Exercise Induced Bronchospasm
Conditions
Brief summary
This is a multicenter, randomized, double-blind, single-dose, placebo-controlled, 2-period, crossover study to evaluate the efficacy and safety of budesonide/albuterol metered-dose inhaler (BDA MDI/PT027) as compared with a placebo metered-dose inhaler (placebo MDI) on exercise-induced bronchoconstriction (EIB) in adult and adolescent subjects with asthma. Subjects will receive each study treatment on separate visits and undergo a treadmill exercise challenge test for up to 10 minutes so that the effect of study treatment on exercise-induced bronchoconstriction can be evaluated.
Interventions
COMBINATION_PRODUCTBudesonide/albuterol sulfate metered-dose inhaler 160/180 μg
Budesonide/albuterol sulfate combination inhalation aerosol single dose
COMBINATION_PRODUCTPlacebo metered-dose inhaler
Placebo inhalation aerosol single dose
Sponsors
Bond Avillion 2 Development LP
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
12 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
1. Female or male aged 12 to 70 years at the time of informed consent 2. Documented history of asthma for at least 6 months prior to Visit 1 3. Receiving 1 of the following asthma therapies with stable dosing for at least the 4 weeks before Visit 1; no other asthma therapies are permitted during the study: * Short/rapid-acting β 2-adrenoreceptor agonist (SABA) used as needed * Low- to medium-dose maintenance therapy with inhaled corticosteroid (ICS) and SABA used as needed 4. Demonstrate acceptable MDI administration technique (use of a spacer device during the treatment phase is not permitted)
Exclusion criteria
1. Chronic obstructive pulmonary disease or other significant lung disease (eg, chronic bronchitis, emphysema, bronchiectasis with the need of treatment, cystic fibrosis, or bronchopulmonary dysplasia), including regular or occasional use of oxygen 2. Systemic corticosteroids (SCS) use (any dose and any indication) within 3 months before Visit 1 3. History of life-threatening asthma, defined by past intubations for asthma, or intensive care unit admission for asthma within the prior 24 months 4. Receiving regular maintenance treatment with prohibited anti-inflammatory or long-acting bronchodilator asthma medication (inhaled, nebulized, oral, or systemic) within 1 month prior to Visit 1 5. Unable to tolerate the lung function testing performed after exercise challenge test without use of rescue medication 6. Current smokers, former smokers with \>10 pack-years history, or former smokers who stopped smoking \<6 months before Visit 1 (including all forms of tobacco, e-cigarettes \[vaping\], and marijuana) 7. Completed treatment for lower respiratory infection within 6 weeks prior to Visit 1, regardless if resulting in accompanying asthma symptoms aggravation or not 8. Upper respiratory infection involving antibiotic treatment not resolved within 7 days prior to Visit 1 9. Received any marketed (eg, omalizumab, mepolizumab, reslizumab, benralizumab, dupilumab) or investigational biologic within 3 months before Visit 1, or any other prohibited medication 10. Current treatment with any investigational product or within the last 30 days of Visit 1. 11. Historical or current evidence of a clinically significant disease 12. Cancer not in complete remission for at least 5 years before Visit 1 13. Hospitalization for psychiatric disorder or attempted suicide within 1 year of Visit 1 14. History of psychiatric disease or intellectual deficiency 15. Having a scheduled or planned hospitalization during the study 16. Inability (and/or unwillingness) to abstain from protocol-defined prohibited medications during the study. 17. Use of any herbal products by inhalation or nebulizer within 2 weeks of Visit 1 and/or the unwillingness to stop during the study duration. 18. Significant abuse of alcohol or drugs
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Percentage Fall From Post-dose, Pre-exercise Baseline in Forced Expiratory Volume in 1 Second (FEV₁) Observed up to 60 Minutes Post-exercise Challenge | Up to 60 minutes post exercise challenge | Lung function was measured by spirometry. Spirometry assessments were completed 5 minutes before dosing, 30 minutes after dosing (baseline; 5 minutes before the exercise challenge), and then 5, 10, 15, 30, and 60 minutes after the exercise challenge. A reduction in FEV₁ was expected due to the effects of asthma and exercise on breathing and lung function. The percentage fall in FEV₁ was calculated based on the baseline value and maximum percentage fall value during the 60-minute assessment period. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Subjects With a Maximum Percentage Fall in FEV₁ Post-exercise Challenge of <10% | Up to 60 minutes post exercise challenge | The percentage fall in FEV₁ was calculated based on the baseline value and maximum percentage fall value during the 60-minute assessment period, and the percentage of subjects with a maximum percentage fall \<10% was determined. |
Countries
United States
Participant flow
Recruitment details
Subjects included in the study were male and female adults and adolescents 12 to 70 years of age with a diagnosis of asthma as defined by the Global Initiative for Asthma (GINA) criteria and EIB as defined by a \>=20% decrease from pre-exercise challenge best FEV₁ observed within 60 minutes after an exercise challenge at both screening visits. The first subject enrolled on 15 January 2020 and the last subject completed the study on 28 August 2020. Subjects were enrolled at 6 US study centers.
