Search

AVANT was a Phase 3, 24-week, randomized, parallel-group, double-blind, double-dummy, placebo-controlled study to assess the efficacy and safety of aclidinium/formoterol 400 μg/12 μg combination vs monotherapies and aclidinium vs placebo (1:1:1:1) in Asian patients (∼70% of whom were Chinese) with moderate-to-severe stable chronic obstructive pulmonary disease. Endpoints were analyzed hierarchically to incorporate type I error control. At Week 24, aclidinium/formoterol demonstrated improvements from baseline in 1-h morning post-dose forced expiratory volume in 1 s (FEV 1 ) vs aclidinium (least squares [LS] mean 92 mL; 95% confidence interval [CI] 60, 124 mL; p < 0.001), and in trough FEV 1 vs formoterol (LS mean 85 mL; 95% CI 53, 117 mL; p < 0.001). Furthermore, aclidinium provided improvements in trough FEV 1 vs placebo (LS mean 134 mL; 95% CI 103, 166 mL; p < 0.001). There was an improvement in transition dyspnea index focal score at Week 24 for aclidinium/formoterol vs placebo (LS mean 0.8; 95% CI 0.2, 1.3; p = 0.005) but not for aclidinium vs placebo (LS mean 0.4; 95% CI -0.1, 1.0; p = 0.132). Improvements in St George's Respiratory Questionnaire total scores occurred for aclidinium/formoterol vs placebo (LS mean -4.0; 95% CI -6.7, -1.4; p = 0.003) and aclidinium vs placebo (LS mean -2.9; 95% CI -5.5, -0.3; p = 0.031). Aclidinium/formoterol and aclidinium were well tolerated and safety findings were consistent with known profiles; rates of treatment-emergent adverse events (AEs) (aclidinium/formoterol: 54.8%; aclidinium: 47.4%; placebo: 53.9%), serious AEs (7.2, 7.9, and 7.8%, respectively), and AEs leading to discontinuation of study medication (2.3, 1.5, and 2.2%, respectively) were similar between groups., Competing Interests: Declaration of competing interest Sami Daoud, Roopa Trivedi, and Eduard Molins are employees of AstraZeneca and may hold stock. Pranob Bharali is an employee of AstraZeneca who does not hold stock. Esther Garcia Gil was an employee of AstraZeneca at the time of this study. Rosa Lamarca is an employee of Alexion (the rare disease business unit of AstraZeneca) and was an employee of AstraZeneca at the time of this study. Yongchang Sun was the local leading principal investigator of the AVANT study in China. Catherine Stewart is an employee of Plus Project Partnership and was an employee of Phastar, who were contracted to AstraZeneca at the time of this study.., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: As-needed low-dose inhaled corticosteroid (ICS)-formoterol reliever is recommended in patients with asthma prescribed maintenance ICS-formoterol. Clinicians often ask whether ICS-formoterol reliever can be used with other maintenance ICS-long-acting β 2 -agonists., Objective: To evaluate the safety and effectiveness of as-needed formoterol in patients taking maintenance ICS-formoterol or ICS-salmeterol from the RELIEF study., Methods: RELIEF (SD-037-0699) was a 6-month, open-label study that randomized 18,124 patients with asthma to as-needed formoterol 4.5 μg or salbutamol 200 μg on top of maintenance therapy. This post hoc analysis included patients on maintenance ICS-formoterol or ICS-salmeterol (n = 5436). The primary safety outcome was a composite of serious adverse events (SAEs) and/or adverse events leading to discontinuation (DAEs); the primary effectiveness outcome was time-to-first exacerbation., Results: For both maintenance groups and both relievers, similar numbers of patients had ≥1 SAE and/or DAE. In patients taking maintenance ICS-salmeterol, but not ICS-formoterol, significantly more non-asthma-related and nonserious DAEs occurred with as-needed formoterol versus as-needed salbutamol (P = .0066 and P = .0034, respectively). In patients taking maintenance ICS-formoterol, there was a significantly lower risk in time-to-first exacerbation with as-needed formoterol versus as-needed salbutamol (hazard ratio [HR]: 0.82, 95% confidence interval [CI]: 0.70, 0.95; P = .007). In patients taking ICS-salmeterol maintenance, time-to-first exacerbation was not significantly different between treatment arms (HR: 0.95, 95% CI: 0.84, 1.06; P = .35)., Conclusions: As-needed formoterol significantly reduced exacerbation risk compared with as-needed salbutamol when added to maintenance ICS-formoterol, but not to maintenance ICS-salmeterol. More DAEs were seen with ICS-salmeterol maintenance therapy plus as-needed formoterol. Further research is needed to assess whether this is relevant to as-needed combination ICS-formoterol., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Rationale: The SYGMA (Symbicort Given as Needed in Mild Asthma) studies evaluated the efficacy and safety of as-needed budesonide (BUD)-formoterol (FORM) in patients whose asthma was uncontrolled on as-needed inhaled short-acting bronchodilators (subgroup 1) or controlled on inhaled corticosteroids (ICS) or leukotriene receptor antagonists (subgroup 2). Objectives: To assess the influence of prestudy treatment in a post hoc analysis of the SYGMA studies. Methods: In the SYGMA 1 (NCT022149199) and SYGMA 2 (NCT02224157) 52-week, double-blind, randomized, parallel-group studies, 6,735 patients with mild asthma were randomized to as-needed BUD-FORM, low-dose BUD + as-needed terbutaline (BUD maintenance), or as-needed terbutaline (SYGMA 1 only). Exacerbation rates and changes in symptom control and lung function were compared among treatments for both subgroups. Results: In a pooled analysis of SYGMA 1 and 2, the annual severe exacerbation rate in subgroup 1 was significantly lower with as-needed BUD-FORM (0.08 [95% confidence interval (CI), 0.06-0.10]) than with BUD maintenance (0.10 [95% CI, 0.09-0.13]) (rate ratio [RR], 0.74 [95% CI, 0.56-0.98]; P  = 0.03), and similar results were shown in subgroup 2 with BUD-FORM (0.12 [95% CI, 0.10-0.14]) and BUD maintenance (0.10 [95% CI, 0.09-0.13]) (RR, 1.10 [95% CI, 0.86-1.41]; P  = 0.44). In SYGMA 1, the annual severe exacerbation rate in both subgroups was significantly lower with as-needed BUD-FORM than with as-needed terbutaline (subgroup 1: RR, 0.34 [95% CI, 0.20-0.58]; P  < 0.001; subgroup 2: RR, 0.37 [95% CI, 0.25-0.54]; P  < 0.001). The number needed to treat to prevent one severe exacerbation with as-needed BUD-FORM and BUD maintenance versus as-needed terbutaline were 20 and 34 in subgroup 1 and 13 and 12 in subgroup 2, respectively. Conclusions: These findings suggest that, for patients with mild asthma currently receiving short-acting β 2 -agonists alone, as-needed low-dose ICS-FORM should be preferred over maintenance ICS as initial controller treatment. For patients whose asthma is controlled on maintenance low-dose ICS, as-needed BUD-FORM is an alternative to maintenance ICS without the need for daily treatment, and both of these options are safer than switching to short-acting β 2 -agonist-only treatment.

