This study will evaluate the effect of triple ICS/LAMA/LABA therapy with BGF MDI 320/14.4/9.6 μg on cardiopulmonary outcomes relative to LAMA/LABA therapy with GFF MDI 14.4/9.6 μg in a population with COPD and elevated cardiopulmonary risk.

This is a Phase III randomized, double-blind, parallel group, multi-center event-driven study comparing BGF MDI 320/14.4/9.6 μg BID with GFF MDI 14.4/9.6 μg BID in participants with COPD who are at risk of a cardiopulmonary event.

Inclusion Criteria:

1. Male or female participants must be 40 to 80 years of age inclusive, at the time of signing

   the ICF.

2. Demonstrate acceptable MDI administration technique at Visit 1 (V1) and Visit 2 (V2)

3. A diagnosis of COPD confirmed by a post-bronchodilator FEV1/FVC ratio < 70%

   at V1.

4. Current or former smokers with a history of at least 10 pack-years of cigarette smoking;

   defined as (number of cigarettes per day/20) x number of years smoked. Previous smokers are defined as those who have stopped smoking for at least 6

   months prior to V1.

5. A baseline peripheral blood eosinophil count of ≥ 100 cells/mm3 assessed at Visit 1 by

   the central laboratory

6. A CAT score of ≥ 10 at Visit 1.

7. Participant must fulfill at least 1 of the 4 CV disease/risk factor criteria below [(a), (b),

   (c), or (d)]:

   1. : Established CV Disease

   2. : Combination of CV risk factors:

      • Hypertension
      • Diabetes Mellitus
      • Chronic Kidney Disease
      • Dyslipidemia
      • Obesity

   3. : High risk of CV disease determined using an established CV risk assessment

      tool.

   4. : CT coronary Artery Calcification

8. Willing and, in the opinion of the investigator, able to adjust current COPD therapy, as

   required by the protocol.

9. Willing to visit at the study site or participate in virtual visits as required per the protocol

   to complete all study assessments.

10. A female is eligible to enter and participate in the study if the female is of:

    • Non-childbearing potential: either permanently sterilized or who are post-menopausal.
    • Childbearing potential: has a negative serum pregnancy test at V1 and must use one

    highly effective form of birth control.

11. Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the ICF and in the protocol.

Exclusion Criteria:

1. Active diagnosis of asthma within the past 5 years (previous diagnosis as a child or adolescent are eligible), asthma-COPD overlap, or any other chronic respiratory disease other than COPD such as alpha-1 antitrypsin deficiency, active tuberculosis, lung fibrosis, sarcoidosis, interstitial lung disease, and pulmonary hypertension.

2. End-stage renal disease requiring renal replacement therapy

3. History of heart or lung transplant or actively listed for heart or lung transplant.

4. Implanted left ventricular assist device or implant anticipated in < 3 months.

5. History of lung cancer and/or treatment for lung cancer within the 5 years prior to Visit 1.

6. Unstable or life-threatening cardiac disease - participants with any of the following at Visit 1 would be excluded:

   1. An MI or unstable angina in the last 8 weeks
   2. Unstable or life-threatening cardiac arrhythmia requiring intervention in the last 8 weeks.

   NOTE: Any participant who experiences unstable or life-threatening cardiac disease during the run-in period will be excluded but can be rescreened 8 weeks after the resolution of the event.

7. Pneumonia and/or moderate or severe COPD exacerbation that has not resolved at least 8 weeks prior to Visit 1

8. Any life-threatening condition, including malignancy, with a life expectancy < 5 years, other than CV disease or COPD, that might prevent the participant from completing the study.

9. Use of maintenance ICS treatment within the past 12 months.

10. Unable to abstain from protocol-defined prohibited medications

11. Participation in another clinical study with a study intervention administered in the last 30 days or 5 half-lives, whichever is longer prior to Visit 1 (any other investigational product that is not identified in protocol is prohibited for use during the duration of the study).

12. Participants with a known hypersensitivity to LAMA, LABA or ICS or any component of the MDI.

13. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).

14. Judgment by the investigator that the participant should not participate in the study if the participant is unlikely to comply with study procedures, restrictions, and requirements.

15. Previous randomization in the present study.

16. For females only - currently pregnant (confirmed with positive pregnancy test) or breastfeeding

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment:

https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure. Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.

AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at:

https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

When a request has been approved AstraZeneca will provide access to the deidentified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.