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Bronchiectasis is a chronic, progressive lung disease believed to result from a vicious cycle of infection and inflammation, with symptoms of chronic cough with sputum production, chronic fatigue, rhinosinusitis, chest pain, breathlessness and haemoptysis. There are currently no established instruments to monitor daily symptoms and exacerbations for use in clinical trials. Following a literature review and three expert clinician interviews, we conducted concept elicitation interviews with 20 patients with bronchiectasis to understand their personal disease experience. Findings from literature and clinician feedback were used to develop a draft version of the Bronchiectasis Exacerbation Diary (BED), which was designed to monitor key symptoms on a daily basis and during exacerbations. Patients were eligible to be interviewed if they were US residents aged ≥18 years, had a computed tomography scan–confirmed diagnosis of bronchiectasis with ≥two exacerbations in the previous 2 years and had no other uncontrolled respiratory conditions. Four waves of five patient interviews each were conducted. Patients (n=20) had a mean±SDage of 53.9±12.8 years, and most were female (85%) and white (85%). A total of 33 symptoms and 23 impacts arose from the patient concept elicitation interviews. The BED was revised and finalised based upon patient feedback. The final BED is a novel, eight-item patient-reported outcome (PRO) instrument for monitoring key exacerbation symptoms on a daily basis with content validity established through comprehensive qualitative research and direct patient insight. The BED PRO development framework will be completed following psychometric evaluations of the data from a phase 3 bronchiectasis clinical trial.

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 β2-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

This qualitative study assessed the experience of patients with chronic rhinosinusitis with nasal polyposis (NP) to inform the development of a novel symptom diary for clinical study use.Concept elicitation and cognitive interviews were conducted with patients who had a physician-verified diagnosis of NP and a history of intranasal corticosteroid use. Concepts were identified via open-ended and follow-up questions. Relative symptom/impact disturbance level was assessed using a scale of 0 (not at all disturbing) to 10 (extremely disturbing).Patients (n = 30) attributed numerous symptoms and impacts to NP; the most prevalent and disturbing were nasal congestion (identified by 100% of patients; average disturbance rating = 7.9), nasal blockage/obstruction (97%; 8.2), difficulty with sense of smell (97%; 7.6), facial pressure (90%; 6.2), postnasal drip (87%; 6.5), runny nose (87%; 6.2), facial pain (80%; 6.3), and headache (77%; 6.5). These symptoms, along with the impact of NP on sleep and daily activities, were included in the Nasal Polyposis Symptom Diary (NPSD). Cognitive interviews confirmed that patients understood the NPSD items and could select a response reflective of their experience at its worst over the past 24 hours using a four-point scale (none, mild, moderate, or severe).The most relevant and disturbing symptoms, according to patients with NP, were included in the NPSD. Interviews confirmed the suitability of NPSD in capturing the daily experience of patients. These findings support the content validity of the NPSD as a suitable tool for capturing NP symptoms and impacts.

Introduction: Severe eosinophilic asthma is increasingly recognised as a heterogeneous phenotype. Benralizumab has a unique ability to deplete blood and tissue eosinophils. Assessing clinical characteristics of patients who have a marked response to treatment (super-responders) can aid our understanding of severe asthma. Methods: ANDHI was a double-blind, placebo-controlled, 6-month study of patients with severe uncontrolled asthma and blood eosinophil levels (EOS) ≥150/µL. Rates and clinical characteristics of super-responders to benralizumab were evaluated (Table). Results: Super-response was achieved in 53% of benralizumab and 35% of placebo patients (OR=2.14; p

