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Phase III study of the long-term safety of aclidinium bromide/formoterol fumarate.
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Patients randomized to BID aclidinium 400 μg/formoterol 12 μg or formoterol 12 μg.
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Aclidinium/formoterol was well tolerated and similar to monotherapy.
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The safety profile was consistent with that seen in two Phase III studies.
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Lung function was improved versus monotherapy and sustained over one year.
Abstract
Trial design
This was a one-year, Phase III randomized, double-blind, parallel-group, active-control study investigating the long-term safety and tolerability of twice-daily aclidinium 400 μg/formoterol 12 μg versus formoterol 12 μg.
Methods
Eligible patients were male or female, current or ex-smokers (history of ≥10 pack-years) aged ≥40 years with a diagnosis of moderate to severe chronic obstructive pulmonary disease (COPD): post-bronchodilator forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) ratio <70%, and post-bronchodilator FEV1≥30% and <80% predicted. Patients were randomized 2:1 to twice-daily aclidinium 400 μg/formoterol 12 μg or formoterol 12 μg, administered via a multidose dry powder inhaler (Genuair™/Pressair®)1. The objective was to evaluate the one-year safety of aclidinium 400 μg/formoterol 12 μg versus formoterol 12 μg.
Results
All 590 patients were included in the safety population; 392 patients received aclidinium 400 μg/formoterol 12 μg and 198 patients received formoterol 12 μg. Of these, 581 patients were included in the intent-to-treat (ITT) population (385 patients received aclidinium 400 μg/formoterol 12 μg; 196 patients received formoterol 12 μg). In the safety population, the percentage of patients with ≥1 treatment-emergent adverse event was similar between aclidinium 400 μg/formoterol 12 μg (71.4%) and formoterol 12 μg (65.7%). Mean baseline post-bronchodilator FEV1 was 51.3% of predicted (ITT population). Aclidinium 400 μg/formoterol 12 μg significantly improved morning pre-dose (trough) FEV1 and trough FVC versus formoterol 12 μg at each assessment, with improvements at Week 1 (least squares mean difference [LSMD]: 87.4 mL and 157.8 mL, respectively) maintained at study end (LSMD: 81.5 mL and 185.4 mL, respectively).
Conclusions
Aclidinium 400 μg/formoterol 12 μg was well tolerated, with a safety profile similar to formoterol 12 μg and consistent with that seen in two Phase III studies. Additionally, aclidinium 400 μg/formoterol 12 μg improved lung function versus formoterol 12 μg, with a sustained effect over one year.
Bronchodilators, including long-acting β2-agonists (LABAs) and long-acting muscarinic antagonists (LAMAs), are mainstays in the treatment of moderate to severe chronic obstructive pulmonary disease (COPD) [
]. LABAs are thought to modulate cholinergic neurotransmission by acting on prejunctional β2-adrenoreceptors to decrease the release of acetylcholine, thereby leading to smooth muscle relaxation and bronchodilation [
]. LAMAs influence the adrenergic system at the post-synaptic level by blocking the muscarinic receptors targeted by acetylcholine, thereby reducing acetylcholine binding and amplifying the bronchodilation induced by the LABA [
As patients with moderate to severe COPD typically require long-term, chronic therapy, treatments must not only be effective, but safe and well tolerated to ensure treatment adherence. Fixed-dose combinations of two bronchodilators with complementary mechanisms of action may improve lung function, dyspnea, health status, and patient adherence without significantly increasing the risk of adverse events compared with monotherapy [
]. While fixed-dose combination treatments combining a LABA with an inhaled corticosteroid (ICS) have been widely used, LAMAs, until recently, have only been available as monotherapy [
]. A fixed-dose combination of a LABA plus a LAMA may provide a valuable therapeutic option.
Twice-daily aclidinium bromide is a LAMA that provides significant and persistent bronchodilation compared with placebo, and has been shown to reduce dyspnea and improve health-related quality of life in patients with 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.
