Escalating and Cumulative-Dose Study of Pharmacokinetics (PK), Pharmacodynamics (PD) and Safety of A006

Study Overview
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Brief Summary
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The main objective is to evaluate the bronchodilatory efficacy, safety and pharmacokinetic profiles of A006 (Albuterol Dry Powder Inhaler (DPI)), in comparison with those of an active control, Proventil-HFA (Albuterol Metered Dose Inhaler (MDI)), and a Placebo DPI in escalating and cumulative-doses up to 1440 mcg, eight (8) times of the proposed clinical dose.

Official Title
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A Randomized, Double- or Evaluator-blinded, Active- and Placebo-controlled, Cumulative-dose, Dose-escalating, Three-arm, Cross-over Study, in 24 Asthma Patients

Conditions
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Asthma, Bronchospasm, Chronic Obstructive Pulmonary Disease (COPD)

Intervention / Treatment
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* Drug: A006
* Drug: Placebo DPI
* Drug: Proventil-HFA


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Body weight ≥ 50 kg for men and ≥ 45 kg for women, and BMI within the range of 18.5 - 30.0 kg/m2 inclusive; Sitting blood pressure ≤ 135/90 mmHg; Demonstrating negative alcohol/drug screen tests; Demonstrating negative HIV, HBsAg and HCV-Ab screen tests; 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 Mean Screening Baseline FEV1 at 50.0 - 85.0 % of predicted normal; Demonstrating a ≥ 15.0% Airway Reversibility in FEV1 within 30(±5) min after inhaling 2 actuations of Proventil-HFA; Demonstrating Peak Inspiratory Flow Rate within 80-150 L/min; Demonstrating proficiency in the use of DPI and MDI after training; Females of child-bearing potential must be non-pregnant, non-lactating, and practicing a clinically acceptable form of birth control; Having properly consented to participate in the trial. Exclusion Criteria: Smoking history of ≥ 10 pack-years, or having smoked within 6 months prior to Screening; Upper respiratory tract infections within 2 wk, or lower respiratory tract infection within 4 wk; Asthma exacerbations that required emergency care or hospitalized treatment, within 4 wk prior; Any current or recent respiratory conditions that might significantly affect pharmacodynamic response to the study drugs, besides asthma; Concurrent clinically significant cardiovascular, hematological, renal, neurologic, hepatic, endocrine, psychiatric, malignancies, or other illnesses that could impact on the conduct, safety and evaluation of the study; Known intolerance or hypersensitivity to any of the ingredients of the A006 or Proventil-HFA; 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; Having donated blood within 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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: T<br>Four doses of A006 taken in 30 minute intervals. Doses will have an escalating number of inhalations (1, 1, 2, and 4 inhalations). Total cumulative Albuterol dose at 90 minutes is 1440 mcg. | Drug: A006<br>* Albuterol DPI with 180 mcg Albuterol/inhalation<br>|
| Active Comparator: R<br>Four doses of Proventil-HFA taken in 30 minute intervals. Doses will have an escalating number of inhalations (2, 2, 4, and 8 inhalations). Total cumulative Albuterol dose at 90 minutes is 1440 mcg. | Drug: Proventil-HFA<br>* Albuterol MDI with 90 mcg Albuterol/inhalation<br>|
| Placebo Comparator: P<br>Four doses of Placebo DPI taken in 30 minute intervals. Doses will have an escalating number of inhalations (1, 1, 2, and 4 inhalations). Total cumulative Albuterol dose at 90 minutes is 0 mcg. | Drug: Placebo DPI<br>* Placebo DPI with 0 mcg Albuterol/inhalation<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Bronchodilatory efficacy after the escalating and cumulative-doses, up to 1,440 mcg. | Area Under the Curve (AUC)0-t of percent change in Forced Expiratory Volume in 1 second (FEV1), which is defined as the area under curve of post-dose FEV1 percentage changes from the Pre-dose Baseline FEV1 (FEV10) versus time. Doses are at 0, 30, 60 and 90 min. | -15 min predose, 15 min post dose 1, 2 and 3 and 15, 45, 90, 120, 180, 240, 360 min post dose 4 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUC0-t of change in FEV1 | AUC of FEV1 volume post-dose changes (change in Volume) from the Pre-dose Baseline FEV1 (FEV10). Doses are at 0, 30, 60 and 90 min. | -15, 15 min post 1, 2, and 3, and 15, 90, 120, 240, and 360min post dose 4 | 
| Time to onset | Time to onset of bronchodilatory effect, determined by linear interpolation as the point where FEV1 % change first reaches ≥ 12% from FEV10. | 0 - 120 min | 
| Peak Response | The peak bronchodilator response, defined as the maximum post-dose FEV1 % change. Doses are at time 0, 30, 60, and 90 min. | 15 min post dose 1, 2 and 3 and 15, 45, 90, 120, 180, 240, and 360 min post dose 4 | 
| Adverse Events | The adverse drug events (ADE) that are observed with Proventil-HFA may be expected with the use of A006 | Time 0, 15, 45, 75, 105, 150, 195, 130, 190, 250, 435 minutes post dose 1 | 
| Blood Analysis | serum glucose and potassium analysis and PK analysis | -15, 10, 25,40, 55, 70, 85, 95, 115, 145, 175, 210, 270, 330, 690 min post dose 1 | 
| Vital Signs and Electrocardiogram (ECG) | vital signs, including pulse and blood pressure and 12-lead ECG | -15, 5, 35, 65, 100, 155, 275, 455, 815 min post dose 1 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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asthma, bronchospasm, COPD, reversibility, efficacy