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Summary Background No consensus exists on how to reduce oral corticosteroids after the initiation of biologics in severe asthma. The PONENTE trial evaluated the effectiveness and safety of a rapid, individualised steroid-reduction algorithm, including adrenal insufficiency monitoring, after benralizumab initiation. Methods This multicentre, open-label, single-arm study was done at 138 clinical asthma treatment centres across 17 countries. We enrolled adult patients (age ≥18 years) with severe, eosinophilic asthma (blood eosinophil count ≥150 cells per μL at enrolment or ≥300 cells per μL in the previous year) requiring maintenance oral corticosteroids for at least 3 months preceding enrolment. Patients received benralizumab 30 mg (subcutaneous injection) every 4 weeks for three doses, then every 8 weeks thereafter. The oral corticosteroid reduction phase began at week 4 with daily oral corticosteroid dosages reduced by 1–5 mg every 1–4 weeks depending on the starting dosage, asthma control, and adrenal function status. Adrenal function was assessed with an early morning serum cortisol measurement, followed by adrenocorticotropic hormone stimulation when required, once patients achieved a daily oral corticosteroid dosage of 5 mg/day for 4 weeks. Repeat cortisol measurements were taken for patients with evidence of adrenal insufficiency at first testing. Asthma control was assessed with the Asthma Control Questionnaire-6 (ACQ-6) weekly throughout the induction and oral corticosteroid reduction phases. The primary endpoints were the percentage of patients eliminating daily oral corticosteroids, sustained for at least 4 weeks, and the percentage achieving elimination or a daily prednisone or prednisolone dosage of 5 mg or less, for at least 4 weeks, if the reason for no further reduction was adrenal insufficiency. Safety and efficacy analyses included all patients who received at least one dose of benralizumab and were descriptive. We present results after the oral corticosteroid reduction phase; a maintenance phase is ongoing. The trial is registered with ClinicalTrials.gov , NCT03557307 . Findings Between April 1, 2018, and Sept 5, 2020, of 705 patients assessed for eligibility, 598 were recruited and all received at least one dose of benralizumab. Overall, 376 (62·88%, 95% CI 58·86–66·76) of 598 patients eliminated oral corticosteroids and 490 (81·94%, 78·62–84·94) of 598 eliminated use or achieved a dosage of 5 mg or less if the reason for stopping the reduction was adrenal insufficiency. Subgroup analysis showed that dosage reductions were achieved irrespective of baseline eosinophil count, baseline oral corticosteroid dosage, or oral corticosteroid treatment duration. Adrenal insufficiency was detected in 321 (60%) of 533 patients at first assessment and in 205 (38%) of 533 patients 2–3 months later. The safety profile was consistent with previous experience. Most patients (448 [75%] of 598) had no asthma exacerbations during the oral corticosteroid reduction phase with an annualised exacerbation rate of 0·63. Of 598 patients, 38 (6%) experienced a total of 46 exacerbations resulting in emergency department or urgent care visits or hospitalisations. Interpretation Despite a high prevalence of adrenal insufficiency, most patients with eosinophilic asthma treated with benralizumab achieved elimination of oral corticosteroids or maximal possible reduction using a personalised dosage-reduction algorithm. Funding AstraZeneca.

