A Study to Assess the Safety of Budesonide/Glycopyrronium/Formoterol Fumarate With a Next-Generation Propellant in Participants With Moderate to Very Severe Chronic Obstructive Pulmonary Disease

Inclusion Criteria:

1. Participant must be 40 to 80 years of age inclusive, at the time of signing the ICF;

2. Participants who have a documented history of physician-diagnosed COPD as defined bythe ATS/ERS (Celli et al 2004) or by locally applicable guidelines;

3. Participants who have been regularly using dual ICS/LABA, LAMA/LABA, orICS/LAMA/LABA (open or fixed-dose combinations) inhaled maintenance therapies forthe management of their COPD for at least 6 weeks prior to Screening;

4. Participants who have pre-bronchodilator FEV1 of < 80% predicted normal at Visit 1;

5. Participants who have post-bronchodilator FEV1/FVC ratio of < 0.70 andpost-bronchodilator FEV1 of ≥ 25% to < 80% predicted normal at Visit 2;

6. Participants who have CAT score ≥ 10 at Visit 1;

7. Participants who are current/former smokers with a history of at least 10 pack-yearsof tobacco smoking (1 pack year = 20 cigarettes smoked per day for 1 year);

8. Participants who are willing and, in the opinion of the Investigator, able to adjustcurrent COPD therapy, as required by the protocol;

9. Participants must be able to demonstrate acceptable MDI administration andspirometry technique;

10. Participants who are willing to remain at the study center as required per protocolto complete all visit assessments;

11. Females must either be not of childbearing potential, or using a form of highlyeffective birth control as defined below:

• Women not of childbearing potential are defined as women who are eitherpermanently sterilized (hysterectomy, bilateral oophorectomy, or bilateralsalpingectomy), or who are postmenopausal. Women will be consideredpostmenopausal if they have been amenorrhoeic for 52 weeks (12 months) prior tothe planned date of randomization without an alternative medical cause. Thefollowing age-specific requirements apply:

• Women < 50 years old would be considered postmenopausal if they have beenamenorrhoeic for 52 weeks (12 months) or more following cessation of exogenoushormonal treatment and follicle stimulating hormone levels in thepostmenopausal range.

• Women ≥ 50 years old would be considered postmenopausal if they have beenamenorrhoeic for 52 weeks (12 months) or more following cessation of allexogenous hormonal treatment.

12. Female participants of childbearing potential must use one highly effective form ofbirth control. A highly effective method of contraception is defined as one that canachieve a failure rate of less than 1% per year when used consistently andcorrectly. At enrollment, women of childbearing potential who are sexually activewith a non-sterilized male partner should be stable on their chosen method of highlyeffective birth control, as defined below, and willing to remain on the birthcontrol until at least 14 days after last dose of study intervention. Cessation ofcontraception after this point should be discussed with a responsible physician.Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhea method are notacceptable methods of contraception. Female condom and male condom should not beused together.

• All women of childbearing potential must have a negative serum pregnancy testresult at Visit 1

• Women <50 years of age with amenorrhea for 12 months without an alternativemedical cause must have a serum LH and FSH test (within 21-28 days before Visit

3. for study eligibility Highly effective birth control methods are listed below:

• Sexual abstinence defined as complete abstinence from heterosexual intercourseduring the entire period of risk associated with the study treatments. Thereliability of sexual abstinence needs to be evaluated in relation to theduration of the clinical trial and the preferred and usual lifestyle of theparticipant

• Combined (estrogen and progestogen containing) hormonal contraceptionassociated with inhibition of ovulation:

• Oral

• Intravaginal

• Transdermal

• Progestogen-only hormonal contraception associated with inhibition ofovulation:

• Oral

• Injectable

• Implantable

• Intrauterine device or intrauterine hormone-releasing system

• Male partner sterilization/vasectomy with documentation of azoospermia prior tothe female participant's entry into the study, and this male is the solepartner for that participant. The documentation on male sterility can come fromthe site personnel's review of participant's medical records, medicalexamination and/or semen analysis or medical history interview provided by heror her partner.

