Uncontrolled Persistent Asthma Research Articles

Dupilumab improves symptoms, quality of life, and productivity in uncontrolled persistent asthma

BackgroundIn a pivotal, phase 2b study (NCT01854047) in patients with uncontrolled persistent asthma, despite using medium-to-high-dose inhaled corticosteroids plus long-acting β2 agonists, dupilumab improved lung function, reduced severe exacerbations, and showed an acceptable safety profile. ObjectiveTo assess the impact of dupilumab on asthma control, symptoms, quality of life (QoL), and productivity. MethodsData are shown for the intention-to-treat population receiving dupilumab 200/300 mg every 2 weeks (doses being assessed in phase 3; NCT02414854), or placebo. Predefined analyses of total scores were conducted at week 24 for the 5-item Asthma Control Questionnaire (ACQ-5), patient-reported morning/evening (AM/PM) asthma symptoms, Asthma Quality of Life Questionnaire (AQLQ), and asthma-related productivity loss. Responder rate analyses for these measures, subgroup analyses by baseline characteristics, and asthma-related productivity loss analyses were conducted post hoc. ResultsData from 465 patients were analyzed (158 placebo; 307 dupilumab). Both dupilumab doses significantly improved scores through week 24 (all outcomes, overall population). The proportion of patients meeting or exceeding the minimal clinically important difference for the overall population were significantly greater vs placebo (P < .05) for ACQ-5 (range, 72.6%-76.7% vs 61.4%), for AM/PM asthma symptoms score (48.7%-54.1% vs 34.2% and 52.7%-53.5% vs 34.2%, respectively) and for AQLQ (64.0%-65.0% vs 51.3%). The effect of dupilumab was consistent across most subgroups. Productivity loss was significantly higher in placebo- vs dupilumab-treated patients (P < .0001). ConclusionDupilumab produced significant, clinically meaningful improvements in asthma control, symptoms, QoL, and productivity. RegistrationClinicalTrials.gov Identifier: NCT01854047.

Raising the Clinical Bar Beyond Current Biologics in Uncontrolled Persistent Asthma: Translating Emerging Data in Future Clinical Decisions

Asthma is a heterogeneous disease with multiple phenotypes, caused by a complex interplay of inflammatory pathways. Up to 70% of patients with asthma have Type 2 inflammation, characterised by the presence of interleukin (IL)-4, IL-5, and IL-13. Uncontrolled persistent asthma represents a considerable disease burden associated with a higher rate of exacerbations, more frequent hospitalisations, greater oral corticosteroid (OCS) use, more impaired lung function, reduced health-related quality of life (QoL), and Type 2 inflammatory comorbidities versus controlled asthma. There remains an unmet need for new therapies for patients with uncontrolled persistent asthma. Several agents targeting mediators of Type 2 inflammation are in clinical development for severe asthma, including prostaglandin D2 receptor 2 (DP2)/chemoattractant receptor-homologous molecule expressed on Th2 (CRTh2) antagonists and monoclonal antibodies (mAb) that specifically bind IL-33, IL-25, thymic stromal lymphopoietin (TSLP), and IL-4 receptor (IL-4Rα). Dupilumab blocks signalling of IL-4 and IL-13 and is under investigation in various diseases driven by Type 2 inflammation. In Phase III clinical trials in patients with uncontrolled, persistent asthma, dupilumab was well tolerated and demonstrated significant efficacy versus placebo in reducing the rate of asthma exacerbations, and improving lung function, asthma symptoms, and QoL. This article summarises the proceedings of a symposium held at the European Academy of Allergy and Clinical Immunology (EAACI) 2018 Congress, which brought together an international faculty of experts to explore current understandings of asthma pathophysiology, with particular focus on Type 2 inflammatory pathways, and to provide an overview of current therapies, unmet medical needs, and the potential role of emerging biologics in the treatment of uncontrolled persistent asthma.

