Effect of aclidinium/formoterol fixed-dose combinations on respiratory symptoms in patients with COPD

Background: Two 24-week studies (ACLIFORM, AUGMENT) investigated two fixed-dose combinations (FDCs) of aclidinium bromide/formoterol fumarate in patients with chronic obstructive pulmonary disease (COPD). Both FDCs were found to improve lung function vs placebo and monotherapy components.

Aim: To investigate respiratory symptoms in patients with COPD who were participating in ACLIFORM and AUGMENT.

Methods: Patients were randomized to placebo, formoterol 12 µg, aclidinium 400 µg, FDC 400/6 µg or FDC 400/12 µg BID. Respiratory symptoms were evaluated by the Transition Dyspnea Index (TDI) focal score, change from baseline in EXACT-Respiratory Symptoms (E-RS) total score, and use of rescue medication.

Results: Both FDCs significantly improved TDI focal scores above the minimum clinically important difference (MCID) of 1 unit at Week 24 (Table) and at all other time points compared with placebo; both FDCs also showed numerically greater improvements vs monotherapies (intent-to-treat populations: ACLIFORM, N= 1726; AUGMENT, N= 1668). The MCID was achieved by more FDC-treated patients than either placebo or monotherapies. There was a significant improvement in E-RS scores for both FDCs vs placebo and monotherapies. Furthermore, both FDCs significantly reduced average daily rescue medication use over 24 weeks compared with placebo.

Conclusions: In patients with moderate-to-severe COPD, FDCs of aclidinium/formoterol improved respiratory symptoms compared with placebo and monotherapies over 6 months.

Tab. 1: Symptom improvements from baseline to Week 24 (ITT population)

*p < 0.05 vs placebo; †p < 0.05 vs aclidinium monotherapy; ‡p < 0.05 vs formoterol monotherapy. Mean TDI focal scores, changes in E-RS total score, and changes in rescue medication use were analyzed using a mixed-model for repeated measures. MCID outcomes (improvement ≥ 1 unit). were analyzed using a logistic regression model and p-values were based on odds ratios. All models included baseline values, age, sex, and smoking status as fixed-effect factors. BID, twice daily; E-RS, EXACT Respiratory Symptoms; FDC, aclidinium/formoterol fixed-dose combination; ITT, intent-to-treat; LS, least squares; MCID, minimal clinically important difference; TDI, Transition Dyspnea Index.
ACLIFORM (NCT01462942)
		FDC	FDC	Aclidinium	Formoterol
	Placebo	400/12 µg	400/6 µg	400 µg	12 µg
	BID	BID	BID	BID	BID
	n = 194	n = 385	n = 381	n = 385	n = 384
TDI focal score, LS mean	1.2	2.5*	2.4*	2.1*	2.1*
TDI focal score, Patients who achieved MCID, %	45.5	64.8*	63.7*	56.5*	61.3*
Overall average daily E-RS total score, LS mean change	-1.7	-2.5*†‡	-2.8*†‡	-1.6	-1.8
Overall average daily rescue medication use, LS mean change	-1.0	-1.6*†	-1.7*†	-1.3	-1.4*
AUGMENT (NCT01437397)
		FDC	FDC	Aclidinium	Formoterol
	Placebo	400/12 µg	400/6 µg	400 µg	12 µg
	BID	BID	BID	BID	BID
	n = 332	n = 335	n = 333	n = 337	n = 332
TDI focal score, LS mean	0.6	2.0*	2.0*	1.6*	1.5*
TDI focal score, patients who achieved MCID, %	36.6	58.1*	64.2*†‡	54.8*	51.7*
Overall average daily E-RS total score, LS mean change	-0.9	-2.3*	-2.7*†‡	-2.0*	-1.8*
Overall average daily rescue Medication use, LS mean change	-0.7	-1.9*†	-1.8*†	-1.4*	-1.6*

Funding: This study was supported by Almirall S.A., Barcelona, Spain and by Forest Laboratories LCC, a subsidiary of Actavis plc, New York, NY, USA.