Ferran Chuecos

Efficacy and Safety of Aclidinium Bromide Compared with Placebo and Tiotropium in Patients with Moderate-to-Severe Chronic Obstructive Pulmonary Disease: Results from a 6-week, Randomized, Controlled Phase Iiib Study

Abstract Background: This randomized, double-blind, Phase IIIb study evaluated the 24-hour bronchodilatory efficacy of aclidinium bromide versus placebo and tiotropium in patients with moderate-to-severe chronic obstructive pulmonary disease (COPD). Methods: Patients received aclidinium 400 μg twice daily (morning and evening), tiotropium 18 μg once daily (morning), or placebo for 6 weeks. The primary endpoint was change from baseline in forced expiratory volume in 1 second area under the curve for the 24-hour period post-morning dose (FEV1 AUC0–24) at week 6. Secondary and additional endpoints included FEV1 AUC12–24, COPD symptoms (EXAcerbations of chronic pulmonary disease Tool-Respiratory Symptoms [E-RS] total score and additional symptoms questionnaire), and safety. Results: Overall, 414 patients were randomized and treated (FEV1 1.63 L [55.8% predicted]). Compared with placebo, FEV1 AUC0–24 and FEV1 AUC12–24 were significantly increased from baseline with aclidinium (∆ = 150 mL and 160 mL, respectively; p < 0.0001) and tiotropium (∆ = 140 mL and 123 mL, respectively; p < 0.0001) at week 6. Significant improvements in E-RS total scores over 6 weeks were numerically greater with aclidinium (p < 0.0001) than tiotropium (p < 0.05) versus placebo. Only aclidinium significantly reduced the severity of early-morning cough, wheeze, shortness of breath, and phlegm, and of nighttime symptoms versus placebo (p < 0.05). Adverse-event (AE) incidence (28%) was similar between treatments. Few anticholinergic AEs (<1.5%) or serious AEs (<3%) occurred in any group. Conclusions: Aclidinium provided significant 24-hour bronchodilation versus placebo from day 1 with comparable efficacy to tiotropium after 6 weeks. Improvements in COPD symptoms were consistently numerically greater with aclidinium versus tiotropium. Aclidinium was generally well tolerated.

Characterisation and impact of reported and unreported exacerbations: results from ATTAIN

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 &mgr;g, aclidinium 400 &mgr;g 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 &mgr;g 1.00 and aclidinium 400 &mgr;g 0.98 per patient per year) versus HCRU (placebo 0.60, aclidinium 200 &mgr;g 0.43 and aclidinium 400 &mgr;g 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 &mgr;g 0.72 and aclidinium 400 &mgr;g 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. There are twice as many unreported exacerbation events as reported events; both have similar impact on health status http://ow.ly/AwJVf

Aclidinium Bromide, a Long-Acting Antimuscarinic, Does Not Affect QT Interval in Healthy Subjects

In this phase I trial, the effect of aclidinium, a novel, inhaled long‐acting muscarinic antagonist, on QT interval was evaluated, and its cardiovascular safety was assessed in 272 healthy subjects. Aclidinium 200 μg, aclidinium 800 μg, matching placebo, or open‐label moxifloxacin 400 mg was administered daily for 3 days. The primary outcome was mean change in individual heart rate‐corrected QT interval (QTcI). Secondary measures included Bazettcorrected QT interval (QTcB), Fridericia‐corrected (QTcF) intervals, 12‐lead electrocardiogram (ECG) readings, and 24‐hour 12‐lead Holter ECG parameters. Adverse events, vital signs, and laboratory and pharmacokinetic parameters were also assessed. Maximum mean QTcI change from time‐matched baseline on day 3 was −1.0 milliseconds at 2 hours for aclidinium 200 μg, −1.8 milliseconds at 5 minutes for 800 μg, +11.0 milliseconds at 4 hours for moxifloxacin, and −1.2 milliseconds at 23.5 hours for placebo. Aclidinium had no significant effects on secondary ECG measures. Aclidinium plasma concentrations were generally below the lower limit of quantitation (0.05 ng/mL) after 200 μg and were detected only up to 1 hour after the 800‐μg dose in the majority of cases. It is concluded that aclidinium bromide, at doses up to 800 μg, has a favorable cardiovascular safety profile with no effect on QT interval.