]. Formoterol fumarate, a LABA that improves bronchodilation with a rapid onset (<5 min) and a sustained duration of action (≥12 h), also improves dyspnea [
]. The recent approval of a fixed-dose combination of aclidinium 400 μg and formoterol 12 μg for maintenance bronchodilator treatment to relieve symptoms in patients with COPD in the European Union was supported by results from two 24-week, Phase III trials, in which a fixed-dose combination of aclidinium 400 μg and formoterol 12 μg provided rapid and sustained bronchodilation with a positive safety profile [
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/formoterol fumarate fixed-dose combinations compared with individual components and placebo in patients with COPD (ACLIFORM-COPD): a multicentre, randomised study.
The objective of this study was to evaluate the one-year safety and tolerability of aclidinium 400 μg/formoterol 12 μg compared with formoterol 12 μg monotherapy in patients with moderate to severe COPD.
2. Methods
2.1 Ethical conduct & study design
This study was conducted in compliance with the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) guidelines and the US Food and Drug Administration (FDA) guidelines for good clinical practice, and in accordance with the ethical principles originating from the Declaration of Helsinki and the US FDA Code of Federal Regulations Title 21, section 312.120. All enrolled participants provided voluntary, written informed consent and Health Insurance Portability and Accountability Act (HIPAA) authorization prior to study participation. The institutional review boards of all participating centers approved all study materials. There were no important changes to the methods or trial outcomes after trial commencement.
This Phase III, parallel-group, active-control study (NCT01437540) was conducted to fulfill FDA safety requirements and comprised a 2–3-week run-in period, 52-week double-blind treatment period, and a follow-up phone call 4 weeks after the last treatment dose. Patients from 127 centers in the US were randomized 2:1 to aclidinium 400 μg/formoterol 12 μg or formoterol 12 μg monotherapy administered twice daily, once in the morning and once in the evening, via a multidose dry powder inhaler (Genuair™/Pressair®).
Registered trademarks of the AstraZeneca group of companies, for use within the USA as Pressair® and as Genuair™ within all other licensed territories.
Randomization was carried out by assigning patient identification numbers via an interactive web response system provided by Premier Research Group Limited (East Hartford, Connecticut, USA).
2.2 Patients
Eligible patients were male and female current or ex-smokers (history of ≥10 pack-years) aged ≥40 years with a diagnosis of moderate to severe COPD: post-bronchodilator forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) ratio <70%, and post-bronchodilator FEV1≥30% and <80% predicted.
Patients were not eligible if they had any respiratory infection or COPD exacerbation ≤6 weeks before screening; pulmonary rehabilitation within 3 months of screening or an intention to start during the trial; clinically significant cardiovascular conditions, including myocardial infarction ≤6 months; newly diagnosed arrhythmia ≤3 months; unstable angina; unstable arrhythmia that had required changes in pharmacological therapy or other interventions ≤6 months; use of an automated implantable cardioverter-defibrillator; history of thoracic surgery ≤1 year of screening; hospitalization ≤12 months for heart failure (New York Heart Association [NYHA] class III) or history of thoracic surgery ≤1 year of screening and NYHA class IV [
]; QTcB >470 ms at rest; or body mass index≥40 kg/m2.
2.3 Concomitant medications
Patients were permitted treatment with albuterol as needed, but not within 6 h before a visit. ICS and oral or parenteral corticosteroids at doses ≤10 mg/day, theophylline and H1-antihistamine were permitted for chronic use provided the dosage was stable for ≥4 weeks prior to screening and throughout the trial. Chronic use of oxygen therapy was permitted for up to 15 h/day provided the dosage was stable for ≥4 weeks prior to screening. Indacaterol was not allowed within 15 days prior to screening or during the trial. Select β1-blocking agents (atenolol, metoprolol, nebivolol) were permitted for chronic use if the dosage was stable for ≥2 weeks prior to screening.