BACKGROUND Clinically meaningful improvement in the Sino-Nasal Outcome Test-22 (SNOT-22) was observed in patients with severe, eosinophilic asthma, and nasal polyposis (NP) treated with benralizumab in the ANDHI trial. A post hoc assessment of the effects of benralizumab on SNOT-22 response and asthma efficacy measures in these patients was conducted for further characterization of the efficacy and safety of benralizumab for patients with severe asthma and NP. METHODS Adults with severe, eosinophilic asthma who had experienced ≥2 prior-year exacerbations despite high-dosage inhaled corticosteroid plus additional controller[s] were randomized to 24 weeks of benralizumab or placebo. Patients with physician-diagnosed chronic rhinosinusitis with NP of any severity ongoing at baseline who consented to participate were included in the current ANDHI NP substudy population. Effect on NP symptoms was assessed by the SNOT-22, with an improvement of at least 8.9 defined as clinically significant (responder). Effects on chronic asthma outcomes were assessed by means of annualized asthma exacerbation rate (AER), St. George's Respiratory Questionnaire (SGRQ) total score, forced expiratory volume in one second (FEV1 ), and Asthma Control Questionnaire-6 (ACQ-6). All p-values were nominal. RESULTS Of the ANDHI population (n = 656), 23% (n = 153) participated in the NP substudy (n = 96 benralizumab; n = 57 placebo). Patients were 50% female, with mean age of 53 years, had prior-year AER = 3.3; mean pre-bronchodilator FEV1 = 55% predicted; and median blood eosinophil count ​= 510 cells/µl. For patients with high baseline SNOT-22 scores (>30), benralizumab treatment improved symptoms of NP as measured by SNOT-22 from baseline to Week 24 compared with placebo (Week 24: -10.44 [p = .0176]). Percentage of responders to SNOT-22 was greater for benralizumab vs. placebo (71.3% vs. 45.5%; p = .0036), and effect was enhanced for patients with high baseline SNOT-22 scores (>30). A 69% reduction vs. placebo in annualized AER (0.77 vs. 2.47; p

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

BackgroundThere is no published algorithm predicting asthma crisis events (accident and emergency [A&E] attendance, hospitalisation, or death) using routinely available electronic health record (EHR) data.AimTo develop an algorithm to identify individuals at high risk of an asthma crisis event.Design and settingDatabase analysis from primary care EHRs of people with asthma across England and Scotland.MethodMultivariable logistic regression was applied to a dataset of 61 861 people with asthma from England and Scotland using the Clinical Practice Research Datalink. External validation was performed using the Secure Anonymised Information Linkage Databank of 174 240 patients from Wales. Outcomes were ≥1 hospitalisation (development dataset) and asthma-related hospitalisation, A&E attendance, or death (validation dataset) within a 12-month period.ResultsRisk factors for asthma-related crisis events included previous hospitalisation, older age, underweight, smoking, and blood eosinophilia. The prediction algorithm had acceptable predictive ability with a receiver operating characteristic of 0.71 (95% confidence interval [CI] = 0.70 to 0.72) in the validation dataset. Using a cut-point based on the 7% of the population at greatest risk results in a positive predictive value of 5.7% (95% CI = 5.3% to 6.1%) and a negative predictive value of 98.9% (95% CI = 98.9% to 99.0%), with sensitivity of 28.5% (95% CI = 26.7% to 30.3%) and specificity of 93.3% (95% CI = 93.2% to 93.4%); those individuals had an event risk of 6.0% compared with 1.1% for the remaining population. In total, 18 people would need to be followed to identify one admission.ConclusionThis externally validated algorithm has acceptable predictive ability for identifying patients at high risk of asthma-related crisis events and excluding those not at high risk.

