This study will evaluate the effects of budesonide (using Symbicort which is budesonide and formoterol) and fluticasone (using Advair which is fluticasone and salmeterol) on the airway microorganisms of patients with moderate-to-severe chronic obstructive pulmonary disease (COPD). This is a randomized, parallel group, two-centered clinical trial study to evaluate the effects of a 12 week treatment with Symbicort 400 mcg BID and Advair 250 mcg BID (via Diskus) on airway microbiota in patients with moderate-to-severe COPD. The control arm of this study will be Oxeze 12 ug BID.

This is a randomized, non-placebo controlled study to evaluate the effects of Symbicort 400 mcg twice daily (BID) and Advair 250 mcg BID over 12 weeks. As the standard of therapy for COPD is a long-acting muscarinic antagonist (LAMA) treatment, a placebo only group cannot be ethically justified. The control arm of this study will thus be Oxeze 12 ug BID. The study will recruit approximately 69 subjects, from St. Paul's Hospital and British Columbia Cancer Agency, randomized 1:1:1 to the 3 arms in blocks. We anticipate 10 to 15% drop out rate, which will enable approximately 60 subjects for full analysis.

After the initial enrolment and confirmation of the entry criteria, subjects will perform spirometry before and following bronchodilation with salbutamol (up to 400 ug). They will then enter a 4-week run-in period during which all subjects will be withdrawn from inhaled corticosteroid containing products. They will then be treated with formoterol via Turbuhaler 12 ug BID and short-acting beta-2 agonists as needed (PRN). Subjects may also have LAMA (either tiotropium 18 ug once daily or glycopyrronium 50 ug once daily) at the discretion of the attending physician. At the end of the run-in phase, eligibility will be confirmed and then subjects will undergo pre and post-spirometry, low-dose thoracic computed tomography (CT) and bronchoscopy. One week post-bronchoscopy, the subjects will be randomized to a 12-week treatment period. Subjects may also have LAMA at the discretion of the attending physician. At the end of the 12 week treatment period, the subjects will undergo pre- and post-spirometry and 2nd bronchoscopy. The subjects will be re-evaluated one week following bronchoscopy and then discharged from the study. All subjects with pulmonary nodule requiring follow-up will be evaluated by the attending physician and the pulmonary nodule will be investigated as per guidelines of the Fleischner Society.

Inclusion Criteria:

• Provision of informed consent prior to any study specific procedures.
• History of moderate to very severe COPD with a post-bronchodilator forced expiratory volume/forced vital capacity (FEV1/FVC) <0.70 and a post-bronchodilator FEV1>20% and ≤80% of predicted normal value at screening.
• Current smoker or ex-smoker with a tobacco history of ≥10 pack-years (1 pack year= 20 cigarettes smoked per day for 1 year).

Exclusion Criteria:

• Clinically important pulmonary disease other than COPD (e.g. active lung infection, clinically significant bronchiectasis, pulmonary fibrosis, cystic fibrosis, hypoventilation syndrome associated with obesity, and primary ciliary dyskinesia) and/ or radiological findings suggestive of a respiratory disease other than COPD that is contributing to the subject's respiratory symptoms.

• Any disorder, including, but not limited to, cardiovascular, gastrointestinal, hepatic, renal, neurological, musculoskeletal, infectious, endocrine, metabolic, haematological, psychiatric, or major physical impairment that is not stable in the opinion of the Investigator and could:

  1. Affect the safety of the subject throughout the study
  2. Influence the findings of the study or their interpretation
  3. Impede the subject's ability to complete the entire duration of study Subjects who have epilepsy must be on a stable dose of medication for 30 days prior to Visit 4.

• Unstable ischemic heart disease, or uncontrolled arrhythmia, cardiomyopathy, heart failure, and renal failure, or uncontrolled hypertension as defined by the Investigator, or any other relevant cardiovascular disorder as judged by the Investigator

• Treatment with systemic corticosteroids and/or antibiotics, and/or hospitalization for a COPD exacerbation within 8 weeks prior to enrolment (Visit 1), based on last dose of steroids or last date of hospitalization whatever occurred later.

• Acute upper or lower respiratory infection requiring antibiotics or antiviral medication within 2 weeks prior to enrolment (Visit 1).

• Pneumonia within 8 weeks prior to enrolment (Visit 1), based on the last day of antibiotic treatment or hospitalization date, whatever occurred later.

• Pregnant, breastfeeding, or lactating women.

• Any clinically significant abnormal findings in physical examination, vital signs, haematology, clinical chemistry, or urinalysis during screening/run-in period, which, in the opinion of the Investigator, may put the subject at risk because of his/her participation in the study, or may influence the results of the study, or the subject's ability to complete entire duration of the study.

• Use of immunosuppressive medication, including rectal corticosteroids, high potency topical corticosteroids and systemic steroids within 28 days prior to randomization.

• Receipt of blood products within 30 days prior to enrollment (Visit 1).

• Receipt of any investigational non-biologic product within 30 days or 5 half-lives prior to Visit 1.

• History of alcohol or drug abuse within the past year, which may compromise the study data interpretation as judged by Investigator or Study Physician.

• Subjects who in the opinion of the investigator or qualified designee have evidence of active tuberculosis (TB), either treated or untreated.

• Scheduled in-patient hospitalization or surgical procedure during the course of the study.

• Asthma as a primary or main diagnosis according to the Global Initiative for Asthma (GINA, http://www.ginasthma.org/) guidelines or other accepted guidelines. Subjects with a past medical history of asthma (e.g. childhood or adolescence) may be included.

• The male partner of someone who may become pregnant during the course of the study