Beatriz Seoane

A randomised, placebo- and active-controlled dose-finding study of aclidinium bromide administered twice a day in COPD patients.

This Phase IIb, double-blind, double-dummy, placebo- and active-comparator-controlled crossover study (ClinicalTrials.gov identifier: NCT01120093) assessed efficacy and safety of three doses of aclidinium bromide in patients with moderate to severe chronic obstructive pulmonary disease. Patients were randomised to one of five treatment sequences each consisting of twice-daily (BID) aclidinium 100 μg, 200 μg, 400 μg (via Genuair®*), formoterol 12 μg (via Aerolizer®) and matched placebo for 7 days, with a 5- to 9-day washout period. Primary endpoint was mean change from baseline in forced expiratory volume in 1 s (FEV1) normalised area under the curve (AUC)0-12 on Day 7. Secondary endpoints were: change from baseline in FEV1 normalised AUC12-24, FEV1 normalised AUC0-24 and morning pre-dose FEV1 on Day 7. Adverse events were monitored throughout the study. Of 79 randomised patients, 68 (86.1%) completed the study. After 7 days of treatment, aclidinium and formoterol produced statistically significantly greater changes from baseline in FEV1 normalised AUC0-12 vs placebo (p<0.0001). FEV1 normalised AUC12-24, FEV1 normalised AUC0-24, and morning pre-dose FEV1 were also statistically significantly greater with all aclidinium doses vs placebo (p<0.0001). Improvements in primary and secondary endpoints were statistically significantly greater with aclidinium 400 μg vs 100 μg. The safety profile of aclidinium was comparable to placebo. These results demonstrated that twice-daily aclidinium produced dose-dependent clinically meaningful improvements in FEV1 compared with placebo. This study also confirmed the use of an aclidinium BID dosing regimen and established aclidinium 200 μg and 400 μg as suitable doses for further investigation in Phase III trials.

Efficacy and safety of aclidinium/formoterol versus salmeterol/fluticasone: a phase 3 COPD study

The efficacy and safety of twice-daily aclidinium bromide/formoterol fumarate was compared with that of salmeterol/fluticasone propionate in patients with stable, moderate-to-severe chronic obstructive pulmonary disease (COPD). AFFIRM COPD (Aclidinium and Formoterol Findings in Respiratory Medicine COPD) was a 24-week, double-blind, double-dummy, active-controlled study. Patients were randomised (1:1) to aclidinium/formoterol 400/12 µg twice-daily via Genuair/Pressair or salmeterol/fluticasone 50/500 µg twice-daily via Accuhaler. The primary end-point was peak forced expiratory volume in 1 s (FEV1) at week 24. Other end-points included Transition Dyspnoea Index (TDI) focal score at week 24, TDI and St Georges Respiratory Questionnaire (SGRQ) responders, COPD Assessment Test and SGRQ scores, assessment of COPD symptoms and exacerbations, use of reliever medication, and device preference. Adverse events were monitored throughout. In total, 933 patients were eligible (mean age 63.4 years, 65.1% male). Aclidinium/formoterol was superior to salmeterol/fluticasone in peak FEV1 and noninferior in TDI. Health status and reduction in exacerbation risk were similar in both groups. While both treatments were well tolerated, pneumonia occurred less frequently with aclidinium/formoterol than salmeterol/fluticasone. In stable COPD, aclidinium/formoterol significantly improved bronchodilation versus salmeterol/fluticasone, with equivalent benefits in symptom control and reduction in exacerbation risk. Both treatments were well tolerated and treatment-related adverse events were less common with aclidinium/formoterol. Aclidinium/formoterol achieves significantly greater bronchodilation than salmeterol/fluticasone in stable COPD http://ow.ly/5txx301kAoZ

Preference, satisfaction and critical errors with Genuair and Breezhaler inhalers in patients with COPD: a randomised, cross-over, multicentre study.