Background Eosinophilic inflammation has been implicated in the pathogenesis, severity, and treatment responsiveness of chronic rhinosinusitis with nasal polyps (CRSwNP). Objective We sought to assess the efficacy and safety of benralizumab-mediated eosinophil depletion for treating CRSwNP. Methods The phase 3 OSTRO study enrolled patients with severe CRSwNP who were symptomatic despite treatment with intranasal corticosteroids and who had a history of systemic corticosteroid (SCS) use and/or surgery for nasal polyps (NP). Patients were randomized 1:1 to treatment with benralizumab 30 mg or placebo every 4 weeks for the first 3 doses and every 8 weeks thereafter. Coprimary end points were change from baseline to week 40 in NP score (NPS) and patient-reported mean nasal blockage score reported once every 2 weeks. Results The study population comprised 413 randomized patients (207 in the benralizumab group and 206 in the placebo group). Benralizumab significantly improved NPS and nasal blockage score compared to placebo at week 40 (P ≤ .005). Improvements in Sinonasal Outcome Test 22 score at week 40, time to first NP surgery and/or SCS use for NP, and time to first NP surgery were not statistically significant between treatment groups. Nominal significance was obtained for improvement in difficulty in sense of smell score at week 40 (P = .003). Subgroup analyses suggested influences of comorbid asthma, number of NP surgeries, sex, body mass index, and baseline blood eosinophil count on treatment effects. Benralizumab was safe and well tolerated. Conclusion Benralizumab, when added to standard-of-care therapy, reduced NPS, decreased nasal blockage, and reduced difficulty with sense of smell compared to placebo in patients with CRSwNP. Trial registration: ClinicalTrials.gov NCT03401229

SummaryBackgroundBenralizumab did not significantly reduce exacerbations compared with placebo in the phase 3 GALATHEA and TERRANOVA trials of benralizumab for patients with chronic obstructive pulmonary disease (COPD). We aimed to identify clinical and physiological characteristics of patients with COPD that could help to identify people who are likely to have the greatest treatment effect with benralizumab.MethodsWe analysed individual study and pooled results from GALATHEA and TERRANOVA. At study enrolment, patients from GALATHEA and TERRANOVA were aged 40–85 years, had moderate to very severe airflow limitation, had elevated blood eosinophil counts, and at least two exacerbations or one severe exacerbation in the previous year despite dual inhaled therapy (inhaled corticosteroids plus long-acting β2-agonists or long-acting β2-agonists plus long-acting muscarinic antagonists) or triple inhaled therapy (inhaled corticosteroids plus long-acting β2-agonists plus long-acting muscarinic antagonists). We analysed data for 3910 patients who received benralizumab (30 mg or 100 mg subcutaneously every 8 weeks; first three doses every 4 weeks) or placebo with dual or triple therapy to identify factors consistently associated with annual exacerbation rate reduction. We evaluated the annual exacerbation rate for benralizumab versus placebo as the primary endpoint. GALATHEA and TERRANOVA are registered with ClinicalTrials.gov, NCT02138916 and NCT02155660, respectively.FindingsFor 2665 patients with elevated blood eosinophil counts, treatment effect with benralizumab every 8 weeks at 100 mg, but not at 30 mg, occurred for patients with a history of more frequent exacerbations, poorer baseline lung function, or greater baseline lung function improvement with short-acting bronchodilators. Patients with baseline blood eosinophil counts of 220 cells per μL or greater with: three or more exacerbations in the previous year receiving benralizumab every 8 weeks versus placebo, had rate ratios (RRs) of 0·69 (95% CI 0·56–0·83) for 100 mg and 0·86 (0·71–1·04) for 30 mg; postbronchodilator FEV1 of less than 40% had RRs of 0·76 (0·64–0·91) for 100 mg and 0·90 (0·76–1·06) for 30 mg; and postbronchodilator response of at least 15% had RRs of 0·67 (0·54–0·83) for 100 mg and 0·87 (0·71–1·07) for 30 mg. When combined factors were examined, patients with elevated baseline blood eosinophil counts, with three or more exacerbations in the previous year, and who were receiving triple therapy were identified as likely to benefit from benralizumab 100 mg every 8 weeks versus placebo (RR 0·70 [95% CI 0·56–0·88]). Benralizumab 30 mg every 8 weeks did not benefit patients meeting these criteria compared with placebo (RR 0·99 [95% CI 0·79–1·23]).InterpretationElevated blood eosinophil counts combined with clinical characteristics identified a subpopulation of patients with COPD who had reductions in exacerbations with benralizumab treatment. These hypothesis-generating analyses identified the potential efficacy of benralizumab 100 mg for this subpopulation. These findings require prospective evaluation in clinical trials.FundingAstraZeneca.