The Long-Term Omalizumab Therapy in Children with Severe Persistent Uncontrolled Asthma: Evaluation of the Outcomes According to the Data of the Hospital Patient Registry

научный биометрический журнал, который знакомит читателя с клиническими рекомендациями и особенностями применения лекарственных и вакцинных средств у детей, предоставляет исчерпывающую информацию о воздействии лекарственных средств на плод, о проводимых в

Exacerbation Risk and Type 2 Inflammation in Placebo Patients During a Phase 2b Study of Dupilumab in Patients With Uncontrolled Persistent Asthma

Exacerbation Risk and Type 2 Inflammation in Placebo Patients During a Phase 2b Study of Dupilumab in Patients With Uncontrolled Persistent Asthma

Knowledge of Inhaled Therapy and Responsibility for Asthma Management Among Young Teens With Uncontrolled Persistent Asthma

ObjectivesTo compare the abilities of teens with uncontrolled persistent asthma and their caregivers to identify inhaled medications and state correct indications for use; examine medication responsibility within dyads; and determine whether responsibility is associated with knowledge about inhaled therapies. MethodsIn the baseline survey for the School-Based Asthma Care for Teens (SB-ACT) trial, we separately asked caregivers and teens to: 1) identify the teen's inhaled asthma therapies by name and from a picture chart (complete matches considered “concordant”); 2) describe indications of use for each medication; and 3) describe the allocation of responsibility for medication use within dyads. We limited analyses to dyads in which either member reported at least one rescue and one inhaled controller medication; we used McNemar and Pearson chi-square tests. ResultsA total of 136 dyads were analyzed. More caregivers than teens concordantly identified medications (63% vs 31%, P < .001). There was no difference between caregivers and teens in the ability to state correct indications for use (56% vs 54%, P = .79). More teens than caregivers endorsed “full teen responsibility” for rescue medication (65% vs 27%, P < .001) and controller medication use (50% vs 15%, P < .001). Neither concordant identification nor knowing indications for use was associated with reported medication responsibility. ConclusionsMedication responsibility within dyads of caregivers and teens with persistent asthma is not associated with knowledge about inhaled therapies. Targeting both members of the dyad with education and self-management strategies before responsibility transitions start may allow providers to avoid a missed opportunity to support these emerging stakeholders to adherence.

Efficacy and safety of dupilumab in perennial allergic rhinitis and comorbid asthma

Dupilumab, an anti-IL-4 receptor α mAb, inhibits IL-4/IL-13 signaling, key drivers of type 2/TH2 immune diseases (eg, atopic/allergic disease). In a pivotal, phase 2b study (NCT01854047), dupilumab reduced severe exacerbations, improved lung function and quality of life, and was generally well tolerated in patients with uncontrolled persistent asthma despite using medium-to-high-dose inhaled corticosteroids plus long-acting β2-agonists. To examine dupilumab's effect on the 22-item Sino-Nasal Outcome Test (SNOT-22) total score and its allergic rhinitis (AR)-associated items in asthma patients with comorbid perennial allergic rhinitis (PAR). A post hoc analysis reporting data from the phase 2b study for the 200 and 300mg every 2week (q2w) doses under investigation in phase 3 (NCT02414854) was carried out. PAR was defined at study entry as a specific response to typical perennial antigens (IgE≥0.35 Ku/L). Overall, 241 (61%) patients had PAR. In asthma patients with PAR, dupilumab 300mg q2w versus placebo significantly improved SNOT-22 total score (least squares mean difference, -5.98; 95% CI, -10.45 to -1.51; P=.009) and all 4 AR-associated symptoms evaluated (nasal blockage, -0.60; 95% CI, -0.96 to -0.25; runny nose, -0.67; 95% CI, -1.04 to -0.31; sneezing, -0.55; 95% CI, -0.89 to -0.21; postnasal discharge, -0.49; 95% CI, -0.83 to -0.16; all P<.01). Dupilumab 200mg q2w demonstrated numerical, but not statistically significant, decreases in SNOT-22 total score (-1.82; 95% CI, -6.46 to 2.83; P=.443 vs placebo) and in each AR-associated symptom. In patients without PAR, no differences were observed for these measures versus placebo. Dupilumab 300mg q2w significantly improved AR-associated nasal symptoms in patients with uncontrolled persistent asthma and comorbid PAR.

