Efficacy in COPD Maintenance

Description of ACLIFORM Study

ACLIFORM-COPD was a 24-week double-blind, parallel-group, active- and placebo-controlled, multicenter phase III study. Patients aged ≥40 years were eligible if they were current or former smokers (≥10 pack-years) and diagnosed with stable, moderate-to-severe COPD according to GOLD guidelines (post-bronchodilator forced expiratory volume in 1 second FEV₁/FVC <70% and FEV₁ ≥30% and <80% predicted).

Main exclusion criteria were: COPD exacerbation or respiratory tract infection ≥6 weeks (≥3 months if hospitalized for exacerbation) before screening; clinically significant respiratory conditions (including asthma); clinically significant cardiovascular (CV) conditions including myocardial infarction (Ml) within 6 months prior to screening; unstable angina; and, unstable arrhythmia that required changes in pharmacological therapy or other intervention within the previous 12 months.

Co-primary endpoints were change from baseline to Week 24 in 11-hour morning post-dose FEV₁ and change from baseline to Week 24 in morning pre-dose (trough) FEV₁. The primary endpoints were met.¹¹

FVC = forced vital capacity; FEV₁ = forced expiratory volume in 1 second; GOLD = Global Initiative for Chronic Obstructive Lung Disease

Description of AUGMENT Study

AUGMENT-COPD was a 24-week double-blind, parallel-group, active- and placebo-controlled, multicenter phase III study. Patients with stable COPD were equally randomized to twice-daily treatment (once in the morning and once in the evening). Patients aged ≥40 years were eligible if they were current or former smokers (≥10 pack-years) and diagnosed with stable, moderate-to-severe expiratory airflow obstruction according to GOLD guidelines (post-bronchodilator forced expiratory volume in 1 second [FEV₁]/forced vital capacity [FVC] <70% and FEV₁ ≥30% and <80% predicted).

Main exclusion criteria were: COPD exacerbation or respiratory tract infection ≥6 weeks (≥3 months if hospitalized for exacerbation) before screening; clinically significant respiratory conditions (including asthma); clinically significant cardiovascular (CV) conditions including myocardial infarction (Ml) within the previous 6 months; unstable angina; and, unstable arrhythmia that required changes in pharmacological therapy or other intervention within the previous 6 months.

Co-primary endpoints were change from baseline to Week 24 in
1-hour morning post-dose FEV₁ (FDCs versus aclidinium) and change from baseline to Week 24 in morning pre-dose (trough) FEV₁ (FDCs versus formoterol). The primary endpoints were met.⁶

FDC = fixed dose combination
GOLD = Global Initiative for Chronic Obstructive Lung Disease

Description of AMPLIFY Study

AMPLIFY is a 24-week treatment, multicenter, randomized, double-blind, double dummy, parallel-group trial to assess the efficacy and safety of aclidinium bromide/formoterol fumarate 400 mcg/12 mcg twice daily compared to its component parts (aclidinium bromide 400 mcg twice daily or formoterol fumarate 12 mcg twice daily) and once-daily tiotropium 18 mcg in a total of 1594 moderate-to-very severe stable COPD patients. The study enrolled adult male and female patients aged ≥40, current or former smokers, with a smoking history of ≥10 pack-years, had an FEV₁ <80% predicted normal and a ratio of FEV₁/FVC <0.7, and symptomatic patients with a CAT score ≥10.

The primary outcome measures were to demonstrate:

• A change from baseline morning pre-dose (trough) FEV₁ for twice-daily aclidinium bromide/formoterol fumarate 400 mcg/12 mcg vs twice-daily formoterol 12 mcg at Week 24
• A change from baseline in morning 1 hour post-dose (peak) FEV₁ for twice-daily aclidinium bromide/formoterol fumarate 400 mcg/12 mcg vs twice-daily aclidinium bromide 400 mcg at Week 24
• A change from baseline in morning pre-dose (trough) FEV₁ at Week 24 comparing twice-daily aclidinium bromide 400 mcg vs once-daily tiotropium 18 mcg to demonstrate non-inferiority
• Other objectives were to assess the safety of aclidinium bromide/formoterol fumarate 400 mcg/12 mcg, as well as to further characterize the effect of the combination on bronchodilation and health-related quality of life
• A subset of patients participated in a 24-hour sub-study; serial spirometry was additionally performed between 4 and 24 hours on Day 1 and at Week 24. Change from baseline in FEV₁, normalized AUC _0-12/12h, AUC _12-24/12h, AUC _0-24/24h FEV₁, and FVC, overall nighttime and early morning symptom severity, and rescue medication were evaluated

DUAKLIR (aclidinium bromide/formoterol fumarate 400 mcg/12 mcg twice-daily) met the primary endpoints, demonstrating a statistically significant and clinically relevant improvement in lung function in moderate-to-very severe COPD patients.³

FEV₁ = forced expiratory volume in 1 second; FVC = forced vital capacity; CAT = COPD Assessment Test; AUC = area under the curve.

Description of ASCENT Study

ASCENT-COPD was a double-blind, randomized, placebo-controlled, phase IV study of up to 3 years in 3630 patients with moderate-to-very severe COPD. The study comprised a 2-week washout period, followed by a double-blind treatment phase in which patients were randomized 1:1 to aclidinium 400 mcg or placebo BID. The study enrolled patients with a clinical diagnosis of moderate-to-very severe COPD who were >40 years, were current or former smokers with a smoking history of >10 pack-years, had an FEV₁ <80% predicted normal, and a ratio of FEV₁/FVC <0.7. Patients also had a history of significant cardiovascular (CV) or cerebrovascular disease and/or significant risk factors.* The primary efficacy endpoint was rate of moderate-to-very severe COPD exacerbations per patient per year during the first year of treatment versus placebo. The primary safety endpoint was the time to first major adverse CV event (MACE). The primary endpoints were met.¹¹

*Documented cerebrovascular disease (eg, stroke or transient ischemic attack, carotid stenosis). Documented coronary artery disease (eg, angioplasty/stent/bypass, angina, DMI). Documented peripheral vascular disease or history of claudication. Two or more of the following CV risk factors as determined by the investigator: male >65 years or female >70 years, diabetes, dyslipidemia, hypertension, waist circumference >40 inches for males and >38 inches for females, evidence of renal dysfunction (estimated Glomerular Filtration Rate <60), and microalbuminuria (defined as>30-300 mcg/mg creatinine on a spot urine test or >30 mg creatinine on a 24-hour urine test; renal dysfunction criteria were added after the initiation of patient enrollment).
BID = twice daily
FEV₁ - forced expiratory volume in 1 second
FVC = forced vital capacity