Cynthia Caracta

Efficacy and safety of twice-daily aclidinium bromide in COPD patients: the ATTAIN study

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 (FEV1) at week 24. Other end-points included peak FEV1, health status (St Georges 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 FEV1 (99 and 128 mL; both p<0.0001) and peak FEV1 (185 and 209 mL; both p<0.0001). Peak FEV1 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.

Efficacy and Safety of a 12-week Treatment with Twice-daily Aclidinium Bromide in COPD Patients (ACCORD COPD I)

Abstract Background: This Phase III study evaluated the efficacy and safety of twice-daily aclidinium 200 μg and 400 μg versus placebo in the treatment of moderate-to-severe COPD. Methods: In this 12-week, double-blind, multicenter trial, patients were randomized (1:1:1) to inhaled twice-daily aclidinium 200 μg, aclidinium 400 μg, or placebo. Primary and secondary endpoints were changes from baseline in trough FEV1 and peak FEV1 at Week 12, respectively. Health status (St. Georges Respiratory Questionnaire [SGRQ]), COPD symptoms (Transitional Dyspnea Index [TDI], night and early morning symptoms), and safety were also assessed. Results: A total of 561 patients (mean age, 64 ± 9 years) with a mean baseline FEV1 of 1.36 ± 0.54 L (47.2% of predicted value) were randomized. At Week 12, aclidinium 200 μg and 400 μg showed significant improvements from baseline in mean (95% CI) trough FEV1 compared with placebo by 86 (45, 127) mL and 124 (83,164) mL, respectively, and in peak FEV1 by 146 (101, 190) mL and 192 (148, 236) mL, respectively (p ≤ 0.0001 for all). Both aclidinium doses also provided significant improvements in SGRQ, TDI and almost all COPD symptom scores compared with placebo (p < 0.05 for all). Incidences of adverse events (AEs) were similar across treatment groups. The incidence of anticholinergic AEs was low and similar across groups (dry mouth: 0.5%–1.6%; constipation: 0%-1.1%). Conclusions: Treatment of moderate-to-severe COPD patients with twice-daily aclidinium 200 μg and 400 μg was associated with significant improvements in bronchodilation, health status, and COPD symptoms. Both doses were well tolerated and had safety profiles similar to placebo. Trial Registration: This ACCORD I study (AClidinium in Chronic Obstructive Respiratory Disease I) was registered on clinicaltrials.gov (NCT00891462) as “Efficacy and Safety of Aclidinium Bromide for Treatment of Moderate to Severe Chronic Obstructive Pulmonary Disease (COPD)”.

Efficacy of aclidinium bromide 400 μg twice daily compared with placebo and tiotropium in patients with moderate to severe COPD.

BACKGROUND The efficacy and safety of aclidinium bromide bid, a novel, long-acting, muscarinic antagonist, was assessed in patients with moderate to severe COPD. METHODS In this phase IIa randomized, double-blind, double-dummy, crossover trial, patients with moderate to severe COPD received aclidinium 400 μg bid, tiotropium 8 μg once daily, and placebo for 15 days, with a 9- to 15-day washout between treatment periods. Treatments were administered through the Genuair or HandiHaler dry powder inhalers. The primary end point was mean change from baseline in FEV(1) AUC(0-12/12h) (area under the curve where the numbers represent the time period for which data were collected divided by the number of hours over which the data are averaged [eg, 0-12 h postdose divided by 12 h]) on day 15. Secondary end points were changes from baseline in FEV(1) AUC(12-24/12h), FEV(1) AUC(0-24/24h), morning predose FEV(1), peak FEV(1), and COPD symptom scores. RESULTS Thirty patients with COPD were randomized, and 27 completed the study. Mean change from baseline in FEV(1) AUC(0-12/12h) at day 15 was significantly greater for aclidinium and tiotropium over placebo (P < .0001). Mean changes from baseline in FEV(1) AUC(12-24/12h), FEV(1) AUC(0-24/24h), morning predose FEV(1), and peak FEV(1) at day 15 were significantly greater for aclidinium and tiotropium over placebo (P < .0001 for all except P < .001 for FEV(1) AUC(12-24/12h) tiotropium vs placebo). Improvements were significantly greater with aclidinium vs tiotropium on day 1 for all of the normalized AUC values of FEV(1) as well as on day 15 for FEV(1) AUC(12-24/12h) (P < .05 for all). COPD symptoms were significantly improved from baseline with aclidinium vs placebo (P < .05) but not with tiotropium. CONCLUSIONS In patients with COPD, aclidinium 400 μg bid compared with placebo provided clinically meaningful improvements in 24-h bronchodilation that generally were comparable to tiotropium 18 μg daily but with significant differences in favor of aclidinium observed in the average nighttime period. Larger studies with longer treatment duration are ongoing to confirm the efficacy of aclidinium 400 μg bid on bronchodilation and COPD symptoms. TRIAL REGISTRY ClinicalTrials.gov; No.: NCT00868231; URL: www.clinicaltrials.gov.