P204 Dupilumab reduces exacerbations and improves lung function in uncontrolled persistent asthma patients across baseline exacerbations

P204 Dupilumab reduces exacerbations and improves lung function in uncontrolled persistent asthma patients across baseline exacerbations

Azithromycin reduced exacerbations and improved QoL in symptomatic asthma despite inhaled maintenance therapy

Source Citation Gibson PG, Yang IA, Upham JW, et al. Effect of azithromycin on asthma exacerbations and quality of life in adults with persistent uncontrolled asthma (AMAZES): a randomised, double-blind, placebo-controlled trial. Lancet. 2017;390:659-68. 28687413

Assessment of The Efficacy of The Two-Year Treatment With Omalizumab, According to The Pediatric Registry of The Children with Severe Persistent Uncontrolled Asthma

The goal of asthma management is to achieve the disease control. Asthma questionnaires provide additional useful information about the disease in children with severe persistent uncontrolled asthma (SPUA). To analyze the efficacy of the 2 years therapy with Omalizumab and the impact on the quality of life (QoL) of children with SPUA, according to the pediatric patient registry. Data of 34 children (average age 12,2 years) with SPUA were analyzed. All children received the treatment with Omalizumab from January 2015 till June 2017. Such criteria as “symptoms”, “activity limitation” and “emotions” of all the children were assessed by the questionnaire PAQLQ(S): before the therapy with Omalizumab, after 16 weeks, after 1 year and after 2 years. Before Omalizumab therapy all the children had low scores on each questionnaire’s PAQLQ(S) domains, low scores of ACT-test - 13 points (Me 14 [9; 17]), and high doses of daily basic therapy – 654,422 µg/day (Me 500 [500;1000]). After the start of the therapy with Omalizumab the domain “activity limitation” improved progressively in 16 weeks, 1 year and 2 years – 17,89%, 27,34%, 27,92% (p=0,000), respectively; “symptoms” - by 18.89%, 27.46%, of 27.08%(p=0,000); and “emotional function” - by 18%, 26.36%, 28,39% (p=0,000). During the therapy with Omalizumab: the number of exacerbations and the requirement of quick-relief medications have been reduced (in 16 weeks at 76,7%, p=0.000), asthma control has been improved (in 16 weeks the ACT-test results were improved by 23,96%, p=0.000); there was no severe exacerbation requiring emergency admissions. The basic therapy volume was reduced by half two years after the start of the therapy with Omalizumab in 5 children. The analysis of the questionnaire PAQLQ(S) reflects the dynamics of asthma. Our results confirmed that the QoL assessment is a reliable and important instrument for obtaining information about the disease development.

The Two-Year Therapy with Omalizumab in Children with Severe Persistent Uncontrolled Asthma: Dynamics of Quality of Life

The Two-Year Therapy with Omalizumab in Children with Severe Persistent Uncontrolled Asthma: Dynamics of Quality of Life