Current understanding of risk factors for asthma attacks in children is based on studies of small but well-characterised populations or pharmaco-epidemiology studies of large but poorly characterised populations. We describe an observational study of factors linked to future asthma attacks in large number of well-characterised children. From two UK primary care databases (Clinical Practice Research Datalink and Optimum Patient Care research Database), a cohort of children was identified with asthma aged 5–12 years and where data were available for ≥2 consecutive years. In the “baseline” year, predictors included treatment step, number of attacks, blood eosinophil count, peak flow and obesity. In the “outcome” year the number of attacks was determined and related to predictors. There were 3776 children, of whom 525 (14%) had ≥1 attack in the outcome year. The odds ratio (OR) for one attack was 3.7 (95% Confidence Interval (CI) 2.9, 4.8) for children with 1 attack in the baseline year and increased to 7.7 (95% CI 5.6, 10.7) for those with ≥2 attacks, relative to no attacks. Higher treatment step, younger age, lower respiratory tract infections, reduced peak flow and eosinophil count >400/μL were also associated with small increases in OR for an asthma attack during the outcome year. In this large population, several factors were associated with a future asthma attack, but a past history of attacks was most strongly associated with future attacks. Interventions aimed at reducing the risk for asthma attacks could use primary care records to identify children at risk for asthma attacks., Childhood asthma: prediction from past attacks A past history of asthma attacks in young children is a strong predictor for future attacks and should be factored into treatment regimes. Childhood asthma attacks take considerable toll on sufferers and their carers, yet risk factors for future attacks are unclear. David Price at the Observational and Pragmatic Research Institute in Singapore and co-workers searched UK primary care databases to find at least two years’ worth of consecutive data on children with asthma aged 5 to 12. The team analyzed data from 3,776 children. Their results showed that past attacks are the strongest predictor for future attacks; of 638 patients who experienced more than one asthma attack during the first year, 240 (38%) had attacks in the second year. Other risk factors included reduced peak flow, lower respiratory tract infections and younger age.

Introduction Une analyse post-hoc a ete menee sur l’etude de Phase IIIb ANDHI afin d’evaluer la reponse complete au benralizumab sur la base de criteres lies a la polypose nasosinusienne (PNS) et a l’asthme. Methodes Des patients adultes atteints d’asthme severe a eosinophiles ont ete randomises pour recevoir un traitement par benralizumab ou un placebo pendant 24 semaines. Ceux presentant une PNS en cours, diagnostiquee par le medecin a l’inclusion, ont ete integres dans cette analyse. La reponse complete a ete definie comme l’obtention d’une amelioration cliniquement significative de −8,9 unites au test d’impact des symptomes sino-nasaux 22 (Sino-Nasal Outcome Test-22 [SNOT-22]) et des resultats cliniquement significatifs concernant quatre autres criteres : – le taux d’exacerbations d’asthme [asthma exacerbation rate (AER) : 0 exacerbation] ; – le questionnaire respiratoire de St. George [St George's Respiratory Questionnaire (SGRQ) ; variation ≤ −4 unites] ; – le VEMS [amelioration ≥ 200 mL] ; – et le questionnaire de controle de l’asthme [ACQ-6 ; variation ≤ −0,5]. Resultats A l’inclusion, les patients (n = 96 benralizumab ; n = 57 placebo) avaient un âge moyen de 53 ans, un nombre median d’eosinophiles sanguins peripheriques = 510 cellules/μL, un AER moyen dans l’annee precedente a 3,3, un VEMS moyen pre-bronchodilatateur a 55 % de la valeur predite, un SNOT-22 moyen a 50,2, un score total SGRQ moyen a 53,1, et un ACQ-6 moyen a 2,9 ( Fig. 1 ). Le pourcentage de patients ayant une amelioration cliniquement significative du SNOT-22 a la fin du traitement (semaine 24) etait plus important sous benralizumab (69,8 %) vs placebo (43,9 %). A la semaine 24, le pourcentage de patients ayant une reponse complete («bon repondeurs») etait plus important dans le bras benralizumab (42,7 %) vs placebo (5,3 %). Le pourcentage de bon repondeurs augmentait pour les patients atteignant le seuil de significativite de 3, 2 ou 1 critere supplementaire (jusqu’a 53,1 % vs 12,3 %, 60,4 %, vs 24,6 % et 64,6 % vs 29,8 % pour le bras benralizumab vs le bras placebo respectivement). Conclusion La majorite des patients ayant un asthme et une PNS traites par benralizumab etait des repondeurs au test SNOT-22 ; la plupart parvenait a atteindre une amelioration cliniquement significative de plusieurs criteres d’evaluation de l’asthme (exacerbations, qualite de vie, fonction pulmonaire ou controle de l’asthme).

