODS: Data were collected in the U.S. in 2013-2016 in the Adelphi Respiratory Disease Specific Programme, a cross-sectional survey. Participating physicians (n = 258) each completed a record form for eligible patients, who were receiving medium/high-dosage ICS/LABA treatment with self-reported moderate/high adherence, completed the Asthma Control Test (ACT) and the Work Productivity and Activity Impairment (WPAI) questionnaire, and were included in the analyses. RESULTS: Patients (n = 428) had a mean of 59% symptom-free days in the past month. Wheezing was the most troublesome symptom for 25% of patients. In the previous 12 months, the mean number of exacerbations was 1.3; 15% of exacerbations required emergency room treatment and/or hospitalization. Mean physician visits for asthma was 5.7. Asthma impacted leisure/personal time frequently/constantly for 11% of patients, with 20% overall work impairment. Asthma was poorly controlled (ACT score ≤15) in 18% of patients; poorer asthma control was associated with higher rates of exacerbations, work impairment, and HCRU. CONCLUSION: Given the substantial burden described, greater attention to asthma monitoring and management is necessary. Identification of novel treatments may be important for patients not responding to medium/high-dosage ICS/LABA treatment.

Benralizumab efficacy by atopy status and serum immunoglobulin E for patients with severe, uncontrolled asthma.

BACKGROUND: Patients with severe asthma can have eosinophilic inflammation and/or allergen sensitization. Benralizumab is an anti-eosinophilic monoclonal antibody indicated for add-on maintenance treatment of patients with severe asthma aged 12 years and older, and with an eosinophilic phenotype. OBJECTIVE: To investigate the efficacy of benralizumab by atopic status and serum immunoglobulin E (IgE) concentrations. METHODS: We analyzed pooled results from the SIROCCO (NCT01928771) and CALIMA (NCT01914757) phase III studies. Patients 12 to 75 years old with severe, uncontrolled asthma on high-dosage inhaled corticosteroids plus long-acting ß2-agonists received 30 mg of subcutaneous benralizumab every 4 weeks or every 8 weeks (first 3 doses every 4 weeks) or placebo every 4 weeks. The analysis stratified patients who did and did not meet similar omalizumab-qualifying criteria of atopy and serum IgE levels 30 to 700 kU/L. Patients also categorized as having high serum IgE (≥150 kU/L) or low serum IgE (<150 kU/L) and as having atopy or no atopy. Efficacy outcomes were for all patients and by blood eosinophil counts and included annual exacerbation rate ratio and pre-bronchodilator forced expiratory volume in 1 second change at treatment end vs placebo. RESULTS: Benralizumab every 8 weeks decreased exacerbations by 46% (95% confidence interval 26-61, P = .0002) and increased forced expiratory volume in 1 second by 0.125 L (95% confidence interval 0.018-0.232, P = .0218) vs placebo for patients with at least 300 eosinophils/µL who met the atopy and IgE criteria. For patients with eosinophilia and high or low IgE, treatment with benralizumab every 8 weeks resulted in 42% and 43% decreases in exacerbation rate (P ≤ .0004) and 0.123- and 0.138-L increases in forced expiratory volume in 1 second (P ≤ .0041) vs placebo, respectively. CONCLUSION: Benralizumab treatment decreased exacerbations and improved lung function for patients with severe, uncontrolled eosinophilic asthma regardless of serum IgE concentrations and atopy status.

Seasonal variability of exacerbations of severe, uncontrolled eosinophilic asthma and clinical benefits of benralizumab.