Anxiety Contributes to Poorer Asthma Outcomes in Inner-City Black Adolescents

The factors associated with poor asthma control, exacerbations, and health care utilization in black adolescents are complex and not well understood. Although psychological comorbidities such as anxiety are common in patients with asthma, these have not been studied in this population. This study characterized anxiety and associated asthma features in a cohort of black inner-city adolescents with persistent asthma and determined the association between anxiety symptoms, persistent uncontrolled asthma, and prospective health care utilization over 1 year. Eighty-six black adolescents were enrolled, phenotyped, and screened for anxiety symptoms with the Hospital Anxiety and Depression Scale anxiety subscale (HADS-A). Participants were telephoned every 2 months and a second study visit was completed at 1 year. Primary outcomes included persistent uncontrolled asthma, asthma exacerbations requiring systemic corticosteroids, and unscheduled health care utilization during the 1-year study period. A total of 31% (n= 27) of adolescents had probable anxiety (ie, HADS-A score >7) and 27% (n= 23) had possible anxiety (ie, HADS-A score 5-7) at the baseline visit. Anxiety symptoms were associated with poorer asthma control, more impaired quality of life, and more insomnia symptoms. Adolescents with probable anxiety disorders also had increased odds of persistent uncontrolled asthma and emergency department utilization, with no differences in physician visits or systemic corticosteroid receipt. Inner-city black adolescents with persistent asthma have a high prevalence of anxiety symptoms associated with poorer asthma control, impaired quality of life, insomnia, and increased prospective emergency department utilization for asthma. Routine screening for anxiety disorders may be useful in the clinical management of adolescents with asthma.

Effect of azithromycin on asthma exacerbations and quality of life in adults with persistent uncontrolled asthma (AMAZES): a randomised, double-blind, placebo-controlled trial

Exacerbations of asthma cause a substantial global illness burden. Adults with uncontrolled persistent asthma despite maintenance treatment require additional therapy. Since macrolide antibiotics can be used to treat persistent asthma, we aimed to assess the efficacy and safety of oral azithromycin as add-on therapy in patients with uncontrolled persistent asthma on medium-to-high dose inhaled corticosteroids plus a long-acting bronchodilator. We did a randomised, double-blind, placebo controlled parallel group trial to determine whether oral azithromycin decreases the frequency of asthma exacerbations in adults (≥18 years) with symptomatic asthma despite current use of inhaled corticosteroid and long-acting bronchodilator, and who had no hearing impairment or abnormal prolongation of the corrected QT interval. Patients were randomly assigned (1:1) to receive azithromycin 500 mg or placebo three times per week for 48 weeks. Patients were centrally allocated using concealed random allocation from a computer-generated random numbers table with permuted blocks of 4 or 6 and stratification for centre and past smoking. Primary efficacy endpoints were the rate of total (severe and moderate) asthma exacerbations over 48 weeks and asthma quality of life. Data were analysed on an intention-to-treat basis. The trial is registered at the Australian and New Zealand Clinical Trials Registry (ANZCTR), number 12609000197235. Between June 12, 2009, and Jan 31, 2015, 420 patients were randomly assigned (213 in the azithromycin group and 207 in the placebo group). Azithromycin reduced asthma exacerbations (1·07 per patient-year [95% CI 0·85-1·29]) compared with placebo (1·86 per patient-year [1·54-2·18]; incidence rate ratio [IRR] 0·59 [95% CI 0·47-0·74]; p<0·0001). The proportion of patients experiencing at least one asthma exacerbation was reduced by azithromycin treatment (127 [61%] patients in the placebo group vs 94 [44%] patients in the azithromycin group, p<0·0001). Azithromycin significantly improved asthma-related quality of life (adjusted mean difference, 0·36 [95% CI 0·21-0·52]; p=0·001). Diarrhoea was more common in azithromycin-treated patients (72 [34%] vs 39 [19%]; p=0·001). Adults with persistent symptomatic asthma experience fewer asthma exacerbations and improved quality of life when treated with oral azithromycin for 48 weeks. Azithromycin might be a useful add-on therapy in persistent asthma. National Health and Medical Research Council of Australia, John Hunter Hospital Charitable Trust.