Pamela L Zeitlin,1 Mila Leong,2 Jeremy Cole,3 Raburn M Mallory,4 Vivian H Shih,5 Richard F Olsson,6 Mitchell Goldman5 On behalf of the ALIZE study investigators 1Department of Pediatrics, National Jewish Health, Denver, CO, USA; 2Pediatric Pulmonary and Asthma Associates, Northfield, NJ, USA; 3OK Clinical Research, LLC, Edmond, OK, USA; 4MedImmune LLC, Gaithersburg, MD, USA; 5AstraZeneca, Gaithersburg, MD, USA; 6AstraZeneca, Gothenburg, Sweden Background and objectives: Benralizumab is a humanized, afucosylated monoclonal antibody against the IL-5Rα. Initial monthly followed by every-other-month injections result in rapid and nearly complete eosinophil depletion. We evaluated whether three doses of benralizumab modifies antibody response to seasonal influenza vaccination for adolescent/young adult patients with moderate to severe asthma.Methods: ALIZE (NCT02814643) was a Phase IIIb randomized controlled trial of patients aged 12–21 years receiving medium- to high-dosage inhaled corticosteroids/long-acting β2-agonists. Patients received benralizumab 30 mg or placebo at Weeks 0, 4, and 8, plus tetravalent influenza vaccination at Week 8. At Week 12, strain-specific antibody responses following vaccination were assessed for four influenza antigens by hemagglutination inhibition (HAI) and microneutralization (MN) assays.Results: A total of 103 patients were randomized and received benralizumab (n=51) or placebo (n=52). There were no consistent differences in HAI or MN antibody responses at Week 12 between patients receiving benralizumab or placebo. HAI geometric mean fold rises (GMFRs) for all influenza strains tested were 3.3–4.2 for benralizumab vs 3.4–3.9 for placebo; MN GMFRs were 2.8–5.1 for benralizumab vs 3.2–4.4 for placebo. A ≥4-fold rise in HAI from Weeks 8 to 12 occurred in 44.0%–56.0% and 30.6%–49.0% of patients receiving benralizumab and placebo, respectively. At Week 12, 78.0%–100% vs 79.6%–100% of patients receiving benralizumab and placebo, respectively, achieved a ≥40 HAI antibody titer. There were no significant safety findings.Conclusion: Benralizumab did not impair the antibody response to seasonal virus vaccination in adolescents and young adult patients with moderate to severe asthma. Keywords: benralizumab, interleukin-5, interleukin-5 receptor, influenza vaccination, eosinophils, antibody response, asthma

Background: In GALATHEA/TERRANOVA Phase III trials (N Engl J Med. 2019; May 20), exacerbation reduction with benralizumab for patients with COPD did not reach statistical significance. Aims and Objectives: We evaluated baseline factors to identify patients demonstrating greater benralizumab efficacy. Methods: We pooled data from GALATHEA/TERRANOVA (N=3,910) for patients randomized to placebo or benralizumab (56 weeks). We ran prespecified statistical analyses to detect baseline factors that identified patients demonstrating greater reduction of moderate to severe COPD exacerbations with benralizumab 30 mg or 100 mg. Results: We identified several baseline efficacy factors: history of frequent exacerbations, lesser post-BD FEV1, greater post-BD FEV1 response, prior triple inhaled therapy use (figure). These factors identified greater efficacy with benralizumab 100 mg vs. placebo for patients with baseline eosinophils ≥220 cells/µL than for the overall population. Patients receiving benralizumab 100 mg with a combination of prior triple inhaled therapy use, baseline blood eosinophils ≥220 cells/µL, and ≥3 exacerbations (previous 12 months) demonstrated the greatest response (rate ratio vs. placebo [95% CI]: 0.70 [0.56, 0.88]). Conclusions: We identified a subpopulation of patients with specific traits who demonstrated a clinically meaningful benralizumab response. A Phase III trial is ongoing to evaluate benralizumab efficacy for these patients.

