Aclidinium bromide/formoterol fixed-dose combination therapy for COPD: the evidence to date

Figures & data

Table 1 Comparison of various drugs in development of combination therapy with respect to frequency of dosage, rapidity of action, and quantum of improvement in trough FEV₁

Therapies	Manufacturer	Dosage	Time to onset	Trough FEV1 (difference from placebo)
LABA
Formoterol^Citation14	Mercka	Twice daily 4.5 μg (MDI) and 12 μg (DPI)	5 min	50–90 mL
Indacaterol^Citation48	Novartis	Once daily 150 and 300 μg (EU) (DPI)	5 min	130–180 mL (P<0.001)
Indacaterol^Citation48	Novartis	Once daily 75 μg (US) (DPI)	5 min	≥120 mL (P<0.001)
Olodaterol^Citation49	Boehringer Ingelheim	Once daily 5 and 10 μg (Respimat^®)	Not available	61–132 mL (P<0.01)
Vilanterol^Citation50	GSK	Once daily 25 and 50 μg (DPI)	Median 6 min	137–165 mL (P<0.001)
LAMA
Aclidinium^Citation18,Citation51	Almirall/Forest Laboratories	Twice daily 200–400 μg (DPI)	10–30 min	86–124 mL (P<0.0001)
Glycopyrronium^Citation52,Citation53	Novartis	Once daily 50 μg (DPI)	5 min	91–108 mL (P<0.001)
Glycopyrrolate^Citation52	Pearl Therapeutics	Twice daily 36 μg (MDI)	5 min	Statistically superior to placebo (P<0.0001)
GSK233705^Citation54	GSK	Twice daily 200 μg	Not available	130 mL (P<0.001)
Tiotropium^Citation55	Boehringer Ingelheim	Once daily 18 μg (DPI) and 5 μg (SMI)	15 min	120–150 mL (P<0.001)

Notes:

a Other companies are developing formoterol as part of a fixed-dose combination. Adapted from Tashkin DP, Ferguson GT. Combination bronchodilator therapy in the management of chronic obstructive pulmonary disease. Respir Res. 2013;14:49.⁵⁶

Abbreviations: FEV₁, forced expiratory volume in 1 second; MDI, metered dose inhaler; DPI, dry powder inhaler; SMI, Soft Mist™ inhaler; LABA, long-acting β₂ agonist; LAMA, long-acting muscarinic antagonist; EU, European Union.