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.

Efficacy and safety of once-daily aclidinium in chronic obstructive pulmonary disease

BackgroundThe 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).MethodsIn 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 Georges Respiratory Questionnaire (SGRQ) and time to first moderate or severe COPD exacerbation.ResultsAt 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.ConclusionAclidinium is effective and well tolerated in patients with moderate to severe COPD.Trial registrationClinicalTrials.gov: NCT00363896 (ACCLAIM/COPD I) and NCT00358436 (ACCLAIM/COPD II).

Efficacy and safety of fixed-dose combinations of aclidinium bromide/formoterol fumarate: the 24-week, randomized, placebo-controlled AUGMENT COPD study

BackgroundCombining two long-acting bronchodilators with complementary mechanisms of action may provide treatment benefits to patients with chronic obstructive pulmonary disease (COPD) that are greater than those derived from either treatment alone. The efficacy and safety of a fixed-dose combination (FDC) of aclidinium bromide, a long-acting muscarinic antagonist, and formoterol fumarate, a long-acting β2-agonist, in patients with moderate to severe COPD are presented.MethodsIn this 24-week double-blind study, 1692 patients with stable COPD were equally randomized to twice-daily treatment with FDC aclidinium 400μg/formoterol 12μg (ACL400/FOR12 FDC), FDC aclidinium 400μg/formoterol 6μg (ACL400/FOR6 FDC), aclidinium 400μg, formoterol 12μg, or placebo administered by a multidose dry powder inhaler (Genuair®/Pressair®)*. Coprimary endpoints were change from baseline to week 24 in 1-hour morning postdose FEV1 (FDCs versus aclidinium) and change from baseline to week 24 in morning predose (trough) FEV1 (FDCs versus formoterol). Secondary endpoints were change from baseline in St. George’s Respiratory Questionnaire (SGRQ) total score and improvement in Transition Dyspnea Index (TDI) focal score at week 24. Safety and tolerability were also assessed.ResultsAt study end, improvements from baseline in 1-hour postdose FEV1 were significantly greater in patients treated with ACL400/FOR12 FDC or ACL400/FOR6 FDC compared with aclidinium (108 mL and 87 mL, respectively; p < 0.0001). Improvements in trough FEV1 were significantly greater in patients treated with ACL400/FOR12 FDC versus formoterol (45 mL; p = 0.0102), a numerical improvement of 26 mL in trough FEV1 over formoterol was observed with ACL400/FOR6 FDC. Significant improvements in both SGRQ total and TDI focal scores were observed in the ACL400/FOR12 FDC group at study end (p < 0.0001), with differences over placebo exceeding the minimal clinically important difference of ≥4 points and ≥1 unit, respectively. All treatments were well tolerated, with safety profiles of the FDCs similar to those of the monotherapies.ConclusionsTreatment with twice-daily aclidinium 400μg/formoterol 12μg FDC provided rapid and sustained bronchodilation that was greater than either monotherapy; clinically significant improvements in dyspnea and health status were evident compared with placebo. Aclidinium/formoterol FDC may be an effective and well tolerated new treatment option for patients with COPD.Trial registrationClinicaltrials.gov NCT01437397.*Registered trademarks of Almirall S.A., Barcelona, Spain; for use within the US as Pressair® and Genuair® within all other licensed territories.

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.