Background: Medication adherence is challenging for adolescents. In mild asthma, as-needed budesonide-formoterol (BUD-FORM) reduces severe exacerbations compared with as-needed short-acting beta 2 -agonists, similar to the reduction with maintenance budesonide., Objective: This post hoc pooled analysis of Symbicort Given as-needed in Mild Asthma (SYGMA) 1 and 2 assessed the efficacy and safety of as-needed BUD-FORM in adolescents., Methods: SYGMA 1 and 2 were 52-week, double-blind studies (NCT022149199; NCT02224157) in patients 12 years or older with mild asthma. Patients were randomized to twice-daily placebo + as-needed BUD-FORM 200/6 μg, twice-daily BUD 200 μg + as-needed terbutaline (BUD maintenance), or twice-daily placebo + as-needed terbutaline 0.5 mg (SYGMA 1 only). Annualized severe exacerbation rates, maintenance treatment adherence, and safety (including change in height) were compared between treatment groups in adolescents (aged ≥12 to <18 years)., Results: Severe exacerbation rate was similar with as-needed BUD-FORM and BUD maintenance (pooled analysis: 0.08 vs 0.07/y; P = .634), and was significantly lower with as-needed BUD-FORM versus as-needed terbutaline (SYGMA 1: 0.04 vs 0.17/y; P = .005). Median adherence was 73% in SYGMA 1 and 51% in SYGMA 2. Change in height from baseline in adolescents aged ≥12 years to <14 years was significantly greater with as-needed BUD-FORM (4.8 cm) versus BUD maintenance (3.9 cm) (pooled: P < .046), and was similar between as-needed BUD-FORM (4.5 cm) and as-needed terbutaline (4.1 cm) (SYGMA 1: P = .500). No new or unexpected safety concerns were identified., Conclusions: In adolescents with mild asthma, as-needed BUD-FORM was superior to as-needed terbutaline for severe exacerbation reduction, with similar efficacy to BUD maintenance. As-needed BUD-FORM provides an alternative treatment option for adolescents with mild asthma, without needing daily treatment., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Budesonide-formoterol taken as needed is an emerging treatment for mild asthma., Objective: We used data from the SYGMA studies to assess the safety of As-needed budesonide-formoterol compared with As-needed terbutaline and compared with maintenance budesonide., Methods: SYGMA 1 and 2 were 52-week, double-blind, parallel-group studies in patients aged ≥ 12 years with physician-assessed mild asthma. Patients were randomized to As-needed budesonide-formoterol 200/6 μg, twice-daily budesonide 200 μg as maintenance plus As-needed terbutaline 0.5 mg, and As-needed terbutaline 0.5 mg (SYGMA 1 only). Adverse events (AEs), serious AEs (SAEs), discontinuations due to AEs (DAEs), and study-defined asthma-related discontinuations from corresponding treatment groups in both studies were pooled. SYGMA 1 data were used for comparisons with As-needed terbutaline alone., Results: The pooled analysis included 3366 patients in the As-needed budesonide-formoterol group and 3369 in the budesonide maintenance group, with AEs in 40.8% and 42.5% of patients, respectively. Common AEs included viral upper respiratory tract infection (viral URTI) and URTI. SAE, DAE, and asthma-related discontinuation rates were similar with As-needed budesonide-formoterol and maintenance budesonide. Potential local and systemic corticosteroid class effects were reported in ≤ 1% of patients for each budesonide-containing regimen. In SYGMA 1, AEs were more common in the As-needed terbutaline (n = 1277) than As-needed budesonide-formoterol (n = 1277) groups (42.7 vs. 38.0%), as were DAEs (2.9 vs. 0.8%) and asthma-related discontinuations (1.6 vs. 0.3%)., Conclusions: Budesonide-formoterol anti-inflammatory reliever therapy is generally well-tolerated in patients with mild asthma and has a safety profile similar to that of daily budesonide. No new safety signals were identified. CLINICALTRIAL., Gov Identifiers: NCT02149199 (SYGMA 1) and NCT02224157 (SYGMA 2).

