Albuterol DPI (A006) Clinical Study-B3:Efficacy, Dose-ranging and Safety Evaluation

Study Overview
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Brief Summary
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This study evaluates the efficacy, dose-ranging and safety profiles of A006, an Albuterol dry powder inhaler (DPI), in the dose range of 110 to 220 mcg per dose in comparison to a DPI Placebo Control and an Albuterol metered dose inhaler (MDI) Active Control.

Detailed Description
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This study is designed to evaluate the efficacy and safety profiles of A006 and to assist in identifying the optimum dose of A006 for future clinical studies. Proventil® HFA MDI, a currently marketed Albuterol MDI product, will be used as an Active Control. The study also employs a Placebo Control DPI, which has the same configuration as the A006 DPI except that it contains no active ingredient.

Official Title
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Efficacy, Dose-ranging and Safety Evaluation (A Randomized, Double- or Evaluator-blinded, Active- and Placebo-controlled, Single Dose, Five-arm, Crossover, and Dose-ranging Study of A006 in Adult Asthma Patients)

Conditions
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Asthma

Intervention / Treatment
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* Drug: A006 DPI
* Drug: A006 DPI
* Other: Placebo DPI
* Drug: Proventil® MDI
* Drug: Proventil® MDI


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Generally healthy, male and female adults, 18-55 years of age at Screening With mild-to-moderate persistent asthma for at least 6 months prior to Screening, and having used inhaled β-agonist(s) for asthma control Demonstrating a Screening Baseline FEV1 at 50.0 - 85.0% of predicted normal Demonstrating a ≥ 15.0% Airway Reversibility in FEV1 within 30 min after inhaling 2 actuations of Proventil® MDI (180 mcg) at Screening Demonstrating Peak Inspiratory Flow Rate (PIF) within 80-150 L/min (after training), for at least 2 times consecutively with a maximum of 5 attempts Demonstrating proficiency in the use of a DPI and an MDI after training Females of child-bearing potential must be non-pregnant, non-lactating; both males and females enrolled into the study must agree to practice a clinically acceptable form of birth control (including but not limited to, abstinence, double barrier, etc) Having properly consented to participate in the trial Exclusion Criteria: A smoking history of ≥ 5 pack-years, or having smoked within 6 months prior to Screening Upper respiratory tract infections or lower respiratory tract infection within 6 weeks, prior to Screening Asthma exacerbations that required emergency care or hospitalized treatment, within 4 weeks prior to Screening Any current or recent respiratory conditions that, per investigator discretion, might significantly affect pharmacodynamic response to the study drugs, including cystic fibrosis, bronchiectasis, tuberculosis, emphysema, and other significant respiratory diseases besides asthma Concurrent clinically significant cardiovascular (e.g. hypertension and tachyarrhythmia and bradyarrhythmia), hematological, renal, neurologic, hepatic, endocrine, psychiatric, malignant, or other illnesses that in the opinion of the investigator could impact on the conduct, safety and evaluation of the study Known intolerance or hypersensitivity to any of the ingredients of the study drug DPI or Proventil® HFA MDI (i.e., Albuterol, sulfate, lactose, milk protein, HFA-134a, oleic acid, and ethanol) Baseline ECG at Screening or Visit 1 showing any single or multiple premature ventricular contractions (PVC) Baseline ECG at Screening or Visit 1 with a confirmed (through performing a second ECG) QTc reading greater than 450ms Use of prohibited drugs or failure to observe the drug washout restrictions Having been on other clinical drug/device studies in the last 30 days prior to Screening.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 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: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Treatment T1<br>One inhalation of 110 mcg A006 DPI. Total 110 mcg. | Drug: A006 DPI<br>* Single dose 110 mcg, 1 inhalation<br>* Other names: Albuterol DPI;|
