Efficacy and Safety of a 12-week Treatment with Twice-daily Aclidinium Bromide in COPD Patients (ACCORD COPD I) Efficacy and safety of twice-daily aclidinium bromide in COPD patients: the ATTAIN study Efficacy and safety of once-daily aclidinium in chronic obstructive pulmonary disease Efficacy and safety of fixed-dose combinations of aclidinium bromide/formoterol fumarate: the 24-week, randomized, placebo-controlled AUGMENT COPD study 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 Efficacy and safety of aclidinium bromide/formoterol fumarate fixed-dose combinations compared with individual components and placebo in patients with COPD (ACLIFORM-COPD): a multicentre, randomised study Preference, satisfaction and errors with two dry powder inhalers in patients with COPD Aclidinium bromide provides long-acting bronchodilation in patients with COPD. Bronchodilatory effects of aclidinium bromide, a long-acting muscarinic antagonist, in COPD patients. A randomised, placebo- and active-controlled dose-finding study of aclidinium bromide administered twice a day in COPD patients. Safety and pharmacokinetics of single doses of aclidinium bromide, a novel long-acting, inhaled antimuscarinic, in healthy subjects. Efficacy of aclidinium bromide 400 μg twice daily compared with placebo and tiotropium in patients with moderate to severe COPD. Onset of Effect of Aclidinium, a Novel, Long-Acting Muscarinic Antagonist, in Patients with COPD One-Year Extension Study of ACCORD COPD I: Safety and Efficacy of Two Doses of Twice-daily Aclidinium Bromide in Patients with COPD Activity of aclidinium bromide, a new long-acting muscarinic antagonist: a phase I study. Safety and pharmacokinetics of multiple doses of aclidinium bromide, a novel long-acting muscarinic antagonist for the treatment of chronic obstructive pulmonary disease, in healthy participants. Aclidinium bromide improves exercise endurance and lung hyperinflation in patients with moderate to severe COPD. ACCORD COPD II: A Randomized Clinical Trial to Evaluate the 12-Week Efficacy and Safety of Twice-Daily Aclidinium Bromide in Chronic Obstructive Pulmonary Disease Patients Aclidinium bromide, a long-acting antimuscarinic, does not affect QT interval in healthy subjects. Long-term safety and efficacy of twice-daily aclidinium bromide in patients with COPD. Peak inspiratory flow through the Genuair inhaler in patients with moderate or severe COPD.
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 r and omized ( 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. George 's Respiratory Question naire [ 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 r and omized . 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 clinical trials.gov ( NCT00891462 ) as “ Efficacy and Safety of Aclidinium Bromide for Treatment of Moderate to Severe Chronic Obstructive Pulmonary Disease ( COPD ) ” 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 r and omised 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 George 's Respiratory Question naire ; SGRQ ) and dyspnoea ( Transitional Dyspnoea Index ; TDI ) . Overall , 828 patients were r and omised . 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 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 , ACCL AIM / COPD I ( n = 843 ) and II ( n = 804 ) , patients were r and omised 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 Question naire ( SGRQ ) and time to first moderate or severe COPD exacerbation . Results At 12 and 28 weeks , aclidinium  improved trough FEV1 versus placebo in ACCL AIM / COPD I ( by 61 and 67 mL ; both p < 0.001 ) and ACCL AIM / 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 ACCL AIM / COPD I ( 48.1 % versus 39.5 % ; p = 0.025 ) and ACCL AIM / COPD II ( 39.0 % versus 32.8 % ; p = 0.074 ) . The time to first exacerbation was significantly delayed by aclidinium in ACCL AIM / COPD II ( hazard ratio [ HR ] 0.7 ; 95 % confidence interval [ CI ] 0.55 to 0.92 ; p = 0.01 ) , but not ACCL AIM / 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 Clinical Trials.gov : NCT00363896 ( ACCL AIM / COPD I ) and NCT00358436 ( ACCL AIM / COPD II ) Background Combining 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 . Methods In this 24-week double-blind study , 1692 patients with stable COPD were equally r and omized 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 ® )*. Co primary 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 Question naire ( SGRQ ) total score and improvement in Transition Dyspnea Index ( TDI ) focal score at week 24 . Safety and tolerability were also assessed . Results At 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 clinical ly 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 . Conclusions Treatment with twice-daily aclidinium 400μg/formoterol 12μg FDC provided rapid and sustained bronchodilation that was greater than either monotherapy ; clinical ly 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 registration Clinical trials.gov NCT01437397.