Azithromycin in uncontrolled asthma

Asthma is a highly prevalent chronic airway disease affecting more than 300 million people worldwide. Despite treatment with inhaled corticosteroids and long-acting bronchodilators, asthma is uncontrolled in a substantial number of patients who remain symptomatic and are at risk of asthma exacerbations. These asthma attacks are often triggered by viral respiratory infections and might lead to emergency room visits, hospitalisations, and rarely, death; they result in a huge personal and societal burden. 1 Beran D Zar HJ Perrin C Menezes AM Burney P Burden of asthma and chronic obstructive pulmonary disease and access to essential medicines in low-income and middle-income countries. Lancet Respir Med. 2015; 3: 159-170 Summary Full Text Full Text PDF PubMed Scopus (96) Google Scholar Although targeted add-on therapy with monoclonal antibodies such as anti-IgE (omalizumab) and anti-IL5 (mepolizumab and reslizumab) has been shown to be efficacious in specific phenotypes of severe asthma, 2 Castro M Zangrilli J Wechsler ME et al. Reslizumab for inadequately controlled asthma with elevated blood eosinophil counts: results from two multicentre, parallel, double-blind, randomised, placebo-controlled, phase 3 trials. Lancet Respir Med. 2015; 3: 355-366 Summary Full Text Full Text PDF PubMed Scopus (832) Google Scholar , 3 Ortega HG Liu MC Pavord ID et al. Mepolizumab treatment in patients with severe eosinophilic asthma. N Engl J Med. 2014; 371: 1198-1207 Crossref PubMed Scopus (1510) Google Scholar the high costs preclude widespread use in many parts of the world. Therefore, affordable, effective, and safe add-on therapies in patients with poorly controlled asthma are needed. Previous studies have shown a beneficial effect of macrolide antibiotics such as azithromycin on asthma symptoms, but their effect on asthma exacerbations has been inconclusive due to a lack of large long-term trials. 4 Kew KM Undela K Kotortsi I Ferrara G Macrolides for chronic asthma. Cochrane Database Syst Rev. 2015; 9 (CD002997.) PubMed Google Scholar , 5 Reiter J Demirel N Mendy A et al. Macrolides for the long-term management of asthma—a meta-analysis of randomized clinical trials. Allergy. 2013; 68: 1040-1049 Crossref PubMed Scopus (69) Google Scholar Effect of azithromycin on asthma exacerbations and quality of life in adults with persistent uncontrolled asthma (AMAZES): a randomised, double-blind, placebo-controlled trialAdults with persistent symptomatic asthma experience fewer asthma exacerbations and improved quality of life when treated with oral azithromycin for 48 weeks. Azithromycin might be a useful add-on therapy in persistent asthma. Full-Text PDF

Expression of cd35 and cd57 in placenta of women with asthma

Background. Prevalence of asthma (BA) among pregnant women reaches 12%. Obstetric complications (preeclampsia, placental insufficiency, IUGR, etc.) mainly occur in the absence of control of asthma. Aspects of the placenta status in women with chronic allergic respiratory disease are not well understood.&#x0D; Purpuses and tasks — studying the expression of markers of immature dendritic cells (CD35) and natural killer (CD57) cells in the placenta of patients with asthma, depending on the of severity, control and the type of therapy.&#x0D; Materials and methods. The study involved 200 pregnant women, including 170 with asthma (44 patients with mild intermittent, 52 with mild persistent, 61 with moderate and 13 with severe asthma), and 30 patients without pulmonary and allergic diseases. We analized complications and pregnancy outcomes, conducted the immunohistochemical study of placental samples of 134 patients for the expression of CD35 (marker of immature dendritic cells) and CD57 (marker of NK cells) on cryostat sections, immunomorphological study of the placenta with determination of the fixation of pathogenic immune complexes (PIC), IL-6, IL- 4, IL-10 in the placenta.&#x0D; Results. CD35 expression in the placenta of women with asthma is increased, while in patients undergoing preeclampsia CD35 expression is lower, especially in cases of uncontrolled asthma in the 3rd trimester. In all cases with persistent and incompletely controlled asthma, the expression of the natural killer marker (CD57) in the placenta correlates with the presence of PIC, IL-6, IL-4, IL-10 and inflammatory changes in the placenta. Conclusions. The results of the study suggest that a decrease in CD35 expression in cases with the combination of uncontrolled persistent asthma and preeclampsia seems to deplete the mechanisms of the immune response. Increased NK cell marker expression (CD57) in the placenta of women with uncontrolled and persistent asthma indicates on the cytotoxic role of this subpopulation of cells, leading to morphological and immune changes in the placenta that adversely affect the fetus and newborn.

