Dataset Information

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.

ABSTRACT:

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 randomised 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

ClinicalTrials.gov: NCT01462942.

SUBMITTER: Singh D

PROVIDER: S-EPMC4273456 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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Publications

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.

Singh Dave D Jones Paul W PW Bateman Eric D ED Korn Stephanie S Serra Cristina C Molins Eduard E Caracta Cynthia C Gil Esther Garcia EG Leselbaum Anne A

BMC pulmonary medicine 20141118

<h4>Background</h4>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.<h4>Methods</h4>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 capaci ...[more]

PMID: 25404569

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Project description: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 400 μg/formoterol 12 μg (ACL400/FOR12 FDC), FDC aclidinium 400 μg/formoterol 6 μg (ACL400/FOR6 FDC), aclidinium 400 μg, formoterol 12 μg, 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 400 μg/formoterol 12 μg 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.

Project description:BackgroundThe combination of aclidinium bromide, a long-acting anticholinergic, and formoterol fumarate, a long-acting beta2-agonist (400/12 μg twice daily) achieves improvements in lung function greater than either monotherapy in patients with chronic obstructive pulmonary disease (COPD), and is approved in the European Union as a maintenance treatment. The effect of this combination on symptoms of COPD and exacerbations is less well established. We examined these outcomes in a pre-specified analysis of pooled data from two 24-week, double-blind, parallel-group, active- and placebo-controlled, multicentre, randomised Phase III studies (ACLIFORM and AUGMENT).MethodsPatients ≥40 years with moderate to severe COPD (post-bronchodilator forced expiratory volume in 1 s [FEV1]/forced vital capacity <70 % and FEV1 ≥30 % but <80 % predicted normal) were randomised (ACLIFORM: 2:2:2:2:1; AUGMENT: 1:1:1:1:1) to twice-daily aclidinium/formoterol 400/12 μg or 400/6 μg, aclidinium 400 μg, formoterol 12 μg or placebo via Genuair™/Pressair®. Dyspnoea (Transition Dyspnoea Index; TDI), daily symptoms (EXAcerbations of Chronic pulmonary disease Tool [EXACT]-Respiratory Symptoms [E-RS] questionnaire), night-time and early-morning symptoms, exacerbations (Healthcare Resource Utilisation [HCRU] and EXACT definitions) and relief-medication use were assessed.ResultsThe pooled intent-to-treat population included 3394 patients. Aclidinium/formoterol 400/12 μg significantly improved TDI focal score versus placebo and both monotherapies at Week 24 (all p < 0.05). Over 24 weeks, significant improvements in E-RS total score, overall night-time and early-morning symptom severity and limitation of early-morning activities were observed with aclidinium/formoterol 400/12 μg versus placebo and both monotherapies (all p < 0.05). The rate of moderate or severe HCRU exacerbations was significantly reduced with aclidinium/formoterol 400/12 μg compared with placebo (p < 0.05) but not monotherapies; the rate of EXACT-defined exacerbations was significantly reduced with aclidinium/formoterol 400/12 μg versus placebo (p < 0.01) and aclidinium (p < 0.05). Time to first HCRU or EXACT exacerbation was longer with aclidinium/formoterol 400/12 μg compared with placebo (all p < 0.05) but not the monotherapies. Relief-medication use was reduced with aclidinium/formoterol 400/12 μg versus placebo and aclidinium (p < 0.01).ConclusionsAclidinium/formoterol 400/12 μg significantly improves 24-hour symptom control compared with placebo, aclidinium and formoterol in patients with moderate to severe COPD. Furthermore, aclidinium/formoterol 400/12 μg reduces the frequency of exacerbations compared with placebo.Trial registrationNCT01462942 and NCT01437397 (ClinicalTrials.gov).