Background: In mild asthma, as-needed budesonide-formoterol reduces long-term exacerbation risk compared with as-needed short-acting β 2 -agonist (SABA), with a similar or increased reduction versus maintenance with budesonide plus as-needed SABA, despite a lower budesonide dose. In this post-hoc analysis of the SYmbicort Given as needed in Mild Asthma (SYGMA) 1 study, we investigated the short-term risk of severe exacerbations after a single day with various levels of reliever use., Methods: SYGMA 1 was a 52-week, double-blind, randomised, controlled, phase 3 trial, in which patients aged 12 years or older with mild asthma were randomly assigned (1:1:1) to placebo twice daily plus as-needed terbutaline 0·5 mg, placebo twice daily plus as-needed budesonide-formoterol 200-6 μg, or budesonide 200 μg twice daily plus as-needed terbutaline (ie, budesonide maintenance group). In this post-hoc analysis, we assessed the frequency of reliever use and the risk of a severe exacerbation in the 21 days after first use of more than two, four, six, or eight reliever inhalations in 24 h. SYGMA 1 is registered with ClinicalTrials.gov, NCT02149199, and is now complete., Findings: Of 5721 patients enrolled in SYGMA 1, 3849 were randomly assigned to as-needed terbutaline (n=1280), as-needed budesonide-formoterol (n=1279), or budesonide maintenance (n=1290), of whom 3836 had evaluable data (n=1277 as-needed terbutaline, n=1277 as needed budesonide-formoterol, and n=1282 budesonide maintenance). Median reliever use was 0·32 (IQR 0·08-0·91) inhalations per day for the as-needed terbutaline group, 0·29 (0·07-0·72) for the as-needed budesonide-formoterol group, and 0·16 (0·04-0·52) for the budesonide maintenance group. Compared with as-needed terbutaline, after adjustment for age, sex, randomly assigned treatment, pre-study treatment group, baseline % predicted post-bronchodilator FEV 1 , and severe exacerbation in the 12 months before enrolment in the study, the hazard ratio (HR) for severe exacerbation in the 21 days after a single day with more than two as-needed inhalations was 0·27 (95% CI 0·12-0·58; p=0·0008) with as-needed budesonide-formoterol and 0·39 (0·19-0·79; p=0·0091) with budesonide maintenance; after a single day of more than four as-needed inhalations the HR was 0·24 (0·10-0·62; p=0·0030) with as-needed budesonide-formoterol and 0·30 (0·13-0·72; p=0·0065) with budesonide maintenance; and after a single day of more than six as-needed inhalations the HR was 0·14 (0·02-1·06; p=0·057) with as-needed budesonide-formoterol and 0·43 (0·14-1·26; p=0·12) with budesonide maintenance. HRs were not calculated for more than eight as-needed inhalations due to the small number of events., Interpretation: In mild asthma, as-needed budesonide-formoterol reduces the short-term risk of severe exacerbations after a single day of higher use (more than two as-needed inhalations), even when overall use is infrequent. Use of an anti-inflammatory reliever might reduce the risk of short-term severe exacerbations by the timely provision of increased doses of as-needed inhaled corticosteroids and formoterol when symptoms occur. These findings should be further assessed in prospective randomised clinical trials., Funding: AstraZeneca., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Purpose: Moderate and severe COPD exacerbations are a significant health-care burden, but patients also experience "mild" exacerbations, or COPD symptom-related attacks, which often go unreported. We aimed to define and then determine the incidence of COPD symptom-related attacks and their impact on future risk of moderate/severe exacerbations, health-related quality of life (HRQoL), and lung function. The effect of COPD maintenance therapy on the attack definition was then evaluated by comparing budesonide/formoterol with formoterol alone., Patients and Methods: This post hoc analysis of the RISE study defined COPD symptom-related attacks as ≥2 consecutive days of both worsening symptoms and increased daily rescue medication use based upon thresholds of >2 and >4 short-acting β 2 -agonist (SABA) inhalations/day above baseline. The impact of these events on subsequent moderate/severe exacerbation risk was estimated using a time-varying Cox proportional hazards model. The effects of COPD symptom-related attacks on St George's Respiratory Questionnaire (SGRQ) total score and pre-bronchodilator forced expiratory volume in 1 second (FEV 1 ) were evaluated as average changes from baseline to first post-attack measurement. Rates of attacks were compared between treatment groups using negative binomial regression models., Results: COPD symptom-related attacks elevated the risk of subsequent moderate/severe exacerbations at both >2 and >4 inhalations/day above baseline (HR 1.86 and 2.21, respectively; p<0.0001), with a cumulative increase in risk with increasing attacks. HRQoL and lung function were reduced for patients with ≥1 versus no COPD symptom-related attacks at both rescue medication thresholds. There were fewer COPD symptom-related attacks with budesonide/formoterol versus formoterol alone, with no increased risk of pneumonia and lower respiratory tract infections., Conclusion: COPD symptom-related attacks are common and typically unreported. Importantly, these attacks can account for considerable morbidity and should not be regarded as "mild". Detection of such exacerbations may be valuable in identifying patients at greater risk and guiding preventive therapeutic interventions., Competing Interests: GTF reports grants, personal fees and non-financial support from AstraZeneca as part of the study. He has also received grants, personal fees and non-financial support from Boehringer Ingelheim, Novartis, AstraZeneca/Pearl Therapeutics, GlaxoSmithKline and Sunovion; grants and personal fees from Verona, Theravance and Sanofi; grants from Altavant; and personal fees from Innoviva, Mylan and Circassia outside the submitted work. FT, IG, LN, RL and TS are employees and shareholders of AstraZeneca. RL has patents EP2100598A1, EP2100599A1, and EP2666465 issued. AA and DL are employees of Phastar, which received funding from AstraZeneca to complete the statistical analyses. The authors report no other conflicts of interest in this work., (© 2020 Ferguson et al.)