2.4 Outcomes and analyses
Safety evaluations included treatment-emergent adverse events (TEAEs) and serious AEs (SAEs) that occurred or worsened on or after the date of the first dose of double-blind treatment and within 30 days of the last dose. Major adverse cardiac events (MACE) were evaluated and classified according to the criteria prespecified by three blinded independent expert cardiologists not participating in the study. MACE were expressed as a composite of the total cardiovascular deaths, non-fatal myocardial infarction, and non-fatal stroke. Clinical hematology, biochemical, and urinalysis parameters, vital signs, and electrocardiograms (ECGs) were evaluated. Although COPD exacerbation was an efficacy endpoint of the study, it was not collected as an AE; however, the number and percentage of patients experiencing a COPD exacerbation are reported.
As long-term safety and tolerability of aclidinium 400 μg/formoterol 12 μg was the primary objective of the trial, all efficacy outcomes were pre-defined as additional endpoints: change from baseline in morning pre-dose (trough) FEV1 and FVC at Weeks 1, 12, 24, 38, and 52; change from baseline in total daily rescue medication use over the 52-week treatment period; and rate of COPD exacerbations (defined as an increase in COPD symptoms that required a change in COPD treatment) per patient per year.
Originally, 450 patients were to be randomized, as it was considered sufficient to meet the safety objectives of the study and to obtain long-term safety data for regulatory requirements; it was not based on statistical power to meet an efficacy objective. AEs were summarized descriptively. Statistical analyses comparing the baseline demographics and characteristics and incidence of AEs between groups were not part of the pre-planned analyses; however, they were performed post-hoc. A mixed-effects model for repeated measures (MMRM) was used to analyze lung function and rescue medication use in the intent-to-treat (ITT) population (all randomized patients who received ≥1 dose of study medication and had a baseline and ≥1 post-baseline FEV1 assessment). The change from baseline in trough FEV1/FVC was analyzed using an MMRM, with corresponding baseline, pre- and post-bronchodilator (albuterol) FEV1/FVC, and age as covariates, and treatment group, visit, sex, smoking status, and treatment group-by-visit interaction as fixed-effect factors. The change from baseline in rescue medication used was analyzed using an MMRM, with the baseline rescue medication used as a covariate, and treatment group, visit and treatment group-by-visit interaction as factors. The rate of COPD exacerbations per patient per year was analyzed using a negative binomial regression model with age as a covariate and treatment group, sex, smoking status, baseline ICS use, and baseline COPD severity as factors in the ITT-exacerbation population (all randomized patients who took ≥1 dose of study medication).
3. Results
3.1 Patient disposition, demographics and clinical characteristics
Data were collected between September 2011 and March 2013. The safety population comprised 392 patients allocated to the aclidinium 400 μg/formoterol 12 μg group and 198 patients allocated to the formoterol 12 μg group; 581 patients were included in the ITT population (385 in the aclidinium 400 μg/formoterol 12 μg group and 196 in the formoterol 12 μg group; Fig. 1). Similar percentages of patients completed treatment in each group (aclidinium 400 μg/formoterol 12 μg, 67.6%; formoterol 12 μg, 67.2%), with discontinuations balanced between treatments. The most common reasons for discontinuation were consent withdrawal (aclidinium 400 μg/formoterol 12 μg, 7.9%; formoterol 12 μg, 7.6%), discontinuation due to an AE (6.6% and 7.1%, respectively), and protocol violation (6.1% for both). Mean baseline FEV1 was similar between groups: 1.35 L in the aclidinium 400 μg/formoterol 12 μg group compared with 1.26 L in the formoterol 12 μg group. Baseline FVC was balanced between treatment arms, with a mean of 2.62 L in the aclidinium 400 μg/formoterol 12 μg group and 2.54 L in the formoterol 12 μg group. The percentage of patients with ≥1 exacerbation in the previous 12 months was 22.7 for the aclidinium 400 μg/formoterol 12 μg group compared with 26.3 in the formoterol 12 μg group. Other baseline demographics and characteristics were also similar between groups (Table 1).