*Registered trademarks of Almirall S.A. , Barcelona , Spain ; for use within the US as Pressair ® and Genuair ® within all other licensed territories Abstract Background : This r and omized , 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 question naire ) , and safety . Results : Overall , 414 patients were r and omized 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 Background Aclidinium/formoterol is a twice-daily ( BID ) fixed-dose combination ( FDC ) in development for chronic obstructive pulmonary disease ( COPD ) . The efficacy and safety of aclidinium/formoterol versus monotherapy and placebo in patients with COPD was assessed . Methods In this 24-week double-blind , parallel-group , active- and placebo-controlled , multicentre Phase III study , patients ( ≥40 years , post-bronchodilator forced expiratory volume in 1 second [FEV1]/forced vital capacity < 70 % and FEV1 ≥30 % but < 80 % predicted normal ) were r and omised 2:2:2:2:1 to aclidinium/formoterol 400/12 μg ( n = 385 ) or 400/6 μg ( n = 381 ) , aclidinium 400 μg ( n = 385 ) , formoterol 12 μg ( n = 384 ) or placebo ( n = 194 ) BID via Genuair ® /Pressair ® a . Results At Week 24 , aclidinium/formoterol 400/12 μg and 400/6 μg lead to significant improvements from baseline in 1-hour post-dose FEV1  versus aclidinium ( 125 mL [ 95 % CI : 90 , 160 ; p < 0 · 001 ] and 69 mL [ 95 % CI : 34 , 105 ; p < 0.001 ] , respectively ) and trough FEV1 versus formoterol ( 85 mL [ 95 % CI : 51 , 119 ; p < 0.001 ] and 53 mL [ 95 % CI : 19 , 87 ; p < 0.01 ] , respectively ; co- primary endpoints ) . Additionally , aclidinium/formoterol 400/12 μg and 400/6 μg provided significant improvements in Transition Dyspnoea Index ( TDI ) focal score versus placebo ( 1.29 units [ 95 % CI : 0.73 , 1.86 ; p < 0.001 ] and 1.16 units [ 95 % CI : 0.59 , 1.73 ; p < 0.001 ] , respectively ; secondary endpoint ) . All treatments were well tolerated , with safety profiles of the FDCs similar to those of placebo and monotherapy . Conclusions Both aclidinium/formoterol BID doses significantly improved bronchodilation versus monotherapy , and dyspnoea versus placebo , with no increase in safety risk . Aclidinium/formoterol may be an effective treatment for patients with COPD .Trial registration Clinical Trials.gov : NCT01462942 Objective : To assess preference , satisfaction and critical errors with a novel , breath-actuated , multi-dose dry powder inhaler ( DPI ; Genuair ® /Pressair ™ ) , versus a widely used , single-dose DPI ( H and iHaler ® ) in patients with moderate-to-severe chronic obstructive pulmonary disease . Methods : In this r and omised , open-label , multicentre , cross-over study , patients ( aged ≥ 40 years )  inhaled placebo once daily through both inhalers for 2 weeks in addition to current medication . The primary end point was percentage of patients who preferred Genuair to H and iHaler  . Overall patient satisfaction ( 5-point scale : 1 = very dissatisfied ; 5 = very satisfied ) , critical errors and willingness to continue using each inhaler ( 0 = not willing ; 100 = definitely willing ) were assessed . Results : Of 130 patients r and omised , 105 were included in the intent-to-treat population ( 71.4 % male ; mean age 65.7 years ) . After 2 weeks , significantly more patients preferred Genuair than H and iHaler ( 79.1 vs 20.9 % ; p < 0.0001 ) . Overall satisfaction scores ( 4.6 vs 3.8 ; p < 0.0001 ) and willingness to continue use scores ( 84.0 vs 62.5 ; p < 0.0001 ) were significantly higher with Genuair versus H and iHaler . Significantly fewer patients made ≥ 1 critical error  with Genuair only compared with H and iHaler only ( 2.9 vs 19.0 % ; p < 0.0001 ) . Conclusion : After 2 weeks ' practice , patients preferred and were more willing to continue using Genuair than H and iHaler . Genuair was associated with higher