Introduction: Many patients with chronic obstructive pulmonary disease or asthma experience difficulties in coordinating inhalation with pressurized metered-dose inhaler (pMDI) actuation. The use of a spacer device can improve drug delivery in these patients. The aim of this study was to establish the relative bioavailability of single doses of Symbicort ® (budesonide/formoterol) pMDI 160/4.5 μg/actuation (2 actuations) used with and without a spacer device. In addition, an in vitro study was conducted to characterize performance of the inhaler when used in conjunction with a spacer device., Methods: A Phase I, randomized, open-label, single-dose, single-center, crossover study in 50 healthy volunteers (NCT02934607) assessed the relative bioavailability of single-dose Symbicort ® pMDI 160/4.5 μg/actuation (2 actuations) with and without a spacer (AeroChamber Plus ® Flow-Vu ® ). Inhaled doses were administered without or with activated charcoal (taken orally) to estimate total systemic exposure and exposure through the lung, respectively. The in vitro study characterized the effect of the spacer with respect to delivered dose, fine particle dose, and dose during simulated breathing of budesonide and formoterol., Results: In terms of total systemic exposure, use of the spacer increased the relative bioavailability determined by AUC (0-last) and C max by 68% (spacer:no spacer treatment ratio, 167.9%; 90% CI, 144.1 to 195.6) and 99% (ratio, 198.7%; 90% CI, 164.4 to 240.2) for budesonide, and 77% (ratio, 176.6%; 90% CI, 145.1 to 215.0) and 124% (ratio, 223.6%; 90% CI, 189.9 to 263.3) for formoterol, respectively, compared with pMDI alone. Similarly, the lung exposure of budesonide and formoterol increased (AUC (0-last) and C max by 146% [ratio, 246.0%; 90% CI, 200.7 to 301.6] and 127% [ratio, 226.5%; 90% CI, 186.4 to 275.4] for budesonide, and 173% [ratio, 272.8%; 90% CI, 202.5 to 367.4] and 136% [ratio, 236.2%; 90% CI, 192.6 to 289.6] for formoterol, respectively) when the pMDI was administered through the spacer. When assessed by AUC (0-last) quartile without spacer, subjects in the lowest exposure quartile (indicating poor inhalation technique) with Symbicort ® pMDI 160/4.5 μg/actuation (2 actuations) had markedly increased total systemic and lung exposure when the same dose was administered with the spacer. In contrast, for subjects in the highest exposure quartile with pMDI alone, total systemic and lung exposure of formoterol and budesonide was similar with and without the spacer. In the in vitro study, the fine particle dose (<5 μm) of both budesonide and formoterol from the spacer at delay time (i.e. pause period after actuation) = 0 s (instantaneous) after actuation was similar to the fine particle dose when not using the spacer. The delivered doses of budesonide and formoterol from the spacer were both lower compared with the doses administered without the spacer. There was also a decrease in delivered dose with increasing delay time., Conclusions: The clinical study demonstrated that in subjects with poor inhalation technique the use of the AeroChamber Plus ® Flow-Vu ® spacer increased the bioavailability of Symbicort ® pMDI to a level observed in subjects with good inhalation technique without a spacer. The findings from the in vitro study support the fine particle dose characteristics of Symbicort ® pMDI with the AeroChamber Plus ® Flow-Vu ® spacer., (Copyright © 2018. Published by Elsevier Ltd.)