Specific features of bronchial inflammation in asthma patients with airway hyper-responsiveness to cold and osmotic stimuli

Background. Excessive airway reaction to combined effects of environmental factors is very common in patients with asthma. The understanding of the molecular-cellular mechanisms of this hyperresponsiveness is very important. Aim. The aim of the work was to study granulocyte segment of bronchial inflammation in correlation with cytokine regulation and lipid peroxidation in patients with airway hyperresponsiveness to cold and osmotic stimuli. Materials and м ethods. In 43 patients with partially controlled and uncontrolled persistent asthma with cold and osmotic airway hyperresponsiveness (group 1) asthma symptoms and lung function were assessed, the level of IL-5, IL-12 in exhaled breath condensate (EBC) and the total amount of myeloperoxidase (MPO) in induced sputum (IS) were measured; the number of neutrophils and eosinophils in smears of IS was counted. Basing on cytological and cytochemical analysis of smears of IS, the activity coefficients of MPO in granular leukocytes, the degree of cell destruction and the intensity of cytolysis were calculated. The contents of lipid hydroperoxide (LHP) and MPO in the blood serum were measured. A control group (group 2) consisted of asthma patients without airway reaction to cold and osmotic stimuli (11 people). Results. In the first group in comparison with the second one high levels of IL-12 were found (2,94 ± 0,09 vs. 2,53 ± 0,13 pg/mL; р = 0,024), IL-5 (3,64 ± 0,37 vs. 2,15 ± 0,14 pg/mL; р = 0,0001); the increase of neutrophils in IM (35,4 ± 3,5 vs. 17,2 ± 2,0%; р = 0,014); higher granulocytes cytolysis (0,38 ± 0,02 vs. 0,26 ± 0,02; р = 0,013), which correlated for neutrophils with the level of IL-12 (r = 0,46; р = 0,026); there was found out the increase of MPO concentration in IS (199,7 ± 49,0 vs. 81,4 ± 26,2 pixels; р = 0,039). The increased level of LHP in the blood serum correlated with the level of MPO in IS (r = 0,48; р = 0,039) and IL-5 in EBC (r = 0,71; р = 0,031). Conclusion. Airway hyperresponsiveness to cold and osmotic stimuli in patients with asthma is characterized by the relationship between the nature of Th1 and Th2 cytokine profile, the structure of granulocyte segment of bronchial inflammation, the enzymatic function of granulocytes, MPO activity and systemic formation of suboxidized lipid peroxidation products. Activation of granulocyte segment of inflammatory pattern in patients with asthma may be considered a factor of influence on the development and maintenance of airway hyperresponsiveness due to the escalation of oxidative stress and persistent inflammation.

Randomized, dose-ranging study of a fluticasone propionate multidose dry powder inhaler in adolescents and adults with uncontrolled asthma not previously treated with inhaled corticosteroids