patient satisfaction and fewer critical errors  than H and iHaler Aclidinium bromide is a novel , long-acting , muscarinic antagonist in phase III development for the maintenance treatment of COPD . This phase IIb study investigated the efficacy and safety of aclidinium for the treatment of moderate to severe COPD to establish the optimal dose for phase III studies . A total of 464 patients with moderate to severe stable COPD were r and omised to double-blind , once-daily treatment with aclidinium ( 25 , 50 , 100 , 200 , or 400microg ) , placebo , or open-label tiotropium ( 18microg ) for 4 weeks . Spirometric measurements were performed at 22 - 24h after the first dose and then at weekly intervals , and from 0.5 to 6h post-dose on day 1 and day 29 . Compared with placebo , aclidinium 200microg and 400microg significantly increased trough FEV(1 ) on day 29 versus baseline . During the first 6h post-dose , the bronchodilatory effect of aclidinium ( all doses ) on day 1 was comparable to that on day 29 . Time to peak FEV(1 ) was 3h for aclidinium 100 - 400microg . Aclidinium was well tolerated , with no dose-dependent effect on ECG , laboratory parameters , or adverse events . The incidence of AEs was generally comparable to placebo . Aclidinium produced sustained bronchodilation over 24h and was well tolerated during this short-term study . Based on these data , aclidinium 200microg was selected as the investigational dose for future clinical trials in COPD 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 , r and omised , placebo-controlled , crossover study was conducted in patients with moderate to severe COPD ( forced expiratory volume in 1s [ FEV(1 ) ] < 65 % predicted ) . Patients were r and omly 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 This Phase IIb , double-blind , double-dummy , placebo- and active-comparator-controlled crossover study ( Clinical Trials.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 r and omised 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 r and omised 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 clinical ly 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 OBJECTIVE Aclidinium bromide is a novel antimuscarinic being developed for the treatment of chronic obstructive pulmonary disease . The objective of this Phase I study was to determine the maximum tolerated dose ( MTD ) as well as the tolerability , safety and pharmacokinetics of aclidinium in healthy subjects . MATERIAL S AND METHODS 16 healthy subjects were r and omized to receive 5 single ascending doses of aclidinium 600 - 6,000 microg or placebo inhaled via dry powder inhaler , with 7 day washouts . Safety measurements included adverse events ( AEs ) , physical examination , vital signs , pupillometry examination , clinical laboratory tests , and 12-lead electrocardiogram . Pharmacokinetic parameters of aclidinium and its metabolites were assessed . RESULTS The incidence of AEs was comparable between aclidinium and placebo at all doses . Most AEs were mild to moderate with no dose-related or anticholinergic/cardiac AEs . At doses > or= 2,400 microg , only 13 AEs were considered treatment related . Aclidinium ( 600 - 6,000 microg ) did not produce function-limiting or severe AEs in > or= 50 % of subjects ; hence , the prospect ively-defined MTD was not established . Aclidinium was rapidly converted in plasma into alcohol and carboxylic acid metabolites , and was no longer detectable after 3 hours post-dose for all doses . At lower doses , aclidinium was quantifiable only up to 1 hour post-dose in the majority of subjects . Maximum plasma concentrations for aclidinium were reached within 5 - 7 minutes ( all doses ) and declined rapidly . Mean elimination half-lives of aclidinium > 2,400 microg were approximately 1 hour . AUC and Cmax increased proportionately up to 4,800 microg . CONCLUSIONS Aclidinium appears to be safe and well tolerated in single doses of 600 - 6,000 microg 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 r and omized , 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 H and iHaler 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 r and omized , 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 clinical ly 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 Clinical Trials.gov ; No. : NCT00868231 ; URL : www . clinical trials.gov ABSTRACT Aclidinium bromide is a novel , long-acting , inhaled