Background: Patients with mild asthma often rely on inhaled short-acting β 2 -agonists for symptom relief and have poor adherence to maintenance therapy. Another approach might be for patients to receive a fast-acting reliever plus an inhaled glucocorticoid component on an as-needed basis to address symptoms and exacerbation risk., Methods: We conducted a 52-week, double-blind, multicenter trial involving patients 12 years of age or older who had mild asthma and were eligible for treatment with regular inhaled glucocorticoids. Patients were randomly assigned to receive twice-daily placebo plus budesonide-formoterol (200 μg of budesonide and 6 μg of formoterol) used as needed or budesonide maintenance therapy with twice-daily budesonide (200 μg) plus terbutaline (0.5 mg) used as needed. The primary analysis compared budesonide-formoterol used as needed with budesonide maintenance therapy with regard to the annualized rate of severe exacerbations, with a prespecified noninferiority limit of 1.2. Symptoms were assessed according to scores on the Asthma Control Questionnaire-5 (ACQ-5) on a scale from 0 (no impairment) to 6 (maximum impairment)., Results: A total of 4215 patients underwent randomization, and 4176 (2089 in the budesonide-formoterol group and 2087 in the budesonide maintenance group) were included in the full analysis set. Budesonide-formoterol used as needed was noninferior to budesonide maintenance therapy for severe exacerbations; the annualized rate of severe exacerbations was 0.11 (95% confidence interval [CI], 0.10 to 0.13) and 0.12 (95% CI, 0.10 to 0.14), respectively (rate ratio, 0.97; upper one-sided 95% confidence limit, 1.16). The median daily metered dose of inhaled glucocorticoid was lower in the budesonide-formoterol group (66 μg) than in the budesonide maintenance group (267 μg). The time to the first exacerbation was similar in the two groups (hazard ratio, 0.96; 95% CI, 0.78 to 1.17). The change in ACQ-5 score showed a difference of 0.11 units (95% CI, 0.07 to 0.15) in favor of budesonide maintenance therapy., Conclusions: In patients with mild asthma, budesonide-formoterol used as needed was noninferior to twice-daily budesonide with respect to the rate of severe asthma exacerbations during 52 weeks of treatment but was inferior in controlling symptoms. Patients in the budesonide-formoterol group had approximately one quarter of the inhaled glucocorticoid exposure of those in the budesonide maintenance group. (Funded by AstraZeneca; SYGMA 2 ClinicalTrials.gov number, NCT02224157 .).

Background: In patients with mild asthma, as-needed use of an inhaled glucocorticoid plus a fast-acting β 2 -agonist may be an alternative to conventional treatment strategies., Methods: We conducted a 52-week, double-blind trial involving patients 12 years of age or older with mild asthma. Patients were randomly assigned to one of three regimens: twice-daily placebo plus terbutaline (0.5 mg) used as needed (terbutaline group), twice-daily placebo plus budesonide-formoterol (200 μg of budesonide and 6 μg of formoterol) used as needed (budesonide-formoterol group), or twice-daily budesonide (200 μg) plus terbutaline used as needed (budesonide maintenance group). The primary objective was to investigate the superiority of as-needed budesonide-formoterol to as-needed terbutaline with regard to electronically recorded weeks with well-controlled asthma., Results: A total of 3849 patients underwent randomization, and 3836 (1277 in the terbutaline group, 1277 in the budesonide-formoterol group, and 1282 in the budesonide maintenance group) were included in the full analysis and safety data sets. With respect to the mean percentage of weeks with well-controlled asthma per patient, budesonide-formoterol was superior to terbutaline (34.4% vs. 31.1% of weeks; odds ratio, 1.14; 95% confidence interval [CI], 1.00 to 1.30; P=0.046) but inferior to budesonide maintenance therapy (34.4% and 44.4%, respectively; odds ratio, 0.64; 95% CI, 0.57 to 0.73). The annual rate of severe exacerbations was 0.20 with terbutaline, 0.07 with budesonide-formoterol, and 0.09 with budesonide maintenance therapy; the rate ratio was 0.36 (95% CI, 0.27 to 0.49) for budesonide-formoterol versus terbutaline and 0.83 (95% CI, 0.59 to 1.16) for budesonide-formoterol versus budesonide maintenance therapy. The rate of adherence in the budesonide maintenance group was 78.9%. The median metered daily dose of inhaled glucocorticoid in the budesonide-formoterol group (57 μg) was 17% of the dose in the budesonide maintenance group (340 μg)., Conclusions: In patients with mild asthma, as-needed budesonide-formoterol provided superior asthma-symptom control to as-needed terbutaline, assessed according to electronically recorded weeks with well-controlled asthma, but was inferior to budesonide maintenance therapy. Exacerbation rates with the two budesonide-containing regimens were similar and were lower than the rate with terbutaline. Budesonide-formoterol used as needed resulted in substantially lower glucocorticoid exposure than budesonide maintenance therapy. (Funded by AstraZeneca; SYGMA 1 ClinicalTrials.gov number, NCT02149199 .).