Background Observational research is essential to evaluate the real-life effectiveness of asthma treatments and can now make use of outcomes derived from electronic medical records. Aim The aim of this study was to investigate the utility of several database outcome measures in asthma. Methods This study identified cohorts of patients with active asthma from a UK primary care database – Optimum Patient Care Research Database – approximately 10% of which was prospectively supplemented with questionnaire data. The “Questionnaire cohort” included patients aged 18–60 years with valid questionnaire data and 1 year of continuous primary care data. Separate “ICS initiation” and “ICS step-up” cohorts included patients aged 5–60 years initiated on inhaled corticosteroids (ICSs), who had 1 year of continuous primary care data before, and after, this index visit. Database measures of asthma symptom control and exacerbations were identified in the Optimum Patient Care Research Database and cross-tabulated with corresponding patient-reported (questionnaire) data. Responsiveness of the database outcomes was analyzed, using McNemar’s and Wilcoxon’s signed rank tests, and Poisson regression was used to estimate the association between database outcomes and future risk of database exacerbations, in the ICS initiation cohort. Results The final study included 2,366 Questionnaire cohort patients and 51,404 ICS initiation patients. Agreement between patient-reported and database-recorded exacerbations was fair (kappa 0.35). Following the initiation of ICS, database risk domain asthma control (based on exacerbations) improved (proportion of patients with uncontrolled asthma decreased from 24.9% to 18.6%; P, Video abstract

The phase 4 COMPASS-3 study evaluated whether a singular endpoint produces clinically meaningful outcomes in patients with pulmonary arterial hypertension (PAH). The relationship between cardiac magnetic resonance imaging (cMRI)-derived parameters and right heart catheterization (RHC) measurements was also examined. In COMPASS-3 (ClinicalTrials.gov NCT00433329), 100 patients with PAH received bosentan monotherapy for 16 weeks. Patients continued monotherapy if their 6-min walk distance (6MWD) was ≥380 m, or otherwise received add-on sildenafil for an additional 12 weeks. 6MWD, RHC, and cMRI were performed at baseline, week 16, and week 28 (6MWD and cMRI). Baseline median 6MWD was 274 m and 82% of patients had WHO Functional Class III/IV. At week 16, 17% (n = 16) of remaining patients achieved the 6MWD threshold and 78 (83%) did not. In the intention-to-treat population, median 6MWD increased significantly relative to baseline (week 16 = 308 m; week 28 = 327 m; P

Background: Efficacy trials suggest that extra-fine particle beclometasone dipropionate-formoterol (efBDP-FOR) is comparable to fluticasone propionate-salmeterol (FP-SAL) in preventing asthma exacerbations at a clinically equivalent dosage. However, switching from FP-SAL to efBDP-FOR has not been evaluated in real-world asthma patients. Aims: The REACH (Real-world Effectiveness in Asthma therapy of Combination inHalers) study investigated the clinical and cost effectiveness of switching typical asthma patients from FP-SAL to efBDP-FOR. Methods: A retrospective matched (1:3) observational study of 1,528 asthma patients aged 18–80 years from clinical practice databases was performed. Patients remaining on FP-SAL (n=1,146) were compared with those switched to efBDP-FOR at an equivalent or lower inhaled corticosteroid (ICS) dosage (n=382). Clinical and economic outcomes were compared between groups for the year before and after the switch. Non-inferiority (at least equivalence) of efBDP-FOR was tested against FP-SAL by comparing exacerbation rates during the outcome year. Results: efBDP-FOR was non-inferior to FP-SAL (adjusted exacerbation rate ratio 1.01 (95% CI 0.74 to 1.37)). Switching to efBDP-FOR resulted in significantly better (p