BACKGROUND: Benralizumab is a humanized, afucosylated, monoclonal antibody that targets interleukin-5 receptor alpha and induces direct, rapid, and nearly complete depletion of eosinophils via enhanced antibody-dependent cell-mediated cytotoxicity. In the United States, benralizumab is indicated for add-on maintenance treatment of patients ≥12 years old with severe asthma and an eosinophilic phenotype. OBJECTIVE: This study evaluated the effect of benralizumab treatment on seasonal asthma exacerbation rates for patients with severe, uncontrolled asthma. METHODS: This was a post hoc analysis of pooled data from the phase III SIROCCO (ClinicalTrials.gov identifier: NCT01928771) and CALIMA (NCT01914757) trials. The primary analysis population was patients ages 12-75 years treated with high-dosage inhaled corticosteroids and long-acting beta-2 agonists who had baseline blood eosinophil counts of ≥300 cells/µL. Patients received benralizumab 30 mg subcutaneously every 4 weeks or every 8 weeks (the first three doses every 4 weeks) or placebo every 4 weeks. Crude exacerbation rates (asthma exacerbations per patient-year) were determined for each month and season. Marginal asthma exacerbation rates and exacerbation rate ratios were estimated by season or month by using a negative binomial model that included covariates for study code, treatment, region, use of maintenance oral corticosteroids, and number of exacerbations in the previous year. Hemispheric seasons were accounted for by normalizing the study site locations. RESULTS: Observed crude exacerbation rates were higher in the fall and winter than in the spring and summer for all the patients. For the patients who received placebo, benralizumab every 4 weeks, and benralizumab every 8 weeks, crude exacerbation rates were the following: fall, 1.52, 0.86, and 0.81, respectively; winter, 1.44, 0.91, and 0.82, respectively; spring, 1.11, 0.66, and 0.52, respectively; and summer, 1.02, 0.55, and 0.51, respectively. Rate reductions in seasonal marginal annual exacerbation rates were 37-50% versus placebo at each season (p < 0.001). CONCLUSION: Benralizumab significantly and consistently reduced asthma exacerbations across all seasons versus placebo for patients with severe, uncontrolled eosinophilic asthma.

Characterizing patients with asthma who received Global Initiative for Asthma steps 4-5 therapy and managed in a specialty care setting.

BACKGROUND: Severe asthma is recognized in the European Respiratory Society/American Thoracic Society guidelines as a major unmet need in the management of asthma. OBJECTIVE: The study objective was to describe the clinical burden of Global Initiative for Asthma (GINA) steps 4-5 asthma for patients treated by specialists in the U.S. community setting. METHODS: Patients, ages ≥12 years, with asthma who received GINA step 4 or 5 treatment and were treated at a large U.S. allergy practice network between January 1, 2010, and April 30, 2016, were retrospectively identified by using electronic health records. Clinical outcomes included lung function (forced expiratory volume in one second of expiration [FEV1] and FEV1% predicted), symptom control (Asthma Control Test [ACT]), the fractional exhaled nitric oxide (FeNO) value (FeNO ≥25 ppb indicates airway inflammation), and asthma medication use. The change in outcomes from baseline to 12 and 24 months after the index date was calculated. RESULTS: Of 120,116 patients with asthma, 12,922 (10.8%) had severe asthma, 68% (n = 8751) while on step 4 therapy. The mean baseline prebronchodilation FEV1% predicted was 79.7%, and the mean baseline ACT score was 17.0. With uncontrolled asthma defined as an ACT score of ≤19 and/or an FEV1 value of <80% predicted and/or oral corticosteroid use of ≥2 bursts, 52.5% and 57.7% of patients on step 4 and step 5 therapy, respectively, had uncontrolled asthma at baseline. Of a subset of patients, 40.9% had an eosinophil count of ≥300 cells/mm3 and 44% had an FeNO concentration of ≥25 ppb. Small increases in the FEV1 value were observed from baseline to 12 months (n = 4022) and 24 months (n = 2326) postindex (0.07 and 0.04 L, respectively). CONCLUSION: A considerable proportion of patients had uncontrolled asthma while on current GINA steps 4-5 treatment, which indicated that additional therapies may be required to reduce the clinical burden of severe asthma.

Comparative effectiveness of budesonide/formoterol combination and fluticasone/salmeterol combination among chronic obstructive pulmonary disease patients new to controller treatment: a US administrative claims database study.

