title: Aclidinium bromide and formoterol fumarate as a fixed-dose combination in COPD: pooled analysis of symptoms and exacerbations from two six-month, multicentre, randomised studies (ACLIFORM and AUGMENT).
abstract: BACKGROUND
  The 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).
  
  
  METHODS
  Patients ≥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.
  
  
  RESULTS
  The 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).
  
  
  CONCLUSIONS
  Aclidinium/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.
  
  
  BACKGROUND
  NCT01462942 and NCT01437397 (ClinicalTrials.gov).
authors.affiliation: Division of Pulmonology, Department of Medicine, University of Cape Town, George Street, Mowbray, 7700, Cape Town, South Africa. eric.bateman@uct.ac.za.
authors.forename: Eric D
authors.initials: ED
authors.lastname: Bateman
authors.affiliation: Asthma & Airway Centre, University Health Network, Toronto Western Hospital, Toronto, ON, Canada. kchapman@ca.inter.net.
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Chapman
authors.affiliation: University of Manchester, Medicines Evaluation Unit, University Hospital of South Manchester, Manchester, UK. dsingh@meu.org.uk.
authors.forename: Dave
authors.initials: D
authors.lastname: Singh
authors.affiliation: Department of Family and Community Medicine, University of Toronto, Toronto, ON, Canada. tonydurzo@sympatico.ca.
authors.forename: Anthony D
authors.initials: AD
authors.lastname: D'Urzo
authors.affiliation: R&D Centre, AstraZeneca PLC (former employee of Almirall S.A.), Barcelona, Spain. eduard.molins@astrazeneca.com.
authors.forename: Eduard
authors.initials: E
authors.lastname: Molins
authors.affiliation: Former employee of Almirall S.A., Barcelona, Spain. aleselbaum1@gmail.com.
authors.forename: Anne
authors.initials: A
authors.lastname: Leselbaum
authors.affiliation: R&D Centre, AstraZeneca PLC (former employee of Almirall S.A.), Barcelona, Spain. esthergarciagil@astrazeneca.com.
authors.forename: Esther Garcia
authors.initials: EG
authors.lastname: Gil
mesh_terms: D000280:Administration, Inhalation; D058666:Adrenergic beta-2 Receptor Agonists / Q000008:administration & dosage; D000368:Aged; D000924:Anticholesteremic Agents / Q000008:administration & dosage; D018450:Disease Progression; D004311:Double-Blind Method; D004338:Drug Combinations; D005260:Female; D000068759:Formoterol Fumarate / Q000008:administration & dosage*; D006801:Humans; D008297:Male; D008875:Middle Aged; D029424:Pulmonary Disease, Chronic Obstructive / Q000175:diagnosis* / Q000188:drug therapy*; D013997:Time Factors; D014326:Tropanes / Q000008:administration & dosage*
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D000924:Anticholesteremic Agents; D004338:Drug Combinations; D014326:Tropanes; C542859:aclidinium bromide; D000068759:Formoterol Fumarate