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 (R) (budesonide/formoterol) pMDI 160/4.5 mu g/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 mu g/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 mu g/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 mu m) 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 (R) Flow-Vu (R) spacer increased the bioavailability of Symbicort (R) 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 (R) pMDI with the AeroChamber Plus Flow-Vti spacer.

Background Concerns have been raised that treatment of COPD with inhaled corticosteroids may increase pneumonia risk. Responding to a request from the European Medicines Agency Pharmacovigilance Risk Assessment Committee, a pooled analysis of interventional studies compared pneumonia risk with inhaled budesonide-containing versus non-budesonide-containing treatments and the impact of other clinically relevant factors. Methods AstraZeneca-sponsored, parallel-group, double-blind, randomized controlled trials meeting the following criteria were included: >8 weeks’ duration; ≥60 patients with COPD; inhaled budesonide treatment arm (budesonide/formoterol or budesonide); and non-budesonide-containing comparator arm (formoterol or placebo). Primary and secondary outcomes were time to first pneumonia treatment-emergent serious adverse event (TESAE) and treatment-emergent adverse event (TEAEs), respectively, analyzed using Cox regression models stratified by study. Results Eleven studies were identified; 10,570 out of 10,574 randomized patients receiving ≥1 dose of study treatment were included for safety analysis (budesonide-containing, n=5,750; non-budesonide-containing, n=4,820). Maximum exposure to treatment was 48 months. The overall pooled hazard ratio (HR), comparing budesonide versus non-budesonide-containing treatments, was 1.15 for pneumonia TESAEs (95% confidence interval [CI]: 0.83, 1.57) and 1.13 for pneumonia TEAEs (95% CI: 0.94, 1.36). The annual incidence of pneumonia TESAEs was 1.9% and 1.5% for budesonide-containing and non-budesonide-containing treatments, respectively. Comparing budesonide/formoterol with non-budesonide-containing treatment, the HRs for pneumonia TESAEs and TEAEs were 1.00 (95% CI: 0.69, 1.44) and 1.21 (95% CI: 0.93, 1.57), respectively. For budesonide versus placebo, HRs were 1.57 for pneumonia TESAEs (95% CI: 0.90, 2.74) and 1.07 for pneumonia TEAEs (95% CI: 0.83, 1.38). Conclusion This pooled analysis found no statistically significant increase in overall risk for pneumonia TESAEs or TEAEs with budesonide-containing versus non-budesonide-containing treatments. However, a small increase in risk with budesonide-containing treatment cannot be ruled out; there is considerable heterogeneity in study designs and patient characteristics, particularly in the early budesonide studies, and each study contributes <40 pneumonia TESAEs.

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 beta(2)-agonist. Children symptomatic during a 7-28-day run-in on low-dose ICS, 1 inhalation of budesonide dry powder inhaler 90 mu g twice daily (BID), were randomized to receive 2 inhalations of budesonide/formoterol pMDI 80/4.5 mu g (160/9 mu g) BID (n = 92), budesonide/formoterol pMDI 80/2.25 mu g (160/4.5 mu g) BID (n = 95), or budesonide pMDI 80 mu g (160 mu g) 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 flow1 hour after dosing at week 12 were statistically significantly greater forbudesonide/formoterol 160/9 mu g vs budesonide (P <= .015 for all comparisons), but not for budesonide/formoterol 160/4.5 mu g 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 mu g showed statistically significant and clinically meaningful lung function improvements vs budesonide pMDI 160 mu g, 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. (C) 2017 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Background/Objective: To demonstrate therapeutic equivalence of terbutaline via two different Turbuhaler((R)) devices by evaluating its protective effect against methacholine-induced bronchoconstriction in stable asthma.Methods: In this double-blind, double-dummy, multicentre, single-dose, 4-way crossover study, patients with stable mild-to-moderate asthma (FEV1 >= 80% predicted) were randomised to 0.5 or 1.5 mg terbutaline via either Turbuhaler((R)) M2 or Turbuhaler((R)) M3 followed by a methacholine challenge test. The primary outcome variable was the concentration of methacholine causing a 20% drop in FEV1 (PC20). Patients had a PC20 methacholine < 8 mg/mL that was reproducible after 2 weeks, and a stable baseline FEV1 at all visits (90-110% of enrolment value).Results: 60 patients (mean age 31.1 years [range:18-64]; mean FEV1 92.1% predicted normal [78.4 -120.6%]) were randomised to treatment; all completed the study. There was a clear dose-response for both devices. The within-device ratios (1.5 mg:0.5 mg) were 1.79 and 1.87 for Turbuhaler((R)) M3 and M2, respectively (both p < 0.001). The between-device ratios (M3:M2) were 0.92 (95% CI: 0.75-1.13) for 0.5 mg and 0.88 (95% CI 0.72-1.08) for 1.5 mg. Both confidence intervals lie inside the interval 0.67-1.50, which was the pre-specified condition for equivalent effect.Conclusions: Bronchoprotection using a standardised methacholine challenge model proved to be an effective design to elucidate therapeutic equivalence between devices in patients with mild-to-moderate asthma. The findings indicate that patients may switch from one type of Turbuhaler((R)) to the other without adjustment of therapy. Moreover, they show the robustness and utility of this study design and its suitability for investigating therapeutic equivalence. (c) 2017 Elsevier Ltd. All rights reserved.

