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

A Randomized, Double-Blind, 12-Week (With an Extension to 52 Weeks in a Subset of Participants), Multi-Center Study to Assess the Safety of Budesonide, Glycopyrronium, and Formoterol Fumarate (BGF) Delivered by MDI HFO Compared to BGF Delivered by MDI HFA in Participants With Moderate to Very Severe Chronic Obstructive Pulmonary Disease (COPD)

This is a 12-week (with an extension to 52 weeks in a subset of participants) study comparing the safety of BGF MDI HFO twice daily (BID) with BGF MDI HFA BID in participants with moderate to very severe COPD.

Study Overview

• Status: Active, not recruiting
• Conditions: Chronic Obstructive Pulmonary Disease (COPD)
• Intervention / Treatment: Drug: BGF MDI HFO 320/14.4/9.6 μg; Drug: BGF MDI HFA 320/14.4/9.6 μg

Detailed Description

This is a Phase 3 randomized, double-blind, 12-week (with an extension to 52 weeks in a subset of participants) study comparing the safety of BGF MDI HFO 320/14.4/9.6 μg twice daily (BID) with BGF MDI HFA 320/14.4/9.6 μg BID in participants with moderate to very severe COPD. For the 12-week study, 542 participants will be randomized to treatments BGF MDI HFO and BGF MDI HFA in a 1:1 ratio. Randomization will be stratified by region (Americas, Europe) and COPD disease severity (percent predicted FEV1 ≥ 50%, percent predicted FEV1 < 50%). Subsequently, the 120 participants per treatment arm who were randomized to the extended study will continue and remain on the randomized treatment to 52 weeks.

• Study Type: Interventional
• Enrollment (Actual): 558
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: AstraZeneca Clinical Study Information Center; Phone Number: 1-877-240-9479; Email: information.center@astrazeneca.com

