Discussion
An FDC comprising bronchodilators with complementary mechanisms of action may improve lung function, while offering patients the convenience of drug delivery via a single device without increasing the risk for adverse events [
20]. Though the interaction between LAMAs and LABAs has not been definitively determined, LABAs have been shown to enhance the bronchodilatory effect of LAMAs through a decrease in acetylcholine transmission that leads to a reduction in bronchoconstriction, while LAMAs amplify the effect of LABAs by blocking the muscarinic receptors targeted by acetylcholine, resulting in further bronchodilation [
3],[
21],[
22]. Thus, a fixed-dose combination of a LAMA and LABA is an important therapeutic option, providing patients with more convenient drug delivery and the potential for improved compliance.
In this trial, treatment with the LAMA/LABA fixed dose combination of aclidinium/formoterol FDC 400/12μg for 24 weeks resulted in statistically significant and clinically meaningful improvements for the coprimary measures of lung function: 1-hour morning postdose FEV1 versus aclidinium monotherapy (contribution of formoterol) and morning trough FEV1 versus formoterol (contribution of aclidinium).
The coprimary endpoints in the AUGMENT COPD study reported here reflect FDA guidance regarding fixed-dose combination drugs (ie, each component of the fixed-dose combination must make a contribution to the claimed effects [
23]). One aspect behind the rationale for combining aclidinium and formoterol for this FDC was the difference in time course for effective bronchodilation between the two drugs. Formoterol was expected to provide a rapid onset of action while the contribution of aclidinium was expected to occur over many hours (at trough) [
11],[
24]. The trial was thus powered to detect differences in the prespecified coprimary endpoint comparisons: 1-hour morning postdose FEV
1 for the FDCs versus aclidinium (to observe the early contribution of formoterol) and trough FEV
1 for the FDCs versus formoterol (to observe the contribution of aclidinium over many hours). Any other comparisons for these outcomes were considered supportive in nature.
At study end, the aclidinium/formoterol 400/12μg FDC provided an additional 45 mL in trough FEV1 from baseline (contribution of aclidinium), while the contribution of formoterol to the FDC (aclidinium/formoterol FDC 400/12μg versus aclidinium) was 28 mL, indicating that aclidinium provided greater bronchodilation. Results for trough FEV1 over the course of the study support the endpoint observation that the contribution of formoterol as a component of the FDC was smaller than that of aclidinium. Additionally, trough FEV1 values for both FDCs were numerically greater than aclidinium at all timepoints throughout the study, a result that is supportive of the observation that the FDCs provide greater bronchodilation than either monotherapy component alone.
Throughout the study, improvements in lung function with aclidinium/formoterol FDC 400/12μg, which were numerically greater than those with aclidinium/formoterol FDC 400/6μg, were generally similar to the results observed in a similarly designed study (ACLIFORM COPD) [
25]. Results from this trial also demonstrate rapid bronchodilation with aclidinium/formoterol FDC treatment (within 5 minutes of dosing) that was sustained and clinically meaningful in patients with COPD. Both aclidinium/formoterol FDCs had safety profiles generally similar to that of each monotherapy, though there were a numerically greater percentage of FDC- and aclidinium-treated patients who experienced any AE compared with those treated with formoterol. The incidence of MACE was comparable among all active treatment groups. Together, these results indicate that treatment with a fixed-dose combination of aclidinium/formoterol achieves a level of bronchodilation greater than either monotherapy component and is well-tolerated in patients with moderate to severe COPD. The therapeutic benefits on lung function derived from treatment with the aclidinium/formoterol FDCs exceeded the recommended MCID of 100 mL in 1-hour morning postdose FEV
1 versus placebo and were consistently significantly greater than those of the monotherapies. These improvements were observed from the first timepoint assessed until the end of the study, demonstrating sustained bronchodilation throughout 24 weeks of treatment.