ABSTRACTObjective: A novel, inhalation-driven, multidose dry powder inhaler (MDPI) eliminates the need to coordinate actuation with inhalation. To characterize dose response, efficacy, and safety of fluticasone propionate (Fp) MDPI, a dose-ranging study was conducted with placebo and active comparators. Methods: This 12-week, double-blind, parallel-group study randomized patients aged ≥12 years with uncontrolled persistent asthma not previously treated with inhaled corticosteroid therapy (N = 622) to twice-daily treatment with Fp MDPI (12.5, 25, 50, or 100 µg), placebo MDPI, or open-label Fp dry powder inhaler (DPI) 100 µg. The primary efficacy endpoint was change from baseline over 12 weeks in trough (morning pre-dose and pre-rescue bronchodilator) forced expiratory volume in 1 second (FEV1). Blood samples were collected from a patient subset to evaluate pharmacokinetics. Adverse events were monitored. Results: Fp MDPI 25, 50, and 100 µg significantly improved change from baseline in trough FEV1 over 12 weeks compared with placebo (p < 0.01). There were no substantial differences in FEV1 change from baseline over 12 weeks between any Fp MDPI dose and Fp DPI 100 µg. Maximum observed concentration (Cmax) of Fp increased with increasing Fp MDPI doses; time of Cmax was similar across doses and treatments. Systemic exposures for Fp MDPI 25 and 50 µg were lower than that for Fp DPI 100 µg. The safety profile of Fp MDPI was consistent with that of Fp DPI. Conclusions: In this study, Fp MDPI 25 and 50 µg provided comparable efficacy and safety to Fp DPI 100 µg, with lower systemic exposure.

PRM63 - Pediatric Registry Of Patients With Severe Persistent Uncontrolled Asthma Receiving Omalizumab

PRM63 - Pediatric Registry Of Patients With Severe Persistent Uncontrolled Asthma Receiving Omalizumab

Efficacy and safety of a CXCR2 antagonist, AZD5069, in patients with uncontrolled persistent asthma: a randomised, double-blind, placebo-controlled trial

Airway neutrophilic inflammation is a pathological feature in some patients with severe asthma. Stimulation of the chemokine receptor CXCR2 mediates neutrophil migration into the airways. We investigated the safety and efficacy of AZD5069, a CXCR2 antagonist, as an add-on therapy in patients with uncontrolled severe asthma. In this multicentre, randomised, double-blind, placebo-controlled, dose-finding trial, we enrolled patients aged 18 years or older with uncontrolled asthma despite combination therapy with long-acting β2 agonists and medium-dose or high-dose inhaled corticosteroids. Patients were randomised in a 1:1:1:1 ratio via an interactive voice-response or web-response system to receive 5, 15, or 45 mg oral AZD5069 twice daily or matched placebo. The primary endpoint was the number of severe asthma exacerbations in 6 months. Safety was assessed in the 6-month treatment period and an optional 6-month safety extension. This trial is registered with ClinicalTrials.gov, number NCT01704495. 640 patients with a mean age of 52 (SD 11·8) years were randomised, 478 to receive AZD5069 (5 mg n=160, 15 mg n=156, and 45 mg n=162) and 162 placebo. No dose of AZD5069 reduced the rate of severe exacerbations compared with placebo (rate ratio for 5 mg 1·29, 90% CI 0·79-2·11; for 15 mg 1·53, 0·95-2·46; and for 45 mg 1·56, 0·98-2·49). Treatment with AZD5069 was generally well tolerated. The most commonly reported adverse event overall was nasopharyngitis, seen in 18 (11·5%) receiving 5 mg, 13 (8·5%) receiving 15 mg, and 18 (11·2%) receiving 45 mg AZD5069, and 31 (19·5%) of those receiving placebo. Treatment with this selective CXCR2 antagonist did not reduce the frequency of severe exacerbations in patients with uncontrolled severe asthma. These findings bring into question the role of CXCR2-mediated neutrophil recruitment in the pathobiology of exacerbations in severe refractory asthma. AstraZeneca.

