| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Severe and inadequately controlled asthma |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10003553 |
| E.1.2 | Term | Asthma |
| E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
|
| 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 |
Main Objective of D5982C00007
1. To assess the effect of Budesonide, Glycopyrronium, and Formoterol Fumarate Metered Dose Inhaler (BGF MDI) relative to Budesonide and Formoterol Fumarate (BFF) MDI and Symbicort Pressurized MDI on lung function in participants with inadequately controlled asthma.
Main Objective of Pooled Studies D5982C00007 and D5982C00008
1. To assess the effect of BGF MDI relative to BFF MDI or Symbicort pMDI on asthma exacerbations in participants with inadequately controlled asthma. |
|
| E.2.2 | Secondary objectives of the trial |
Secondary Objectives of D5982C00007
1. To assess the effect of BGF MDI relative to BFF MDI or Symbicort pMDI on lung function in participants with inadequately controlled asthma.
2. To assess the effect of BGF MDI relative to BFF MDI or Symbicort pMDI on lung function, PROs, and symptoms in participants with inadequately controlled asthma.
Secondary Objectives of Pooled Studies D5982C00007 and D5982C00008
1. To assess the effect of BGF MDI relative to BFF MDI or Symbicort pMDI on asthma exacerbations in participants with inadequately controlled asthma. |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
1. 12-Hour Pharmacokinetic Sub-Study Objective (Feb 21, 2023; Version 4)
To characterize the steady state pharmacokinetics (PK) of budesonide, glycopyrronium, and formoterol fumarate based on PK assessments in participants with inadequately controlled asthma.
2. 24-Hour Holter Monitor Sub-Study Objective (Feb 21, 2023; Version 4)
To assess the cardiovascular safety of BGF MDI relative to BFF MDI or Symbicort pMDI as evaluated by 24-hour Holter monitoring.
3. 12-Hour Spirometry Sub-Study Objective (Feb 21, 2023; Version 4)
To assess the effect of BGF MDI relative to BFF MDI or Symbicort pMDI on pulmonary function test (PFT) parameters over 12 hours in participants with inadequately controlled asthma. |
|
| E.3 | Principal inclusion criteria |
1. 12 to 80 years of age, male and female, BMI <40 kg/m2; females
must be not of childbearing potential or using a form of highly effective birth control.
2. Documented history of physician-diagnosed asthma > and/or = 1 year prior to V1.
3. Regularly using a stable daily ICS/LABA regimen (including a stable
ICS dose) with medium-to-high ICS doses for at least 4 weeks prior to
V1.
4. ACQ-7 total score ≥1.5 at Visits 1, 3, and 5 (pre-randomization).
5. FEV1 % (assessed as an average of the 60 and 30 minute pre-dose
assessments) predicted normal at V1, 2, 3, 4, and 5 (pre-randomization)
• Participants > and/or = 18 years of age: < 80%
• Participants 12 to <18 years of age: < 90%
6. FEV1 post-albuterol at V2 or V3 (if repeat needed).
• Participants > and/or = 18 years of age: Increase > and/or = 12%
and > and/or = 200 mL.
• Participants 12 to <18 years of age: Increase =12% either in the 12
months prior to Visit 1 or at Visit 2, or at Visit 3.
• Note: Even if there is documented history of reversibility, all
participants must be assessed for reversibility at Visit 2 (and Visit 3, if
reversibility is not demonstrated at Visit 2) to provide reversibility
baseline data for characterization.
7. Willing and, in the opinion of the Investigator, able to adjust current asthma therapy, as required by the protocol.
8. Demonstrate acceptable MDI/pMDI administration technique.
9. Received no asthma medication other than run-in BFF MDI BID and
albuterol as needed during screening (except for allowed medications as defined in Table 9 and systemic corticosteroid or ICS for the treatment of an asthma exacerbation).
10. eDiary 14-day compliance ≥70% during screening (defined as
completing the daily eDiary for any 10 mornings and any 10 evenings and answering "Yes" to taking 2 puffs of run-in BFF MDI for any 10 mornings and 10 evenings in the last 14 days prior to randomization).
11. No respiratory infection in the 4 weeks prior to randomization, or
asthma exacerbation treated with systemic corticosteroid and/or additional ICS treatment in the 4 weeks prior to randomization. |
|
| E.4 | Principal exclusion criteria |
1. Completed treatment for respiratory infection or asthma exacerbation with systemic corticosteroids within 4 weeks of V1.
2a. Participants where, in the opinion of the Investigator, treatment with biological therapy for asthma would be appropriate.
2b. Any marketed or investigational biologics within 3 months or 5 halflives of V1, whichever is longer and must not be used during study duration.