Study Locations

• Argentina
  • Buenos Aires, Argentina, C1414AIF
    • Research Site
  • Buenos Aires, Argentina, C1425BEN
    • Research Site
  • Quilmes, Argentina, B1878FNR
    • Research Site
  • Rosario, Argentina, S2000DEJ
    • Research Site
  • San Fernando, Argentina, B1646EBJ
    • Research Site
• Bulgaria
  • Blagoevgrad, Bulgaria, 2700
    • Research Site
  • Dupnitsa, Bulgaria, 2602
    • Research Site
  • Lom, Bulgaria, 3600
    • Research Site
  • Pernik, Bulgaria, 2300
    • Research Site
  • Sandanski, Bulgaria, 2800
    • Research Site
  • Sevlievo, Bulgaria, 5400
    • Research Site
  • Sofia, Bulgaria, 1618
    • Research Site
  • Veliko Tarnovo, Bulgaria, 5000
    • Research Site
  • Vidin, Bulgaria, 3700
    • Research Site
• Canada
  • Quebec, Canada, G1G 3Y8
    • Research Site
  • Quebec, Canada, G1V 4G5
    • Research Site
  • Quebec, Canada, G2J 0C4
    • Research Site
  • Nova Scotia
    • Truro, Nova Scotia, Canada, B2N 1L2
      • Research Site
  • Ontario
    • Ajax, Ontario, Canada, L1S 2J5
      • Research Site
    • Burlington, Ontario, Canada, L7N 3V2
      • Research Site
    • Guelph, Ontario, Canada, N1H 6J2
      • Research Site
  • Quebec
    • Montréal, Quebec, Canada, H1M 1B1
      • Research Site
    • St Charles Borromee, Quebec, Canada, J6E 2B4
      • Research Site
    • Trois-Rivières, Quebec, Canada, G8T 7A1
      • Research Site
• Germany
  • Berlin, Germany, 10969
    • Research Site
  • Berlin, Germany, 10629
    • Research Site
  • Berlin, Germany, 10787
    • Research Site
  • Berlin, Germany, 13156
    • Research Site
  • Berlin, Germany, 12159
    • Research Site
  • Dresden, Germany, 01069
    • Research Site
  • Elsterwerda, Germany, 04910
    • Research Site
  • Essen, Germany, 45359
    • Research Site
  • Halle, Germany, 06108
    • Research Site
  • Hamburg, Germany, 20253
    • Research Site
  • Hannover, Germany, D-30173
    • Research Site
  • Hannover, Germany, 30449
    • Research Site
  • Hannover, Germany, 30159
    • Research Site
  • Karlsruhe, Germany, 76137
    • Research Site
  • Koblenz, Germany, 56068
    • Research Site
  • Magdeburg, Germany, 39120
    • Research Site
  • Rheine, Germany, 48431
    • Research Site
  • Schwerin, Germany, 19055
    • Research Site
  • Wiesbaden, Germany, 65189
    • Research Site
  • Witten, Germany, 58452
    • Research Site
• Mexico
  • Cuernavaca, Mexico, 62290
    • Research Site
  • Culiacán, Mexico, 80200
    • Research Site
  • Merida, Mexico, 97130
    • Research Site
  • Monterrey, Mexico, 64020
    • Research Site
  • México, Mexico, 03300
    • Research Site
• Poland
  • Bydgoszcz, Poland, 85-231
    • Research Site
  • Będzin, Poland, 42-500
    • Research Site
  • Grodzisk Mazowiecki, Poland, 05-825
    • Research Site
  • Inowrocław, Poland, 88-100
    • Research Site
  • Jelenia Góra, Poland, 58-506
    • Research Site
  • Kraków, Poland, 31-011
    • Research Site
  • Lublin, Poland, 20-412
    • Research Site
  • Piaseczno, Poland, 05-500
    • Research Site
  • Skórzewo, Poland, 60-185
    • Research Site
  • Szczecin, Poland, 70-111
    • Research Site
  • Zamość, Poland, 22-400
    • Research Site
  • Łódź, Poland, 91-053
    • Research Site
• Turkey
  • Ankara, Turkey, 06620
    • Research Site
  • Istanbul, Turkey, 34020
    • Research Site
  • Izmir, Turkey, 35110
    • Research Site
  • Mersin, Turkey, 33343
    • Research Site
  • Pamukkale, Turkey, 20070
    • Research Site
• United Kingdom
  • Blackpool, United Kingdom, FY3 7EN
    • Research Site
  • Corby, United Kingdom, NN17 2UR
    • Research Site
  • Liverpool, United Kingdom, L1 9ED
    • Research Site
  • Poole, United Kingdom, BH15 2HX
    • Research Site
  • Thetford, United Kingdom, IP24 1JD
    • Research Site
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85032
      • Research Site
  • California
    • Newport Beach, California, United States, 92663
      • Research Site
  • Florida
    • Miami, Florida, United States, 33175
      • Research Site
    • Sarasota, Florida, United States, 34239
      • Research Site
    • Tampa, Florida, United States, 33606
      • Research Site
  • Indiana
    • Valparaiso, Indiana, United States, 46383
      • Research Site
  • Louisiana
    • Crowley, Louisiana, United States, 70526
      • Research Site
  • Massachusetts
    • North Dartmouth, Massachusetts, United States, 02747
      • Research Site
  • Missouri
    • Saint Louis, Missouri, United States, 63141
      • Research Site
  • North Carolina
    • Charlotte, North Carolina, United States, 28209
      • Research Site
    • Wilmington, North Carolina, United States, 28401
      • Research Site
  • Ohio
    • Dublin, Ohio, United States, 43016
      • Research Site
  • Oregon
    • Grants Pass, Oregon, United States, 97527
      • Research Site
    • Portland, Oregon, United States, 97202
      • Research Site
  • South Carolina
    • Anderson, South Carolina, United States, 29621
      • Research Site
    • Columbia, South Carolina, United States, 29204
      • Research Site
    • Gaffney, South Carolina, United States, 29340
      • Research Site
  • Texas
    • Longview, Texas, United States, 75605
      • Research Site
    • McKinney, Texas, United States, 75069
      • Research Site
  • Virginia
    • Richmond, Virginia, United States, 23219
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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 by the ATS/ERS (Celli et al 2004) or by locally applicable guidelines;
3. Participants who have been regularly using dual ICS/LABA, LAMA/LABA, or ICS/LAMA/LABA (open or fixed-dose combinations) inhaled maintenance therapies for the 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 and post-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-years of 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 adjust current COPD therapy, as required by the protocol;
9. Participants must be able to demonstrate acceptable MDI administration and spirometry technique;
10. Participants who are willing to remain at the study center as required per protocol to complete all visit assessments;