BACKGROUND:Budesonide is approved for delivery using a nebulized solution and dry-powder inhaler, but its use through a pressurized metered-dose inhaler (pMDI) in pediatric patients with asthma has not been determined. OBJECTIVE:To examine the efficacy and safety of 160 μg twice daily of budesonide through a pMDI vs placebo in children 6 to younger than 12 years with asthma and a demonstrated need for inhaled corticosteroids. METHODS:A 6-week, international, multicenter, double-blinded, parallel-group, phase 2 study randomized 304 pediatric patients (mean age, 9 years; 21.7% <8 years) 1:1 to 160 μg (80 μg × 2 inhalations) twice daily of budesonide through a pMDI or placebo after a 7- to 21-day run-in period. The primary efficacy end point was change from baseline in morning peak expiratory flow (PEF); safety end points included adverse events, vital signs, and discontinuations. RESULTS:Budesonide treatment significantly improved morning PEF vs placebo; mean treatment effect (budesonide vs placebo) was 13.6 L/min (P < .0001). Budesonide also showed significant improvements vs placebo for forced expiratory volume in 1 second, evening PEF, forced expiratory flow at 25% to 75% of pulmonary volume, reliever medication use, nighttime awakenings, awakenings with reliever use, and percentage of patients with at least 15- and at least 30-L/min increase in morning PEF from baseline. The numbers of patients experiencing adverse events and discontinuations were smaller in the budesonide than in the placebo group. No serious adverse events were reported. CONCLUSION:Budesonide at 160 μg twice daily through a pMDI was generally well tolerated and significantly improved lung function, symptoms, rescue medication use, and nighttime awakenings vs placebo in children 6 to younger than 12 years with asthma and a demonstrated need for inhaled corticosteroids.

Objective: The efficacy and safety of budesonide/formoterol maintenance and reliever therapy (MRT) has been demonstrated in phase III clinical studies, but limited data are available in a real-life setting. We examined the pattern of maintenance and as-needed inhaler use in routine clinical practice among patients with asthma receiving budesonide/formoterol MRT (NCT00505388). Methods: This 12-month European observational study enrolled patients prescribed budesonide/formoterol MRT and grouped them based on regimen: 80/4.5 mu g one inhalation twice daily (b.i.d.); 160/4.5 mu g one inhalation b.i.d.; 160/4.5 mu g two inhalations b.i.d. (all plus as needed). Patient data were collected daily using an interactive voice- or web-response system. The primary outcome measure was total number of budesonide/formoterol inhalations/day. Results: Overall, 4,581 patients were included (64% female; mean age 48.4 years; regimen: 80/4.5 mu g, n = 119; 160/4.5 mu g, n = 3,106; 2 x 160/4.5 mu g, n = 1,355). Mean (median) total numbers of budesonide/formoterol inhalations/day were 2.48 (2.11), 2.53 (2.14); and 4.27 (4.05) for 80/4.5 mu g b.i.d., 160/4.5 mu g b.i.d., and 2 x 160/4.5 mu g b.i.d., respectively; corresponding mean (median) number of as-needed inhalations/day were 0.68 (0.17), 0.73 (0.26), and 1.08 (0.45), respectively. As-needed budesonide/formoterol use was generally low with a mean of 61 - 66% of reliever-free days; over 4 reliever inhalations/day occurred on a mean of 0.4 - 2.5% of days for all budesonide/formoterol MRT regimens. Conclusions: In routine clinical practice, all budesonide/formoterol MRT regimens were associated with a high proportion of reliever-free days and low incidence of high reliever-use days, indicating acceptable levels of asthma control with this symptom-adjusted controller regimen.

