Dataset Information

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

ABSTRACT:

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, 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 George's Respiratory Questionnaire (SGRQ) and time to first moderate or severe COPD exacerbation.

Results

At 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.

Conclusion

Aclidinium is effective and well tolerated in patients with moderate to severe COPD.

Trial registration

ClinicalTrials.gov: NCT00363896 (ACCLAIM/COPD I) and NCT00358436 (ACCLAIM/COPD II).

SUBMITTER: Jones PW

PROVIDER: S-EPMC3098801 | biostudies-literature | 2011 Apr

REPOSITORIES: biostudies-literature

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Publications

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

Jones Paul W PW Rennard Stephen I SI Agusti Alvar A Chanez Pascal P Magnussen Helgo H Fabbri Leonardo L Donohue James F JF Bateman Eric D ED Gross Nicholas J NJ Lamarca Rosa R Caracta Cynthia C Gil Esther Garcia EG

Respiratory research 20110426

<h4>Background</h4>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).<h4>Methods</h4>In 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 c ...[more]

PMID: 21518460

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Project description:IntroductionWe report the results of the first direct comparison of the once-daily fixed-dose long-acting muscarinic antagonist/long-acting β2-agonist (LAMA/LABA) combinations umeclidinium/vilanterol (UMEC/VI) and tiotropium/olodaterol (TIO/OLO) in patients with COPD.MethodsThis was a randomized, two-period crossover open-label study in symptomatic patients with COPD [age 40 years or older, postbronchodilator forced expiratory volume in 1 s (FEV1) of 70% or less and 50% or more of predicted normal values, and modified Medical Research Council Dyspnoea Scale score of 2 or greater] not receiving inhaled corticosteroid therapy. Patients were randomized to receive UMEC/VI (62.5/25 µg once daily) via a multidose dry powder inhaler (ELLIPTA) followed by TIO/OLO (5/5 µg once daily) via a soft mist inhaler (Respimat), each for 8 weeks with an interim 3-week washout or vice versa. The primary end point was the change from baseline in trough FEV1 at week 8 with a noninferiority margin of - 50 mL in the per-protocol (PP) population. The incidence of adverse events was also assessed.ResultsIn total, 236 patients (mean age 64.4 years, 60% male) were included in the intent-to-treat population and 227 were included in the PP population. UMEC/VI treatment was noninferior in the PP population and superior in the intent-to-treat population to TIO/OLO treatment with regard to trough FEV1 at week 8 [FEV1 change from baseline 180 mL vs 128 mL; difference 52 mL (95% confidence interval 28-77 mL); p < 0.001]. Patients receiving UMEC/VI had twofold increased odds of experiencing a clinically meaningful increase (100 mL or more) from baseline in trough FEV1 at week 8 compared with patients receiving TIO/OLO (odds ratio 2.05; 95% confidence interval 1.34-3.14). Adverse events occurred in 25% of patients in the UMEC/VI group and in 31% of patients in the TIO/OLO group.ConclusionIn this first direct comparison of two once-daily fixed-dose LAMA/LABA combinations, superiority was observed for the primary end point of trough FEV1 at week 8 with UMEC/VI compared with TIO/OLO in patients with symptomatic COPD. Both treatments had similar safety profiles. These findings confirm the results of previous indirect LAMA/LABA comparisons, and show that an efficacy gradient exists within the LAMA/LABA class.Trial registrationClinicalTrials.gov identifier NCT02799784.FundingGlaxoSmithKline.

Project description:Background'Clinically important deterioration' (CID) is a composite endpoint measuring worsening of the key clinical features of chronic obstructive pulmonary disease (COPD), namely lung function, patient-reported outcomes, and exacerbations. ACLIFORM and AUGMENT were two 24-week, randomized, double-blind, phase III studies assessing twice-daily (BID) aclidinium bromide (AB) 400 μg/formoterol fumarate (FF) 12 μg. This pooled post-hoc analysis assessed the effects of AB/FF 400/12 μg on both first and sustained CID events versus placebo and monotherapies in patients with moderate to severe COPD.MethodsA first CID event was defined as the occurrence of a moderate/severe exacerbation or the worsening from baseline in ≥1 of the following: trough forced expiratory volume in 1 second (FEV1; ≥100 mL), Transition Dyspnea Index (TDI) focal score (≥1 unit), or St George's Respiratory Questionnaire (SGRQ) total score (≥4 units). A 'sustained' CID was defined as a worsening maintained at all subsequent visits from appearance to week 24 or a moderate/severe exacerbation at any time. CID events were assessed at three visits (weeks 4, 12, and 24); trough FEV1 was also measured at weeks 1 and 18.ResultsAB/FF 400/12 μg reduced the risk of a first CID event by 45% versus placebo (hazard ratio [HR] 0.55, p < 0.001), 18% versus FF 12 μg (HR 0.82, p < 0.01), and 15% versus AB 400 μg (HR 0.85, p < 0.05). Similarly, AB/FF 400/12 μg reduced the risk of a sustained CID event by 48% versus placebo (HR 0.52, p < 0.001) and 22% versus FF 12 μg (HR 0.78, p < 0.01). AB/FF 400/12 μg reduced the risk of a first or sustained CID event for all four components versus placebo (trough FEV1 and TDI, first and sustained CID, all p < 0.001; SGRQ first CID p < 0.001; SGRQ sustained CID, p < 0.01; exacerbations first and sustained CID, both p < 0.05) and TDI and SGRQ versus FF 12 μg (TDI, first and sustained CID both p < 0.05; SGRQ first CID p < 0.01), and SGRQ versus AB 400 μg (first CID, p < 0.05).ConclusionsAB/FF 400/12 μg BID may provide greater airway stability and fewer exacerbations or deteriorations in lung function, health status, or dyspnea compared with placebo or monotherapies.Trial registrationClinicaltrials.gov NCT01462942 (ACLIFORM); registered 26 October 2011. Clinicaltrials.gov NCT01437397 (AUGMENT); registered 19 September 2011.

