Asthma
Conditions
Brief summary
This is a variable length study to evaluate the efficacy and safety of budesonide/glycopyrronium/formoterol inhaler in adults and adolescents with severe asthma inadequately controlled with standard of care
Detailed description
This is a randomized, double-blind, double dummy, parallel group, multicenter 24 to 52 week variable length study to assess the efficacy and safety of budesonide, glycopyrronium, and formoterol fumarate metered dose inhaler (MDI) relative to budesonide and formoterol fumarate MDI and Symbicort® pressurized MDI in adult and adolescent participants with inadequately controlled asthma. Approximately 2200 participants will be randomized globally.
Interventions
Budesonide, glycopyrronium, and formoterol fumarate metered dose inhaler
Budesonide, glycopyrronium, and formoterol fumarate metered dose inhaler
Budesonide and formoterol fumarate metered dose inhaler
Budesonide/formoterol fumarate pressurized metered dose inhaler
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
12 Years to 80 Years
Healthy volunteers
No
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 ≥ 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.
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 half-lives 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 Chronic Obstructive Pulmonary Disease (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 Long-Acting Muscarinic Antagonist (LAMA), either alone or as part of an inhaled combination therapy, in the 12 weeks prior to V1. 7\. Use of oral beta2-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. Please refer to the study protocol for the complete inclusion and
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in FEV1 AUC0-3 (L) at Week 24 | Week 24 | Change from baseline in forced expiratory volume in 1 second (FEV1) area under the curve 0 to 3 hours (AUC0-3) at Week 24. Treatment policy was implemented to handle all intercurrent events (ICEs) with the exception of initiation of new asthma therapy or use of prohibited medications thought to impact efficacy in conjunction with premature discontinuation of study intervention, for which the composite strategy was implemented. |
| Pooled (KALOS/LOGOS): Rate of Severe Asthma Exacerbations | Up to 52 weeks | Rate of severe asthma exacerbations was assessed in a pre-specified pooled analysis across replicate studies D5982C00007 and D5982C00008 (NCT04609904). An asthma exacerbation was severe if it resulted in at least 1 of the following: a course of systemic corticosteroids for 3 days to treat symptoms of asthma worsening, an ER/urgent care visit that required treatment with systemic corticosteroids, an inpatient hospitalization, or death related to asthma. Consecutive exacerbations with start/stop days ≤7 days apart were considered the same event of the highest severity. Treatment policy was implemented to handle all ICEs with the exception of initiation of new asthma therapy or use of prohibited medications thought to impact efficacy in conjunction with premature discontinuation of study intervention, for which the composite strategy was implemented. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Responders in AQLQ(s)+12 (≥0.5 Increase Equals Response) at Week 24 | Week 24 | Percentage of responders in the Asthma Quality of Life Questionnaire for 12 years and older (AQLQ(s)+12) (≥0.5 increase equals response) at Week 24. Treatment policy was implemented to handle all ICEs with the exception of initiation of new asthma therapy or use of prohibited medications thought to impact efficacy in conjunction with premature discontinuation of study intervention, for which the composite strategy was implemented. |
| Percentage of Responders in SGRQ (≥4.0 Decrease Equals Response) at Week 24 | Week 24 | Percentage of responders in the St. George's Respiratory Questionnaire (SGRQ) (≥4.0 decrease equals response) at Week 24. Treatment policy was implemented to handle all ICEs with the exception of initiation of new asthma therapy or use of prohibited medications thought to impact efficacy in conjunction with premature discontinuation of study intervention, for which the composite strategy was implemented. |