Background: The efficacy and safety of budesonide/formoterol pressurized metered-dose inhaler (pMDI) have been demonstrated in patients with asthma at least 12 years old., Objective: To evaluate the efficacy of 2 formoterol doses added to budesonide as fixed combinations vs budesonide alone in children 6 to younger than 12 years with asthma., Methods: This randomized, double-blinded, parallel-group, multicenter study (NCT02091986; CHASE 3) included children 6 to younger than 12 years with asthma previously receiving a medium-dose inhaled corticosteroid (ICS) or an ICS plus a long-acting β 2 -agonist. Children symptomatic during a 7-28-day run-in on low-dose ICS, 1 inhalation of budesonide dry powder inhaler 90 μg twice daily (BID), were randomized to receive 2 inhalations of budesonide/formoterol pMDI 80/4.5 μg (160/9 μg) BID (n = 92), budesonide/formoterol pMDI 80/2.25 μg (160/4.5 μg) BID (n = 95), or budesonide pMDI 80 μg (160 μg) BID (n = 92) for 12 weeks., Results: Change in forced expiratory volume in 1 second from baseline to 1 hour after dosing (primary end point), change in forced expiratory volume in 1 second 15 minutes after dosing, and peak expiratory flow 1 hour after dosing at week 12 were statistically significantly greater for budesonide/formoterol 160/9 μg vs budesonide (P ≤ .015 for all comparisons), but not for budesonide/formoterol 160/4.5 μg vs budesonide. Bronchodilator effects, evident 15 minutes after the dose on day 1, were maintained at week 12. Incidence of protocol-defined asthma exacerbations and improvements in asthma symptom-related and quality-of-life outcomes were similar across treatments. There were no notable safety differences among treatments., Conclusion: Budesonide/formoterol pMDI 160/9 μg showed statistically significant and clinically meaningful lung function improvements vs budesonide pMDI 160 μg, demonstrating appropriateness as a therapeutic option for children 6 to younger than 12 years with asthma symptomatic on ICS alone., Trial Registration: ClinicalTrials.gov Identifier: NCT02091986., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

We investigated the effect of the long-acting muscarinic antagonist aclidinium bromide on chronic obstructive pulmonary disease (COPD) exacerbations by pooling data from five randomized, placebo-controlled, parallel-group Phase III studies of 3-6 months' duration. Data were pooled from the aclidinium 400 μg twice-daily (BID) and placebo arms (N  =  2,521) and stratified by Global initiative for chronic Obstructive Lung Disease (GOLD) group (A, B, C and D). Results showed that fewer patients experienced ≥1 exacerbation with aclidinium (any severity: 12.5%; moderate to severe: 10.9%) compared with placebo (any severity: 15.7%; moderate to severe: 13.3%) and the odds of experiencing ≥1 exacerbation of any severity were reduced in patients receiving aclidinium (odds ratio  =   0.78, p  =  0.039). Furthermore, aclidinium reduced the rate of exacerbations compared with placebo (any severity: rate ratio  =  0.79, p  =  0.026; moderate to severe: 0.80, p  =  0.044). The time to first exacerbation of any severity was delayed with aclidinium compared with placebo (hazard ratio  =  0.79, p  =  0.026) and there was a numerical delay in time to first moderate-to-severe exacerbation. Finally, the effects of aclidinium on exacerbations versus placebo were greater in patients in GOLD Groups B and D; however, it is of note that only 10.7% of patients were classified in Group A or C. In summary, the results indicate that aclidinium 400 μg BID reduces the frequency of COPD exacerbations compared with placebo and that these effects are greater in symptomatic patients.

Background: Reducing the severity of respiratory symptoms is a key goal in the treatment of chronic obstructive pulmonary disease (COPD). We evaluated the effect of aclidinium bromide 400 μg twice daily (BID) on respiratory symptoms, assessed using the Evaluating Respiratory Symptoms in COPD (E-RS(™): COPD) scale (formerly EXACT-RS)., Methods: Data were pooled from the aclidinium 400 μg BID and placebo arms of two 24-week, double-blind, randomized Phase III studies evaluating aclidinium monotherapy (ATTAIN) or combination therapy (AUGMENT COPD I) in patients with moderate to severe airflow obstruction. Patients were stratified by Global initiative for chronic Obstructive Lung Disease (GOLD) Groups A-D. Change from baseline in E-RS scores, proportion of responders (patients achieving pre-defined improvements in E-RS scores), and net benefit (patients who improved minus patients who worsened) were analyzed., Results: Of 1210 patients, 1167 had data available for GOLD classification. Mean (standard deviation) age was 63.2 (8.6) years, 60.7 % were male, and mean post-bronchodilator forced expiratory volume in 1 s was 54.4 % predicted. Compared with placebo, aclidinium 400 μg BID significantly improved RS-Total (2.38 units vs 0.79 units, p < 0.001) and domain scores (all p < 0.001) at Week 24, and doubled the likelihood of being an RS-Total score responder (p < 0.05), irrespective of GOLD group. The net benefit for RS-Total (Overall: 56.9 % vs 19.4 %; A + C: 65.7 % vs 6.3 %; B + D: 56.0 % vs 20.8 %, for aclidinium 400 μg BID and placebo respectively; all p < 0.05) and domain scores (all p < 0.05) was significantly greater with aclidinium compared with placebo, in both GOLD Groups A + C and B + D., Conclusions: Aclidinium 400 μg BID significantly improved respiratory symptoms regardless of the patients' level of symptoms at baseline. Net treatment benefit was similar in patients with low or high levels of symptoms., Trial Registration: ATTAIN (ClinicalTrials.gov identifier: NCT01001494 ) and AUGMENT COPD I (ClinicalTrials.gov identifier: NCT01437397 ).