| Active Comparator: Treatment T2<br>One inhalation of 220 mcg A006 DPI. Total 220 mcg. | Drug: A006 DPI<br>* Single dose 220 mcg, 1 inhalation<br>* Other names: Albuterol DPI;|
| Placebo Comparator: Placebo<br>One inhalation of placebo DPI . Total 0 mcg | Other: Placebo DPI<br>* Placebo, 1 inhalation<br>* Other names: Placebo;|
| Active Comparator: Treatment R1<br>One inhalation of Proventil® MDI Total 90 mcg | Drug: Proventil® MDI<br>* Single dose 90 mcg, 1 inhalation<br>* Other names: Proventil®;|
| Active Comparator: Treatment R2<br>Two inhalations of Proventil® MDI, 180 mcg total | Drug: Proventil® MDI<br>* Single dose 90 mcg, 2 inhalations<br>* Other names: Proventil®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Curve (AUC[0-6h]) of Post-Dose FEV1 Percentage Change (∆%FEV1) from the Same-Day Pre-Dose Baseline | The forced expiratory volume in the 1st second (FEV1) is measured with a clinically accepted model of spirometer. Subjects perform a pre-dose baseline FEV1 prior to dosing and perform subsequent FEV1 tests at 5, 15 and 30 minutes and 1, 1.5, 2, 3, 4, 5, and 6 hours after dosing during each treatment period. Area under the curve (AUC), from baseline to 6 hours post-dose, for the treatment period is calculated using the trapezoidal rule. Statistical analysis is performed using a one-sided t-test. | Within 30 minutes prior to dosing (baseline) to 6 hours post-dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Curve (AUC[0-6h]) of Placebo Adjusted Post-Dose FEV1 Percentage Change (∆∆%FEV1) from the Same-Day Pre-Dose Baseline | The forced expiratory volume in the 1st second (FEV1) is measured with a clinically accepted model of spirometer. Subjects perform a pre-dose baseline FEV1 prior to dosing and perform subsequent FEV1 tests at 5, 15 and 30 minutes and 1, 1.5, 2, 3, 4, 5, and 6 hours after dosing during each treatment period. ∆∆FEV1% for the study visit is calculated by subtracting the mean ∆%FEV1 for subjects in a randomized treatment arm from their ∆%FEV1. Area under the curve (AUC), from baseline to 6 hours post-dose, for the study visit is calculated using the trapezoidal rule. | Within 30 minutes prior to dosing (baseline) to 6 hours post-dose | 
| Area Under the Curve (AUC[0-6h]) of Post-Dose FEV1 Volume Changes (∆FEV1) from the Same-Day Pre-Dose Baseline | The forced expiratory volume in the 1st second (FEV1) is measured with a clinically accepted model of spirometer. Subjects perform a pre-dose baseline FEV1 prior to dosing and perform subsequent FEV1 tests at 5, 15 and 30 minutes and 1, 1.5, 2, 3, 4, 5, and 6 hours after dosing during each treatment period. Area under the curve (AUC), from baseline to 6 hours post-dose, for the treatment period is calculated using the trapezoidal rule. | Within 30 minutes prior to dosing (baseline) to 6 hours post-dose | 
| Time to Onset of Bronchodilator Effect (t[onset]) | The forced expiratory volume in the 1st second (FEV1) is measured with a clinically accepted model of spirometer. Subjects perform a pre-dose baseline FEV1 prior to dosing and perform subsequent FEV1 tests at 5, 15 and 30 minutes and 1, 1.5, 2, 3, 4, 5, and 6 hours after dosing during each treatment period. t[onset] is the point where post-dose ∆%FEV1 first reaches ≥ 12% over the pre-dose baseline. Determined by linear interpolation. | Within 30 minutes prior to dosing (baseline) to 6 hours post-dose | 
| Peak Bronchodilator Response (F[max]) | The forced expiratory volume in the 1st second (FEV1) is measured with a clinically accepted model of spirometer. Subjects perform a pre-dose baseline FEV1 prior to dosing and perform subsequent FEV1 tests at 5, 15 and 30 minutes and 1, 1.5, 2, 3, 4, 5, and 6 hours after dosing during each treatment period. F[max] is the maximum post-dose ∆%FEV1. | Within 30 minutes prior to dosing (baseline) to 6 hours post-dose | 
