Asthma
Conditions
Brief summary
This is a 24 week study to evaluate the efficacy and safety of budesonide and formoterol fumarate metered dose inhaler in adults and adolescents with inadequately controlled asthma.
Detailed description
This is a Phase III randomized, double-blind, active comparison, parallel group, multicenter study comparing BFF MDI 320/9.6 μg to BD MDI 320 µg and open-label Symbicort TBH 320/9 μg in adult and adolescent participants who have asthma which remains inadequately controlled (ACQ-7 total score ≥ 1.5) despite treatment with medium dose ICS or ICS/LABA. Budesonide and Formoterol Fumarate MDI 160/9.6 μg is included in this study to evaluate dose response by comparing to BFF MDI 320/9.6 μg. All doses represent the sum of 2 actuations. All study interventions will be administered BID for 24 weeks. This study will be conducted at approximately 125 sites worldwide and will randomize approximately 630 adult and adolescent participants.
Interventions
Budesonide/ Formoterol Fumarate (BFF) metered-dose inhaler (MDI), 320/9.6 μg
Budesonide/ Formoterol Fumarate (BFF) metered-dose inhaler (MDI), 160/9.6 μg
DRUGBD MDI 320 μg
Budesonide MDI (BD MDI), 320 μg
DRUGOpen-label Symbicort TBH 320/9 μg
Open-label Symbicort Turbuhaler 320/9 μg
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Open Label for Symbicort TBH
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. Participants who have a documented history of physician-diagnosed asthma ≥ 6 months prior to Visit 1, according to GINA guidelines \[GINA 2020\]. Healthcare records for one year prior to Visit 1 must be provided for adolescent participants (12 to \< 18 years of age) to ensure consistent evaluation and follow-up of treatment in those participants. 3. Participants who have been regularly using a stable daily ICS or an ICS/LABA regimen (including a stable ICS dose), with the ICS doses, for at least 8 weeks prior to Visit 1. 4. ACQ-7 total score ≥ 1.5 at Visits 1 and 4. 5. Pre-bronchodilator/pre-dose FEV1 \<90% predicted normal value at Visits 1, 2 and 3, and a pre-dose FEV1 of 50% to 90% at Visit 4 (pre-randomization). 6. Reversibility to albuterol, defined as a post-albuterol increase in FEV1 of ≥ 12% and ≥ 200 mL for participants ≥ 18 years of age OR a post-albuterol increase in FEV1 of ≥ 12% for participants 12 to \< 18 years of age, either in the 12 months prior to Visit 1 or at Visit 2 or Visit 3. 7. A pre-bronchodilator/pre-dose FEV1 at Visits 2, 3, and 4 that have not changed 20% or more (increase or decrease) from the pre-bronchodilator/pre-dose FEV1 recorded at the previous visit. 8. Asthma stability during run-in based on Investigator discretion using the symptom worsening assessment. 9. Willing and, in the opinion of the Investigator, able to adjust current asthma therapy, as required by the protocol. 10. Demonstrate acceptable MDI administration technique. 11. eDiary compliance ≥ 70% during screening, defined as completing the daily eDiary and answering "Yes" to taking 2 puffs of run-in BD MDI for any 10 mornings and 10 evenings in the last 14 days prior to randomization.