The efficacy of aclidinium/formoterol on lung function and symptoms in patients with COPD categorized by symptom status: a pooled analysis

Background Patients with chronic obstructive pulmonary disease (COPD) experience respiratory symptoms, which impair quality of life. This pooled analysis of two Phase III studies assessed the impact of aclidinium/formoterol on patients with COPD categorized by symptom status. Methods Data were pooled from two 24-week, randomized, placebo-controlled studies of twice-daily aclidinium/formoterol 400/12 µg in moderate-to-severe COPD (ACLIFORM [NCT01462942] and AUGMENT [NCT01437397]). These post hoc analyses evaluated the efficacy of aclidinium/formoterol versus placebo or monotherapies in patients defined as less/more symptomatic by a) Evaluating Respiratory Symptoms (E-RS™) score ≥10/<10 and b) Baseline Dyspnea Index score <7/≥7. Endpoints included trough and 1-hour morning postdose forced expiratory volume in 1 second (FEV1), Transition Dyspnea Index, E-RS total score, early-morning and nighttime symptom severity, early-morning limitation of activities, and exacerbation rate. Results Data for 3,394 patients were analyzed (mean age: 63.5 years; 60.5% male). In both definitions of less and more symptomatic patients, aclidinium/formoterol improved 1-hour morning postdose FEV1 from baseline at week 24 versus placebo (P<0.001) and both monotherapies (P<0.05). Aclidinium/formoterol improved trough FEV1 from baseline in both groups versus placebo (P<0.05) and formoterol (P<0.05); improvements were greater in more symptomatic patients. Improvements versus aclidinium were also observed in more symptomatic patients (P<0.05). Aclidinium/formoterol improved dyspnea, early-morning symptom severity, and limitation of activities versus placebo in both less and more symptomatic patients (P<0.001). In more symptomatic patients, aclidinium/formoterol also improved E-RS total score and severity of nighttime symptoms from baseline versus placebo and one or both monotherapies (P<0.05). The rate of moderate/severe exacerbations was reduced with aclidinium/formoterol versus placebo in more symptomatic patients. Conclusion Aclidinium/formoterol 400/12 µg provided consistent improvements in bronchodilation and symptoms versus monotherapies and reduced exacerbations versus placebo in more symptomatic patients with moderate-to-severe COPD, regardless of the definition used. Furthermore, patients with a low symptom burden achieved benefits with aclidinium/formoterol versus monotherapies in postdose FEV1, dyspnea, and early-morning symptoms.

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.

Improvement in 24-hour bronchodilation and symptom control with aclidinium bromide versus tiotropium and placebo in symptomatic patients with COPD: post hoc analysis of a Phase IIIb study

Background A previous Phase IIIb study (NCT01462929) in patients with moderate to severe COPD demonstrated that 6 weeks of treatment with aclidinium led to improvements in 24-hour bronchodilation comparable to those with tiotropium, and improvement of symptoms versus placebo. This post hoc analysis was performed to assess the effect of treatment in the symptomatic patient group participating in the study. Methods Symptomatic patients (defined as those with Evaluating Respiratory Symptoms [E-RS™] in COPD baseline score ≥10 units) received aclidinium bromide 400 μg twice daily (BID), tiotropium 18 μg once daily (QD), or placebo, for 6 weeks. Lung function, COPD respiratory symptoms, and incidence of adverse events (AEs) were assessed. Results In all, 277 symptomatic patients were included in this post hoc analysis. Aclidinium and tiotropium treatment improved forced expiratory volume in 1 second (FEV1) from baseline to week 6 at all time points over 24 hours versus placebo. In addition, improvements in FEV1 from baseline during the nighttime period were observed for aclidinium versus tiotropium on day 1 (aclidinium 157 mL, tiotropium 67 mL; P<0.001) and week 6 (aclidinium 153 mL, tiotropium 90 mL; P<0.05). Aclidinium improved trough FEV1 from baseline versus placebo and tiotropium at day 1 (aclidinium 136 mL, tiotropium 68 mL; P<0.05) and week 6 (aclidinium 137 mL, tiotropium 71 mL; P<0.05). Aclidinium also improved early-morning and nighttime symptom severity, limitation of early-morning activities, and E-RS Total and domain scores versus tiotropium (except E-RS Chest Symptoms) and placebo over 6 weeks. Tolerability showed similar incidence of AEs in each arm. Conclusion In this post hoc analysis of symptomatic patients with moderate to severe COPD, aclidinium 400 μg BID provided additional improvements compared with tiotropium 18 μg QD in: 1) bronchodilation, particularly during the nighttime, 2) daily COPD symptoms (E-RS), 3) early-morning and nighttime symptoms, and 4) early-morning limitation of activity.