Onset of bronchodilation (>15% increase from baseline in FEV
1) with aclidinium/formoterol FDC 400/12μg was observed as early as 5 minutes after the first dose, similar to that of formoterol–a LABA known to have a fast onset of action [
26]. The improved efficacy with the aclidinium/formoterol LAMA/LABA combination over the monotherapy components and placebo may be attributed to complementary pharmacodynamic profiles of these 2 bronchodilators: direct bronchodilation by the β
2-agonist, formoterol, provides rapid onset of action, while reduction in bronchoconstriction by the antimuscarinic, aclidinium, prolongs duration of bronchodilation [
24],[
27]. As rapid onset of effect has been associated with better patient compliance [
28],[
29], the onset of action observed with the aclidinium/formoterol FDCs may have a positive effect on medication adherence in clinical practice.
Although spirometric outcomes are important in assessing airflow obstruction in patients with COPD, clinical measures of health status have been shown to correlate better with symptoms such as breathlessness [
30],[
31] one of the most troublesome symptoms of the disease that often contributes to limitations in patients’ activities [
30]-[
32]. Following 24 weeks of treatment, improvements in SGRQ total score exceeded the MCID over placebo in patients treated with either aclidinium/formoterol FDC 400/12μg or aclidinium monotherapy. Patients treated with aclidinium/formoterol FDC 400/12μg also experienced improvements in TDI focal score that exceeded the MCID over placebo. Compared with placebo, a significantly greater percentage of aclidinium/formoterol FDC 400/12μg and 400/6μg-treated patients reached the MCID for both SGRQ and TDI at all study visits. These results support the clinical benefit of aclidinium/formoterol FDCs in improving health status and in reducing breathlessness, important treatment goals for the effective management of COPD [
32].
A recently published review of the applicability of MCIDs in COPD trials outlines numerous challenges when comparing combination therapies to monotherapy [
33]. The authors indicate that improvements in various outcome measures with combination therapy over monotherapy should not be expected to exceed those of monotherapy over placebo or to produce a result that would reach an MCID. Further, the authors suggest that MCIDs or responder rates derived from trials comparing a single active agent to placebo may not be applicable to combination therapy trials in which the comparison is to each monotherapy component. It is not surprising that the observed differences between monotherapy and placebo are often greater than the differences between combination therapy and the monotherapy components [
34]. To describe the additional proportion of patients who may experience improvements at or above the MCID following the addition of one active treatment to another, the concept of a “minimum worthwhile incremental advantage” has been proposed [
33]. In light of the caveats inherent in combination versus monotherapy trials, as well as the recognition that patients may experience advantages with combination therapy that are not readily measurable by certain outcome criteria, it is reasonable to conclude that the improvements in lung function and symptoms observed with the aclidinium/formoterol FDCs over each monotherapy in this trial may have clinical benefits for the moderate to severe COPD patient.
Due to the circadian nature of cholinergic tone, more impaired lung function is observed in the evening versus daytime in patients with COPD [
35]. This in turn may be related to the prevalence of sleep disturbance in a majority of patients with COPD [
36],[
37], as well as reports of nighttime and early morning being the worst times of day for COPD patients due to breathlessness and other symptoms [
38]. Twice-daily aclidinium has been shown to significantly improve lung function at night compared with once-daily tiotropium [
8], while other twice-daily COPD medications, including formoterol, reportedly improve nighttime symptoms [
39]-[
42]. In the trial reported here, aclidinium/formoterol FDCs significantly reduced both nighttime and early morning symptoms compared with placebo-measured by the newly developed NiSCI and EMSCI patient reported outcome measures-while treatment with the monotherapy components generally did not reach statistical significance in these outcomes. The disparity between nighttime symptoms outcomes with aclidinium monotherapy in this trial with those in a previously conducted study [
43] could be due to the manner in which nighttime symptoms were evaluated as both the NiSCI and the EMSCI are currently undergoing empirical testing.