Project description:Aclidinium-formoterol 400/12 µg is a long-acting muscarinic antagonist (LAMA) and a long-acting ?2-agonist in a fixed-dose combination used in the management of patients with COPD. This study aimed to assess the cost-effectiveness of aclidinium-formoterol 400/12 µg against the long-acting muscarinic antagonist aclidinium bromide 400 µg.A five-health-state Markov transition model with monthly cycles was developed using MS Excel to simulate patients with moderate-to-severe COPD and their initial lung-function improvement following treatment with aclidinium-formoterol 400/12 µg or aclidinium 400 µg. Health states were based on severity levels defined by Global Initiative for Chronic Obstructive Lung Disease 2010 criteria. The analysis was a head-to-head comparison without step-up therapy, from the NHS Scotland perspective, over a 5-year time horizon. Clinical data on initial lung-function improvement were provided by a pooled analysis of the ACLIFORM and AUGMENT trials. Management, event costs, and utilities were health state-specific. Costs and effects were discounted at an annual rate of 3.5%. The outcome of the analysis was expressed as cost (UK£) per quality-adjusted life-year (QALY) gained. The analysis included one way and probabilistic sensitivity analyses to investigate the impact of parameter uncertainty on model outputs.Aclidinium-formoterol 400/12 µg provided marginally higher costs (£41) and more QALYs (0.014), resulting in an incremental cost-effectiveness ratio of £2,976/QALY. Sensitivity analyses indicated that results were robust to key parameter variations, and the main drivers were: mean baseline forced expiratory volume in 1 second (FEV1), risk of exacerbation, FEV1 improvement from aclidinium-formoterol 400/12 µg, and lung-function decline. The probability of aclidinium-formoterol 400/12 µg being cost-effective (using a willingness-to-pay threshold of £20,000/QALY) versus aclidinium 400 µg was 79%.In Scotland, aclidinium-formoterol 400/12 µg can be considered a cost-effective treatment option compared to aclidinium 400 µg alone in patients with moderate-to-severe COPD.

Project description:ObjectiveChronic obstructive pulmonary disease (COPD) is mainly treated pharmaceutically with bronchodilators. The purpose of this study was to evaluate the clinical benefits of two-times-per-day aclidinium bromide (Acli-BID) compared with once-a-day tiotropium bromide hydrate (Tio-QD) in patients with COPD.DesignThis study was a multicentre, open-label, randomised study.SettingFourcentres in Kagawa prefecture, Japan.ParticipantPatients who were diagnosed to have COPD Grade 2-3 according to the Global Initiative for Chronic Obstructive Lung Disease 2015 criteria were enrolled.InterventionsPatients were randomly assigned to receive Acli-BID or Tio-QD at a 1:1 ratio, and followed for 8 weeks. Acli-BID was administered in the morning and night, and Tio-QD was administered in the night.Primary and secondary outcome measuresPrimary outcome was forced expiratory volume in one second area under the curve (FEV1AUC0-3), and secondary outcomes were pulmonary function, physical activity, St George's Respiratory Questionnaire (SGRQ), modified Medical Research Council (mMRC), the 8-item Short-Form Health Survey (SF-8) and COPD exacerbations. Adverse events were evaluated during the study.Results44 patients were included in this study. FEV1AUC0-3 at week 8 was 4.62±1.43 L·hour in Acli-BID and 4.73±1.60 L·hour in Tio-QD (mean difference (MD) -0.11 L·hour; 95% CI), -1.04 to 0.83). Significant improvement was observed in activity-related subscales of SGRQ (MD -7.78; 95% CI -14.61 to -0.94) and SF-8 (MD 4.01; 95% CI 0.37 to 7.65), mMRC (MD -0.66; 95% CI -1.19 to -0.13) and rate ratio (0.52, 95% CI 0.27 to 0.99) of exacerbations in the Acli-BID compared with the Tio-QD. Acli-BID and Tio-QD significantly improved sedentary behaviour (MD -35.20 min; 95% CI -67.41 to -2.94 and MD -55.40 min; 95% CI -98.15 to -12.77) within each group, but there was no significant difference between the two groups.ConclusionAcli-BID as with Tio-QD could be one of the therapeutic options for patients with COPD to improve pulmonary function. Also, our results suggest that intervention with bronchodilators enhanced physical activity in patients with COPD.Trial registration numberUMIN 000020020.