Stage II (moderate): FEV1/FVC <0.70 and 50% ≤ FEV1<80% predicted; Stage III (severe): FEV1/FVC <0.70 and 30% ≤ FEV1<50% predicted; 2 patients were classified as Stage 1 (mild), 4 were Stage IV (severe), and data were missing for 2 patients.
a For continuous variables, a t-test was performed.
b For categorical variables, a chi-square test was performed.
c Stage II (moderate): FEV1/FVC <0.70 and 50% ≤ FEV1<80% predicted; Stage III (severe): FEV1/FVC <0.70 and 30% ≤ FEV1<50% predicted; 2 patients were classified as Stage 1 (mild), 4 were Stage IV (severe), and data were missing for 2 patients.
d Post-bronchodilator test at screening (Visit 1).
e Where 25% of values were less than 5 with a categorical variable, a Fisher’s exact test was performed.
f ITT population: aclidinium 400 μg/formoterol 12 μg, n = 385; formoterol 12 μg, n = 196.
The percentage of patients reporting any TEAE was numerically greater with aclidinium 400 μg/formoterol 12 μg (71.4%) than formoterol 12 μg (65.7%). Most events were mild or moderate in intensity. TEAEs reported by at least 3% of patients in either treatment group are presented in Table 2. Urinary tract infection, anxiety, and cough were the only potential anticholinergic or β2-agonist AEs reported by >5% of patients in either treatment group. Anxiety was recorded by aclidinium 400 μg/formoterol 12 μg-treated patients with an incidence of at least 3% and twice that of formoterol 12 μg (aclidinium 400 μg/formoterol 12 μg, 5.9%; formoterol 12 μg, 2.5%). Conversely, TEAEs that occurred in formoterol 12 μg-treated patients with an incidence of at least 3% and twice that of aclidinium 400 μg/formoterol 12 μg were: dyspnea (aclidinium 400 μg/formoterol 12 μg, 1.8%; formoterol 12 μg, 4.5%), nausea (1.8% and 5.6%, respectively), constipation (1.5% and 3.5%, respectively), diarrhea (1.5% and 4.0%, respectively) and gastroesophageal reflux disease (1.0% and 3.5%, respectively). There were no changes in urinary retention and changes in laboratory parameters, including liver and renal function, were generally small and deemed to be not clinically relevant by the study investigator.
Table 2Treatment-emergent adverse events (≥3% in either treatment group; safety population).
Events leading to discontinuation were low in both treatment groups, with similar proportions of patients withdrawing due to an AE (aclidinium 400 μg/formoterol 12 μg, 6.6%; formoterol 12 μg, 7.1%). In patients treated with aclidinium 400 μg/formoterol 12 μg, ventricular tachycardia was the most commonly reported TEAE that resulted in discontinuation (n = 2, 0.5%). In addition, there were two cases (0.5%) of sudden death (discussed below). For those treated with formoterol 12 μg, two patients (1.0%) discontinued due to dyspnea. Similar proportions of patients reported an SAE (aclidinium 400 μg/formoterol 12 μg, 9.7%; formoterol 12 μg, 10.6%). The most common SAE, pneumonia, was reported by four patients (1.0%) treated with aclidinium 400 μg/formoterol 12 μg and by one patient (0.5%) treated with formoterol 12 μg; all of the patients recovered and none of the events were considered related to treatment. No other SAE was reported by more than three patients (≥0.5%) in either treatment group. One patient in the aclidinium 400 μg/formoterol 12 μg group with a history of hypertension and myocardial infarction experienced severe ventricular tachycardia on Day 152 and recovered from the event on Day 153.
A total of six deaths occurred during treatment or within 30 days after the last dose of study medication. Five patients (1.3%) treated with aclidinium 400 μg/formoterol 12 μg died; adjudicated causes of death were sudden cardiac death of unknown etiology (n = 2), suicide (n = 1), metastatic lung cancer (n = 1), and cardiopulmonary arrest (n = 1). One patient (0.5%) treated with formoterol 12 μg died due to a COPD exacerbation. No deaths were considered related to study medication by the investigator.