3. Current smokers, former smokers with >10 pack-years history, or former smokers who stopped smoking <6 months prior to V1 (including all forms of tobacco, e-cigarettes or other vaping devices, and marijuana).
4. Current evidence of COPD.
5a. Oral and IV corticosteroid use (any dose) within 4 weeks of V1.
5b. Use of systemic corticosteroids for any other reason except for the acute treatment of severe asthma exacerbation is prohibited for the duration of the study.
5c. Depot corticosteroid use for any reason within 3 months of V1.
6. Use of LAMA, either alone or as part of an inhaled combination
therapy, in the 12 weeks prior to V1.
7. Use of oral beta 2-agonist within 3 months of V1.
8. Use of any immunomodulators or immunosuppressive medication within 3 months or 5 half-lives, whichever is longer, and must not be used during the study duration.
9. Narrow angle glaucoma not adequately treated and/or change in vision that may be relevant, in the opinion of the Investigator, within 3 months of Visit 1.
10. Life-threatening asthma defined as a history of significant asthma episode(s) requiring intubation associated with hypercapnia, respiratory arrest, hypoxic seizures, or asthma-related syncopal episode(s).
11. Hospitalization for asthma within 2 months of Visit 1.
12. Known history of drug or alcohol abuse within 12 months of Visit 1.
13. Regular use of a nebulizer or a home nebulizer for receiving asthma medications.
14. Using any herbal products by inhalation or nebulizer within 4 weeks of Visit 1 and does not agree to stop during the study duration.
15. Participation in another clinical study with a Study Intervention
administered in the last 30 days or 5 half-lives, whichever is longer. Any other Study Intervention that is not identified in the protocol is
prohibited for use during study duration.
16. Participants with a known hypersensitivity to beta2-agonists, corticosteroids, anticholinergics, or any component of the MDI or pMDI.
17. Study Investigators, sub-Investigators, coordinators, and their employees or immediate family members.
18. For women only – currently pregnant (confirmed with positive highly sensitive pregnancy test), breast-feeding, or planned pregnancy during the study or not using acceptable contraception measures, as judged by the Investigator. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary end point(s) of D5982C00007.
1. Europe (EU): Change from baseline in morning pre-dose trough FEV1 over 24 Weeks.
Primary end point(s) of Pooled Studies D5982C00007 and D5982C00008.
1. Rate of severe asthma exacerbations. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
D5982C00007.
Baseline to week 24.
Pooled Studies D5982C00007 and D5982C00008.
Treatment period (between week 1 to week 52). |
|
| E.5.2 | Secondary end point(s) |
Secondary end point(s) of D5982C00007.
1. Onset of action on Day 1: Absolute change in FEV1 at 5 minutes on Day 1.
2. Change from baseline in FEV1 AUC0-3 over 24 weeks.
3. Percentage of responders in ACQ-7 (≥0.5 decrease equals response) over 24 weeks.
4. Percentage of responders in ACQ-5 (≥0.5 decrease equals response) over 24 weeks.
5. Percentage of responders in the Asthma Quality of Life Questionnaire for 12 years and older (AQLQ(s) +12) (≥0.5 increase equals response) over 24 weeks.
6. Percentage of responders in the St. George’s Respiratory Questionnaire (SGRQ) (≥4.0 unit decrease equals response) at Week 24.
7. Rate of severe asthma exacerbations over the Treatment Period
Secondary end point(s) of Pooled Studies D5982C00007 and D5982C00008.
1. Time to first severe asthma exacerbation.
2. Rate of moderate/severe asthma exacerbations.
3. Time to first moderate/severe asthma exacerbation.
4. Rate of severe asthma exacerbations for participants with percent
predicted FEV1 ≤ 55% at baseline.
5. Rate of severe asthma exacerbations for participants with ≥ 1 severe exacerbation in the 12 months prior to Visit 1. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
D5982C00007.
Baseline to week 24.
Pooled Studies D5982C00007 and D5982C00008.
Treatment period (between week 1 to week 52). |
|
| 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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
|
| 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 | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| 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 | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 76 |
| 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 |
| Chile |
| New Zealand |
| Peru |
| Philippines |
| Taiwan |
| Canada |
| India |
| Japan |
| Korea, Republic of |
| Thailand |
| United States |
| Viet Nam |
| Belgium |
| Bulgaria |
| Hungary |
| Italy |
| Poland |
| Romania |
| Spain |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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 24 Visit and subsequent 2-week follow-up phone call. If study intervention was discontinued prior to the Week 24 Visit, then study will end at the completion of the Week 24 Visit. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | 1 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 6 |
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