A feature increasingly utilized in clinical trial practice is to allow a study to stop early when it seems unlikely to achieve its primary efficacy objectives. This is commonly referred to as stopping for futility, and can be motivated by ethical and financial considerations. A number of methods for addressing futility have been described in the literature, including rules based upon conditional power, predictive probability, beta spending functions, and others. We consider futility stopping from the point of view of quantifying and providing an objective sensible balance between risks of incorrect decisions (e.g., stopping trials which should continue, and continuing trials which should stop), and discuss how specific considerations within a trial can lead to choice of a sensible scheme. This approach is not specific to any particular scales in the literature such as those just mentioned, and we describe interrelationships among criteria expressed on different scales. As futility may be evaluated multiple times in a long-term trial and the amount of information available at scheduled interim analyses may be difficult to predict in advance, we present a specific optimality criterion and discuss which of the familiar scales tend to produce schemes simple to describe and implement, and with better behavior across different timepoints at which futility might be evaluated.

Impaired temporal processing has historically been viewed as a hallmark feature of attention deficit hyperactivity disorder. Recent evidence suggests temporal processing deficits may also be characteristic of autism spectrum disorder (ASD). However, little is known about the factors that impact temporal processing in children with ASD. The purpose of this study was to assess the effects of co-morbid attention problems, working memory (WM), age, and their interactions, on time reproduction in youth with and without ASD. Twenty-seven high-functioning individuals with ASD and 25 demographically comparable typically developing individuals (ages 9-17; 85% male) were assessed on measures of time reproduction, auditory WM, and inattention/hyperactivity. The time reproduction task required depression of a computer key to mimic interval durations of 4, 8, 12, 16, or 20 sec. Mixed effects regression analyses were used to model accuracy and variability of time reproduction as functions of diagnostic group, interval duration, age, WM, and inattention/hyperactivity. A significant group by age interaction was detected for accuracy, with the deficit in the ASD group being greater in younger children. There was a significant group by WM interaction for consistency, with the effects of poor WM on performance consistency being more pronounced in youth with ASD. All participants tended to underestimate longer interval durations and to be less consistent for shorter interval durations; these effects appeared more pronounced in those who were younger or who had poorer WM performance. Inattention/hyperactivity symptoms in the ASD group were not related to either accuracy or consistency. This study highlights the potential value of temporal processing as an intermediate trait of relevance to multiple neurodevelopmental disorders.

Bipolar disorder is a chronic illness with substantial psychosocial and occupational morbidity. Several studies have shown that, after a manic episode, the majority of patients with bipolar disorder continue to exhibit significant impairment in role functioning, despite symptomatic recovery (1–6). A recent review of outcome studies concluded that 57–65% of patients with bipolar disorder were unemployed (as compared to 6% of the general population), and up to 80% were considered to have at least partial vocational disability following syndromal recovery from a first-lifetime manic or mixed episode (7). It is generally believed that the depressive pole of bipolar disorder is more consistently and strongly associated with functional disability (8, 9) than is the hypomanic/manic pole (10, 11). However, one of the few large-scale outcome studies of first-episode mania found that while the majority of patients (72%) had achieved symptomatic recovery within two years of their initial hospitalization, less than half (43%) had achieved functional recovery, defined as regaining one’s premorbid occupational and residential status (6). Despite its prevalence and cost in both personal and societal terms, the reasons for persistent work disability in patients with bipolar disorder remain unclear. Factors other than mood symptoms may contribute to poor occupational functioning (12, 13). In particular, there is increasing evidence that impairment in specific cognitive domains, i.e., executive function, verbal memory, attention, and processing speed, persists in some patients with bipolar disorder even during periods of euthymia [(14); (see 15, 16 for meta-analyses)]. Impairments in executive functioning, verbal memory, and speed of processing have been consistently associated with poorer functional outcome in schizophrenia (17–19). There is also mounting evidence that cognitive impairment in these domains may contribute to functional disability in bipolar disorder patients (20–24). A recent review of the literature concluded that in the majority of studies (six out of eight) of euthymic patients with bipolar disorder, poorer cognitive function was associated with worse functional outcome, even after controlling for residual mood symptoms, age, and other clinical variables (25). However, most of these studies used very general measures of functional outcome, such as the Global Assessment of Functioning (GAF) (26), which does not separate clinical symptom severity from functional status in the rating of level of overall functioning. Additionally, the relationship between neurocognitive impairment and the ability to resume normal occupational functioning after an acute manic episode resolves has rarely been studied (27). To our knowledge, only one prior study has examined changes in neurocognitive function over time as a predictor of outcome in bipolar disorder patients (28). In this study, positive changes in composite neurocognitive performance over one year emerged as a significant predictor of improved functioning (as assessed by the GAF) over the follow-up period. The purpose of this study was to assess the cross-sectional and prospective longitudinal association between neurocognition and occupational function in subjects with bipolar disorder who had recently achieved symptomatic recovery following a manic episode. Using the Life Functioning Questionnaire (LFQ) (29), a gender-neutral measure of occupational function that assesses both quality and quantity of work impairment, we sought to answer the following questions: (i) Does neurocognitive function at the time of symptomatic recovery from a manic episode differentiate patients who achieve occupational recovery from those who do not? (ii) In those who do not achieve occupational recovery concurrently with symptomatic recovery, does neurocognitive function at the time of symptomatic recovery predict short-term occupational recovery? (iii) Is change in cognitive function, either globally or in specific domains, associated with short-term occupational recovery? Given prior findings, in both patients with schizophrenia and bipolar disorder, which indicate deficits in executive functions, verbal memory, and speed of processing are associated with poor functional outcome, we hypothesized that better baseline neurocognitive function in these domains would be associated with concurrent occupational recovery, and that cognitive improvement in these domains over time would be associated with occupational recovery over the follow-up period.