BACKGROUND: Inhaled corticosteroid/long-acting ß2-agonist combinations (ICS/LABA) have emerged as first line therapies for chronic obstructive pulmonary disease (COPD) patients with exacerbation history. No randomized clinical trial has compared exacerbation rates among COPD patients receiving budesonide/formoterol combination (BFC) and fluticasone/salmeterol combination (FSC) to date, and only limited comparative data are available. This study compared the real-world effectiveness of approved BFC and FSC treatments among matched cohorts of COPD patients in a large US managed care setting. METHODS: COPD patients (≥40 years) naive to ICS/LABA who initiated BFC or FSC treatments between 03/01/2009-03/31/2012 were identified in a geographically diverse US managed care database and followed for 12 months; index date was defined as first prescription fill date. Patients with a cancer diagnosis or chronic (≥180 days) oral corticosteroid (OCS) use within 12 months prior to index were excluded. Patients were matched 1-to-1 on demographic and pre-initiation clinical characteristics using propensity scores from a random forest model. The primary efficacy outcome was COPD exacerbation rate, and secondary efficacy outcomes included exacerbation rates by event type and healthcare resource utilization. Pneumonia objectives included rates of any diagnosis of pneumonia and pneumonia-related healthcare resource utilization. RESULTS: Matching of the identified 3,788 BFC and 6,439 FSC patients resulted in 3,697 patients in each group. Matched patients were well balanced on age (mean=64 years), gender (BFC: 52% female; FSC: 54%), prior COPD-related medication use, healthcare utilization, and comorbid conditions. During follow-up, no significant difference was seen between BFC and FSC patients for number of COPD-related exacerbations overall (rate ratio [RR]=1.02, 95% CI=[0.96,1.09], p=0.56) or by event type: COPD-related hospitalizations (RR=0.96), COPD-related ED visits (RR=1.11), and COPD-related office/outpatient visits with OCS and/or antibiotic use (RR=1.01). The proportion of patients diagnosed with pneumonia during the post-index period was similar for patients in each group (BFC =17.3%, FSC =19.0%, odds ratio=0.92 [0.81,1.04], p=0.19), and no difference was detected for pneumonia-related healthcare utilization by place of service. CONCLUSION: This study demonstrated no difference in COPD-related exacerbations or pneumonia events between BFC and FSC treatment groups for patients new to ICS/LABA treatment in a real-world setting. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01921127 .

Fixed airflow obstruction in asthma: a descriptive study of patient profiles and effect on treatment responses.

BACKGROUND: The role of fixed airflow obstruction (FAO) in asthma is unclear. OBJECTIVE: To assess the relationship between FAO and clinical features of asthma and the effect of FAO on treatment response. METHODS: Post hoc descriptive analysis of data stratified by FAO category (screening post-albuterol FEV1/FVC

Bronchodilator effect of single-dose formoterol administered by pressurized metered-dose inhaler in children with asthma aged 6 to <12 years receiving budesonide.

Dose-response of formoterol via pressurized metered-dose inhaler (pMDI) has not been determined in asthmatic pediatric patients aged 6 to <12 years. This study was designed to assess the bronchodilating dose-response of three formoterol pMDI doses in children with stable asthma aged 6 to <12 years receiving twice-daily (b.i.d.) budesonide 160 micrograms. A U.S., multicenter, five-way crossover study compared single doses of formoterol, a long-acting beta-agonist, via pMDI (2.25, 4.5, and 9 micrograms) or dry powder inhaler (12 micrograms; active comparator) and placebo, with a 3- to 14-day washout period between doses. Budesonide pMDI 160 micrograms, an inhaled corticosteroid, was given b.i.d. throughout the study. Fifty-four pediatric patients (mean age, 9.2 years; mean asthma history, 6.1 years) were randomized. All formoterol doses showed significantly higher average 12-hour forced expiratory volume in 1 second (FEV1; area under the curve) versus placebo (primary efficacy). Formoterol pMDI 4.5 and 9 micrograms showed significantly greater average 12-hour FEV1 than formoterol 2.25 micrograms (p = 0.0007 and p = 0.0001, respectively). Formoterol also resulted in significant improvement in maximum FEV1 during the 12-hour treatment period (secondary efficacy) with formoterol 4.5-, 9-, and 12-microgram doses versus placebo and the formoterol 2.25-microgram dose. Bronchodilation was not maintained during the 12-hour dosing interval with formoterol 2.25 micrograms. No serious adverse events were reported. Formoterol pMDI showed generally dose-proportional pharmacokinetics to 9 micrograms, as determined by urinary excretion. Single doses of formoterol pMDI showed a dose-response, with formoterol 9 micrograms exhibiting a maximum response, in pediatric patients aged 6 to <12 years with persistent stable asthma maintained on b.i.d. budesonide pMDI 160 micrograms. Clinical trial NCT01136655, www.clinicaltrials.gov.

Validation of the Onset of Effect Questionnaire in Participants With Chronic Obstructive Pulmonary Disease.