| Time to Peak ∆FEV1 Effect (t[max]) | The forced expiratory volume in the 1st second (FEV1) is measured with a clinically accepted model of spirometer. Subjects perform a pre-dose baseline FEV1 prior to dosing and perform subsequent FEV1 tests at 5, 15 and 30 minutes and 1, 1.5, 2, 3, 4, 5, and 6 hours after dosing during each treatment period. The time to peak ∆FEV1 effect, t[max], is defined as the time of F[max]. | Within 30 minutes prior to dosing (baseline) to 6 hours post-dose | 
| Area Under the Curve (AUC[0-6h]) of Post-Dose FEV1 in Volume from the Same-Day Pre-Dose Baseline | The forced expiratory volume in the 1st second (FEV1) is measured with a clinically accepted model of spirometer. Subjects perform a pre-dose baseline FEV1 prior to dosing and perform subsequent FEV1 tests at 5, 15 and 30 minutes and 1, 1.5, 2, 3, 4, 5, and 6 hours after dosing during each treatment period. Area under the curve (AUC), from baseline to 6 hours post-dose, for the treatment period is calculated using the trapezoidal rule. | Within 30 minutes prior to dosing (baseline) to 6 hours post-dose | 
| F[max] of Post-Dose FEV1 in Volume | The forced expiratory volume in the 1st second (FEV1) is measured with a clinically accepted model of spirometer. Subjects perform a pre-dose baseline FEV1 prior to dosing and perform subsequent FEV1 tests at 5, 15 and 30 minutes and 1, 1.5, 2, 3, 4, 5, and 6 hours after dosing during each treatment period. F[max] of post-dose FEV1 in volume is the maximum post-dose FEV1. | Within 30 minutes prior to dosing (baseline) to 6 hours post-dose | 
| Efficacy Duration-1 | The forced expiratory volume in the 1st second (FEV1) is measured with a clinically accepted model of spirometer. Subjects perform a pre-dose baseline FEV1 prior to dosing and perform subsequent FEV1 tests at 5, 15 and 30 minutes and 1, 1.5, 2, 3, 4, 5, and 6 hours after dosing during each treatment period. Efficacy Duration-1 is total duration of bronchodilator effects when ∆%FEV1 is ≥ 12% above the baseline. | Within 30 minutes prior to dosing (baseline) to 6 hours post-dose | 
| Efficacy Duration-2 | The forced expiratory volume in the 1st second (FEV1) is measured with a clinically accepted model of spirometer. Subjects perform a pre-dose baseline FEV1 prior to dosing and perform subsequent FEV1 tests at 5, 15 and 30 minutes and 1, 1.5, 2, 3, 4, 5, and 6 hours after dosing during each treatment period. Efficacy Duration-2 is total duration of bronchodilator effects when ∆FEV1 is ≥ 200 mL above the baseline. | Within 30 minutes prior to dosing (baseline) to 6 hours post-dose | 
| Efficacy Duration-3 | The forced expiratory volume in the 1st second (FEV1) is measured with a clinically accepted model of spirometer. Subjects perform a pre-dose baseline FEV1 prior to dosing and perform subsequent FEV1 tests at 5, 15 and 30 minutes and 1, 1.5, 2, 3, 4, 5, and 6 hours after dosing during each treatment period. Efficacy Duration-3 is total duration of bronchodilator effects when ∆FEV1 is ≥ 100 mL above the baseline. | Within 30 minutes prior to dosing (baseline) to 6 hours post-dose | 
| Bronchodilator Response | The forced expiratory volume in the 1st second (FEV1) is measured with a clinically accepted model of spirometer. Subjects perform a pre-dose baseline FEV1 prior to dosing and perform subsequent FEV1 tests at 5, 15 and 30 minutes and 1, 1.5, 2, 3, 4, 5, and 6 hours after dosing during each treatment period. Subjects that demonstrate a ≥ 12% increase for ∆%FEV1 will be classified as having a bronchodilator response. | Within 30 minutes prior to dosing (baseline) to 6 hours post-dose | 
| Dose Response Curve | The forced expiratory volume in the 1st second (FEV1) is measured with a clinically accepted model of spirometer. Subjects perform a pre-dose baseline FEV1 prior to dosing and perform subsequent FEV1 tests at 5, 15 and 30 minutes and 1, 1.5, 2, 3, 4, 5, and 6 hours after dosing during each treatment period. The dose response curve is the AUC[0-6h] of ∆%FEV1 versus study drug dosage. | Within 30 minutes prior to dosing (baseline) to 6 hours post-dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Asthma, Mild-to-moderate persistent asthma, Mild asthma, Moderate asthma, Persistent asthma