| Change From Baseline in Morning Pre-dose Trough FEV1 (L) at Week 24 | Week 24 | Change from baseline in morning pre-dose trough forced expiratory volume in 1 second (FEV1) at Week 24. Treatment policy was implemented to handle all ICEs with the exception of initiation of new asthma therapy or use of prohibited medications thought to impact efficacy in conjunction with premature discontinuation of study intervention, for which the composite strategy was implemented. |
| Onset of Action on Day 1: Absolute Change in FEV1 (L) at 5 Minutes on Day 1 | Day 1 | Onset of action on Day 1: Absolute change in FEV1 at 5 minutes on Day 1. Treatment policy was implemented to handle all ICEs with the exception of initiation of new asthma therapy or use of prohibited medications thought to impact efficacy in conjunction with premature discontinuation of study intervention, for which the composite strategy was implemented. |
| Pooled (KALOS/LOGOS): Rate of Severe Asthma Exacerbations for Participants With Percent Predicted FEV1 ≤55% at Baseline | Up to 52 weeks | Rate of severe asthma exacerbations for participants with percent predicted FEV1 ≤55% at baseline was assessed in a pre-specified pooled analysis across replicate studies D5982C00007 and D5982C00008 (NCT04609904). An asthma exacerbation was severe if it resulted in at least 1 of the following: a course of systemic corticosteroids for 3 days to treat symptoms of asthma worsening, an ER/urgent care visit that required treatment with systemic corticosteroids, an inpatient hospitalization , or death related to asthma. Consecutive exacerbations with start/stop days ≤7 days apart were considered the same event of the highest severity. Treatment policy was implemented to handle all ICEs with the exception of initiation of new asthma therapy or use of prohibited medications thought to impact efficacy in conjunction with premature discontinuation of study intervention, for which the composite strategy was implemented. |
| Pooled (KALOS/LOGOS): Rate of Severe Asthma Exacerbations for Participants With ≥1 Severe Exacerbation in the 12 Months Prior to Visit 1 | Up to 52 weeks | Rate of severe asthma exacerbations for participants with ≥1 severe exacerbation in the 12 months prior to Visit 1 was assessed in a pre-specified pooled analysis across replicate studies D5982C00007 and D5982C00008 (NCT04609904). An asthma exacerbation was considered severe if it resulted in at least 1 of the following: a course of systemic corticosteroids for 3 days to treat symptoms of asthma worsening, an ER/urgent care visit that required treatment with systemic corticosteroids, an inpatient hospitalization, or death related to asthma. Consecutive exacerbations with start/stop days ≤7 days apart were considered the same event of the highest severity. Treatment policy was implemented to handle all ICEs with the exception of initiation of new asthma therapy or use of prohibited medications thought to impact efficacy in conjunction with premature discontinuation of study intervention, for which the composite strategy was implemented. |
| Pooled (KALOS/LOGOS): Time to First Severe Asthma Exacerbation | Up to 52 weeks | Time to first severe asthma exacerbation was assessed in a pre-specified pooled analysis across replicate studies D5982C00007 and D5982C00008 (NCT04609904). Time to first severe asthma exacerbation was the time from the first dose of study medication to the time of onset of the first severe asthma exacerbation. Treatment policy was implemented to handle all ICEs with the exception of initiation of new asthma therapy or use of prohibited medications thought to impact efficacy in conjunction with premature discontinuation of study intervention, for which the composite strategy was implemented. |
| Pooled (KALOS/LOGOS): Rate of Moderate or Severe Asthma Exacerbations | Up to 52 weeks | Rate of moderate or severe asthma exacerbations was assessed in a pre-specified pooled analysis across replicate studies D5982C00007 and D5982C00008 (NCT04609904). An asthma exacerbation was severe if it resulted in at least 1 of the following: a course of systemic corticosteroids for 3 days to treat symptoms of asthma worsening, an ER/urgent care visit that required systemic corticosteroids, an inpatient hospitalization, or death related to asthma. A moderate asthma exacerbation was a worsening of symptoms that resulted in an additional ICS for 3 days. Consecutive exacerbations with start/stop days ≤7 days apart were considered the same event of the highest severity. Treatment policy was implemented to handle all ICEs with the exception of initiation of new asthma therapy or use of prohibited medications thought to impact efficacy in conjunction with premature discontinuation of study intervention, for which the composite strategy was implemented. |
