The purpose of this study is to identify the optimal once-daily dose of CHF 4226 to be further developed for the treatment of patients with COPD.

Inclusion Criteria:

• Patient has signed an IRB-/Ethics Committee-approved Informed Consent form

• Patient is a male or non-pregnant female between the ages of 40 - 75 years, inclusive

• Patient has a current or past smoking history of at least 15 pack-years

• Patient has a clinical diagnosis of COPD in accordance with the recommendations of the National Heart Lung and Blood Institute/World Health Organization (NHLBI/WHO) Global Initiative for Chronic Obstructive Lung Disease (GOLD)

• Patient meets the following requirements after an FEV1 albuterol reversibility test (i.e., 30 minutes following 200 mcg (metered dose) albuterol/salbutamol pMDI):

• FEV1 is at least 0.9L

• FEV1 of 40% - 70%, inclusive, of patient's predicted normal value

• Change in FEV1 > 4% of patient's predicted normal value

  • If change in FEV1 < 4% of patient's predicted normal value, then this requirement must be met after retesting during the run-in period, at least 24 hours prior to Day -1

• FEV1/FVC < 70%

Exclusion Criteria:

• Patient has a history of asthma, allergic rhinitis, or atopy
• Patient has a blood eosinophil count > 500/microliter
• Patient had a COPD exacerbation or a lower respiratory tract infection within 8 weeks prior to screening, or during the run-in period, that resulted in the use of an antibiotic, or oral or parenteral corticosteroids
• Patient is on an inhaled corticosteroid that has been initiated, or the effective dose has been changed, within 4 weeks prior to screening or during the run-in period
• Patient has an uncontrolled cardiovascular (e.g., uncontrolled hypertension), respiratory, hematologic, immunologic, renal, neurologic, hepatic, endocrine (e.g., uncontrolled diabetes mellitus) or other disease, or any condition that might, in the judgment of the Investigator, place the patient at undue risk or potentially compromise the results or interpretation of the study
• Patient has a history of coronary artery disease, cerebrovascular disease, cardiac arrhythmias
• Patient has a concomitant disease of poor prognosis (e.g., cancer)
• Patient has a serum potassium value ≤ 3.5 mEq/L or >5.5mEq/L and/or a fasting serum glucose value ≥ 140 mg/dL
• Patient has an abnormal QTc Fridericia interval value in the Screening visit ECG test (i.e., > 450 msec in males or > 470 msec in females)
• Patient has developed Cor Pulmonale
• Patient is receiving long term oxygen therapy, i.e., ≥ 16 hours/24-hour period, every day
• Patient has a known intolerance/hypersensitivity to Beta2-adrenergic agonists, propellant gases/excipients
• Patient is receiving treatment with a tricyclic antidepressant or a monoamine oxidase inhibitor (MAOI)
• Patient has received a live-attenuated virus vaccination within two weeks prior to screening or during the run-in
• Patient is pregnant or lactating female, or female at risk of pregnancy (i.e., not using an adequate contraceptive method)
• Patient is mentally or legally incapacitated
• Patient has participated in another investigational study within 30 days prior to screening
• Patient abuses alcohol or other substances
• Patient is potentially non-compliant or unable to perform required outcome measurements of the protocol