Exclusion criteria
1. Life-threatening asthma as defined as a history of significant asthma episode(s) requiring intubation associated with hypercapnia, respiratory arrest, hypoxic seizures, or asthma related syncopal episode(s). 2. Any respiratory infection or asthma exacerbation treated with systemic corticosteroids and/or additional ICS treatment in the 8 weeks prior to Visit 1 and throughout the Screening Period. 3. Hospitalization for asthma within 8 weeks of Visit 1. 4. Historical or current evidence of a clinically significant disease including, but not limited to: cardiovascular, hepatic, renal, hematological, neurological, endocrine, gastrointestinal, or pulmonary (eg, active tuberculosis, bronchiectasis, pulmonary eosinophilic syndromes, and COPD). Significant is defined as 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 analysis. 5. Known history of drug or alcohol abuse within 12 months of Visit 1. 6. Unresectable cancer that has not been in complete remission for at least 5 years prior to Visit 1. 7. 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 this protocol is prohibited for use during study duration. 8. Previous or current randomization into studies within the AEROSPHERE program including KALOS, LOGOS, VATHOS, LITHOS, or any glycopyrronium studies (PT001). 9. Use of a nebulizer or a home nebulizer for receiving asthma medications. 10. Do not meet the stable dosing period prior to Visit 1 or unable to abstain from protocol-defined prohibited medications during Screening and Treatment Periods. 11. Receipt of COVID-19 vaccine (regardless of vaccine delivery platform, eg, vector, lipid nanoparticle) \< 7 days prior to Visit 1 (from last vaccination or booster dose). 12. Participants with known hypersensitivity to beta2-agonists, corticosteroids, or any component of the MDI. 13. 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. 14. Current smokers, former smokers with \> 10 pack-years history, or former smokers who stopped smoking \< 6 months prior to Visit 1 (including all forms of tobacco, e-cigarettes or other vaping devices, and marijuana). 15. Planned hospitalization during the study. 16. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site). 17. Study Investigators, sub-Investigators, coordinators, and their employees or immediate family members. 18. Judgment by the Investigator that the participant is unlikely to comply with study procedures, restrictions, and requirements. 19. For women only - currently pregnant (confirmed with positive highly sensitive urine pregnancy test), breast-feeding, or planned pregnancy during the study or not using acceptable contraception measures, as judged by the Investigator.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) Area Under the Curve 0 to 3 Hours (AUC0-3) at Week 24 | At 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. FEV1 AUC0-3 is calculated from 0-3 hours post-dose using the trapezoidal rule, divided by the observation time to report the result in liters. Treatment policy is implemented to handle all intercurrent events with the exception of initiation of new asthma therapy or administration of prohibited medications thought to impact efficacy in conjunction with premature discontinuation of randomised study intervention, for which the composite strategy is implemented. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Morning Pre-dose Trough FEV1 at Week 24 | At 24 Weeks | Change from baseline in morning pre-dose trough FEV1 at Week 24. Treatment policy is implemented to handle all intercurrent events with the exception of initiation of new asthma therapy or administration of prohibited medications thought to impact efficacy in conjunction with premature discontinuation of randomised study intervention, for which the composite strategy is implemented. |
| Onset of Action on Day 1: Absolute Change in FEV1 at 5 Minutes on Day 1 | On Day 1 | Onset of action on Day 1: Absolute change in FEV1 at 5 minutes on Day 1. Treatment policy is implemented to handle all intercurrent events with the exception of initiation of new asthma therapy or administration of prohibited medications thought to impact efficacy in conjunction with premature discontinuation of randomised study intervention, for which the composite strategy is implemented. |
| Change From Baseline in the Mean Number of Puffs of Rescue Medication Use (Puffs/Day) Over 24 Weeks | Over 24 Weeks | Change from baseline in the mean number of puffs of rescue medication use (puffs/day) over 24 Weeks. Baseline is the average during the last 7 days before randomization. Over 24 weeks is the average from randomization up to week 24. Treatment policy is implemented to handle all intercurrent events with the exception of initiation of new asthma therapy or administration of prohibited medications thought to impact efficacy in conjunction with premature discontinuation of randomised study intervention, for which the composite strategy is implemented. |
| Percentage of Responders in ACQ-7 (≥ 0.5 Decrease Equals Response) at Week 24 | At Week 24 | Percentage of responders in ACQ-7 at Week 24, where responders are defined as participants with a ≥0.5 decrease in total score from baseline. Treatment policy is implemented to handle all intercurrent events with the exception of initiation of new asthma therapy or administration of prohibited medications thought to impact efficacy in conjunction with premature discontinuation of randomised study intervention, for which the composite strategy is implemented. |