muscarinic antagonist in development for the treatment of chronic obstructive pulmonary disease ( COPD ) . The aim of this study was to assess the rate of onset of bronchodilation with aclidinium compared with placebo and tiotropium . This was a double-blind , double-dummy , multicenter , crossover study in COPD patients with a post-bronchodilator forced expiratory volume in 1 second ( FEV1 ) ≥30 % and < 60 % predicted . On study days , patients received single doses of aclidinium 200 μg , tiotropium 18 μg , or placebo . Serial spirometry was conducted from 10 minutes to 3 hours post-dose . The primary variable was the percentage of patients with an increase in FEV1 of ≥10 % above baseline at 30 minutes post-dose . Other assessment s included change from baseline in FEV1 and dyspnea over 3 hours post-dose . A total of 115 patients entered the study . Significantly more patients had an increase in FEV1 of ≥10 % above baseline at 30 minutes with aclidinium and tiotropium versus placebo ( 49.5 % and 51.8 % versus 13.8 % ; p < 0.0001 ) . At 30 minutes , the relative increase from baseline in FEV1 was significantly higher for aclidinium and tiotropium versus placebo ( 12 % and 11 % versus 3 % ; p < 0.0001 ) . Aclidinium and tiotropium  also significantly increased FEV1 ( p < 0.01 ) and improved the perception of dyspnea compared with placebo at all measured time points from 10 minutes to 3 hours post-dose . In conclusion , aclidinium  provided effective bronchodilation , similar to that seen with tiotropium , with significant improvements compared with placebo observed from 10 minutes post-dose Abstract This was a 52-week , double-blind , extension study in which COPD patients previously treated with twice-daily ( BID ) aclidinium bromide 200 μg or 400 μg during a 12-week lead-in study ( ACCORD COPD I ) continued the same treatment , while patients previously receiving placebo  were rer and omized ( 1:1 ) to aclidinium 200 μg or 400 μg BID . The primary objective of this study was to evaluate the long-term safety and tolerability of aclidinium  treatment . Efficacy outcomes included bronchodilation , health status , and rescue medication use . A total of 467 patients completed the lead-in study and 291 patients consented to participate in the extension . At study end , the percentages of patients who reported a treatment-emergent adverse event ( TEAE ) were similar for both treatments ( 200 μg , 77.4 % ; 400 μg , 73.7 % ) . Incidence of anticholinergic TEAEs was low and similar for both treatments , with dry mouth reported in only 1 patient ( 400 μg ) . Cardiac TEAEs were reported by a similarly low percentage of patients ( < 5 % for any event in any group ) with no apparent dose dependence . Improvements from baseline in lung function were greatest for patients who received continuous aclidinium treatment and those who were rer and omized from placebo to aclidinium 400 μg ; these improvements were generally sustained throughout the study . Health status and overall rescue medication use was improved from baseline for both treatments . The safety profile of twice-daily aclidinium and sustained improvements in lung function and health status throughout the 52-week extension study support its use as a long-term maintenance treatment for patients with COPD . ( Clinical trial registration number NCT00970268 ) AIM Aclidinium bromide is a muscarinic antagonist in development for the treatment of chronic obstructive pulmonary disease ( COPD ) . This phase I trial in healthy subjects investigated the bronchodilator activity of aclidinium and its ability to reduce methacholine-induced bronchoconstriction . METHODS This double-blind , partial-crossover study r and omized 12 subjects to treatment with single doses of aclidinium ( 50 , 300 or 600 microg ) or placebo .  