Purpose Correct use of inhaler devices is fundamental to effective asthma management but represents an important challenge for patients. The correct inhalation manoeuvre differs markedly for different inhaler types. The objective of this study was to compare outcomes for patients prescribed the same inhaler device versus mixed device types for asthma controller and reliever therapy. Methods This retrospective observational study identified patients with asthma (ages 4-80 years) in a large primary care database who were prescribed an inhaled corticosteroid (ICS) for the first time. We compared outcomes for patients prescribed the same breath-actuated inhaler (BAI) for ICS controller and salbutamol reliever versus mixed devices (BAI for controller and pressurised metered-dose inhaler [pMDI] for reliever). The 2-year study included 1 baseline year before the ICS prescription (to identify and correct for confounding factors) and 1 outcome year. Endpoints were asthma control (defined as no hospital attendance for asthma, oral corticosteroids, or antibiotics for lower respiratory tract infection) and severe exacerbations (hospitalisation or oral corticosteroids for asthma). Results Patients prescribed the same device (n=3,428) were significantly more likely to achieve asthma control (adjusted odds ratio, 1.15; 95% confidence interval [CI], 1.02-1.28) and recorded significantly lower severe exacerbation rates (adjusted rate ratio, 0.79; 95% CI, 0.68-0.93) than those prescribed mixed devices (n=5,452). Conclusions These findings suggest that, when possible, the same device should be prescribed for both ICS and reliever therapy when patients are initiating ICS.

Summary Background Selection of inhaler device type appears to influence real-world effectiveness of inhaled corticosteroids (ICS), but data are lacking on the role of inhaler device in ICS and long-acting β2-agonist (LABA) combination therapy for asthma. Methods This retrospective matched cohort study compared 1-year asthma outcomes for UK patients initiating fixed-dose combination (FDC) fluticasone–salmeterol delivered by pressurised metered-dose inhaler (pMDI) versus dry powder inhaler (DPI). Patients with asthma aged 4–80 years receiving a first prescription for FDC fluticasone–salmeterol by pMDI or DPI were matched on baseline demographic and asthma severity measures. Co-primary outcomes were asthma control (a composite measure comprising no recorded hospital attendance for asthma, oral corticosteroids, or antibiotics for lower respiratory infection) and exacerbation rate. Results Compared with the DPI cohort ( n = 1567), patients in the pMDI cohort ( n = 1567) had significantly greater odds of achieving asthma control during the outcome year (odds ratio [OR] 1.19; 95% confidence interval [CI] 1.01 to 1.40). Exacerbation rate was lower but not significantly in the pMDI cohort (adjusted rate ratio for pMDI cohort, 0.82; 95% CI 0.66 to 1.00). The odds of treatment success (defined as no exacerbations and no change in asthma therapy) was significantly greater in the pMDI cohort (OR 1.23; 95% CI, 1.07 to 1.42). Conclusions For UK primary care patients, pMDIs appear to achieve better asthma control outcomes than DPIs for delivery of FDC fluticasone–salmeterol. Pragmatic trials are needed to further investigate real-world outcomes with different inhaler devices for combination therapy.

Introduction: Our aims were to describe the prevalence of asthma exacerbation among an unselected population and to identify factors which might be used to identify children at risk for exacerbation. Methods: Data collected between 1990 and 2011 were obtained from two primary care research databases. Inclusion criteria were age 5–12 years, with an asthma diagnosis and with 12 month baseline period (during which blood eosinophil count was determined) and 12 months follow up. Exacerbation was defined as receipt of oral corticosteroid (OCS), attendance in emergency department or admission to hospital. Results: There were 3776 children, mean age 9.0 years, 47% had raised eosinophil count (>0.4. x109/L). 525 (14%) children had ≥1 exacerbation during follow up. The risk of exacerbation was independently increased in association with the following: younger age (the odds for ≥1 exacerbation reduced by 7% per year increase in age [95% CI 3, 11]), raised eosinophil count (OR 1.5 [1.2, 1.8]), daily inhaled corticosteroid dose >100 microg (OR 1.7 [1.3, 2.2] compared to none), >300 microg/day short acting beta agonist (1.7 [1.2, 2.4], relative to none/day), primary care consultation for respiratory infection (OR 1.5 [1.2, 2.0]) and receipt of one course of OCS (OR 3.7 [2.9, 4.8]) or two courses of OCS (OR 7.7 [5.6, 10.7] relative to none). In a subset of 2228 children where peak expiratory flow (PEF) was measured, the risk of exacerbation reduced by 0.5% per unit increase in %PEF. Conclusions: It is possible to identify an individual's risk for exacerbation using routinely acquired data. A past exacerbation is strongly predictive of future exacerbation and tests such as eosinophil count and PEF are weakly predictive.

