A Study to Assess the Efficacy and Safety of Budesonide/Albuterol Metered Dose Inhaler (BDA MDI/PT027) Used 4 Times Daily in Adults and Children 4 Years of Age or Older With Asthma

Study Overview
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Brief Summary
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This is a randomized, double-blind, placebo-controlled, multicenter, parallel group study to compare 2 dose levels of budesonide/albuterol BDA MDI (PT027) to its components budesonide BD MDI (PT008) and albuterol AS MDI (PT007) on improvement in lung function and asthma symptoms after 12 weeks of treatment in adult, adolescent, and child subjects with symptomatic asthma currently being treated with a short/rapid-acting β2-adrenoreceptor agonist (SABA) as needed alone or with low-dose inhaled corticosteroid (ICS) maintenance therapy plus SABA as needed.

Official Title
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A 12-week, Randomized, Double-blind, Placebo-controlled, Multicenter, Parallel Group, Phase III Study Evaluating the Efficacy and Safety of PT027 Compared to PT008 and PT007 Administered QID in Adults and Children 4 Years of Age or Older With Asthma

Conditions
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Asthma

Intervention / Treatment
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* Combination Product: Budesonide/albuterol sulfate metered dose inhaler / BDA MDI 160/180 μg (high dose)
* Combination Product: Budesonide/albuterol sulfate metered dose inhaler / BDA MDI 80/180 μg (low dose)
* Drug: Budesonide metered dose inhaler / BD MDI 160 µg
* Drug: Albuterol sulfate metered dose inhaler / AS MDI 180 μg
* Other: Placebo metered-dose inhaler / Placebo MDI


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Female or male aged ≥4 years at the time of informed consent Physician diagnosis of asthma with a documented history of the last 6 months Receiving 1 of the following inhaled asthma medications with stable dosing for at least 30 days prior to Visit 1: Only short/rapid-acting β2-adrenoreceptor agonist (SABA) used as needed Stable low-dose inhaled corticosteroid in addition to as-needed use of SABA Pre-bronchodilator FEV1 of ≥50 to <85% predicted normal value for adults (≥18 years of age) and ≥50% predicted normal value for subjects aged 4 to 17 years after withholding SABA ≥6 hours at Visit 1. Demonstrate reversibility of airflow limitation defined as a ≥15% increase in FEV1 relative to baseline after administration of Sponsor-provided SABA (Ventolin) at either Visit 1 or Visit 1a. Demonstrate acceptable spirometry performance acceptability/repeatability criteria Taken Ventolin on ≥2 days out of 7 days prior to Visit 2 Demonstrate acceptable metered dose inhaler (MDI) administration technique as assessed by the investigator. Able to perform acceptable and reproducible peak expiratory flow measurements as assessed by the investigator Exclusion Criteria: Chronic obstructive pulmonary disease or other significant lung disease (eg, chronic bronchitis, emphysema, bronchiectasis with the need of treatment, cystic fibrosis, or bronchopulmonary dysplasia) Systemic corticosteroids (SCS) use (any dose and any indication) within 3 months before Visit 1 Chronic (≥3 weeks) use of SCS within 6 months prior to Visit 1 Received any marketed (eg, omalizumab, mepolizumab, reslizumab, benralizumab) or investigational biologic within 3 months or 5 half-lives before Visit 1, whichever is longer, or any other prohibited medication 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) Life-threatening asthma defined as any history of significant asthma episode(s) requiring admission to an intensive care unit, intubation associated with hypercapnia, respiratory arrest, hypoxic seizures, or asthma-related syncopal episode(s) within 5 years of Visit 1 Completed treatment for lower respiratory infection within 6 weeks prior to Visit 1 Upper respiratory infection involving antibiotic treatment not resolved within 7 days prior to Visit 1 Hospitalizations due to asthma within 6 months prior to Visit 1 Have taken ≥12 actuations per day of Sponsor-provided Ventolin during the run-in period prior to Visit 2 according to the below criteria: ≥2 days out of 14 days of run-in ≥3 days out of 15 to 21 days of run-in ≥4 days out of 22 or more days of run-in Unable to comply with study procedures including non-compliance with diary completion (ie, <70% subject completion of diary assessments in the last 7 days preceding Visit 2 or 4-times daily dosing, <80% compliance during the placebo run-in period). Historical or current evidence of a clinically significant disease Cancer not in complete remission for at least 5 years before Visit 1 Hospitalization for psychiatric disorder or attempted suicide within 1 year of Visit 1 History of psychiatric disease, intellectual deficiency, poor motivation, or other conditions if their magnitude is limiting informed consent validity Significant abuse of alcohol or drugs, in the opinion of the investigator