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

    • Women not of childbearing potential are defined as women who are either permanently sterilized (hysterectomy, bilateral oophorectomy, or bilateral salpingectomy), or who are postmenopausal. Women will be considered postmenopausal if they have been amenorrhoeic for 52 weeks (12 months) prior to the planned date of randomization without an alternative medical cause. The following age-specific requirements apply:
    • Women < 50 years old would be considered postmenopausal if they have been amenorrhoeic for 52 weeks (12 months) or more following cessation of exogenous hormonal treatment and follicle stimulating hormone levels in the postmenopausal range.
    • Women ≥ 50 years old would be considered postmenopausal if they have been amenorrhoeic for 52 weeks (12 months) or more following cessation of all exogenous hormonal treatment.

12. Female participants of childbearing potential must use one highly effective form of birth control. A highly effective method of contraception is defined as one that can achieve a failure rate of less than 1% per year when used consistently and correctly. At enrollment, women of childbearing potential who are sexually active with a non-sterilized male partner should be stable on their chosen method of highly effective birth control, as defined below, and willing to remain on the birth control until at least 14 days after last dose of study intervention. Cessation of contraception 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 not acceptable methods of contraception. Female condom and male condom should not be used together.

    • All women of childbearing potential must have a negative serum pregnancy test result at Visit 1
    • Women <50 years of age with amenorrhea for 12 months without an alternative medical 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 intercourse during the entire period of risk associated with the study treatments. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the participant
    • Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation:
    • Oral
    • Intravaginal
    • Transdermal
    • Progestogen-only hormonal contraception associated with inhibition of ovulation:
    • Oral
    • Injectable
    • Implantable
    • Intrauterine device or intrauterine hormone-releasing system
    • Male partner sterilization/vasectomy with documentation of azoospermia prior to the female participant's entry into the study, and this male is the sole partner for that participant. The documentation on male sterility can come from the site personnel's review of participant's medical records, medical examination and/or semen analysis or medical history interview provided by her or her partner.
    • Bilateral tubal ligation
13. Capable of giving signed informed consent as described in Appendix A which includes compliance with the requirements and restrictions listed in the ICF and in this protocol

Exclusion Criteria:

1. Participants who have a documented history of physician-diagnosed asthma in the opinion of the Investigator based on thorough review of medical history and medical records, 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 disease including, but not limited to: cardiovascular, hepatic, renal, hematological, neurological, endocrine, gastrointestinal, or pulmonary. Significant is defined as any 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 could affect 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, cystic fibrosis, significant bronchiectasis (high resolution CT evidence of bronchiectasis that causes repeated acute exacerbations), immune deficiency disorders, severe neurological disorders affecting control of the upper airway, sarcoidosis, idiopathic interstitial pulmonary fibrosis, primary pulmonary hypertension, or pulmonary thromboembolic disease;
6. Participant with moderate or severe COPD exacerbation or respiratory infection ending 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 or during the Screening Period or that required hospitalization at any time prior to Visit 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 [endobronchial blockers, airway bypass, endobronchial valves, thermal vapor ablation, biological sealants, 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 the Investigator, or any other relevant cardiovascular disorder as judged by the Investigator;
12. Participant with narrow angle glaucoma not adequately treated and/or change in vision that may be relevant, in the opinion of the Investigator; Note: All medications approved for control of intraocular pressures are allowed including topical ophthalmic nonselective beta-blockers and prostaglandin analogs.
13. Symptomatic prostatic hypertrophy or bladder neck obstruction/urinary retention that, in the opinion of the Investigator, is clinically significant; Note: Participants with trans-urethral resection of prostate or full resection of the prostate 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 years prior to Visit 1; Note: Squamous cell and basal cell carcinomas of the skin are not exclusionary
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 function testing at each applicable study visit;
17. Participant is unable to abstain from protocol-defined prohibited medications during Screening 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, muscarinic antagonists, or corticosteroids, or any component of the MDI;
20. Participation in another clinical study with an intervention administered in the last 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 Kidney Disease Epidemiology Collaboration (CKD-EPI) formula;
23. Any clinically relevant abnormal findings in physical examination, clinical chemistry, hematology, vital signs, or ECG, which in the opinion of the Investigator, may put the participant at risk because of his/her participation in the study; Note: Participants with ECG QTcF interval (corrected for heart rate using Fridericia's formula [QTcF]) > 480 msec will be excluded. Participants with high degree atrioventricular block II or III, or with sinus node dysfunction with clinically significant pauses who are not treated with pacemaker will also be excluded.
24. Planned hospitalization during the study;
25. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site);
26. Study Investigators, sub-Investigators, coordinators, and their employee or immediate family members;
27. Judgment by the Investigator that the participant is unlikely to comply with study procedures, restrictions and requirements;
28. For women only - currently pregnant (confirmed with positive pregnancy test), breast feeding, or planned pregnancy during the study or women of childbearing potential not using acceptable contraception measures (see Inclusion criterion 12 in Section 5.1).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: BGF MDI HFO 320/14.4/9.6μg; Budesonide, Glycopyrronium, and Formoterol Fumarate (BGF) Delivered by MDI HFO (HFO-1234ze)	Drug: BGF MDI HFO 320/14.4/9.6 μg; Budesonide, Glycopyrronium, and Formoterol Fumarate; Other Names: BGF MDI HFO
Active Comparator: BGF MDI HFA 320/14.4/9.6 μg; Budesonide, Glycopyrronium, and Formoterol Fumarate (BGF) Delivered by MDI HFA	Drug: BGF MDI HFA 320/14.4/9.6 μg; Budesonide, Glycopyrronium, and Formoterol Fumarate; Other Names: BGF MDI HFA