Pre-assignment details
The randomized treatment phase started after a 1 to 2 week screening period (Visits 1 and 2). In addition to the 60 subjects randomized, 71 subjects were screened but did not participate (70 screen failures, 1 withdrawal by subject).
Participants by arm
| Arm | Count |
|---|---|
| A/B - Treatment With BDA MDI 160/180 Followed by Treatment With Placebo MDI Subjects randomized to receive single dose of BDA MDI (PT027) at Visit 3/Period 1, and a single dose of placebo MDI at Visit 4/Period 2.
Visit 3/Period 1 (Day 1) - Budesonide/albuterol sulfate metered-dose inhaler 160/180 μg: Budesonide/albuterol sulfate combination inhalation aerosol single dose
Visit 4/Period 2 (Day 8 +/- 6 days) - Placebo metered-dose inhaler: Placebo inhalation aerosol single dose | 29 |
| B/A - Treatment With Placebo MDI Followed by Treatment With BDA MDI 160/180 Subjects randomized to receive single dose of placebo MDI at Visit 3/Period 1, and a single dose of BDA MDI (PT027) at Visit 4/Period 2.
Visit 3/Period 1 (Day 1) - Placebo metered-dose inhaler: Placebo inhalation aerosol single dose
Visit 4/Period 2 (Day 8 +/- 6 days) - Budesonide/albuterol sulfate metered-dose inhaler 160/180 μg: Budesonide/albuterol sulfate combination inhalation aerosol single dose | 31 |
| Total | 60 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Period 2 (Second Treatment Intervention) | Subject did not meet the pre-dose FEV₁ criterion of >70% predicted at Visit 4/Visit 4 repeat. | 1 | 0 |
Baseline characteristics
| Characteristic | A/B - Treatment With BDA MDI 160/180 Followed by Treatment With Placebo MDI | B/A - Treatment With Placebo MDI Followed by Treatment With BDA MDI 160/180 | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 1 Participants | 1 Participants | 2 Participants |
| Age, Categorical >=65 years | 1 Participants | 0 Participants | 1 Participants |
| Age, Categorical Between 18 and 65 years | 27 Participants | 30 Participants | 57 Participants |
| Age, Continuous | 39.1 years STANDARD_DEVIATION 12.28 | 41.8 years STANDARD_DEVIATION 11.31 | 40.5 years STANDARD_DEVIATION 11.76 |
| Body Mass Index | 29.0 Kilograms per meter squared STANDARD_DEVIATION 5.51 | 28.7 Kilograms per meter squared STANDARD_DEVIATION 5.52 | 28.8 Kilograms per meter squared STANDARD_DEVIATION 5.47 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 3 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 29 Participants | 28 Participants | 57 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Height | 167.0 Centimeters STANDARD_DEVIATION 9.41 | 170.7 Centimeters STANDARD_DEVIATION 10.28 | 168.9 Centimeters STANDARD_DEVIATION 9.96 |
| Maximal Heart Rate at Screening Visit 1 | 167.2 Beats per minute STANDARD_DEVIATION 15.11 | 164.1 Beats per minute STANDARD_DEVIATION 12.71 | 165.6 Beats per minute STANDARD_DEVIATION 13.9 |
| Maximal Heart Rate at Screening Visit 2 | 166.3 Beats per minute STANDARD_DEVIATION 15.83 | 163.3 Beats per minute STANDARD_DEVIATION 12.88 | 164.8 Beats per minute STANDARD_DEVIATION 14.34 |
| Pre-dose pre-ECT FEV₁ | 2.712 Liters STANDARD_DEVIATION 0.5895 | 2.608 Liters STANDARD_DEVIATION 0.6409 | 2.658 Liters STANDARD_DEVIATION 0.6137 |
| Pre-dose pre-ECT FEV₁/FVC | 71.88 Percent STANDARD_DEVIATION 8.143 | 74.97 Percent STANDARD_DEVIATION 9.051 | 73.47 Percent STANDARD_DEVIATION 8.692 |
| Pre-dose pre-ECT FEV₁ % predicted normal | 84.86 Percentage of predicted normal STANDARD_DEVIATION 12.914 | 78.24 Percentage of predicted normal STANDARD_DEVIATION 6.567 | 81.44 Percentage of predicted normal STANDARD_DEVIATION 10.593 |