Background:The specific attributes of inhaler devices can influence patient use, satisfaction and treatment compliance, and may ultimately impact on clinical outcomes in patients with chronic obstructive pulmonary disease (COPD).Aims:To assess patient preference, satisfaction and critical inhaler technique errors with Genuair (a multidose inhaler) and Breezhaler (a single-dose inhaler) after 2 weeks of daily use.Methods:Patients with COPD and moderate to severe airflow obstruction were randomised in a cross-over, open-label, multicentre study to consecutive once-daily inhalations of placebo via Genuair and Breezhaler, in addition to current COPD medication. The primary end point was the proportion of patients who preferred Genuair versus Breezhaler after 2 weeks (Patient Satisfaction and Preference Questionnaire). Other end points included overall satisfaction and correct use of the inhalers after 2 weeks, and willingness to continue with each device.Results:Of the 128 patients enrolled, 127 were included in the safety population (male n=91; mean age 67.6 years). Of the 110 of the 123 patients in the intent-to-treat population who indicated an inhaler preference, statistically significantly more patients preferred Genuair than Breezhaler (72.7 vs. 27.3%; P<0.001). Mean overall satisfaction scores were also greater for Genuair than for Breezhaler (5.9 vs. 5.3, respectively; P<0.001). After 2 weeks, there was no statistically significant difference in the number of patients who made ⩾1 critical inhaler technique error with Breezhaler than with Genuair (7.3 vs. 3.3%, respectively).Conclusions:Patient overall preference and satisfaction was significantly higher with Genuair compared with Breezhaler. The proportion of patients making critical inhaler technique errors was low with Genuair and Breezhaler.

First-in-human study of the safety, tolerability, pharmacokinetics and pharmacodynamics of abediterol (LAS100977), a novel long-acting Β2-agonist

Here we report the results of a first‐in‐human study to evaluate the safety, tolerability pharmacokinetics, and pharmacodynamics of abediterol, a new β2‐adrenergic agonist. Forty‐eight healthy males aged 18–45 years received abediterol doses of 5, 10, 25, or 50 µg, or placebo. Safety and tolerability assessments included adverse event reporting, pulse and blood pressure monitoring, 12‐lead electrocardiograms, laboratory tests, and physical examination. Pharmacodynamic assessments included whole body plethysmography to determine the bronchodilatory effect by means of airway conductance and resistance. Blood and urine samples were obtained for pharmacokinetic analyses. Abediterol showed an overall good safety and tolerability profile in the dose range tested, consistent with the expected characteristics of a β2‐adrenergic agonist. A dose‐dependent increase of systemic treatment‐emergent adverse events was observed, the most frequent being palpitations, tremor, nausea, and asthenia; most were mild in intensity and resolved without the need for intervention. Improvements in airway conductance (increase) and resistance (decrease) were greater for all doses of abediterol tested compared with placebo at all time‐points up to 36 hours. This first‐in‐human study suggests a potent, rapid, and sustained bronchodilatory effect of abediterol in healthy male subjects. Lower doses are currently under investigation in patients with asthma and in patients with COPD.

A dose-ranging study of the bronchodilator effects of abediterol (LAS100977), a long-acting β2-adrenergic agonist, in asthma; a Phase II, randomized study.