The frequency and impact of exacerbations identified using healthcare resource utilisation (HCRU) or the EXAcerbations of Chronic pulmonary disease Tool (EXACT) were compared prospectively in a 24-week, phase III trial (ATTAIN). Patients with moderate-to-severe chronic obstructive pulmonary disease received twice-daily aclidinium 200 μg, aclidinium 400 μg or placebo. All HCRU events were reported to physicians. "EXACT-identified" events were categorised as "EXACT-reported" (detected by EXACT and reported to the physician) and "EXACT-unreported" (detected but not reported). Health status was measured using the St George's Respiratory Questionnaire (SGRQ). Annualised EXACT-identified event rates were higher in all study arms (placebo 1.39, aclidinium 200 μg 1.00 and aclidinium 400 μg 0.98 per patient per year) versus HCRU (placebo 0.60, aclidinium 200 μg 0.43 and aclidinium 400 μg 0.40 per patient per year). Concordance between methods was low (kappa 0.16). Aclidinium reduced EXACT-identified events (rate ratio versus placebo: aclidinium 200 μg 0.72 and aclidinium 400 μg 0.71; both p<0.05); HCRU events were similarly reduced. At week 24, SGRQ scores improved (-6.6 versus baseline) in patients with no event during weeks 1-12; improvements were significantly smaller in patients with HCRU events (-3.4; p=0.036) or EXACT-unreported events (-3.0; p=0.002). Unreported events were more frequent than reported events. Both had similar negative impact on health status. Aclidinium reduced the frequency of both types of event., (©ERS 2014.)

The aim of this study was to determine the presence of oxyiminocephalosporin-resistant (OCR) Gram-negative bacilli and extended-spectrum β-lactamase (ESBL)-producing isolates in stool specimens obtained from paediatric patients hospitalised for acute diarrhoea. We conducted a prospective, multicentre study over a period of 6 months in seven hospitals in the south of France. Samplings were carried out from infants admitted for acute diarrhoea with no previous antibiotic treatment in the last week. Bacteria in stool specimens were screened for the presence of OCR Gram-negative bacilli on Drigalski agar supplemented with ceftazidime and ESBL CHROMagar® media, and confirmed by the Rosco tablets test. Genetic detection was performed by the Check MDR® microarray and by polymerase chain reaction (PCR) and sequencing with bacterial DNA extracted from isolates. The presence of OCR enterobacteria was markedly high (177/1,118 patients, 15.2 %), with an important community origin (66.1 %). The majority of multidrug-resistant (MDR) bacteria were Enterobacter cloacae (106, 59.9 %) and Escherichia coli (61, 34.5 %). The prevalence of ESBL and CTX-M producers represented 5.2 and 4.3 % of the isolates, respectively. The main proportion of these ESBL carriers was found in children less than 1 year of age (53.4 %). One carbapenemase (IMP-1) was detected. The study revealed the wide dissemination of MDR bacteria in infants attending hospitals in the south of France during a non-outbreak situation, in particular, the spread of cefotaximase and the detection of a carbapenemase. This worrisome situation must reinforce the use of hygiene procedures and appropriate antibiotics to control the emergence and spread of OCR organisms.

The objective of this study was to determine the genetic diversity of multidrug-resistant (MDR) Pseudomonas aeruginosa strains isolated over a period of 12 months in two French hospitals and to test their susceptibility to bacteriophages. A total of 47 MDR isolates recovered from hospitalized patients were genotyped using multiple-locus variable number of tandem repeats analysis. The genotypes were distributed into five clones (including 19, 5, 5, 3, and 3 isolates, respectively) and 12 singletons. Comparison to 77 MDR strains from three other countries, and MLST analysis of selected isolates showed the predominance of international MDR clones. The larger clone, CC235, contained 59 isolates displaying different antibiotic resistance mechanisms, including the presence of the GES1, VIM-2, VIM-4, and IMP-1 β-lactamases. Three newly isolated P. aeruginosa bacteriophages were found to lyse 42 of the 44 analyzed strains, distributed into the different clonal complexes. This pilot study suggests that systematic genotyping of P. aeruginosa MDR strains could improve our epidemiological understanding of transmission at both the local (hospital) and the national level and that phage therapy could be an alternative or a complementary treatment to antibiotics for treating MDR-infected patients.