As the current study demonstrated that aclidinium/formoterol administered in the morning significantly improves bronchodilation as rapidly as 5 minutes postdose, the evening dose of this twice-daily treatment may also alleviate impaired airflow at night and reduce breathlessness, potentially providing the added benefit of improving COPD symptoms when they are at their worst. Further analyses are necessary to correlate the clinically meaningful treatment effect of the aclidinium/formoterol FDCs on lung function with the positive effects on COPD symptoms.
Competing interests
AD has received research, consulting, and lecturing fees from Forest Laboratories, GlaxoSmith Kline, Sepracor, Merck Canada, Schering Plough, Novartis Canada/USA, Altana, Boehringer Ingelheim Canada, Methapharm, Pfizer Canada, AstraZeneca, Skye Pharma, Ono Pharma, and Kos Pharmaceuticals. SR has served as a consultant or participated in advisory boards for ABIM, Able Associates, Adelphi Research, Almirall, APT, Aradigm, Argenta, AstraZeneca, BI (ACCP), Biostrategies, BoomCom, Britnall and Nicolini, Capital Research, Chiesi, Clinical Advisors, CommonHealth, Complete Medical Group, Consult Complete, COPDForum, DataMonitor, Decision Resources, Defined Health, Dey, Dunn Group, Easton Associates, Enterprise Analysis, Equinox, Forest, Fulcrum, Gerson Lehman, GSK, Guidepoint, Hoffman LaRoche, IMS, Informed, Inspire, Insyght, KOL Connection, Leerink Swan, M. Pankove, MDRx Financial, MedaCorp, Medimmune, Mpex, Novartis, Nycomed, Oriel, Otsuka, Pearl, Pennside Partners, Pfizer, Pharma Ventures, Pharmaxis, Pick Research, Prescott, Price Waterhouse, Propagate, Pulmatrix, Pulmonary Reviews, Quadrant, Reckner Associates, Recruiting Resource, Reviews and Trends in COPD/Convergent Health Solutions, Roche, Sacoor, Schering, Schlesinger Medical, Scimed, Smith Research, Sudler and Hennessey, Talecris, Theravance, UBC, Uptake Medical, and Vantage Point. He has received lecture fees from AAAAI, Am Col Osteopathic Physicians, Asan Medical Center, ATS, AstraZeneca, California Soc Allergy, Convergent Health Solutions for Reviews and Trends in COPD, COPDFoundation, Creative Educational Concepts, Dey, Duke, France Foundation, Information TV, University of California-Los Angeles, Network for Continuing Education, Novartis, Nycomed, Otsuka, Pfizer, Sarasota Mem Hospital, Spanish Thoracic Society, University of Washington, University of Alabama-Birmingham, University of Pittsburgh, University of British Columbia, University of California-Davis, VA Sioux Falls. He has received industry-sponsored grants from AstraZeneca, Biomarck, Centocor, GlaxoSmithKline, Mpex, Nabi, Novartis, Otsuka, and Pfizer. Peter M.A. Calverley has given presentations at symposia sponsored by Astra Zeneca, Boehringer, GlaxoSmithKline, and Nycomed, and has received fees for advising Astra Zeneca, Boehringer, GlaxoSmithKline, Novartis, and Nycomed. Shawn X. Sun, Stavros Tourkodimitris, and Paul Rowe are employees of Forest Research Institute, Inc. Udo M. Goehring and Dirk Bredenbröker are employees of Takeda Pharmaceuticals International GmbH. EK has served on advisory boards, speaker panels, or received travel reimbursement with AstraZeneca, Forest, Ironwood, Merck, Mylan, Novartis, Pearl, Pfizer, Sanofi Aventis, Sunovion, Targacept, and Theravance; EK has also conducted multicenter clinical research trials for approximately 70 pharmaceutical companies, including Forest Laboratories and Almirall, S.A. VM is an employee of Forest Laboratories, LLC. AL is an employee of Almirall, S.A. CC was an employee of Forest Laboratories, LLC at the time the study was conducted.
This study was funded by Forest Laboratories LLC, a subsidiary of Actavis plc, and by Almirall, S.A. The sponsors did not place any restriction on authors about the statements made in the final paper.