When standard doses of inhaled corticosteroids (ICS) fail to control symptoms in children aged >4 years, guidelines recommend the addition of a long-acting β2-agonist (LABA), with other treatment options being available if symptoms persist. To determine the proportion of initial ‘step-up’ episodes where LABAs were prescribed and to describe characteristics of individuals not stepped up with LABA. Between 1999 and 2011, initial step-up episodes from ICS monotherapy were identified in children aged 5–12 years with asthma and in receipt of ICS. Data sources were the Clinical Practice Research Datalink and Optimum Patient Care Research Database. Initial step-up episodes were identified in 10,793 children. ICS dose was increased in 6,252 children (58%), LABA was introduced in 3,436 (32%; including 1,107 where fixed dose combination inhaler (FDC) replaced the ICS inhaler), and leukotriene receptor antagonist (LTRA) was added in 1,105 (10%). Compared with children stepped up to any LABA, others were younger and prescribed lower doses of ICS and reliever medication. ICS dose increase was more likely in obese children and LTRA prescribing was more likely in children with rhinitis and in receipt of antibiotics. Compared with FDC, step-up to separate LABA inhaler was more likely in younger, obese children who were using less oral steroids. One-third of initial step-up episodes in children with asthma treated with ICS are to add LABA. Different characteristics of children prescribed therapies other than LABA suggest that prescribers tailor treatment in some clinical settings. Clinicians in the UK frequently opt to deviate from the guidelines for increasing treatment choices in children with asthma. When standard doses of inhaled corticosteroids (ICS) fail to control symptoms in children older than four years, guidelines recommend adding long-acting beta agonist (LABA), with other treatment options considered if symptoms persist. Stephen Turner at the University of Aberdeen and co-workers across the UK conducted a historical cohort study of treatment “step-up” choices in 10,793 children aged between 5 and 12. An increased dose of ICS was prescribed for 58% of the children. LABA was introduced for only 32%, combined in some cases with either a change of inhaler type or prescribing leukotriene receptor antagonist. Deviation from treatment guidelines appears to be an active decision based on patient characteristics including obesity, antibiotic therapy and rhinitis.

Background Fractional exhaled nitric oxide (FeNO) is a surrogate marker of eosinophilic airway inflammation and good predictor of corticosteroid response. Aim To evaluate how FeNO is being used to guide primary care asthma management in the United Kingdom (UK) with a view to devising practical algorithms for the use of FeNO in the diagnosis of steroid-responsive disease and to guide on-going asthma management. Methods Eligible patients (n = 678) were those in the Optimum Patient Care Research Database (OPCRD) aged 4–80 years who, at an index date, had their first FeNO assessment via NIOX MINO® or Flex®. Eligible practices were those using FeNO measurement in at least ten patients during the study period. Patients were characterized over a one-year baseline period immediately before the index date. Outcomes were evaluated in the year immediately following index date for two patient cohorts: (i) those in whom FeNO measurement was being used to identify steroid-responsive disease and (ii) those in whom FeNO monitoring was being used to guide on-going asthma management. Outcomes for cohort (i) were incidence of new ICS initiation at, or within the one-month following, their first FeNO measurement, and ICS dose during the outcome year. Outcomes for cohort (ii) were adherence, change in adherence (from baseline) and ICS dose. Outcomes In cohort (i) (n = 304) the higher the FeNO category, the higher the percentage of patients that initiated ICS at, or in the one month immediately following, their first FeNO measurement: 82%, 46% and 26% of patients with high, intermediate and low FeNO, respectively. In cohort (ii) (n = 374) high FeNO levels were associated with poorer baseline adherence (p = 0.005) but greater improvement in adherence in the outcome year (p = 0.017). Across both cohorts, patients with high FeNO levels were associated with significantly higher ICS dosing (p