The overall incidence of MACE was low, with a total of three patients (0.5% in each group) experiencing at least one MACE. In the aclidinium 400 μg/formoterol 12 μg treatment group, two patient deaths initially reported as ‘cause unknown’ or ‘death unexplained’ were later adjudicated to ‘sudden cardiac death.’ In the formoterol 12 μg group, one patient experienced a nonfatal stroke. No nonfatal myocardial infarctions occurred during the study.
Compared with baseline, no clinically relevant changes in clinical hematology, biochemical and urinalysis parameters, vital signs, or ECGs were attributed to aclidinium 400 μg/formoterol 12 μg fixed-dose combination.
3.3 COPD exacerbations
Similar percentages of patients in the aclidinium 400 μg/formoterol 12 μg group (27.3%) and the formoterol 12 μg group (29.8%) reported at least one COPD exacerbation. The proportion of patients who experienced moderate or severe exacerbations was numerically lower in the aclidinium 400 μg/formoterol 12 μg group (25.3%) than in the formoterol 12 μg group (27.8%), with the majority of exacerbations reported as moderate in intensity (81.3%). The rates of moderate or severe exacerbations were 0.52 for the aclidinium 400 μg/formoterol 12 μg group and 0.49 for the formoterol 12 μg group. Binomial regression showed no statistically significant between-groups differences in the rate of moderate or severe exacerbations (p = 0.7741); however, the study was not powered to detect between-groups statistical differences for exacerbations.
3.4 Lung function
At Week 1 (first time point assessed), significant improvements in trough FEV1 from baseline were observed with aclidinium 400 μg/formoterol 12 μg compared with formoterol 12 μg (least squares mean difference [LSMD] 87.4 mL; 95% confidence interval [CI] 57.6, 117.2; p < 0.001). These improvements were maintained over 52 weeks of treatment until study end (LSMD 81.5 mL, 95% CI 12.5, 150.5; p < 0.05). Over the course of the study, LS mean improvements ranged from 47.5 mL to 147.6 mL for aclidinium 400 μg/formoterol 12 μg and from 50.0 mL to 81.5 mL for formoterol 12 μg compared with baseline (Fig. 2).
Fig. 2Change from baseline in morning pre-dose (trough) FEV1(ITT population). Analyses are based on an MMRM for change from baseline in trough FEV1 with corresponding baseline, pre- and post-bronchodilator (albuterol) FEV1, and age as covariates, and treatment group, visit, sex, smoking status, and treatment group-by-visit interaction as fixed-effect factors. Restricted maximum likelihood method was used. *p < 0.05 vs formoterol 12 μg; error bars represent standard error of the mean. AB/FF 400/12 μg, aclidinium bromide 400 μg/formoterol fumarate 12 μg; FEV1, forced expiratory volume in 1 s; FF 12 μg, formoterol fumarate 12 μg; ITT, intent-to-treat; LS, least squares; MMRM, mixed-effects model for repeated measures.
From Week 1, aclidinium 400 μg/formoterol 12 μg significantly improved trough FVC from baseline compared with formoterol 12 μg (LSMD 157.8 mL; 95% CI 102.6, 213.0; p < 0.001). These improvements were maintained for 52 weeks until study end (LSMD 146.1 mL; 95% CI 52.4, 239.8; p < 0.01). Over the course of the study, improvements ranged from 117.8 mL to 208.3 mL for aclidinium 400 μg/formoterol 12 μg and from 25.2 mL to 91.5 mL for formoterol 12 μg compared with baseline (Fig. 3).