Project description:PurposeIn the absence of head-to-head clinical trials comparing the once-daily, long-acting beta2-agonists olodaterol and indacaterol for the treatment of chronic obstructive pulmonary disease (COPD), an indirect treatment comparison by systematic review and synthesis of the available clinical evidence was conducted.MethodsA systematic literature review of randomized, controlled clinical trials in patients with COPD was performed to evaluate the efficacy and safety of olodaterol and indacaterol. Network meta-analysis and adjusted indirect comparison methods were employed to evaluate treatment efficacy, using outcomes based on trough forced expiratory volume in 1 second (FEV1), Transition Dyspnea Index, St George's Respiratory Questionnaire total score and response, rescue medication use, and proportion of patients with exacerbations.ResultsEighteen trials were identified for meta-analysis (eight, olodaterol; ten, indacaterol). Olodaterol trials included patients of all severities, whilst indacaterol trials excluded patients with very severe COPD. Concomitant maintenance bronchodilator use was allowed in most olodaterol trials, but not in indacaterol trials. When similarly designed trials/data were analyzed for change from baseline in trough FEV1 (liters), the following mean differences (95% confidence interval) were observed: trials excluding concomitant bronchodilator: indacaterol 75 mcg versus olodaterol 5 mcg, -0.005 (-0.077 to 0.067), and indacaterol 150 mcg versus olodaterol 5 mcg, 0.020 (-0.036 to 0.077); trials with concomitant tiotropium: indacaterol 150 mcg versus olodaterol 5 mcg, 0.000 (-0.043 to 0.042). In sensitivity analyses of the full network, results for change from baseline in trough FEV1 favored indacaterol, but this dataset suffered from trial design heterogeneity. For the other endpoints investigated, no statistically significant differences were found when analyzed in the full network.ConclusionWhen compared under similar trial conditions, olodaterol and indacaterol have similar efficacy in patients with COPD. This research highlights the importance of considering the concomitant COPD medication when evaluating treatment effects in COPD.

Project description:PurposeChronic obstructive pulmonary disease (COPD) exacerbations are associated with increased risk of major adverse cardiovascular events (MACE) and mortality. Here, we investigate whether the safety and efficacy of aclidinium bromide differ due to exacerbation history in patients with COPD and increased cardiovascular risk.Patients and methodsASCENT-COPD was a Phase 4, multicenter, double-blind, randomized, placebo-controlled, parallel-group study of patients with moderate-to-very severe COPD and increased cardiovascular risk. Patients were randomized 1:1 to receive aclidinium or placebo twice daily for up to 3 years. Outcomes included time to first MACE and all-cause mortality over 3 years, exacerbation rate during the first year on-treatment, and change in baseline pre-dose forced expiratory volume in 1 second (FEV1) over 3 years. This pre-specified subgroup analysis compared outcomes in patients receiving aclidinium vs placebo. The comparison of patients with vs without an exacerbation history was added following a protocol amendment to increase enrollment in the primary study.ResultsOf 3589 patients, 2156 (60.1%) had ≥1 moderate or severe exacerbations in the prior year, compared with 1433 (39.9%) without prior exacerbations. Although patients with an exacerbation history had numerically higher rates of MACE and mortality regardless of treatment, aclidinium did not increase risk of MACE (≥1: hazard ratio [HR] 0.79, 95% confidence interval [CI]: 0.54-1.16; none: HR 1.27, 95% CI: 0.65-2.47; interaction P=0.233) or all-cause mortality (≥1: HR 1.08, 95% CI: 0.81-1.43; none: HR 0.66, 95% CI: 0.36-1.22; interaction P=0.154), regardless of exacerbation history. Aclidinium reduced the exacerbation rate vs placebo irrespective of exacerbation history (≥1: rate ratio [RR] 0.80, 95% CI: 0.68-0.94; none: RR 0.69, 95% CI: 0.54-0.89; interaction P=0.340) and improved FEV1 (interaction P=0.633).ConclusionIn patients with moderate-to-very severe COPD and increased cardiovascular risk, aclidinium did not increase risk of MACE or mortality and reduced exacerbation rate vs placebo, regardless of exacerbation history.Clinical trial registrationClinicalTrials.gov Identifier: NCT01966107.

Dataset Information

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

Background

Methods

Results

Conclusion

Trial registration

Publications

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

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