| Pooled (KALOS/LOGOS): Time to First Moderate or Severe Asthma Exacerbation | Up to 52 weeks | Time to first moderate/severe asthma exacerbation was assessed in a pre-specified pooled analysis across replicate studies D5982C00007 and D5982C00008 (NCT04609904). Time to first moderate or severe asthma exacerbation was the time from the first dose of study medication to the time of onset of the first moderate or severe asthma exacerbation. Treatment policy was implemented to handle all ICEs with the exception of initiation of new asthma therapy or use of prohibited medications thought to impact efficacy in conjunction with premature discontinuation of study intervention, for which the composite strategy was implemented. |
| Pooled (KALOS/LOGOS): Percentage of Responders in ACQ-7 (≥0.5 Decrease Equals Response) at Week 24 | Week 24 | Pooled percentage of responders in ACQ-7 (≥0.5 decrease equals response) at Week 24 was assessed in a pre-specified pooled analysis across replicate studies D5982C00007 and D5982C00008 (NCT04609904). Treatment policy was implemented to handle all ICEs with the exception of initiation of new asthma therapy or use of prohibited medications thought to impact efficacy in conjunction with premature discontinuation of study intervention, for which the composite strategy was implemented. |
| Pooled (KALOS/LOGOS): Percentage of Responders in ACQ-5 (≥0.5 Decrease Equals Response) at Week 24 | Week 24 | Pooled percentage of responders in ACQ-5 (≥0.5 decrease equals response) at Week 24 was assessed in a pre-specified pooled analysis across replicate studies D5982C00007 and D5982C00008 (NCT04609904). Treatment policy was implemented to handle all ICEs with the exception of initiation of new asthma therapy or use of prohibited medications thought to impact efficacy in conjunction with premature discontinuation of study intervention, for which the composite strategy was implemented. |
| Percentage of Responders in ACQ-7 (≥0.5 Decrease Equals Response) at Week 24 | Week 24 | Percentage of responders in the Asthma Control Questionnaire (ACQ)-7 (≥0.5 decrease equals response) at Week 24. Treatment policy was implemented to handle all ICEs with the exception of initiation of new asthma therapy or use of prohibited medications thought to impact efficacy in conjunction with premature discontinuation of study intervention, for which the composite strategy was implemented. |
| Pooled (KALOS/LOGOS): Percentage of Responders in AQLQ(s)+12 (≥0.5 Increase Equals Response) at Week 24 | Week 24 | Pooled percentage of responders in AQLQ(s)+12 (≥0.5 increase equals response) at Week 24 was assessed in a pre-specified pooled analysis across replicate studies D5982C00007 and D5982C00008 (NCT04609904). Treatment policy was implemented to handle all ICEs with the exception of initiation of new asthma therapy or use of prohibited medications thought to impact efficacy in conjunction with premature discontinuation of study intervention, for which the composite strategy was implemented. |
| Percentage of Responders in the ACQ-5 (≥0.5 Decrease Equals Response) at Week 24 | Week 24 | Percentage of responders in ACQ-5 (≥0.5 decrease equals response) at Week 24. Treatment policy was implemented to handle all ICEs with the exception of initiation of new asthma therapy or use of prohibited medications thought to impact efficacy in conjunction with premature discontinuation of study intervention, for which the composite strategy was implemented. |
Countries
Argentina, Belgium, Bulgaria, Canada, Chile, Hungary, India, Italy, Japan, New Zealand, Peru, Philippines, Poland, Puerto Rico, Romania, South Korea, Spain, Taiwan, Thailand, United States, Vietnam
Participant flow
Recruitment details
A total of 2274 subjects were randomized at 378 study centers in 20 countries from 15 December 2020. The last subject completed their last study visit on 21 March 2025. Of the 2274 randomized subjects, all populations excluded 125 subjects due to GCP violations and 5 subjects due to not receiving study therapy.