Fig. 3Change from baseline in morning pre-dose (trough) FVC (ITT population). Analyses are based on an MMRM for change from baseline in trough FVC with corresponding baseline, pre- and post-bronchodilator (albuterol) FVC and age as covariates, and treatment group, visit, sex, smoking status, and treatment group-by-visit interaction as fixed-effect factors. Restricted maximum likelihood method was used. *p < 0.05 vs formoterol 12 μg; error bars represent standard error of the mean. AB/FF 400/12 μg, aclidinium bromide 400 μg/formoterol fumarate 12 μg; FF 12 μg, formoterol fumarate 12 μg; FVC, forced vital capacity; ITT, intent-to-treat; LS, least squares; MMRM, mixed-effects model for repeated measures.
Compared with baseline, total daily rescue medication use (albuterol hydrofluoroalkane, 108 μg per puff was the only rescue medication permitted during the study) was significantly reduced in both groups (p < 0.001; Fig. 4). At each visit over the 52-week study period, patients in the aclidinium 400 μg/formoterol 12 μg group required numerically less rescue medication than those in the formoterol 12 μg group.
Fig. 4Change from baseline in total daily rescue medication use (ITT population). Analysis is based on change from baseline in overall daily average rescue medications use using an MMRM with terms for treatment, visit, and treatment-by-visit interaction as factors and baseline rescue medication use as a covariate. ***p < 0.0001 vs baseline; error bars represent standard error of the mean. AB/FF 400/12 μg, aclidinium bromide 400 μg/formoterol fumarate 12 μg; FF 12 μg, formoterol fumarate 12 μg; ITT, intent-to-treat; LS, least squares; MMRM, mixed-effects model for repeated measures.
Results from this year-long, double-blind, active-comparator study suggest that the fixed-dose combination of aclidinium 400 μg/formoterol 12 μg is both well tolerated and effective for the long-term treatment of moderate to severe COPD. Overall, the safety profile of aclidinium 400 μg/formoterol 12 μg after 52 weeks of treatment was similar to that of formoterol 12 μg monotherapy and to the safety profile observed in two 24-week Phase III placebo-controlled trials [
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/formoterol fumarate fixed-dose combinations compared with individual components and placebo in patients with COPD (ACLIFORM-COPD): a multicentre, randomised study.
], supporting the combined use of bronchodilators with complementary mechanisms of action without increasing the risk for adverse events compared with monotherapy [
Though a slightly greater proportion of patients treated with aclidinium 400 μg/formoterol 12 μg reported TEAEs compared with formoterol 12 μg-treated patients, most events were mild or moderate in intensity. In general, SAEs, AEs leading to discontinuation, and MACE were balanced across treatment arms. Furthermore, the general safety profile was similar to other fixed-dose combination LAMA/LABA treatments (e.g. umeclidinium/vilanterol and tiotropium/olodaterol) observed during one-year trials in patients with COPD [
Safety and tolerability of once-daily umeclidinium/vilanterol 125/25 mcg and umeclidinium 125 mcg in patients with chronic obstructive pulmonary disease: results from a 52-week, randomized, double-blind, placebo-controlled study.
]. While the frequency of pneumonia was greater in patients treated with aclidinium 400 μg/formoterol 12 μg (1%) compared with formoterol 12 μg (0.5%), half of these patients were receiving concomitant ICS and no cases were considered related to study drug. No conclusion could be drawn from this finding due to the small number of patients reporting this event. Similar findings have been reported in the short-term ACLIFORM 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.
Efficacy and safety of fixed-dose combinations of aclidinium bromide/formoterol fumarate: the 24-week, randomized, placebo-controlled AUGMENT COPD study.
]. These results are also similar to those observed in long-term studies of umeclidinium/vilanterol, with a frequency of 2% for the combination, 5% for umeclidinium monotherapy, and 2% for placebo, and with half of affected patients receiving concomitant ICS [
Safety and tolerability of once-daily umeclidinium/vilanterol 125/25 mcg and umeclidinium 125 mcg in patients with chronic obstructive pulmonary disease: results from a 52-week, randomized, double-blind, placebo-controlled study.