Table 2 Currently available LABA and LAMA combinations

Combination	Reference	Reported results
Free combinations
GSK233705: 20 or 50 μg BID; salmeterol: 50 μg BID	Beier et al^Citation57	Larger mean increases from baseline trough FEV1 vs placebo with 20 μg GSK233705 + salmeterol (203 mL) and 50 μg GSK233705 + salmeterol (215 mL) vs monotherapy with tiotropium (101 mL) or salmeterol (118 mL).
Tiotropium: 18 μg QD; arformoterol: 15 μg BID	Tashkin et al^Citation58	Greater improvement in FEV1 AUC from baseline 0–24 with combination (0.22 L) vs monotherapy with either arformoterol (0.10 L) or tiotropium (0.08 L); P<0.001.
Tiotropium: 18 μg QD; formoterol: 20 μg BID	Hanania et al^Citation59	FEV1 AUC0–3 greater with combination (1.57 L) vs tiotropium alone (1.38 L); P<0.0001. Reduced use of rescue medication vs tiotropium alone; P<0.05.
Tiotropium: 18 μg QD; formoterol: 12 μg BID	Tashkin et al^Citation60	Greater improvement in FEV1 AUC0–4 from baseline with combination (0.34 L) vs tiotropium alone (0.17 L); P<0.001. Dyspnea significantly improved with combination at week 8 (1.86) vs tiotropium alone (1.01); P=0.013. Reduced use of rescue medication vs tiotropium alone; P<0.04.
Tiotropium: 18 μg QD; formoterol: 10 μg BID	Vogelmeier et al^Citation61	Improvement in FEV1 2 h postdose after 24 weeks with combination vs formoterol alone (P=0.044).
Tiotropium: 18 μg QD; salmeterol: 50 μg BID	van Noord et al^Citation62	Improved average FEV1 (0–24 h) with combination (0.142 L) vs monotherapy with either tiotropium (0.07 L) or salmeterol (0.045 L); P<0.0001. Combination associated with clinically relevant improvements in TDI focal score (P<0.001).
Fixed-dose combinations
Glycopyrrolate: 36 and 72 μg BID; formoterol: 9.6 μg BID (Pearl Therapeutics)	Reisner et al^Citation63	Increase in FEV1 AUC0–12 on day 7 with combination compared to monotherapy with either of the components, tiotropium, and placebo (P<0.0001).
Glycopyrrolate: 36 and 72 μg BID; formoterol: 9.6 μg BID (Pearl Therapeutics)	Reisner et al^Citation64	Higher morning pretrough and peak IC with combination vs placebo (P<0.0005 and P<0.005, respectively) or tiotropium monotherapy (P<0.05 for all comparisons).
Glycopyrronium: 50 μg QD; indacaterol: 300 μg QD (Novartis)	van Noord et al^Citation65	Improved trough FEV1 with combination: 0.226 L difference in trough FEV1 vs placebo (P<0.001). Greater peak FEV1 with combination (1.709 L) vs 300 μg indacaterol (1.579 L) and 600 μg indacaterol (1.573 L); P<0.0001 for both comparisons.
Glycopyrronium: 100 μg QD; indacaterol: 600 μg QD (Novartis)	Van de Maele et al^Citation66	Increased trough FEV1 with combination (1.61 L) vs indacaterol monotherapy 300 μg (1.46 L); P<0.05.
Glycopyrronium: 50 μg QD; indacaterol: 110 μg QD (Novartis)	Bateman et al^Citation67	Improved trough FEV1 with combination vs placebo (0.20 L mean difference), indacaterol (0.07 L), glycopyrronium (0.09 L), and tiotropium (0.08 L) monotherapy; P<0.001. Improved TDI score with combination vs placebo (mean difference, 1.09); P<0.001 and tiotropium (0.51 mean difference); P<0.05. Improved SGRQ score with combination vs tiotropium (−2.13 mean difference); P<0.05. Reduced use of rescue medication with combination vs monotherapies (−0.30 to −0.54 mean difference); P<0.05.
Glycopyrronium: 50 μg QD; indacaterol: 110 μg QD (Novartis)	Vogelmeier et al^Citation68	Improvement in trough FEV1 with combination vs salmeterol/fluticasone (mean difference 0.103 L); P<0.0001. Improvements in TDI score with combination vs salmeterol/fluticasone (mean difference 0.76); P=0.003. Lower use of rescue medication with combination vs salmeterol/fluticasone (−0.39 puffs/day); P=0.019.
Glycopyrronium: 50 μg QD; indacaterol: 110 μg QD (Novartis)	Dahl et al^Citation69	Combination increased FEV1 and FVC vs placebo over a 52-week period; P<0.001.
Tiotropium: 5 μg QD; olodaterol: 2, 5, and 10 μg QD (Boehringer Ingelheim)	Maltais et al^Citation70	Higher peak FEV1 for all doses of combination investigated vs tiotropium alone (P≤0.05); higher trough FEV1 response with tiotropium + olodaterol 5/10 μg vs tiotropium alone (P=0.034).
Tiotropium: 1.25, 2.5, and 5 μg QD; olodaterol: 5 and 10 μg QD (Boehringer Ingelheim)	Aalbers et al^Citation71	Significant improvements in FEV1 for all doses of combination vs olodaterol alone, with evidence of a dose-dependent response.
Umeclidinium (GSK573719): 500 μg QD; vilanterol: 25 μg QD (GSK)	Feldman et al^Citation72	Adverse-event rate of 26%, with no single adverse event reported in >1 patient. Combination similar to placebo in terms of cardiac parameters. Greater change from baseline in trough FEV1 and FEV1 from 0 to 6 h postdose with combination vs placebo.

Note: Adapted from Tashkin DP, Ferguson GT. Combination bronchodilator therapy in the management of chronic obstructive pulmonary disease. Respir Res. 2013;14:49.⁵⁶

Abbreviations: LABA, long-acting β₂ agonist; LAMA, long-acting muscarinic antagonist; BID, twice a day; FEV₁, forced expiratory volume in 1 second; QD, once a day; AUC, area under the curve; TDI, Transition Dyspnea Index; IC, inspiratory capacity; SGRQ, St George’s Respiratory Questionnaire; FVC, forced vital capacity.