Pre-assignment details
Adult and adolescent subjects with inadequately controlled moderate to severe asthma were randomized to 1 of 4 treatment groups: BGF MDI 320/28.8/9.6 μg, BGF MDI 320/14.4/9.6 μg, BFF MDI 320/9.6 μg, and Symbicort pMDI 320/9 μg. Subjects who were eligible for the study discontinued their medium or high dose ICS/LABA at Visit 1 and initiated run-in BFF MDI until randomization.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Categorical Age group (years) <=18 years | 22 Participants |
| Age, Categorical Age group (years) >=65 years | 148 Participants |
| Age, Categorical Age group (years) Between 18 and 65 years | 432 Participants |
| Baseline Pre-bronchodilator Percent Predicted FEV1 (%) | 58.7 Percentage STANDARD_DEVIATION 12.3 |
| Baseline Reversibility (%) | 23.6 Percentage STANDARD_DEVIATION 19.9 |
| Baseline Severe Asthma Exacerbation History Within the Prior Year 0 exacerbations | 204 Participants |
| Baseline Severe Asthma Exacerbation History Within the Prior Year 1 exacerbation | 272 Participants |
| Baseline Severe Asthma Exacerbation History Within the Prior Year ≥2 exacerbations | 452 Participants |
| Ethnicity (NIH/OMB) Ethnicity Hispanic or Latino | 664 Participants |
| Ethnicity (NIH/OMB) Ethnicity Not Hispanic or Latino | 412 Participants |
| Ethnicity (NIH/OMB) Ethnicity Unknown or Not Reported | 0 Participants |
| Prior Inhaled Corticosteroid (ICS) Dose High | 911 Participants |
| Prior Inhaled Corticosteroid (ICS) Dose Low | 4 Participants |
| Prior Inhaled Corticosteroid (ICS) Dose Medium | 344 Participants |
| Prior Inhaled Corticosteroid (ICS) Dose Missing | 0 Participants |
| Race (NIH/OMB) Race American Indian or Alaska Native | 15 Participants |
| Race (NIH/OMB) Race Asian | 518 Participants |
| Race (NIH/OMB) Race Black or African American | 9 Participants |
| Race (NIH/OMB) Race More than one race | 49 Participants |
| Race (NIH/OMB) Race Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Race Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) Race White | 216 Participants |
| Region of Enrollment Argentina | 102 Participants |
| Region of Enrollment Belgium | 1 Participants |
| Region of Enrollment Bulgaria | 85 Participants |
| Region of Enrollment Canada | 53 Participants |
| Region of Enrollment Chile | 23 Participants |
| Region of Enrollment Hungary | 130 Participants |
| Region of Enrollment India | 42 Participants |
| Region of Enrollment Italy | 3 Participants |
| Region of Enrollment Japan | 52 Participants |
| Region of Enrollment Korea, Republic Of | 9 Participants |
| Region of Enrollment New Zealand | 2 Participants |
| Region of Enrollment Peru | 40 Participants |
| Region of Enrollment Philippines | 111 Participants |
| Region of Enrollment Poland | 58 Participants |
| Region of Enrollment Romania | 71 Participants |
| Region of Enrollment Spain | 4 Participants |
| Region of Enrollment Taiwan, China | 12 Participants |
| Region of Enrollment Thailand | 6 Participants |
| Region of Enrollment United States | 57 Participants |
| Region of Enrollment Viet Nam | 23 Participants |
| Sex: Female, Male Sex Female | 384 Participants |
| Sex: Female, Male Sex Male | 114 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 342 | 1 / 594 | 1 / 606 | 2 / 602 |
| other Total, other adverse events | 81 / 342 | 109 / 594 | 123 / 606 | 119 / 602 |
| serious Total, serious adverse events | 18 / 342 | 32 / 594 | 34 / 606 | 32 / 602 |
Outcome results
None listed