Background: Patient perception of medication onset of effect is important for adherence. Although the Onset of Effect Questionnaire (OEQ) has been validated in patients with asthma, it has not been evaluated in patients with chronic obstructive pulmonary disease (COPD). This study evaluated the COPD-OEQ in patients with COPD. Methods: Two analyses (qualitative and quantitative) were conducted to assess the content validity and psychometric properties of the COPD-OEQ in participants with COPD. In the qualitative analysis, interviews assessed content validity by concept elicitation (CE) and cognitive interviewing (CI). CE included questions to understand patient experience related to onset of medication effect. CI included completion of the COPD-OEQ and assessment of the COPD-OEQ items, response options, and instructions. During the 2-week quantitative analysis, 2 versions of the COPD-OEQ (Weekly and Daily) were administered to assess test-retest reliability, construct validity, and known-groups validity. Results: The qualitative analysis demonstrated that 3 of the 5 COPD-OEQ items were relevant and understood as intended. Qualitative findings demonstrated inconsistent evidence that the COPD-OEQ Weekly and Daily were reliable and valid measures in participants with COPD. Test-retest reliability was observed for the COPD-OEQ Weekly and Daily; however, construct validitywas weak and demonstrated inconsistent correlations among COPD-OEQ items. Overall, known-groups validity was not demonstrated. Conclusion: The weak evidence from the quantitative analysis of the COPD-OEQ Weekly and Daily tools does not support use of the OEQ in general COPD. The study supports the content validity for the assessment of perceived onset of effect in patients with COPD.

Long-Term Use of Maintenance Systemic Corticosteroids is Associated with Multiple Adverse Conditions in a Large, Real-World Cohort of US Adults with Severe Asthma.

There is growing recognition of the adverse consequences of maintenance systemic corticosteroid (mSCS) therapy in severe asthma (SA). The objective of this study was to describe the prevalence of potential adverse effects of long-term mSCS therapy in adults with specialist-confirmed SA in the United States (US). CHRONICLE is an ongoing, noninterventional, observational study of US adults with SA treated by allergists/immunologists and pulmonologists. Once enrolled, patients' duration of mSCS therapy was reported by sites based on medical record review. For patients enrolled between February 2018 and February 2021, the prevalence of SCS-associated conditions was evaluated among those with no reported history of mSCS use, or mSCS use with < 2 years or ≥ 2 years cumulative duration. Prevalence and incidence estimates were adjusted for age and smoking history. Of 2793 patients enrolled, 311 and 231 had mSCS use for < 2 and ≥ 2 years, respectively. In adjusted analyses, adrenal insufficiency, pneumonia, type 2 diabetes, osteoporosis/osteopenia, congestive heart failure, coronary artery disease, hypertension, anxiety, and depression were statistically significantly associated with any mSCS use. By duration, mSCS use ≥ 2 years was associated with osteopenia/osteoporosis, coronary artery disease, adrenal insufficiency, and diabetes-related neuropathy; mSCS use < 2 years was associated with depression and osteopenia/osteoporosis, and diagnoses of depression, anxiety, and hypertension during the 12 months prior to enrollment. Overall, among patients with specialist-confirmed SA, mSCS use was associated with a high prevalence of multiple adverse conditions. Healthcare professionals should employ mSCS-sparing treatment strategies to avoid these negative consequences.

Health-Related Quality of Life and Productivity Among US Patients with Severe Asthma.

BACKGROUND: Health-related quality of life (HRQoL) and productivity of patients with confirmed severe asthma (SA) have not been well characterized in large, real-world populations. PURPOSE: To characterize SA impact on HRQoL, work productivity, and activity impairment in a large, real-world cohort in the United States (US). METHODS: CHRONICLE is an observational study of specialist-treated adults (≥18 years) in the US with SA receiving biologics or maintenance systemic corticosteroids (mSCS), or those persistently uncontrolled by high-dosage inhaled corticosteroids with additional controllers (HD ICS+). At enrollment, patients completed the St. George's Respiratory Questionnaire (SGRQ) and Work Productivity and Activity Impairment (WPAI) questionnaire. Results were analyzed for those enrolled between February 2018 and February 2020. RESULTS: Among patients who completed enrollment questionnaires (n = 1109), mean age was 54 years and most were women (70%). Among SGRQ respondents (n = 960), mean (SD) total score was 43 (23); 51% reported good/very good health. Among WPAI respondents (n = 1057; 566 employed), mean (SD) overall work impairment was 21% (25). Patients receiving biologics (vs mSCS, HD ICS+ only) had better SGRQ total scores (38 vs 59, 48) and lower work impairment (17% vs 34%, 27%). Patients with better SGRQ activity scores relative to symptom scores had better SGRQ impacts scores, total scores, and reported better overall health. CONCLUSION: SA significantly affects HRQoL, work productivity, and activity. The SGRQ is a valuable research instrument for evaluating HRQoL in SA. Due to its association with HRQoL and overall health, activity impairment should be a focus when monitoring patients' disease control. STUDY REGISTRATION: ClinicalTrials.gov Identifier: NCT03373045.