• Bilateral tubal ligation

13. Capable of giving signed informed consent as described in Appendix A which includescompliance with the requirements and restrictions listed in the ICF and in thisprotocol

Exclusion Criteria:

1. Participants who have a documented history of physician-diagnosed asthma in theopinion of the Investigator based on thorough review of medical history and medicalrecords, within 5 years of Visit 1;

2. Participants who have COPD due to α1-Antitrypsin Deficiency;

3. Participants with historical or current evidence of a clinically significant diseaseincluding, but not limited to: cardiovascular, hepatic, renal, hematological,neurological, endocrine, gastrointestinal, or pulmonary. Significant is defined asany uncontrolled disease or any disease that, in the opinion of the Investigator,would put the safety of the participant at risk through participation, or that couldaffect the efficacy or safety analyses;

4. Sleep apnea that, in the opinion of the Investigator, cannot be controlled;

5. Other respiratory disorders including known active tuberculosis, lung cancer, cysticfibrosis, significant bronchiectasis (high resolution CT evidence of bronchiectasisthat causes repeated acute exacerbations), immune deficiency disorders, severeneurological disorders affecting control of the upper airway, sarcoidosis,idiopathic interstitial pulmonary fibrosis, primary pulmonary hypertension, orpulmonary thromboembolic disease;

6. Participant with moderate or severe COPD exacerbation or respiratory infectionending within 4 weeks prior to Visit 1 or during the Screening period;

7. Participant who has had a SARS-CoV-2 infection in the 8 weeks prior to Visit 1 orduring the Screening Period or that required hospitalization at any time prior toVisit 1 or during the Screening Period;

8. Pulmonary resection or lung volume reduction surgery during the 26 weeks (6 months)prior to Visit 1 (ie, lobectomy, bronchoscopy lung volume reduction [endobronchialblockers, airway bypass, endobronchial valves, thermal vapor ablation, biologicalsealants, and airway implants]);

9. Long-term oxygen therapy;

10. Imminent life-threatening COPD (eg, need for mechanical ventilation);

11. Participant who has significant or unstable ischemic heart disease, arrhythmia,cardiomyopathy, heart failure, uncontrolled hypertension as defined by theInvestigator, or any other relevant cardiovascular disorder as judged by theInvestigator;

12. Participant with narrow angle glaucoma not adequately treated and/or change invision that may be relevant, in the opinion of the Investigator; Note: Allmedications approved for control of intraocular pressures are allowed includingtopical ophthalmic nonselective beta-blockers and prostaglandin analogs.

13. Symptomatic prostatic hypertrophy or bladder neck obstruction/urinary retentionthat, in the opinion of the Investigator, is clinically significant; Note:Participants with trans-urethral resection of prostate or full resection of theprostate within 26 weeks (6 months) prior to Visit 1 are excluded from the study

14. Unresectable cancer that has not been in complete remission for at least 5 yearsprior to Visit 1; Note: Squamous cell and basal cell carcinomas of the skin are notexclusionary

15. Known history of drug or alcohol abuse within 52 weeks (12 months) of Visit 1;

16. Unable to withhold short-acting bronchodilators for 6 hours prior to lung functiontesting at each applicable study visit;

17. Participant is unable to abstain from protocol-defined prohibited medications duringScreening and Treatment Periods;

18. Using any herbal products either by inhalation or nebulizer within 2 weeks of Visit 1 and does not agree to stop for the duration of the study;

19. Participants with a known hypersensitivity to beta2-agonists, muscarinicantagonists, or corticosteroids, or any component of the MDI;

20. Participation in another clinical study with an intervention administered in thelast 30 days or 5 half-lives, whichever is longer;

21. Previous randomization in any study using BGF MDI HFO (budesonide/glycopyrronium/formoterol fumarate - HFO);

22. Participants with calculated eGFR ≤ 30 mL/minute/1.73m2 using the Chronic KidneyDisease Epidemiology Collaboration (CKD-EPI) formula;

23. Any clinically relevant abnormal findings in physical examination, clinicalchemistry, hematology, vital signs, or ECG, which in the opinion of theInvestigator, may put the participant at risk because of his/her participation inthe study; Note: Participants with ECG QTcF interval (corrected for heart rate usingFridericia's formula [QTcF]) > 480 msec will be excluded. Participants with highdegree atrioventricular block II or III, or with sinus node dysfunction withclinically significant pauses who are not treated with pacemaker will also beexcluded.

24. Planned hospitalization during the study;

25. Involvement in the planning and/or conduct of the study (applies to both AstraZenecastaff and/or staff at the study site);

26. Study Investigators, sub-Investigators, coordinators, and their employee orimmediate family members;

27. Judgment by the Investigator that the participant is unlikely to comply with studyprocedures, restrictions and requirements;

28. For women only - currently pregnant (confirmed with positive pregnancy test), breastfeeding, or planned pregnancy during the study or women of childbearing potentialnot using acceptable contraception measures (see Inclusion criterion 12 in Section 5.1).