A Study to Investigate the Differential Effects of Inhaled Symbicort and Advair on Lung Microbiota
A Study to Investigate the Differential Effects of Inhaled Symbicort and Advair on Lung Microbiota
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 then enter a 4-week run-in period during which all subjects will be withdrawn from inhaled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