Figure 1 Onset of action of aclidinium, ipratropium, and tiotropium in isolated guinea pig trachea.

Notes: Contraction was induced with 10 μM carbachol and allowed to plateau before the addition of antagonists. Onset was defined as the time from antagonist addition to achieve inhibition of 50% (t_1/2) or 100% (t_max) of the contraction. Data are reported as mean ± SE; n=5–7. ***P<0.001 compared with first observational time point. Copyright © 2009. Reproduced from The American Society for Pharmacology and Experimental Therapeutics. Gavaldà A, Miralpeix M, Ramos I, et al. Characterization of aclidinium bromide, a novel inhaled muscarinic antagonist, with long duration of action and a favorable pharmacological profile. J Pharmacol Exp Ther. 2009;331(2):740–751.¹⁸
Abbreviation: SE, standard error.

Figure 2 Effect of aclidinium and tiotropium on heart rate in conscious beagle dogs.

Notes: Animals were anesthetized in order to deliver the nebulized compounds or vehicle and were allowed to regain consciousness. The effect on heart rate of a dose 100 times higher than that used to achieve submaximal bronchodilation was assessed continuously up to 6 hours and expressed as a percentage change from baseline heart rate. Data are reported as mean ± SE; n=4 for aclidinium and tiotropium; n=3 for vehicle. *P<0.05, **P<0.01, ***P<0.001 compared with vehicle; ^†P<0.05, ^††P<0.01, †††P<0.001 compared with tiotropium. Copyright © 2009. Reproduced from The American Society for Pharmacology and Experimental Therapeutics. Gavaldà A, Miralpeix M, Ramos I, et al. Characterization of aclidinium bromide, a novel inhaled muscarinic antagonist, with long duration of action and a favorable pharmacological profile. J Pharmacol Exp Ther. 2009;331(2):740–751.¹⁸
Abbreviation: SE, standard error.

Figure 3 Mean (± SE) changes in sG_aw (%) over 24 hours as a percentage of baseline value.

Notes: Placebo (Image), 50 mg aclidinium bromide (Image), 300 mg aclidinium bromide (Image), 600 mg aclidinium bromide (Image). © 2010 The Authors. Journal compilation © 2010 The British Pharmacological Society. Reproduced from Schelfhout VJ, Ferrer P, Jansat JM, et al. Activity of aclidinium bro mide, a new long-acting muscarinic antagonist: a phase I study. Br J Clin Pharmacol. 2010;69(5):458–464.²⁶
Abbreviations: sG_aw, specific airway conductance; SE, standard error.

Table 3 Recent clinical trials of aclidinium/formoterol fixed-dose combination therapies

