The goal of this study is to study how 12-weeks daily (and optional 48-weeks) single inhaler triple therapy (fluticasone furoate (FF)-an inhaled corticosteroid; umeclidinium (UMEC)-a long-acting muscarinic antagonist; vilanterol (VI)-a long-acting β2-adrenergic agonist) works to treat adults with COPD. The investigators will compare the effects of this medication on adults with COPD who are at low risk of a flare-up and adults with COPD who are at high risk of a flare-up. The main questions it aims to answer are:

• Does FF/UMEC/VI improve ventilation defect percent as measured on 129-Xenon MRI in adults with moderate-severe COPD
• Evaluate the relationships between the ventilation defect percent and lung function test results

Participants will:

• Take the inhaler FF/UMEC/VI once daily for 12-weeks (optional 48-weeks)
• visit Robarts 2 times (with optional 3rd visit) for tests and imaging

This study will evaluate 60 COPD patients age 50-85 (equal numbers males and females) with persistent, moderate-severe dyspnea, poor health status and either: 1) low risk of exacerbation (n=30) or moderate-high risk of exacerbation (n=30). Two visits at baseline and 12-weeks are proposed with an optional visit at 48-weeks to assess longitudinal effects of therapy.

At all study visits participants will have vital signs recorded and undergo pre- and post-bronchodilator spirometry, plethysmography, oscillometry, pre-bronchodilator forced exhaled nitric oxide (FeNO) and post-bronchodilator diffusing capacity of the lungs for carbon monoxide (DLco). Participants will undergo pre- and post-bronchodilator 129-Xe MRI and post-bronchodilator chest computed tomography (CT). Participants will complete St. George's Respiratory Questionnaire (SGRQ), Modified Medical Research Council (mMRC), COPD Assessment Test (CAT), Borg rating of perceived exertion questionnaire will be completed before and after the six-minute walk test (6MWT). Participants will have a blood draw for complete blood count (CBC).

Inclusion Criteria:

• patient understands study procedures and is willing to participate in the study as indicated by the patient's signature

• provision of written, informed consent prior to any study specific procedures

• males and females 50-85 years of age

• stable COPD, currently on dual therapy LAMA/LABA or ICS/LABA or initial maintenance therapy for at least 3 months

• mMRC score ≥2 and/or CAT score ≥10

• Low risk subgroup: participant has experienced ≤1 exacerbation in the past year and no hospitalizations for COPD High risk subgroup: participant has experienced ≥2 exacerbations in the past year

• Female of childbearing potential (after menarche) must ensure that they are using an effective form of birth control for at least 2 months prior to each imaging visit. Examples of effective birth control include:

  1. True sexual abstinence
  2. A vasectomized sexual partner
  3. Implanon®
  4. Female sterilization by tubal occlusion
  5. Effective intrauterine device (IUD)/levonogestrel intrauterine system (IUS)
  6. Depo-Provera™ injections
  7. Oral contraceptive
  8. Evra Patch™
  9. Nuvaring™

• Female permanently sterile due to: 1) documented hysterectomy, 2) documented bilateral salpingectomy, and 3) documented bilateral oophorectomy

• Postmenopausal female: defined as female with no menses for 12 months without an alternative medical cause

• Females of childbearing potential (after menarche) must agree to use a highly effective form of birth control, as defined above, from enrollment, throughout the study duration, and 8 weeks after last dose of study drug, with negative urine pregnancy test taken within 24 hr of any planned CT examination at Visit-1 through Visit 3

• Male participants who are sexually active with a woman who can still have children, must agree to use a double barrier method of contraception (male condom with diaphragm or male condom with cervical cap) from the first dose of the study drug until 8 weeks after last dose

Exclusion Criteria:

• Patient has an implanted mechanically, electrically, or magnetically activated device or any metal in their body which cannot be removed, including but not limited to pacemakers, neurostimulators, biostimulators, implanted insulin pumps, aneurysm clips, bioprosthesis, artificial limb, metallic fragment or foreign body, shunt, surgical staples (including clips or metallic sutures and/or ear implants) (at the discretion of the MRI Technologist)
• In the investigator's opinion, participant suffers from any physical, psychological or other condition(s) that might prevent performance of the MRI or CT, such as severe claustrophobia
• Participants who are pregnant, breastfeeding or have a positive pregnancy test at initial screening visit
• Participant is unable to perform spirometry or plethysmography maneuvers
• Participant is unable to perform MRI and CT breath-hold maneuvers
• Participant has an unstable cardiovascular, gastro-intestinal, hepatic, renal, neurologic, metabolic or psychiatric disease
• Participation in any clinical trial of an investigational agent or procedure within three months prior to screening or during the study
• Known history of allergy or reaction to the study drug formulation
• Participant has a blood pressure of >150 mmHg systolic or >95 mmHg diastolic on more than 2 measurements done >5 minutes apart at Visit-1
• Participants with a recently (<2 months) documented diagnosis of asthma