Rationale: To assess equivalence of twice daily (bid) budesonide/formoterol (BUD/FM) 160/4.5 mu g via breath-actuated metered-dose inhaler (BAI) versus pressurized metered-dose inhaler (pMDI).Methods: This 12-week, double-blind, multicenter, parallel-group study, randomized adolescents and adults (aged >= 12 years) with asthma (and >= 3 months daily use of inhaled corticosteroids) to BUD/FM BAI 2 x 160/4.5 jig bid, BUD/FM pMDI 2 x 160/4.5 jig bid, or BUD pMDI 2 x 160 mu g bid. Inclusion required prebronchodilator forced expiratory volume in one second (FEV1) >= 45 to <= 85% predicted, and reversibility of >= 12% in FEV1 (ages 12 to <18 years) or >= 12% and 200 mL (ages >= 18 years). Confirmation that 60-min postdose FEV1 response to BUD/FM pMDI was superior to BUD pMDI was required before equivalence testing. Therapeutic equivalence was shown by treatment effect ratio of BUD/FM BAI vs BUD/FM pMDI on 60-min postdose FEV1 and predose FEV1 within confidence intervals (CIs) of 80-125%.Results: Mean age of 214 randomized patients was 42.7 years. BUD/FM pMDI was superior to BUD pMDI (60-min postdose FEV1 treatment effect ratio, 1.10; 95% CI, 1.06-1.14; p < 0.001). Treatment effect ratios for BUD/FM BAI versus pMDI for 60-min postdose FEV1 (1.01; 95% CI, 0.97-1.05) and predose FEV1 (1.03; 95% CI, 0.99-1.08) were within predetermined CIs for therapeutic equivalence. Adverse event profiles, tolerability, and patient reported ease of use were similar.Conclusions: BUD/FM 2 x 160/4.5 mu g bid BAI is therapeutically equivalent to BUD/FM conventional pMDI. The introduction of BUD/FM BAI would expand options for delivering inhaled corticosteroid/long-acting beta(2)-agonist combination therapy to patients with moderate-to-severe asthma. (C) 2015 The Authors. Published by Elsevier Ltd.

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

AZD3480 is a selective agonist of the central α4β2 and α2β2 neuronal nicotinic cholinergic receptors (NNRs). Its effects on cognition were investigated in 567 patients with mild-to-moderate Alzheimer's disease (AD) (Mini Mental State Examination [MMSE] 12-26). Mean baseline MMSE was 21 (SD ± 3.7), with 61% of patients having mild disease (MMSE 21-26). Mean age was 74 (range 58-85) years. Patients were randomized to one of 5 treatment groups: AZD3480 5 mg, 20 mg or 35/100 mg, donepezil 10 mg (active comparator) or placebo, and treated once daily for 12 weeks. The primary outcome measure was change from baseline at Week 12 on the AD Assessment Scale-Cognitive Subscale (ADAS-Cog). Neither AZD3480 nor donepezil showed a statistically significant improvement versus placebo on ADAS-Cog. Improvements in a number of secondary outcome measures (MMSE, AD Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC) and Disability Assessment for Dementia [DAD]) were observed for AZD3480 and for donepezil. A post-hoc analysis on ADAS-Cog, excluding patients with very mild AD (MMSE 25-26) indicated improvement versus placebo for AZD3480 20 mg (-1.4, 95% CI: -3.0; 0.2) and donepezil (-1.0, 95% CI: -2.3; 0.3). AZD3480 was well tolerated. The study did not meet proof of concept criteria: since neither AZD3480 nor donepezil were statistically significantly superior to placebo on ADAS-Cog and was considered to be inconclusive. Further studies are required to determine the therapeutic potential of stimulating α4β2 receptors with NNRs in AD patients.