Study	Dosage	Primary end point	Coprimary end points	Study period and present status
Interventional pilot study (Phase II) [NCT00706914]	Aclidinium bromide/formoterol fumerate FDC QD	Symptomatic differences between treatment groups after 4 weeks of treatment	Differences between groups in change in pulmonary function test results after 4 weeks of treatment	June 2008–September 2011; results not published
Dose-finding clinical trial (Phase II) [NCT00626522]	Aclidinium bromide/formoterol fumerate FDC QD	Pulmonary function tests	Pharmacokinetics and safety	February 2008–July 2010; results not published
Interventional efficacy trial [NCT01049360]	2 FDCs of aclidinium bromide/formoterol fumerate BID	Change from baseline in normalized FEV1 after 14 days of treatment AUC0–12 measurement over 12 h after morning dose of drug at day 14	The secondary efficacy assessments were the change from baseline in morning predose FEV1 and the change from baseline in morning peak FEV1, both at day 14 on treatment	January 2010–September 2011; results not published
Interventional dose-finding study [NCT01078623]	2 FDCs of aclidinium bromide/formoterol fumerate BID	FEV1 AUC 0–12 h after day 14	Morning predose FEV1 and morning peak FEV1 after day 14	March 2010–November 2010; study not published
Interventional study [NCT01551888]	Aclidinium/formoterol 400 μg/12 μg FDC (BID) for 4 days, then QD on day 5 via the Genuair^®	Area under the formoterol plasma concentration–time curve over the dosing interval at steady state Maximum formoterol plasma concentration at steady state	Area under the formoterol plasma concentration–time curve over the dosing interval following a single dose Maximum plasma concentration of formoterol following a single dose	March 2012–August 2012; no study result published
Interventional study (Phase III) [NCT01437540]	FDCs of aclidinium bromide/formoterol fumerate BID (high dose)	AE recording: number of patients to experience a TEAE Vital signs: number of patients to experience a PCS change in pulse rate, systolic and diastolic blood pressure, body temperature, or body weight ECGs: number of patients to experience potentially clinically significant changes in ECG from baseline Clinical laboratory measures: number of patients to experience a PCS change in clinical laboratory values for hematology, chemistry, urinalysis, or theophylline	Not listed	September 2011–April 2013; results not published
Interventional study (Phase III) [NCT01572792]	2 FDCs of aclidinium bromide/formoterol fumerate (low-dose ACL200/FOR12 μg; high-dose ACL400/FOR12 μg, BID)	Safety and tolerability: AE, clinical laboratory parameters, vital sign measurement, and ECG parameters	Not listed	April 2012–June 2013; results not published
Interventional study (Phase III) [NCT01908140]	Aclidinium bromide 400 μg/formoterol fumarate 12 μg BID for 24 weeks	Peak FEV1 at week 24	TDI focal score at week 24	July 2013–September 2014; results not published

Notes: Information of the clinical trials was obtained from the United States clinical trial registry (available at https://clinicaltrials.gov; last accessed on February 2, 2015). Searching of clinical trial database with the keywords – aclidinium + formoterol + COPD yielded 12 results, and among those aclidinium-formoterol FDC was used in ten studies only. We selected those ten studies and incorporated eight unpublished studies into this table. The other two studies are published (viz, the AUGMENT-COPD Study and the ACLIFORM-COPD Study).

Abbreviations: FDC, fixed-dose combinations; QD, once a day; FEV₁, forced expiratory volume in 1 second; ACL, aclidinium; BID, twice a day; AE, adverse event; TEAE, treatment emergent adverse event; PCS, potentially clinically significant; ECGs, electrocardiograms; FOR, formoterol; TDI, Transition Dyspnea Index; COPD, Chronic obstructive pulmonary disease; AUC, area under the curve.

Figure 4 Mean changes from baseline in FEV₁ 0–3 hours (A) on day 1 and (B) at week 24.

Notes: Analyses were based on a mixed model for repeated measures. *P<0.05 vs placebo; ^†P<0.05 vs aclidinium and placebo; ^§P<0.05 vs aclidinium, formoterol, and placebo; ^¥P<0.05 vs aclidinium/formoterol FDC 400/6 μg and placebo. No significant differences between the two FDCs at any time point. Reproduced from D’Urzo AD, Rennard SI, Kerwin EM, Mergel V, Leselbaum AR, Caracta CF; AUGMENT COPD Study Investigators. Efficacy and safety of fixed-dose combinations of aclidinium bromide/formoterol fumarate: the 24-week, randomized, placebo-controlled AUGMENT COPD study. Respir Res. 2014;15(1):123.⁴⁴
Abbreviations: ACL, aclidinium; FOR, formoterol; LS, least squares; FEV₁, forced expiratory volume in 1 second; FDCs, fixed-dose combinations; ACL400/FOR12 FDC, FDC of aclidinium 400 μg and formoterol 12 μg; ACL400/FOR6 FDC, FDC of aclidinium 400 μg and formoterol 6 μg.

Figure 5 Improvement in TDI focal score at 24 weeks (ITT population).

Notes: Data are presented as least squares means (SE). ***P<0.001 vs placebo. Reproduced from Singh D, Jones PW, Bateman ED, et al. 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. BMC Pulm Med. 2014;14:178. http://creativecommons.org/licenses/by/4.0/.⁴⁵
Abbreviations: FDC, aclidinium/formoterol fixed-dose combination; ITT, intent-to-treat; MCID, minimum clinically important difference; SE, standard error; TDI, Transition Dyspnea Index.

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