Drug activity was assessed for 24 h after administration by specific airway conductance ( sGaw ) , airways resistance ( Raw ) and bronchial responsiveness ( PC35 sGaw methacholine ) . RESULTS Aclidinium significantly increased sGaw compared with placebo at all assessment s and doses ( sGaw mean + /- SD AUC ( l kPa(-1 ) h ) for placebo 24.4 + /- 4.37 , for 50 microg 29.0 + /- 7.08 , for 300 microg 31.2 + /- 6.68 and for 600 microg 32.7 + /- 7.95 ) ( P < 0.009 ) , except 50 microg at 1 and 24 h. Significant decreases in Raw were observed with aclidinium 300 and 600 microg compared with placebo at all assessment s ( Raw mean + /- SD AUC ( kPa s(-1 ) l(-1 ) h ) for placebo 7.7 + /- 3.46 , for 300 microg 5.8 + /- 2.33 , for 600 microg 6.3 + /- 3.11 ) ( P < 0.04 ) except 600 microg at 24 h. Differences between aclidinium 300 and 600 microg vs. placebo in PC35 doubling concentration were significant at all assessment s ( mean + /- SD AUC ( mg ml(-1 ) h ) for placebo 100.0 + /- 30.27 , for 50 microg 117.2 + /- 33.33 , for 300 microg 168.9 + /- 28.66 and for 600 microg 179.1 + /- 15.73 ( P < 0.0001 ) . For all endpoints , there was a significant difference between aclidinium 50 microg and the higher doses ( P < 0.0001 ) . Aclidinium was not detected in plasma and was well tolerated . CONCLUSION Aclidinium produced statistically significant and sustained bronchodilation over 24 h , suggesting long-acting efficacy and providing a rationale for future studies in patients with COPD Systemic exposure to anticholinergics used for chronic obstructive pulmonary disease ( COPD ) may lead to side effects . This study assessed safety , tolerability , and pharmacokinetics of multiple doses of aclidinium bromide , a novel , long-acting antimuscarinic . Sixteen healthy participants received aclidinium bromide 200 , 400 , or 800 microg or placebo by dry-powder inhaler for 5 days , with > or = 7 days washout . Aclidinium bromide and metabolite pharmacokinetics were assessed .  Aclidinium bromide plasma levels were below the lower limit of quantification ( LLOQ : 0.05 ng/mL ) after 200 microg and in most participants after 400 microg . Plasma levels in all participants were below the LLOQ at all doses , including the highest dose , beyond 1 hour postdose . AUC(0-t ) and C(max ) at steady state were , respectively , 0.08 ng.h/mL and 0.12 ng/mL ( aclidinium bromide ) , 0.40 ng.h/mL and 0.14 ng/mL ( alcohol metabolite ) , and 13.47 ng.h/mL and 2.26 ng/mL ( acid metabolite ) . The t(max ) for aclidinium bromide 800 microg was 15 minutes ( first kinetic time point ) . Adverse event frequency was comparable between treatment groups and placebo . The most commonly reported adverse events , probably treatment related , were coughing ( n = 2 ) and dysphagia ( n = 1 ) ; 94 % of adverse events were mild . These data suggest a low systemic bioavailability and favorable safety profile for aclidinium bromide with repeated dosing for COPD BACKGROUND Static and dynamic lung hyperinflation are associated with exercise impairment and poor outcomes in COPD patients .  Aclidinium bromide is a novel , long-acting inhaled muscarinic antagonist currently in development for COPD treatment . METHODS Patients with moderate to severe COPD ( N = 181 ) were r and omized to once-daily aclidinium 200 μg or placebo for 6 weeks . Constant work rate cycling exercises at 75 % of peak work rate were performed at baseline , Day 1 , Week 3 , and Week 6 . The primary efficacy measure was change in exercise endurance time ( ET ) from baseline to Week 6 . Secondary outcomes included changes in trough forced expiratory volume in 1 s ( FEV(1 ) ) , inspiratory capacity ( IC ) , IC/total lung capacity ( TLC ) , and functional residual capacity ( FRC ) from baseline to Day 1 , Week 3 , and Week 6 . Borg dyspnea scores during exercise , locus of symptom limitation , and safety measures were assessed . RESULTS Aclidinium significantly improved ET on Day 1 ( P = 0.0002 ) , and improvements were sustained through Week 3 ( P = 0.0007 ) and Week 6 ( P = 0.0042 ) vs placebo . Compared with placebo , aclidinium  improved trough FEV(1 ) , IC , and IC/TLC at Weeks 3 and 6 ( P < 0.05 for all ) . Exertional dyspnea scores at isotime were reduced on Day 1 , Week 3 , and Week 6 for aclidinium vs placebo ( P < 0.05 ) . Furthermore , the likelihood of stopping exercise due to breathing discomfort was lower in the aclidinium group at study end ( P = 0.0208 ) compared with placebo . No differences in safety outcomes were reported between treatments . CONCLUSIONS Aclidinium significantly increased exercise tolerance , improved airflow obstruction and lung hyperinflation , and was safe and well tolerated . REGISTRATION OF TRIAL : This trial was registered with Clinical Trials.gov ( NCT00500318 ) under the name " A Study of Exercise Endurance and Lung Hyperinflation in Patients with Moderate to Severe COPD " Background and Objectives Aclidinium bromide is a long-acting muscarinic antagonist approved for the long-term maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease ( COPD ) . This 12-week phase III study evaluated efficacy and tolerability of aclidinium 200 or 400 μg in patients with moderate-to-severe COPD . Methods In this double-blind study , 544 patients with COPD were r and omized to placebo or twice-daily aclidinium 200 or 400 μg administered by Genuair ® /Pressair ® . Lung function , health status [ measured by the St. George ’s Respiratory Question naire ( SGRQ ) ] , dyspnea [ measured using the Transition Dyspnea Index ( TDI ) ] , and safety were assessed throughout the study . Results Mean changes from baseline in morning trough forced expiratory volume in 1 s ( FEV1 ) at week 12 ( primary endpoint ) were significantly higher for aclidinium than for placebo ( 200 μg , 51 mL ; 400 μg , 72 mL ; both p < 0.05 ) . Aclidinium also significantly improved other lung function outcomes . At week 12 , improvements from baseline were observed with aclidinium  in SGRQ total score ( 200 μg , −6.0 ; 400 μg , −5.4 ) and TDI focal score ( 200 μg , 1.0 ; 400 μg , 1.3 ) . Furthermore , clinical ly important improvements in SGRQ total and TDI focal scores were achieved by 45 and 51 % of patients , respectively , who received aclidinium 400 μg , with a significant difference versus placebo for TDI ( p < 0.05 ) . Anticholinergic-related adverse events ( e.g. , dry mouth ) were infrequent , occurring < 2 % for any event in any treatment group . Both aclidinium doses were well tolerated . Conclusion This study demonstrates efficacy and safety  of aclidinium in COPD patients . Unexpected baseline imbalances between treatment groups may have impacted the aclidinium treatment benefit in this study 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 Bazett-corrected 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 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 r and omized ( 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 , Icel and , Norway , and Switzerl and 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 r and omized 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 clinical ly relevant abnormalities in other safety outcomes . Both aclidinium 200 μg and 400 μg result ed in improvements from baseline to Week 52 in FEV1 , with numerically greater increases observed with the higher dose . Clinical ly 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 The Genuair inhaler is a new multidose dry powder inhaler for the delivery of aclidinium bromide - a novel , long-acting , muscarinic antagonist in development for the treatment of chronic obstructive pulmonary disease ( COPD ) . The primary aim of this study was to assess the inspiratory flow characteristics through Genuair in patients with moderate or severe COPD . Using a three-period cross-over design , 48 patients were r and omised to inhale placebo powder through Genuair , H and iHaler A ( slow , deep inhalation as per manufacturer 's instructions ) or H and iHaler B ( fast , forceful inhalation ) . Three measurements of peak inspiratory flow ( PIF ) , 10min apart , were recorded for each method of administration . The highest and average PIFs for the three attempts ( mean+/-st and ard deviation ) generated through the Genuair inhaler were 97.7+/-15.7 and 92.0+/-15.4L/min , respectively . Furthermore , 97 % of inhalations with the Genuair inhaler were successful ( activation of trigger threshold mechanism ) and optimal ( PIF > or = 45L/min ) . The highest and average PIFs generated through H and iHaler A and B were significantly lower than with the Genuair inhaler . In conclusion , patients with moderate or severe COPD were able to generate sufficient inspiratory airflow through the Genuair inhaler to reliably inhale the full dose and reset the inhaler
BACKGROUND Bronchodilators are the mainstay for symptom relief in the management of stable chronic obstructive pulmonary disease ( COPD ) .
Aclidinium bromide is a new long-acting muscarinic antagonist ( LAMA ) that differs from tiotropium by its higher selectivity for M3 muscarinic receptors with a faster onset of action .
However , the duration of action of aclidinium is shorter than for tiotropium .
It has been approved as maintenance therapy for stable , moderate to severe COPD , but its efficacy and safety in the management of COPD is uncertain compared to other bronchodilators .
OBJECTIVES To assess the efficacy and safety of aclidinium bromide in stable COPD .