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number (and percentage) of participants with adverse Events - AEs (including SAEs, DAEs, AEOSIs, non-serious AEs)	To assess the safety and tolerability of BGF MDI HFO as compared to BGF MDI HFA: AEs (including SAEs, DAEs, AEOSIs, non-serious AEs)	Over 16 or 56 Weeks (if attending 56 weeks study)
Number (and percentage) of participants with potentially clinically significant changes in Digital 12-lead Holter electrocardiogram (ECG)	To assess the safety and tolerability of BGF MDI HFO as compared to BGF MDI HFA: Digital 12-lead Holter electrocardiogram (ECG)	Week 0 and week 12
Number (and percentage) of participants with potentially clinically significant changes in 12-lead ECG	To assess the safety and tolerability of BGF MDI HFO as compared to BGF MDI HFA: 12-lead ECG	Week 4, 8 and 52 (if attending 56 weeks study)
Number (and percentage) of participants with potentially clinically significant changes in laboratory values (hematology, clinical chemistry and urinalysis)	To assess the safety and tolerability of BGF MDI HFO as compared to BGF MDI HFA: Clinical laboratory testing	Week 0, 12 and 52 (if attending 56 weeks study)
Number (and percentage) of participants with potentially clinically significant changes in Blood Pressure	To assess the safety and tolerability of BGF MDI HFO as compared to BGF MDI HFA: Blood Pressure	Over 14 or 54 weeks (if attending 56 weeks study)
Number (and percentage) of participants with potentially clinically significant changes in pulse rate	To assess the safety and tolerability of BGF MDI HFO as compared to BGF MDI HFA: pulse rate	Over 14 or 54 weeks (if attending 56 weeks study)
Number (and percentage) of participants with potentially clinically significant changes in respiratory rate	To assess the safety and tolerability of BGF MDI HFO as compared to BGF MDI HFA: respiratory rate	Over 14 or 54 weeks (if attending 56 weeks study)
Number (and percentage) of participants with potentially clinically significant changes in body temperature	To assess the safety and tolerability of BGF MDI HFO as compared to BGF MDI HFA: body temperature	Over 14 or 54 weeks (if attending 56 weeks study)

Collaborators and Investigators

• Sponsor: AstraZeneca

Study record dates

Study Major Dates

• Study Start (Actual): September 27, 2022
• Primary Completion (Estimated): March 21, 2024
• Study Completion (Estimated): March 21, 2024

Study Registration Dates

• First Submitted: September 19, 2022
• First Submitted That Met QC Criteria: October 6, 2022
• First Posted (Actual): October 10, 2022

Study Record Updates

• Last Update Posted (Actual): March 25, 2024
• Last Update Submitted That Met QC Criteria: March 22, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Respiratory Tract Diseases; Disease Attributes; Chronic Disease; Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive
• Other Study ID Numbers: D5985C00003; 2022-001476-33 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

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.

• IPD Sharing Time Frame: 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.
• IPD Sharing Access Criteria: 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.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No