]. While rates of SAEs were not reported in the long-term study of tiotropium/olodaterol, the AE of pneumonia was reported in each treatment group for 2.3%–3.5% of patients treated with either tiotropium/olodaterol or its monotherapy components [
]. The rate of deaths (1.3% in aclidinium 400 μg/formoterol 12 μg; 0.5% in formoterol 12 μg) did not emerge as a signal in this long-term 52-week study. No deaths were considered related to treatment by the investigator, and the rate of deaths was similar to other 52-week trials of patients with moderate to severe COPD [
Safety and tolerability of once-daily umeclidinium/vilanterol 125/25 mcg and umeclidinium 125 mcg in patients with chronic obstructive pulmonary disease: results from a 52-week, randomized, double-blind, placebo-controlled study.
]. For example, in a 52-week long study comparing tiotropium and olodaterol combination to its monotherapy components, the treatment groups had fatality rates between 1.2% and 1.7%, suggesting that the 1.3% rate observed with aclidinium 400 μg/formoterol 12 μg aclidinium/formoterol may be typical of this patient population [
As no pharmacological treatments have been shown to modify the progressive decline in lung function in patients with COPD, effective treatments should reduce the risk of exacerbations. In this trial, in which patients were randomized 2:1 to aclidinium 400 μg/formoterol 12 μg or formoterol 12 μg, the percentage of patients who experienced moderate or severe exacerbations was numerically lower in the aclidinium 400 μg/formoterol 12 μg group compared with the formoterol 12 μg group; the rate of moderate or severe exacerbations was similar between groups. Additionally, treatment differences are potentially difficult to detect when all patients have been randomized to active treatment with no placebo comparison. Further work would be necessary to fully elucidate the effects of aclidinium 400 μg/formoterol 12 μg on exacerbations in patients with COPD.
Improvements in lung function among patients treated with aclidinium 400 μg/formoterol 12 μg exceeded those of patients treated with formoterol 12 μg monotherapy, with significantly greater improvements in both trough FEV1 and FVC from Week 1 (first time point assessed) through Week 52 (study end). Compared with baseline, patients treated with aclidinium 400 μg/formoterol 12 μg experienced improvements in trough FEV1 that exceeded the minimum clinically important difference (MCID) of 100 mL. Compared with formoterol 12 μg, improvements in trough FEV1 with aclidinium 400 μg/formoterol 12 μg were 48–87 mL greater than formoterol 12 μg monotherapy. In addition, although improvements with aclidinium 400 μg/formoterol 12 μg compared with monotherapy did not reach the 100 mL threshold for MCID, it may be unreasonable to expect combination therapy to provide additive effects, making the concept of MCID less useful when comparing combination therapy with monotherapy [
The limitations of this study are typical of randomized controlled trials in that the results seen here may not be generalizable to the COPD patient population as a whole. Furthermore, because all patients in this study were assigned to active treatment, it is not possible to fully assess the long-term safety of aclidinium 400 μg/formoterol 12 μg compared with placebo; however, short-term studies were conducted for this comparison and the active comparator here may be a more rigorous standard for demonstrating efficacy [
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/formoterol fumarate fixed-dose combinations compared with individual components and placebo in patients with COPD (ACLIFORM-COPD): a multicentre, randomised study.
There are numerous potential advantages of combination therapy for COPD. Clinical experience with combinations of complementary drugs (whether taken in parallel or as a fixed-dose combination) has indicated an improvement in efficacy with two drugs over one [
]. Combination therapy may have a decreased risk for AEs compared with increasing doses of monotherapy, and LAMA/LABA combinations may be particularly beneficial for patients with COPD due to the reciprocal influences of cholinergic and adrenergic systems at pre-synaptic and post-synaptic level [
]. Furthermore, although the use of LABAs is associated with β2-adrenergic-specific effects (headache, cough, muscle spasms, and hypertension) and the use of LAMAs is associated with anticholinergic-related side effects (oropharyngeal pain and dry mouth), a pooled analysis of three studies has found no evidence to suggest that combining aclidinium 400 μg with formoterol 12 μg increases the incidence of these or any other AEs compared with the monotherapies [
]. Moreover, the safety profile of the combination of aclidinium 400 μg with formoterol 12 μg in this study was found to be comparable with the well-established safety profile of formoterol monotherapy [
], further reinforcing the tolerability of the combined treatment.
