A Study to Investigate the Differential Effects of Inhaled Symbicort and Advair on Lung Microbiota (DISARM)

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.

Study Overview

• Status: Unknown
• Conditions: Chronic Obstructive Pulmonary Disease
• Intervention / Treatment: Drug: Fluticasone group; Drug: Budesonide group; Drug: Formoterol group

Detailed Description

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 They will then enter a 4-week run-in period during which all subjects will be withdrawn from inhaled corticosteroid containing products.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.

• Study Type: Interventional
• Enrollment (Anticipated): 69
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada
      • Recruiting
      • BC Cancer Agency
      • Contact: Amy English; Email: aenglish@bccrc.ca
      • Principal Investigator: Stephen Lam, MD
      • Sub-Investigator: Eve-lea Beaudoin, MD
    • Vancouver, British Columbia, Canada, V6Z1Y6
      • Recruiting
      • St. Paul's Hospital
      • Contact: Lynda Lazosky; Phone Number: 64884 604-682-2344; Email: llazosky@providencehealth.bc.ca
      • Principal Investigator: Don Sin, MD
      • Sub-Investigator: Van Eeden Stephanus, MD
      • Sub-Investigator: Leung Janice, MD
      • Sub-Investigator: Shaipanich Tawimas, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Fluticasone group; Advair (fluticasone) 250 mcg to be administered twice daily via Diskus for 12 weeks	Drug: Fluticasone group; Other Names: Advair
Experimental: Budesonide group; Symbicort (budesonide) 400 mcg to be administered twice daily via Turbuhaler for 12 weeks	Drug: Budesonide group; Other Names: Symbicort
Active Comparator: Formoterol group; Oxeze (formoterol) 12 microg to be administered twice daily via Turbuhaler for 12 weeks	Drug: Formoterol group; Other Names: Oxeze

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Change in total bacterial population in the bronchoalveolar lavage fluid	12 weeks
Change in bacterial diversity using Shannon Index based on 16S sequencing.	12 weeks

Secondary Outcome Measures

Outcome Measure	Time Frame
Change in bacterial membership using Beta-diversity	12 weeks
Characterization of bacteria Operational Taxonomic Unit	12 weeks
Change in total cell count in bronchoalveolar lavage fluid	12 weeks
Change in total neutrophil count in bronchoalveolar lavage fluid	12 weeks
Change in total lymphocyte count in bronchoalveolar lavage fluid	12 weeks
Change in total mono-macrophage count in bronchoalveolar lavage fluid	12 weeks
Change in St. George's Respiratory Questionnaire	12 weeks
Change in forced expiratory volume in 1 second	12 weeks
Change in forced vital capacity	12 weeks

Collaborators and Investigators

• Sponsor: University of British Columbia
• Collaborators: AstraZeneca
• Investigators: Principal Investigator: Don Sin, MD, St. Paul's Hospital

Publications and helpful links

General Publications

• Ho CG, Milne S, Li X, Yang CX, Leitao Filho FS, Cheung CY, Yang JSW, Hernandez Cordero AI, Yang CWT, Shaipanich T, van Eeden SF, Leung JM, Lam S, Sin DD. Airway Eosinophilia on Bronchoalveolar Lavage and the Risk of Exacerbations in COPD. Biomedicines. 2022 Jun 15;10(6):1412. doi: 10.3390/biomedicines10061412.
• Akata K, Leung JM, Yamasaki K, Leitao Filho FS, Yang J, Xi Yang C, Takiguchi H, Shaipanich T, Sahin B, Whalen BA, Yang CWT, Sin DD, van Eeden SF. Altered Polarization and Impaired Phagocytic Activity of Lung Macrophages in People With Human Immunodeficiency Virus and Chronic Obstructive Pulmonary Disease. J Infect Dis. 2022 Mar 2;225(5):862-867. doi: 10.1093/infdis/jiab506.
• Leitao Filho FS, Takiguchi H, Akata K, Ra SW, Moon JY, Kim HK, Cho Y, Yamasaki K, Milne S, Yang J, Yang CWT, Li X, Nislow C, van Eeden SF, Shaipanich T, Lam S, Leung JM, Sin DD. Effects of Inhaled Corticosteroid/Long-Acting beta2-Agonist Combination on the Airway Microbiome of Patients with Chronic Obstructive Pulmonary Disease: A Randomized Controlled Clinical Trial (DISARM). Am J Respir Crit Care Med. 2021 Nov 15;204(10):1143-1152. doi: 10.1164/rccm.202102-0289OC.

Study record dates

Study Major Dates

• Study Start: February 1, 2015
• Primary Completion (Anticipated): January 1, 2021
• Study Completion (Anticipated): June 1, 2021

Study Registration Dates

• First Submitted: May 26, 2016
• First Submitted That Met QC Criteria: July 11, 2016
• First Posted (Estimate): July 14, 2016

Study Record Updates

• Last Update Posted (Actual): March 30, 2020
• Last Update Submitted That Met QC Criteria: March 26, 2020
• Last Verified: March 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Anti-Inflammatory Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Adrenergic Agonists; Dermatologic Agents; Bronchodilator Agents; Anti-Asthmatic Agents; Respiratory System Agents; Anti-Allergic Agents; Adrenergic beta-2 Receptor Agonists; Adrenergic beta-Agonists; Budesonide; Fluticasone; Formoterol Fumarate
• Other Study ID Numbers: H14-02277

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No