| Pre-dose pre-ECT FVC | 3.823 Liters STANDARD_DEVIATION 0.977 | 3.546 Liters STANDARD_DEVIATION 1.0576 | 3.680 Liters STANDARD_DEVIATION 1.0204 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants | 13 Participants | 18 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 21 Participants | 18 Participants | 39 Participants |
| Region of Enrollment United States | 29 participants | 31 participants | 60 participants |
| Sex: Female, Male Female | 21 Participants | 17 Participants | 38 Participants |
| Sex: Female, Male Male | 8 Participants | 14 Participants | 22 Participants |
| Time since diagnosis of asthma to randomization | 25.19 years | 28.59 years | 27.36 years |
| Weight | 81.3 Kilograms STANDARD_DEVIATION 18.5 | 84.4 Kilograms STANDARD_DEVIATION 21.6 | 82.9 Kilograms STANDARD_DEVIATION 20.05 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 60 | 0 / 59 |
| other Total, other adverse events | 0 / 60 | 2 / 59 |
| serious Total, serious adverse events | 0 / 60 | 0 / 59 |
Outcome results
Primary
Maximum Percentage Fall From Post-dose, Pre-exercise Baseline in Forced Expiratory Volume in 1 Second (FEV₁) Observed up to 60 Minutes Post-exercise Challenge
Lung function was measured by spirometry. Spirometry assessments were completed 5 minutes before dosing, 30 minutes after dosing (baseline; 5 minutes before the exercise challenge), and then 5, 10, 15, 30, and 60 minutes after the exercise challenge. A reduction in FEV₁ was expected due to the effects of asthma and exercise on breathing and lung function. The percentage fall in FEV₁ was calculated based on the baseline value and maximum percentage fall value during the 60-minute assessment period.
Time frame: Up to 60 minutes post exercise challenge
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Treatment Intervention A - BDA MDI 160/180 - All Subjects | Maximum Percentage Fall From Post-dose, Pre-exercise Baseline in Forced Expiratory Volume in 1 Second (FEV₁) Observed up to 60 Minutes Post-exercise Challenge | 5.45 Maximum percentage fall FEV₁ |
| Treatment Intervention B - Placebo MDI - All Subjects | Maximum Percentage Fall From Post-dose, Pre-exercise Baseline in Forced Expiratory Volume in 1 Second (FEV₁) Observed up to 60 Minutes Post-exercise Challenge | 18.97 Maximum percentage fall FEV₁ |
Comparison: Maximum percentage fall in post-dose pre-exercise FEV₁ up to 60 minutes post-exercise challenge is analyzed using a mixed effects model adjusted for treatment, treatment period, treatment sequence as categorical fixed effects, period-specific pre-dose baseline FEV₁ and average pre-dose baseline FEV₁ as continuous covariates, and a random subject within treatment sequence effect.p-value: <0.00195% CI: [10.09, 16.94]Mixed Models Analysis
Secondary
Percentage of Subjects With a Maximum Percentage Fall in FEV₁ Post-exercise Challenge of <10%
The percentage fall in FEV₁ was calculated based on the baseline value and maximum percentage fall value during the 60-minute assessment period, and the percentage of subjects with a maximum percentage fall \<10% was determined.
Time frame: Up to 60 minutes post exercise challenge
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment Intervention A - BDA MDI 160/180 - All Subjects | Percentage of Subjects With a Maximum Percentage Fall in FEV₁ Post-exercise Challenge of <10% | 47 Participants |
| Treatment Intervention B - Placebo MDI - All Subjects | Percentage of Subjects With a Maximum Percentage Fall in FEV₁ Post-exercise Challenge of <10% | 17 Participants |
Comparison: A generalized linear mixed model with logit link adjusted for treatment, treatment period and treatment sequence as fixed effects, pre-dose baseline FEV₁ and average pre-dose baseline FEV₁ as continuous covariates, and a random subject within treatment sequence effect.p-value: <0.00195% CI: [4.311, 25.805]Mixed Models Analysis