BackgroundLong-acting β2-adrenergic agonists (LABAs) are recommended in combination with inhaled corticosteroids (ICSs) for asthma management. Abediterol is a novel, selective, potent, once-daily LABA in development for treatment of asthma and chronic obstructive pulmonary disease. This study aimed to determine abediterol doses with similar peak bronchodilatory effect to salbutamol 400 μg, and duration of action compatible with once-daily dosing in patients with persistent, stable asthma.MethodsThis was a Phase II, randomized, double-blind, double-dummy, crossover, placebo-controlled, dose-ranging study (ClinicalTrials.gov NCT01425801) in 62 patients with mild-to-moderate asthma who were also receiving an ICS. Patients received single doses of abediterol 0.313, 0.625, 1.25, or 2.5 μg, salbutamol 400 μg, or placebo in the morning. Spirometry was performed up to 36 h post-dose; safety and tolerability were assessed throughout the study. The primary endpoint was change from baseline in peak forced expiratory volume in 1 s (FEV1). Additional endpoints included trough FEV1, normalized area under the FEV1 curve (FEV1 AUC) up to 24 h post-dose, and peak and trough forced vital capacity (FVC).ResultsAbediterol produced dose-dependent improvements in peak FEV1 from baseline compared with placebo, from 0.274 (95% CI 0.221, 0.327) to 0.405 L (95% CI 0.353, 0.458) for abediterol 0.313 to 2.5 μg, respectively (p < 0.0001 all doses). Abediterol 0.625, 1.25, and 2.5 μg had similar magnitude of peak FEV1 effect to salbutamol. Dose-dependent changes from baseline in trough FEV1 versus placebo were 0.219 (95% CI 0.136, 0.302) to 0.400 L (95% CI 0.317, 0.483) for abediterol 0.313 to 2.5 μg, respectively (p < 0.0001). All abediterol doses achieved significant improvements versus placebo in FEV1 AUC 0–6, 0–12, and 0–24 h, and peak and trough FVC (p < 0.05). Less than 10% of patients experienced treatment-related adverse events for each dose of abediterol; most were mild to moderate in intensity and the most common were headache and nasopharyngitis. There were no clinically relevant changes in heart rate.ConclusionsAbediterol 0.625–2.5 μg provided dose-dependent, clinically and statistically significant bronchodilation versus placebo in patients with asthma, with a peak effect similar to salbutamol and duration of action compatible with once-daily dosing. All doses of abediterol were well tolerated.

Effect of aclidinium bromide on cough and sputum symptoms in moderate-to-severe COPD in three phase III trials

Background Cough and sputum are troublesome symptoms in chronic obstructive pulmonary disease (COPD) and are associated with adverse outcomes. The efficacy of aclidinium bromide 400 µg twice daily in patients with stable COPD has been established in two phase III studies (ACCORD COPD I and ATTAIN) and a phase IIIb active-comparator study. This analysis evaluated cough-related symptoms across these studies. Method Patients were randomised to placebo, aclidinium 200 µg or 400 µg twice daily in ACCORD (12 weeks) and ATTAIN (24 weeks), or to placebo, aclidinium 400 µg twice daily or tiotropium 18 µg once daily (6-week active-comparator study). Analysed end points included changes from baseline in Evaluating Respiratory Symptoms (E-RS; formerly known as EXAcerbations of Chronic pulmonary disease Tool), total and cough/sputum scores and frequency/severity of morning and night-time cough and sputum symptoms. Results Data for 1792 patients were evaluated. E-RS cough/sputum domain scores were significantly reduced with aclidinium 400 µg versus placebo in ATTAIN (−0.7 vs −0.3, respectively; p<0.01) and the active-comparator study (−0.6 vs −0.2, respectively; p<0.01). In the active-comparator study, significantly greater improvements were observed with aclidinium versus placebo for severity of morning cough (−0.19 vs −0.02; p<0.01) and phlegm (−0.19 vs −0.02; p<0.05). In ACCORD, aclidinium reduced night-time cough frequency (−0.36 vs 0.1 for placebo; p<0.001) and severity (−0.24 vs −0.1 for placebo; p<0.05), and frequency of night-time sputum production (−0.37 vs 0.05 for placebo; p<0.001). Conclusions Aclidinium 400 µg twice daily improves cough and sputum expectoration versus placebo in stable COPD. Trial registration numbers NCT00891462; NCT01001494; NCT01462929.