In conclusion, aclidinium 400 μg/formoterol 12 μg was well tolerated, with a safety profile generally similar to that of formoterol 12 μg monotherapy. Twice-daily aclidinium 400 μg/formoterol 12 μg administered as a fixed-dose combination via a single inhaler improved lung function, with a sustained effect over a one-year period, and diminished rescue medication use compared with formoterol 12 μg monotherapy. The safety profile and efficacy of the fixed-dose combination comprising aclidinium 400 μg/formoterol 12 μg supports its use as a potential long-term therapeutic option for patients with moderate to severe COPD.
Author contributions
JD and WS participated in the study and contributed to the analysis and interpretation of data. XW, PS, and AL contributed to the design of the study and analysis and interpretation of data. All authors were involved in the creation and critical review of the manuscript and provided approval of the final manuscript.
Conflicts of interest
JFD has served on an advisory board for Forest Research Institute, Inc. for an FDA advisory committee, presented data in an educational video, and received an honorarium and has received travel expenses from Forest Research Institute, Inc. for presentations at national and international meetings and at CHEST. JFD has served as a Consultant/Advisor for AstraZeneca, Boehringer Ingelheim, Forest, GlaxoSmithKline, Meda, Mylan, Novartis, and Sunovion. WS received research funding for this study from Forest Research Institute, Inc., and has received research funding from Genentech, AstraZeneca, Teva, Merck, Novartis, Sanofi, Stallergens, Circassia, Regeneron, Pfizer, Symbio, and Amgen; he has received speaking fees from Genentech, Teva, and Meda and consulting fees from Regeneron and Teva.
XW and PS are employees of Forest Laboratories LLC, a wholly owned subsidiary of Allergan plc. AL was an employee of Almirall S.A. at the time the study was conducted and is currently an employee of AstraZeneca PLC.
This work has been presented, in part, at the American Thoracic Society International Conference, May 16–21, 2014, in San Diego, CA, and at the European Respiratory Society International Congress, September 6–10, 2014, in Munich, Germany.
Trial registration
Safety and Tolerability of Aclidinium Bromide/Formoterol Fumarate Compared With Formoterol Fumarate in Patients With Moderate to Severe Chronic Obstructive Pulmonary Disease (LAC); NCT01437540.
Funding information
This study and the development of this manuscript was supported by Forest Laboratories LLC, a wholly owned subsidiary of Allergan plc, New York, NY, USA, and by Almirall S.A., Barcelona, Spain.
Role of funders
This study was supported by Forest Laboratories LLC, a wholly owned subsidiary of Allergan plc, and by Almirall S.A. Both funders were involved in the study design, and collection, analysis and interpretation of the data. The development of this manuscript was supported by Forest Laboratories, LLC; the decision to submit the manuscript for publication was made jointly by the funders and authors.
Acknowledgments
Medical writing and editing was provided by Mary Clare Kane, PhD, and Kristen A. Andersen, PhD, of Prescott Medical Communications Group (Chicago, IL, US), funded by Forest Laboratories LLC, a wholly owned subsidiary of Allergan plc (Jersey City, NJ, USA), and by Richard Knight, PhD, of Complete Medical Communications (Macclesfield, UK), funded by the AstraZeneca group of companies.
References
Global Initiative for Chronic Obstructive Lung Disease
Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease.
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.
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/formoterol fumarate fixed-dose combinations compared with individual components and placebo in patients with COPD (ACLIFORM-COPD): a multicentre, randomised study.
Safety and tolerability of once-daily umeclidinium/vilanterol 125/25 mcg and umeclidinium 125 mcg in patients with chronic obstructive pulmonary disease: results from a 52-week, randomized, double-blind, placebo-controlled study.
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