AZD3480 is a selective agonist of the central α4β2 and α2β2 neuronal nicotinic receptors (NNRs). 567 mild to moderate AD patients (MMSE 12-26) were randomized to three dose groups of AZD3480: 5 mg, 20 mg, and 35/100 mg (depending on CYP2D6 metabolic status), donepezil (10 mg) or placebo. Treatment was given once daily for 12 weeks. The primary outcome measure was ADAS-Cog 11-item total score change from baseline to Week 12. Secondary outcome measures included global function (ADCS-CGIC), MMSE, CDR computerized test battery, PROs (DAD, CMAI, ZBI, AAIQOL) and safety/tolerability of AZD3480. All p-values are one-sided and descriptive. Mean baseline MMSE score was 21 (SD ±3.7) with 60% of patients having AD of mild severity (MMSE 21-26). Mean age was 73 (range 58-85) years. Neither AZD3480 nor donepezil showed a statistically significant improvement vs. placebo on ADAS-Cog at Week 12 for all patients or when patients were analyzed by severity (mild/moderate). The AZD3480 dose of 20 mg showed an improvement vs. placebo on both ADCS-CGIC (-0.5, p < 0.001) and MMSE (0.9, p = 0.009). AZD3480 showed no improvement vs. placebo in any domain of the CDR. No consistent improvement of AZD3480 vs. placebo was observed across the PROs. A post hoc analysis on ADAS-Cog excluding patients with very mild (MMSE 25-26) AD at baseline indicated improvement for AZD3480 vs. placebo but only at the 20 mg dose (-1.4, p = 0.04). The corresponding figures for donepezil vs placebo were -1.0 (p = 0.065). The frequency of AEs among patients treated with AZD3480 was similar to placebo. There were no signs of withdrawal symptoms during the 2 weeks following end of treatment. The study was inconclusive as the primary outcome measure on ADAS-Cog was not statistically significant vs. placebo for either AZD3480 or donepezil, possibly due to an improvement in the placebo group. In secondary outcome measures, AZD3480 showed an improvement on ADCS-CGIC and MMSE vs. placebo. AZD3480 was well tolerated.

BACKGROUND AND OBJECTIVE:In patients with gastro-oesophageal reflux disease (GORD), dose escalation or drug switching may be considered in those with symptoms that persist despite standard-dose proton pump inhibitor (PPI) therapy. This study set out to assess whether increasing the dosage of oral esomeprazole and pantoprazole improves acid control in GORD patients, and to compare the pharmacodynamic efficacy of esomeprazole and pantoprazole administered at different dosages. METHODS:This was an open-label, randomized, six-way crossover study that included Helicobacter pylori-negative GORD patients (aged 20-60 years) with <30% of time with intragastric pH>4. Patients were treated with oral once-daily esomeprazole 20 mg, 40 mg and 80 mg, and pantoprazole 20 mg, 40 mg and 80 mg, for 5 days. The main outcome measures were time with intragastric pH>4 over 24 hours, median pH over 24 hours and area under the hydrogen ion versus time curve on day 5 for each treatment period. RESULTS:Dose escalation with both PPIs improved acid control. The proportion of time with intragastric pH>4 (day 5) was 46.7% with esomeprazole 20 mg/day, 58.6% with esomeprazole 40 mg/day, and 65.8% with esomeprazole 80 mg/day; the corresponding percentages with pantoprazole were 28.6%, 36.9% and 44.9%, respectively. On a milligram-per-milligram basis, esomeprazole provided greater acid control than pantoprazole (p<0.001). CONCLUSION:Dose escalation with oral esomeprazole and pantoprazole improves acid control in patients with GORD, although esomeprazole provides significantly greater acid control on a milligram-per-milligram basis.