Impaired temporal processing has historically been viewed as a hallmark feature of attention deficit hyperactivity disorder. Recent evidence suggests temporal processing deficits may also be characteristic of autism spectrum disorder (ASD). However, little is known about the factors that impact temporal processing in children with ASD. The purpose of this study was to assess the effects of co-morbid attention problems, working memory (WM), age, and their interactions, on time reproduction in youth with and without ASD. Twenty-seven high-functioning individuals with ASD and 25 demographically comparable typically developing individuals (ages 9-17; 85% male) were assessed on measures of time reproduction, auditory WM, and inattention/hyperactivity. The time reproduction task required depression of a computer key to mimic interval durations of 4, 8, 12, 16, or 20 sec. Mixed effects regression analyses were used to model accuracy and variability of time reproduction as functions of diagnostic group, interval duration, age, WM, and inattention/hyperactivity. A significant group by age interaction was detected for accuracy, with the deficit in the ASD group being greater in younger children. There was a significant group by WM interaction for consistency, with the effects of poor WM on performance consistency being more pronounced in youth with ASD. All participants tended to underestimate longer interval durations and to be less consistent for shorter interval durations; these effects appeared more pronounced in those who were younger or who had poorer WM performance. Inattention/hyperactivity symptoms in the ASD group were not related to either accuracy or consistency. This study highlights the potential value of temporal processing as an intermediate trait of relevance to multiple neurodevelopmental disorders.

Many patients with bipolar disorder do not regain their premorbid level of occupational functioning even after mood episodes have resolved. The reasons for this are not well understood. We evaluated the relationship between neurocognition and occupational function in bipolar disorder patients, following symptomatic recovery.A total of 79 previously employed adults with bipolar I disorder who achieved symptomatic recovery (i.e., at least six weeks clinically euthymic) following a manic episode underwent a neurocognitive evaluation and assessment of occupational functioning. Study participants were evaluated every three months thereafter for up to nine months. Factor analysis was applied to reduce the initial set of neurocognitive variables to five domains: episodic memory, working memory/attention, executive function, visual scanning, and speed of processing. Multiple logistic regression models were used to examine the joint predictive values of these domains for determining occupational recovery.At the time of symptomatic recovery, four of five neurocognitive factors were significant predictors of concomitant occupational recovery and the fifth, executive function, showed a trend in the same direction. For those not occupationally recovered at baseline, longitudinal analyses revealed that changes between baseline and the three-month follow-up timepoint in most cognitive domains were robust and highly significant predictors of occupational recovery at three months.These findings indicate that better neurocognitive function in multiple domains and improvement in these domains over time are strongly predictive of subsequent occupational recovery. Treatments that target cognitive deficit may therefore have potential for improving long-term vocational functioning in bipolar illness.