Dupilumab efficacy and safety in adults with uncontrolled persistent asthma despite use of medium-to-high-dose inhaled corticosteroids plus a long-acting β2 agonist: a randomised double-blind placebo-controlled pivotal phase 2b dose-ranging trial

Dupilumab, a fully human anti-interleukin-4 receptor α monoclonal antibody, inhibits interleukin-4 and interleukin-13 signalling, key drivers of type-2-mediated inflammation. Adults with uncontrolled persistent asthma who are receiving medium-to-high-dose inhaled corticosteroids plus a long-acting β2 agonist require additional treatment options as add-on therapy. We aimed to assess the efficacy and safety of dupilumab as add-on therapy in patients with uncontrolled persistent asthma on medium-to-high-dose inhaled corticosteroids plus a long-acting β2 agonist, irrespective of baseline eosinophil count. We did this randomised, double-blind, placebo-controlled, parallel-group, pivotal phase 2b clinical trial at 174 study sites across 16 countries or regions. Adults (aged ≥18 years) with an asthma diagnosis for 12 months or more based on the Global Initiative for Asthma 2009 Guidelines receiving treatment with medium-to-high-dose inhaled corticosteroids plus a long-acting β2 agonist were eligible for participation. Patients were randomly assigned (1:1:1:1:1) to receive subcutaneous dupilumab 200 mg or 300 mg every 2 weeks or every 4 weeks, or placebo, over a 24-week period. The primary endpoint was change from baseline at week 12 in forced expiratory volume in 1 s (FEV1 in L) in patients with baseline blood eosinophil counts of at least 300 eosinophils per μL assessed in the intention-to-treat population. Safety outcomes were assessed in all patients that received at least one dose or part of a dose of study drug. This trial is registered at ClinicalTrials.gov, number NCT01854047, and with the EU Clinical Trials Register, EudraCT number 2013-000856-16. 769 patients (158 in the placebo group and 611 in the dupilumab groups) received at least one dose of study drug. In the subgroup with at least 300 eosinophils per μL, the greatest increases (200 mg every 2 weeks, p=0·0008; 300 mg every 2 weeks, p=0·0063) in FEV1 compared with placebo were observed at week 12 with doses every 2 weeks in the 300 mg group (mean change 0·39 L [SE 0·05]; mean difference 0·21 [95% CI 0·06-0·36; p=0·0063]) and in the 200 mg group (mean change 0·43 L [SE 0·05]; mean difference 0·26 [0·11-0·40; p=0·0008]) compared with placebo (0·18 L [SE 0·05]). Similar significant increases were observed in the overall population and in the fewer than 300 eosinophils per μL subgroup (overall population: 200 mg every 2 weeks, p<0·0001; 300 mg every 2 weeks, p<0·0001; <300 eosinophils per μL: 200 mg every 2 weeks, p=0·0034; 300 mg every 2 weeks, p=0·0086), and were maintained to week 24. Likewise, dupilumab every 2 weeks produced the greatest reductions in annualised rates of exacerbation in the overall population (70-70·5%), the subgroup with at least 300 eosinophils per μL (71·2-80·7%), and the subgroup with fewer than 300 eosinophils per μL (59·9-67·6%). The most common adverse events with dupilumab compared with placebo were upper respiratory tract infections (33-41% vs 35%) and injection-site reactions (13-26% vs 13%). Dupilumab increased lung function and reduced severe exacerbations in patients with uncontrolled persistent asthma irrespective of baseline eosinophil count and had a favourable safety profile, and hence in addition to inhaled corticosteroids plus long-acting β2-agonist therapy could improve the lives of patients with uncontrolled persistent asthma compared with standard therapy alone. Sanofi-Genzyme and Regeneron Pharmaceuticals.

Dupilumab Suppresses Fractional Exhaled Nitric Oxide (FeNO) and Biomarkers of Type 2 Inflammation in Adult Patients with Persistent Uncontrolled Asthma Despite Use of Medium-to-High Dose Inhaled Corticosteroids Plus Long-Acting Beta-Agonists (ICS/LABAs)

Dupilumab Suppresses Fractional Exhaled Nitric Oxide (FeNO) and Biomarkers of Type 2 Inflammation in Adult Patients with Persistent Uncontrolled Asthma Despite Use of Medium-to-High Dose Inhaled Corticosteroids Plus Long-Acting Beta-Agonists (ICS/LABAs)