Project description:BackgroundLABA (long-acting β2-agonists) and/or LAMA (long-acting muscarinic antagonists) represent the first treatment options for patients with symptomatic COPD. Although both display different mechanisms of activity, in combination they have a stronger broncho-dilating effect than monotherapy; hence, a combination of both LABA and LAMA is particularly recommended for patients whose symptoms cannot be sufficiently improved by a single active ingredient. To date, only few data have been collected regarding the therapeutic outcomes of approved LABA/LAMA fixed-dose combinations (FDCs) under everyday (real-life) conditions in non-clinical trial settings.Objective and methodsThe main objective of the DETECT study was to investigate the impact of aclidinium/formoterol (AB/FF, b.i.d.), glycopyrronium/indacaterol (GLY/IND, q.d.) and umeclidinium/vilanterol (UME/VL, q.d.) in patients with COPD in daily clinical practice. Therefore, a prospective, non-randomized, 12-month, observational study was implemented to assess the effectiveness of these treatments in patients who had been switched to FDC within the last 3 months or for whom such a changeover was intended. Changes in lung function were analyzed by the forced expiratory volume (FEV1) and forced vital capacity (FVC) measures. Quality of life and well-being were evaluated by the COPD Assessment Test (CAT™). Furthermore, a number of exacerbations and early morning COPD symptoms were documented.ResultsIn total, 3653 patients were enrolled. FEV1 and FVC values significantly improved during the study with AB/FF (increase by 0.09 ± 0.40 L and 0.10 ± 0.57 L, respectively; p<0.0001), GLY/IND (0.06±0.38/0.05±0.51 L; p<0.0001 and p=0.0025) and UME/VL (0.12±0.39/0.10±0.52 L; p<0.0001). CAT scores decreased indicating improved COPD (AB/FF, 4.17±8.30; GLY/IND, 3.66±7.88; UME/VL, 4.06±7.96; p<0.0001). Moreover, the number of exacerbations as well as early morning COPD symptoms similarly diminished in all treatment groups. A comparable proportion of patients with adverse drug reactions was recorded: AB/FF, 4.07% of patients; GLY/IND, 3.52%; UME/VL, 3.64%.ConclusionIn summary, AB/FF, GLY/IND and UME/VL provided clinical benefits in lung function, quality of life and early morning COPD symptoms in a broad cohort of COPD patients under routine medical practice conditions. All three treatments were well tolerated.

Project description:In patients with chronic obstructive pulmonary disease (COPD) who experience further exacerbations or symptoms, despite being prescribed dual long-acting muscarinic antagonist (LAMA)/long-acting β2-agonist (LABA) or inhaled corticosteroid (ICS)/LABA therapies, triple ICS/LAMA/LABA therapy is recommended. A previous network meta-analysis showed comparable efficacy of the ICS/LAMA/LABA, budesonide/glycopyrronium bromide/formoterol fumarate (BUD/GLY/FOR) 320/18/9.6 µg, to other fixed-dose and open combination triple therapies at 24 weeks in COPD. Subsequently, the ETHOS study was published, including data for 8509 patients, assessing the efficacy and safety of BUD/GLY/FOR over 52 weeks. This network meta-analysis (NMA) was conducted to compare the relative efficacy, safety, and tolerability of BUD/GLY/FOR 320/18/9.6 µg with other fixed-dose and open combination triple therapies in COPD over 52 weeks, including data from ETHOS. A systematic literature review was conducted to identify ≥ 10-week randomized controlled trials, including ≥ 1 fixed-dose or open combination triple-therapy arm, in patients with moderate-to-very severe COPD. The methodologic quality and risk of bias of included studies were assessed. Study results were combined using a three-level hierarchical Bayesian NMA model to assess efficacy and safety outcomes at or over 24 and 52 weeks. Meta-regression and sensitivity analyses were used to assess heterogeneity across studies. Nineteen studies (n = 37,741 patients) met the inclusion criteria of the review; 15 contributed to the base case network. LAMA/LABA dual combinations were combined as a single treatment group to create a connected network. Across all outcomes for exacerbations, lung function, symptoms, health-related quality of life, safety, and tolerability, the efficacy and safety of BUD/GLY/FOR were comparable to those of other triple ICS/LAMA/LABA fixed-dose (fluticasone furoate/umeclidinium/vilanterol and beclomethasone dipropionate/glycopyrronium bromide/formoterol fumarate) and open combinations at or over 24 and 52 weeks. Sensitivity analyses and meta-regression results for exacerbation outcomes were broadly in line with the base case NMA. In this NMA, BUD/GLY/FOR 320/18/9.6 μg showed comparable efficacy versus other ICS/LAMA/LABA fixed-dose or open combination therapies in terms of reducing exacerbation rates and improving lung function, symptoms and health-related quality of life in patients with moderate-to-very-severe COPD, in line with previously published meta-analysis results of triple combinations in COPD. The safety and tolerability profile of BUD/GLY/FOR was also found to be comparable to other triple combination therapies.

Dataset Information

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.

Background

Methods

Results

Conclusions

Trial registration

Publications

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.

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