Long-Term Evaluation of the Effects of Aclidinium Bromide on Major Adverse Cardiovascular Events and COPD Exacerbations in Patients with Moderate to Very Severe COPD: Rationale and Design of the ASCENT COPD Study

Introduction: Chronic obstructive pulmonary disease (COPD) is a heterogeneous illness characterized by persistent airflow obstruction and exacerbations. Patients typically experience a decline in lung function, increasingly impaired health-related quality of life, and high mortality. Poor lung function and exacerbations are associated with an increased risk of cardiovascular (CV) and cerebrovascular events, and approximately 30% of patients with COPD die from CV‑related disease. Treatment with inhaled long-acting bronchodilators, such as long-acting muscarinic antagonists (LAMAs), is recommended; however, some studies have suggested that LAMAs may increase the risk of CV events. As patients with CV and cerebrovascular conditions are often excluded from clinical trials, an evaluation of the safety of COPD treatments in an at-risk population is vital. Aclidinium bromide is a LAMA approved for the long-term maintenance treatment of COPD. Methods and Objectives: The Phase 4, multicenter, double-blind, randomized, placebo-controlled, parallel-group Aclidinium Bromide on Long-Term Cardiovascular Safety and COPD Exacerbations in PatieNTs with Moderate to Very Severe COPD (ASCENT COPD) study (NCT01966107) is being conducted at 500 sites in the United States and Canada. The primary objectives are to evaluate the long-term effects of twice-daily aclidinium bromide 400 µg on CV safety and exacerbations in patients with moderate to very severe COPD with a history of cerebrovascular, coronary, or peripheral artery disease, or the presence of ≥2 atherothrombotic risk factors. The primary safety and efficacy variables are time to first major adverse CV event (MACE) (on-study analysis) and rate of moderate to severe COPD exacerbations during the first year of treatment (on-treatment analysis), respectively. The study will be terminated after approximately 122 MACE have occurred.

Efficacy, safety, and tolerability of once‐daily abediterol in patients with stable, persistent asthma: a Phase II, randomized, 7‐day, crossover study

Abediterol is a once‐daily, long‐acting β2‐adrenergic agonist in development for the treatment of asthma and chronic obstructive pulmonary disease. We assessed the efficacy, safety, and tolerability of three dose levels of abediterol, given once daily for 7 days in patients with stable, persistent asthma. This was an ascending‐dose, three‐period incomplete crossover study design investigating three dose levels of abediterol versus placebo (EudraCT No. 2008‐003732‐38). Twenty‐eight male patients (25–59 years) were randomized to one of four treatment sequences (1:1:1:1). Follow‐up was 7 days after final treatment. Spirometry was performed regularly up to 24 h postdose Day 1, up to 36 h postdose Day 7, and at follow‐up. Vital signs, 12‐lead electrocardiogram, and clinical laboratory tests were recorded throughout. Abediterol 2.5, 5, and 10 μg provided clinically and statistically significant improvements from baseline (predose, Day 1) in trough forced expiratory volume in 1 sec (FEV1) versus placebo on Day 7 (primary endpoint) of 334, 365, and 294 mL, respectively (all P < 0.01), and peak FEV1 versus placebo on Day 7 of 364 (P < 0.001), 403 (P < 0.001), and 375 mL (P < 0.01), respectively. Days 1 and 7 area under the curve (AUC) parameters within each abediterol group were similar for AUC0–6, AUC0–12, AUC0–24, and AUC12–24, with dose‐dependent effects observed on Day 1. Abediterol (2.5–10 μg) demonstrated a good safety and tolerability profile. Abediterol 2.5, 5, and 10 μg once daily achieved statistically and clinically significant improvements in pulmonary function versus placebo over 7 days and demonstrated a safety and tolerability profile comparable with placebo.

Aclidinium bromide improves symptoms and sleep quality in COPD: a pilot study

In patients with chronic obstructive pulmonary disease (COPD), nighttime and early-morning symptoms are associated with an increased rate of exacerbation, hospital admission and reduced survival [1, 2]. Furthermore, patients with COPD frequently have poor sleep quality [3] and reduced physical activity [4, 5]. We hypothesised that nighttime airflow obstruction in patients with COPD is associated with impaired sleep quality, leading to early-morning symptoms and reduced physical activity. Aclidinium statistically improved symptoms, and sleep and physical activity in moderate COPD http://ow.ly/2chV30adLbW