IRE1α (Inositol-requiring enzyme 1 α), an endoplasmic reticulum (ER)-resident sensor for mammalian unfolded protein response, is a type I transmembrane protein which has a bifunctional enzyme containing kinase and RNase domains. Although the luminal domain and cytosolic domain of IRE1α are thought to play crucial roles in regulating the protein activity, no functional and structural studies of the transmembrane domain exist thus far. Herein, using CD spectroscopy, we report that the transmembrane domain of the IRE1α is alpha-helical in a membrane-like environment. In addition, SDS-PAGE and FRET analyses support that the transmembrane domain forms oligomers in SDS micelles. Thus, the study would provide insights into how the transmembrane domain plays a role in regulating the IRE1α protein activity., (Copyright © 2012 Elsevier Inc. All rights reserved.)

The efficacy and safety of two doses of aclidinium bromide were evaluated in patients with moderate to severe chronic obstructive pulmonary disease (COPD). In this 24-week, double-blind trial, patients were randomised to twice-daily aclidinium (200 μg or 400 μg) or placebo. The primary efficacy end-point was change in trough forced expiratory volume in 1 s (FEV(1)) at week 24. Other end-points included peak FEV(1), health status (St George's Respiratory Questionnaire; SGRQ) and dyspnoea (Transitional Dyspnoea Index; TDI). Overall, 828 patients were randomised. At week 24, significant improvements from baseline were observed with aclidinium 200 μg and 400 μg versus placebo for trough FEV(1) (99 and 128 mL; both p<0.0001) and peak FEV(1) (185 and 209 mL; both p<0.0001). Peak FEV(1) improvements on day 1 were comparable with week 24. Aclidinium 200 μg and 400 μg produced significant improvements over placebo in baseline-adjusted mean SGRQ total score (-3.8 and -4.6 units; p<0.001 and p<0.0001) and TDI focal score (0.6 and 1.0 units; p<0.05 and p<0.001) at week 24. With both aclidinium doses, the incidence of anticholinergic adverse events was low, and similar to placebo. Twice-daily aclidinium significantly improved bronchodilation, health status and dyspnoea, and was well tolerated in patients with COPD.

Background: The long-term efficacy and safety of aclidinium bromide, a novel, long-acting muscarinic antagonist, were investigated in patients with moderate to severe chronic obstructive pulmonary disease (COPD)., Methods: In two double-blind, 52-week studies, ACCLAIM/COPD I (n=843) and II (n=804), patients were randomised to inhaled aclidinium 200 μg or placebo once-daily. Patients were required to have a post-bronchodilator forced expiratory volume in 1 second (FEV1)/forced vital capacity ratio of ≤70% and FEV1<80% of the predicted value. The primary endpoint was trough FEV1 at 12 and 28 weeks. Secondary endpoints were health status measured by St George's Respiratory Questionnaire (SGRQ) and time to first moderate or severe COPD exacerbation., Results: At 12 and 28 weeks, aclidinium improved trough FEV1 versus placebo in ACCLAIM/COPD I (by 61 and 67 mL; both p<0.001) and ACCLAIM/COPD II (by 63 and 59 mL; both p<0.001). More patients had a SGRQ improvement≥4 units at 52 weeks with aclidinium versus placebo in ACCLAIM/COPD I (48.1% versus 39.5%; p=0.025) and ACCLAIM/COPD II (39.0% versus 32.8%; p=0.074). The time to first exacerbation was significantly delayed by aclidinium in ACCLAIM/COPD II (hazard ratio [HR] 0.7; 95% confidence interval [CI] 0.55 to 0.92; p=0.01), but not ACCLAIM/COPD I (HR 1.0; 95% CI 0.72 to 1.33; p=0.9). Adverse events were minor in both studies., Conclusion: Aclidinium is effective and well tolerated in patients with moderate to severe COPD., Trial Registration: ClinicalTrials.gov: NCT00363896 (ACCLAIM/COPD I) and NCT00358436 (ACCLAIM/COPD II).

Background: Aclidinium bromide is a novel, long-acting, inhaled muscarinic antagonist bronchodilator currently in Phase III clinical development for the treatment of chronic obstructive pulmonary disease (COPD). This study evaluated the pharmacodynamics, pharmacokinetics, safety and tolerability of ascending doses of aclidinium bromide in patients with COPD., Methods: This double-blind, randomised, placebo-controlled, crossover study was conducted in patients with moderate to severe COPD (forced expiratory volume in 1s [FEV(1)] <65% predicted). Patients were randomly assigned to one of four treatment sequences of aclidinium bromide 100, 300, 900microg and placebo with a washout period between doses. The primary outcome was area under the FEV(1) curve over the 0-24h time interval., Results: Seventeen patients with COPD were studied. Mean FEV(1) over 24h was 1.583L for placebo, and 1.727L, 1.793L and 1.815L for aclidinium bromide 100, 300 and 900microg, respectively (p<0.001 vs. placebo, all doses). Significant changes from baseline in FEV(1) were detected 15min post-dose for aclidinium bromide 300 and 900microg, with a peak effect 2h post-dose (all doses). Aclidinium bromide was undetected in plasma. The majority of adverse events was unrelated to study medication and did not result in discontinuation., Conclusion: Aclidinium bromide 100-900microg produced sustained bronchodilation over 24h in patients with COPD., (Copyright 2009 Elsevier Ltd. All rights reserved.)