Background: Asthma guidelines recommend stepping down therapy to the lowest dose that maintains asthma control. Objective: We sought to evaluate the effect of dosing frequency and baseline patient and treatment-related factors on database markers of asthma control after inhaled corticosteroid (ICS) dose step-down. Methods: This retrospective observational study evaluated primary care patients (4-80 years old) with asthma prescribed twice-daily (BD) ICS (n=26,834) or ICS/long-acting β-agonist (LABA; n=20,814) for ≥ 1 year before ≥ 50% step-down in ICS dose, when they were switched to once-daily (QD) or remained on BD therapy. Study endpoints included exacerbations (oral corticosteroid prescription, unscheduled asthma-related hospital attendance, or general practice consultation for lower respiratory tract infection) and medication adherence. Results: Significant improvements in most endpoints were recorded during the year after step-down, as compared with the prior year (baseline). The proportion of patients with no exacerbation during the baseline year vs. the year after step-down was as follows (p

Background: ANDHI was done to assess the efficacy of benralizumab, including onset of effect and impact on health-related quality of life (HRQOL), exacerbation rate, lung function, and nasal polyposis symptoms. Methods: This phase 3b, randomised, double-blind, parallel-group, placebo-controlled ANDHI study was completed in adults (aged 18–75 years) with severe eosinophilic asthma with at least 2 exacerbations in the previous year, despite high-dose inhaled corticosteroid plus additional controllers, screening blood eosinophil counts of at least 150 cells per μL, and an Asthma Control Questionnaire 6 (ACQ-6) score of 1·5 or more. Patients who met eligibility criteria were randomly assigned (2:1; stratified by previous exacerbation count [two, or three or more], maintenance oral corticosteroid use, and region), using an integrated web-based response system, to receive benralizumab at 30 mg every 8 weeks (first three doses given 4 weeks apart) or matched placebo for 24 weeks. Primary efficacy measure was annualised asthma exacerbation rate, with rate ratio (RR) calculated over the approximate 24-week follow-up. Secondary efficacy measures included change from baseline to end of treatment (week 24) in St George's Respiratory Questionnaire (SGRQ) total score (key secondary endpoint), FEV1, peak expiratory flow (PEF), ACQ-6, Predominant Symptom and Impairment Assessment (PSIA), Clinician Global Impression of Change (CGI-C), Patient Global Impression of Change (PGI-C), and Sino-Nasal Outcome Test-22 (SNOT-22). All efficacy analyses, except for SNOT-22, were summarised and analysed using the full analysis set on an intention-to-treat population (all randomly assigned patients receiving investigational product, regardless of protocol adherence or continued participation in the study). SNOT-22 was summarised for the subgroup of patients with physician-diagnosed nasal polyposis with informed consent. This study is registered with ClinicalTrials.gov, NCT03170271. Findings: Between July 7, 2017, and Sept 25, 2019, 656 patients received benralizumab (n=427) or placebo (n=229). Baseline characteristics were consistent with severe eosinophilic asthma. Benralizumab significantly reduced exacerbation risk by 49% compared with placebo (RR estimate 0·51, 95% CI 0·39–0·65; p5%) were nasopharyngitis (30 [7%]), headache (37 [9%]), sinusitis (28 [7%]), bronchitis (22 [5%]), and pyrexia (26 [6%]). Fewer serious adverse events were reported for benralizumab (23 [5%]) versus placebo (25 [11%]), and the only common serious adverse event (experienced by >1% of patients) was worsening of asthma, which was reported for nine (2%) patients in the benralizumab group and nine (4%) patients in the placebo group. Interpretation: Our results extend the efficacy profile of benralizumab for patients with severe eosinophilic asthma, showing early clinical benefits in patient-reported outcomes, HRQOL, lung function, and nasal polyposis symptoms. Funding: AstraZeneca.