| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Moderate to Very Severe Chronic Obstructive Pulmonary Disease (COPD) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Chronic Obstructive Pulmonary Disease |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10010952 |
| E.1.2 | Term | COPD |
| E.1.2 | System Organ Class | 100000004855 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| Safety objectives: To assess the safety and tolerability of BGF MDI HFO as compared to BGF MDI HFA over 12 to 52 weeks in participants with moderate to very severe COPD |
|
| E.2.2 | Secondary objectives of the trial |
Exploratory objectives:
1. To assess the safety and tolerability of BGF MDI HFO compared to BGF MDI HFA over 12 to 52 weeks in participants with moderate to very severe COPD
2. To explore the effect of BGF MDI HFO compared to BGF MDI HFA over 12 to 52 weeks on respiratory health status |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Age
1. Participant must be 40 to 80 years of age inclusive, at the time of signing the ICF;
Type of Participant and Disease Characteristics
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;
Sex
11. Females must either be not of childbearing potential, or using a form of highly effective birth control as defined below:
o 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:
o 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.
o 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.
o All women of childbearing potential must have a negative serum pregnancy test result at Visit 1
o 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:
o Sexual abstinence defined as complete abstinence from intercourse when it is the preferred and usual lifestyle of the participant (however, periodic abstinence eg, calendar, ovulation, symptothermal, post-ovulation methods, and withdrawal are not acceptable methods of contraception)
o Contraceptive subdermal implant
o Intrauterine device or intrauterine system
o Oral contraceptive (combined or progesterone only)
o Injectable progestogen
o Contraceptive vaginal ring
o Percutaneous contraceptive patches
o Male partner sterilization 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
o Bilateral tubal ligation
Informed Consent
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 |
|
| E.4 | Principal 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.
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, 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
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
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
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 |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1. AEs (including SAEs, DAEs, AEOSIs, non-serious AEs)
2. Digital 12-lead Holter electrocardiogram (ECG)
3. 12-lead ECG
4. Clinical laboratory testing
5. Vital signs |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Over 16 or 56 Weeks (if attending 56 weeks study)
2. Week 0 and week 12
3. Week 4, 8 and 52 (if attending 56 weeks study)
4. Week 0, 12 and 52 (if attending 56 weeks study)
5. Over 14 or 54 Weeks (if attending 56 weeks study) |
|
| E.5.2 | Secondary end point(s) |
1. Change from pre-dose value in FEV1 at 5, 15, 30, and 60 min post dose
2. Change from baseline COPD Assessment Test (CAT) at 12 and 52 weeks |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Over 12 or 52 Weeks (if attending 56 weeks study)
2. Week 12 and 52 (if attending 56 weeks study) |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
|
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 12 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 50 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Argentina |
| Canada |
| Mexico |
| Turkey |
| United Kingdom |
| United States |
| Bulgaria |
| Germany |
| Poland |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The study will end when the last remaining participant completes his/her Week 52/Visit 9 (Week 12/Visit 6 for participants contributing only to the 12 weeks safety study) and subsequent 2-week follow-up telephone contact. If study intervention is discontinued prior to the Week 52/Visit 9(Week 12/Visit 6 for participants contributing only to the 12 weeks safety study), then study will end at the completion of the Withdrawal Visit and subsequent 2-week follow-up telephone contact. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
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