| Percentage of Responders in ACQ-5 (≥ 0.5 Decrease Equals Response) at Week 24 | At Week 24 | Percentage of responders in ACQ-5 at Week 24, where responders are defined as participants with a ≥0.5 decrease in total score from baseline. Treatment policy is implemented to handle all intercurrent events with the exception of initiation of new asthma therapy or administration of prohibited medications thought to impact efficacy in conjunction with premature discontinuation of randomised study intervention, for which the composite strategy is implemented. |
| 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 | At Week 24 | Percentage of responders in the Asthma Quality of Life Questionnaire for 12 years and older (AQLQ(s)+12) at Week 24, where responders are defined as participants with a ≥0.5 increase in total score from baseline. Treatment policy is implemented to handle all intercurrent events with the exception of initiation of new asthma therapy or administration of prohibited medications thought to impact efficacy in conjunction with premature discontinuation of randomised study intervention, for which the composite strategy is implemented. |
| Rate of Severe Asthma Exacerbation (Pooled LITHOS and VATHOS Data) During the Treatment Period (up to 24 Weeks) | 24 Weeks | As requested by a Health Authority, data from VATHOS and LITHOS (NCT05755906), two studies originally designed to assess lung function, were pooled to analyze the annualized rate of severe asthma exacerbations. This analysis was prespecified, uses data up to 12 weeks for LITHOS and 24 weeks for VATHOS, and was incorporated into the multiple testing procedure. An exacerbation is considered severe if it results in at least one of the following: a course of systemic corticosteroids (SCS) for ≥3 consecutive days to treat symptoms of asthma worsening, an ER or urgent care visit due to asthma requiring treatment with SCS, an in-patient hospitalization due to asthma, or death related to asthma. Treatment policy is implemented to handle all intercurrent events except for initiation of new asthma therapy or administration of prohibited medications thought to impact efficacy in conjunction with premature discontinuation of randomised study intervention, for which the composite strategy is used. |
| Rate of Severe Asthma Exacerbation During the Treatment Period (up to 24 Weeks) | 24 Weeks | Annualized rate of severe asthma exacerbation during the treatment period (up to 24 Weeks). An asthma exacerbation will be considered severe if it results in at least one of the following: a course of systemic corticosteroids for at least 3 consecutive days to treat symptoms of asthma worsening, an ER or urgent care visit due to asthma that required treatment with systemic corticosteroids, an in-patient hospitalization due to asthma, or death related to asthma. Treatment policy is implemented to handle all intercurrent events with the exception of initiation of new asthma therapy or administration of prohibited medications thought to impact efficacy in conjunction with premature discontinuation of randomised study intervention, for which the composite strategy is implemented. |
Countries
Canada, Germany, Italy, Japan, Spain, United States, Vietnam
Participant flow
Recruitment details
Participants who have asthma which remains inadequately controlled (ACQ-7 total score ≥ 1.5) despite treatment with medium dose ICS or ICS/LABA were recruited at 147 sites across 7 countries. Participants were randomized in a 1:2:2:2 scheme to BFF MDI 160/9.6 μg, BFF MDI 320/9.6 μg, BD MDI 320 μg, or open-label Symbicort. Randomization was stratified by baseline asthma treatment and age. The treatment period was 24 weeks in duration with up to 8 in-clinic visits during screening and treatment.
Pre-assignment details
All participants were on stable daily medium dose ICS or ICS/LABA for at least 8 weeks prior to Visit 1. After meeting the screening eligibility criteria, participants discontinued medium dose ICS or ICS/LABA at Visit 1 and initiated run-in BD MDI 320 µg taking BID until the randomization visit. A total of 581 patients were treated and included in the safety population. Of the 645 initially randomized, 64 were excluded (60 from 11 sites with GCP violation and 4 who did not receive therapy).
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 51.3 Years STANDARD_DEVIATION 15.3 |
| Baseline pre-bronchodilator FEV1 (L) | 2.315 Liter STANDARD_DEVIATION 0.666 |
| Baseline reversibility (%) | 18.5 Percentage STANDARD_DEVIATION 11.3 |
| Prior asthma medication ICS | 11 Participants |
| Prior asthma medication ICS/LABA | 141 Participants |
| Prior asthma medication ICS/LAMA/LABA | 0 Participants |
| Race/Ethnicity, Customized Asian | 22 Participants |
| Race/Ethnicity, Customized Black or African American | 66 Participants |
| Race/Ethnicity, Customized Other | 5 Participants |
| Race/Ethnicity, Customized White | 64 Participants |
| Region of Enrollment Global Canada | 13 Participants |
| Region of Enrollment Global Germany | 30 Participants |
| Region of Enrollment Global Italy | 6 Participants |
| Region of Enrollment Global Japan | 9 Participants |
| Region of Enrollment Global Spain | 7 Participants |
| Region of Enrollment Global United States | 317 Participants |
| Region of Enrollment Global Vietnam | 3 Participants |
| Sex: Female, Male Female | 101 Participants |
| Sex: Female, Male Male | 39 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 | 0 / 88 | 0 / 163 | 0 / 168 | 0 / 162 |
| other Total, other adverse events | 31 / 88 | 45 / 163 | 40 / 168 | 39 / 162 |
| serious Total, serious adverse events | 3 / 88 | 3 / 163 | 1 / 168 | 7 / 162 |
Outcome results
None listed