Effect of Aclidinium Bromide on Exacerbations in Patients with Moderate-to-Severe COPD: A Pooled Analysis of Five Phase III, Randomized, Placebo-Controlled Studies

ABSTRACT 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.

P126 Efficacy of aclidinium bromide compared with tiotropium and placebo in symptomatic patients with moderate to severe chronic obstructive pulmonary disease (COPD): post-hoc analysis of a Phase IIIb study

Introduction and objective Maintaining bronchodilation and symptom control throughout the day and night is an important COPD therapeutic aim. Here, we compare 24-hour lung function and symptom control in symptomatic patients with moderate to severe COPD treated with aclidinium or tiotropium, two long-acting, muscarinic antagonists. Methods This was a post-hoc analysis of a 6-week, double-blind, Phase IIIb study comparing aclidinium 400 µg BID with tiotropium bromide 18 µg QD or placebo in patients with moderate to severe COPD (NCT01462929). Symptomatic patients were defined as having an EXAcerbations of Chronic pulmonary disease Tool-Respiratory Symptoms (E-RS) baseline score ≥ 10 units. Primary endpoint: change from baseline in normalised FEV1 AUC over 24-hours post-morning dose (AUC–24/24h) at Week 6. Other endpoints: change from baseline in morning pre-dose (trough) FEV1 and change from baseline in FEV1 AUC0-–2/12h; 12-–4/12h, E-RS, early-morning and night-time symptoms, and limitation of early-morning activities. Results A total of 277/414 symptomatic patients were included; mean age was 62.1 years, 54.5% were current smokers, baseline FEV1 1.41 ± 0.48 L. At Week 6, aclidinium 400 µg BID improved FEV1 over 24 h from baseline vs placebo (Table 1). During the night-time period, aclidinium 400 µg BID improved FEV1 from baseline vs tiotropium 18 µg QD. At Week 6, improvements in trough FEV1 from baseline were observed with aclidinium vs tiotropium and placebo. Aclidinium improved E-RS total score from baseline vs tiotropium and placebo. Moreover, aclidinium improved early-morning and night-time symptom severity from baseline vs tiotropium and placebo over the treatment period (see Table 1 for all results described above). Limitation of early-morning activities caused by COPD symptoms was also improved with aclidinium vs tiotropium and placebo (p < 0.05). Tolerability has been previously reported (Beier COPD 2013) where adverse events (AEs) were similar in each arm, few anticholinergic AEs or serious AEs occurred in any group, and aclidinium was well tolerated.Abstract P126 Table 1 Spirometric and symptomatic variables in symptomatic patients with COPD (baseline E-RS ≥10) Day 1 Week 6 Change from baseline in normalised FEV1 vs placebo, mL Aclidinium 400 µg Tiotropium 18 µg Aclidinium vs tiotropium Aclidinium 400 µg Tiotropium18 µg Aclidinium vs tiotropium FEV1 AUC –24/24h 150* 87* 63† 140** 106* 34 FEV1 AUC12–24/12h (night-time) 157** 67* 90† 153** 90** 63† FEV1 AUC –12 (day time) 147** 112** 35 126* 123* 3 Morning pre-dose (trough) FEV1 136** 68* 68† 137* 70* 65† E-RS Total Score over 6 weeks - - - -2.15* -0.98 -1.17† a Early morning symptom severity over 6 weeks (% reduction) - - - -0.25*(-9.54%) -0.11(-4.33%) -0.14† (-5.21%) b Night-time symptom severity over 6 weeks (% reduction) - - - -0.23*(-10.31%) -0.09(-4.23%) -0.14 † (-6.09%) *p < 0.05 vs placebo; **p ≤ 0.0001 vs placebo; †p < 0.05 vs tiotropium. aLeast squares mean change from baseline in the severity of early morning symptoms over 6 weeks: 1 = No symptoms, 2 = Mild, 3 = Moderate, 4 = Severe, 5 = Very severe. bChange from baseline in the severity of night-time symptoms over 6 weeks: 1 = No symptoms, 2 = Mild, 3 = Moderate, 4 = Severe, 5 = Very severe. AUC, area under the curve; COPD, chronic obstructive pulmonary disease; E-RS, EXAcerbations of Chronic pulmonary disease Tool-Respiratory Symptoms; FEV1, forced expiratory volume in 1 s. Conclusions Aclidinium 400 µg BID improved bronchodilation, particularly during the night-time period, as well as early morning, daily and night-time symptoms, and early-morning limitation of activity in symptomatic patients compared with either tiotropium 18 µg QD or placebo.