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

Long-term safety and efficacy of twice-daily aclidinium bromide in patients with COPD

BACKGROUND Aclidinium is a novel, long-acting muscarinic antagonist indicated for maintenance treatment of COPD. METHODS In this 52-week, parallel-group, double-blind study, patients with moderate-to-severe COPD were randomized (1:1) to receive aclidinium twice-daily (BID) 200 μg or 400 μg via a novel, dry powder inhaler (Genuair(®)/Pressair(®)) [Registered trademarks of Almirall, SA, Barcelona, Spain for use within the European Union, Iceland, Norway, and Switzerland as Genuair(®) and within the United States as Pressair(®)]. Safety, the primary objective, was assessed via adverse events (AEs), clinical laboratory tests, vital signs, and 12-lead electrocardiograms. Efficacy was evaluated using spirometry, SGRQ, and rescue medication use. RESULTS A total of 605 patients were randomized in the study. The percentage of patients reporting any treatment-emergent AE (TEAE) was comparable between groups; most TEAEs were mild or moderate. Anticholinergic TEAEs were reported by low percentages of patients in either treatment group (dry mouth: 200 μg, 1.3%; 400 μg, 2.7%; constipation: 200 μg, 2.9%; 400 μg, 1.7%). Cardiac TEAEs were also reported by a low percentage of patients (<2% for any event in any group) and did not appear to be dose dependent. There were no clinically relevant abnormalities in other safety outcomes. Both aclidinium 200 μg and 400 μg resulted in improvements from baseline to Week 52 in FEV1, with numerically greater increases observed with the higher dose. Clinically important improvements in SGRQ scores and a reduction in rescue medication use were observed throughout the study for both doses. CONCLUSIONS Long-term treatment with aclidinium 200 μg or 400 μg BID was well tolerated, with sustained benefits in lung function and health status in patients with COPD throughout the 1-year study.

Safety and pharmacokinetics of multiple doses of aclidinium bromide administered twice daily in healthy volunteers

Chronic obstructive pulmonary disease (COPD) is characterized by progressive airway obstruction and increased cholinergic tone. The global initiative for chronic obstructive lung disease (GOLD) guidelines recommend long-acting anticholinergics for COPD maintenance treatment. Aclidinium bromide is a novel, long-acting muscarinic antagonist developed for the treatment of COPD. A phase I, randomized, single-blind, multiple-dose clinical trial was conducted to assess the safety and pharmacokinetics (PK) of multiple doses of twice-daily (BID) aclidinium in healthy subjects. Thirty healthy male and female subjects received aclidinium 200 μg, 400 μg, 800 μg, or placebo twice daily for 7 days. Subjects were randomized to 1 of 3 cohorts and 10 subjects in each cohort were randomized (8:2) to either aclidinium or placebo groups. Safety was assessed via adverse events (AEs), laboratory evaluations, vital signs, and ECGs. Plasma samples were obtained at multiple time points throughout the study and analyzed for aclidinium and its inactive acid and alcohol metabolites using a fully validated method of liquid chromatography coupled with tandem mass spectrometry. A total of 9 treatment-emergent AEs were reported (1, placebo; 3, aclidinium 400 μg; 5, aclidinium 800 μg), all of which were mild in severity. No serious AEs were reported. There were no clinically meaningful changes in laboratory parameters or vital signs. PK parameters on Day 7 following BID dosing of aclidinium showed that steady state was achieved for aclidinium and its metabolites. On Days 1 and 7, maximum plasma concentrations (Cmax) of aclidinium were generally observed at the first PK time point (5 min postdose) and rapidly declined, with plasma concentrations generally less than 10% of Cmax by 6 h postdose in all aclidinium groups. Mean effective t(½) after the evening dose on Day 7 ranged from 4.6 to 7.0 h for aclidinium 400 μg and 800 μg, similar to the terminal t(½) observed on Day 1 (4.5-5.9 h). Exposure for aclidinium and both metabolites increased with increasing dose, with the increase in exposure being less than dose proportional between the 400 μg and 800 μg doses. Overall, all doses of aclidinium were safe and well tolerated throughout the study. Pharmacokinetic steady state was reached for aclidinium and both metabolites within the 7-day treatment period for all doses tested. Aclidinium bromide exhibited time-independent PK following dosing to steady state, indicating that similar concentration versus time profiles will occur after repeated administration at the same dose and frequency.