Ages Eligible for Study
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Minimum Age: 4 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BDA MDI (PT027) 160/180 μg<br>Budesonide/Albuterol sulfate BDA MDI (PT027) high dose | Combination Product: Budesonide/albuterol sulfate metered dose inhaler / BDA MDI 160/180 μg (high dose)<br>* Budesonide/albuterol sulfate pressurized metered dose inhaler (BDA MDI) 160/180 micrograms (μg), given as 2 inhalations of BDA MDI 80/90 μg, four times a day (QID)<br>|
| Experimental: BDA MDI (PT027) 80/180 μg<br>Budesonide/Albuterol sulfate BDA MDI (PT027) low dose | Combination Product: Budesonide/albuterol sulfate metered dose inhaler / BDA MDI 80/180 μg (low dose)<br>* Budesonide/albuterol sulfate pressurized metered dose inhaler (BDA MDI) 80/180 micrograms (μg), given as 2 inhalations of BDA MDI 40/90 μg, four times a day (QID)<br>|
| Active Comparator: BD MDI (PT008) 160 µg<br>Budesonide BD MDI (PT008) | Drug: Budesonide metered dose inhaler / BD MDI 160 µg<br>* Budesonide pressurized metered dose inhaler (BD MDI) 160 micrograms (μg), given as 2 inhalations of BD MDI 80 μg, four times a day (QID)<br>|
| Active Comparator: AS MDI (PT007) 180 µg<br>Albuterol sulfate AS MDI (PT007) | Drug: Albuterol sulfate metered dose inhaler / AS MDI 180 μg<br>* Albuterol sulfate pressurized metered dose inhaler (AS MDI) 180 micrograms (μg), given as 2 inhalations of AS MDI 90 μg, four times a day (QID)<br>|
| Placebo Comparator: Placebo MDI<br>Placebo MDI | Other: Placebo metered-dose inhaler / Placebo MDI<br>* Placebo pressurized metered dose inhaler (Placebo MDI), given as 2 inhalations of Placebo MDI, four times a day (QID)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) Area Under the Concentration Curve From 0 to 6 Hours (AUC0-6 Hours) Over 12 Weeks | Lung function will be measured by spirometry. Baseline FEV1 will be taken as the average of the 60- and 30-minute pre-dose spirometry measures on or before randomization. Starting with the first study drug dose at Week 0 and then at Week 12, spirometry assessments will be completed at 60 and 30 minutes before the morning dose and 5, 15, 30, 45, 60, 120, 180, 240, 300, and 360 minutes after dosing. FEV1 AUC0-6 hours will be calculated for changes from baseline (randomization visit) using the trapezoidal rule and will be normalized by dividing by the time (in hours) from dosing to the last measurement included (typically 6 hours). | Baseline and 12 weeks | 
| Change From Baseline in Trough FEV1 | Trough FEV1 is calculated at each clinic visit as the average of the 30- and 60-minute pre-dose FEV1 measurements. Baseline FEV1 is defined as the average of the 30- and 60-minute pre-dose measures collected on the day of randomization. | Baseline and 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to 15% Increase in FEV1 Over the Pre-treatment Value on Day 1 | The time to onset is defined as the time (minutes) from the first inhalation of randomized treatment (Day 1) to the first instance where a percentage change from baseline in FEV1 of at least 15% is observed. Participants were only to be included in the analysis if a percent change from baseline of at least 15% is observed within a nominal 30 minutes post dose assessment time point. Baseline FEV1 is defined as the average of the 30- and 60- minute pre-dose spirometry measures taken at randomization. | From first dose (first inhalation of randomized treatment) up to about 40 minutes post-dose (Day 1). | 
| Duration of 15% Increase in FEV1 Over the Pre-treatment Value on Day 1 | The duration of onset is defined as the time (minutes) of the continual period in which a percentage increase change from baseline in FEV1 of at least 15% is observed. Participants will only be included in the analyses if a percent change from baseline of at least 15% is observed within a nominal 30 minutes post dose assessment. If a participant has multiple periods of onset, only the first will contribute to the summary. Duration of onset can last up to the last assessment during a nominal 6 hour serial spirometry profile. Baseline FEV1 is defined as the average of the 60- and 30- minute pre-dose spirometry taken at randomization. | Onset up to about 40 minutes post-treatment, with duration lasting up to the last assessment of a nominal 6 hour serial spirometry profile (Day 1). | 
| Number of Participants With a Clinically Meaningful Difference on the Asthma Control Questionnaire 7-item Version (ACQ-7) at Week 12. | A responder is defined as a participant who achieves a reduction from baseline in overall ACQ-7 score of at least 0.5. The ACQ-7 has 7 questions, with each question using a 7 point scale, where 0 = totally controlled and 6 = extremely poorly controlled. The overall ACQ-7 score is defined as the averaged score across the 7 questions. The analysis only includes participants who are uncontrolled at basellne, i.e. baseline ACQ-7 >= 1.5. All participants who discontinue treatment prior to Week 12 are classified as non-responders. | Baseline and 12 weeks | 
| Change From Baseline in Trough FEV1 at Week 1. | Trough FEV1 is calculated at each clinic visit as the average of the 60- and 30-minute pre-dose FEV1 measurements. Baseline FEV1 is defined as the average of the 60- and 30-minute pre-dose measures collected on the day of randomization. | Baseline and 1 week |