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

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)

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.

Study Overview

• Status: Completed
• Conditions: Asthma
• Intervention / Treatment: Drug: A006 DPI; Drug: A006 DPI; Other: Placebo DPI; Drug: Proventil® MDI; Drug: Proventil® MDI

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 22
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • San Jose, California, United States, 95117
      • Amphastar Site 0001
  • Oregon
    • Medford, Oregon, United States, 97504
      • Amphastar Site 0025
  • Texas
    • New Braunfels, Texas, United States, 78130
      • Amphastar Site 0030
    • San Antonio, Texas, United States, 78229
      • Amphastar Site 0032

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

5

Arms and Interventions

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

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Systolic and Diastolic Blood Pressure (SBP/DBP) at Screening	Subjects have their vital signs, i.e., blood pressure and heart rate, measured prior to reversibility dosing and 30 minutes after dosing during the Screening Visit.	Within 30 minutes prior to reversibility dosing (baseline) and 30 minutes post-reversibility dosing
Systolic and Diastolic Blood Pressure (SBP/DBP)	Subjects have their vital signs, i.e., blood pressure and heart rate, measured prior to dosing and at 15 and 30 minutes and 1, 1.5, 2, and 6 hours post-dose during each treatment period.	Within 1 hour prior to dosing (baseline) to 6 hours post-dose
Heart Rate (HR) at Screening	Subjects have their vital signs, i.e., blood pressure and heart rate, measured prior to reversibility dosing and 30 minutes after dosing during the Screening Visit.	Within 30 minutes prior to reversibility dosing (baseline) and 30 minutes post-reversibility dosing
Heart Rate (HR)	Subjects have their vital signs, i.e., blood pressure and heart rate, measured prior to dosing and at 15 and 30 minutes and 1, 1.5, 2, and 6 hours post-dose during each treatment period.	Within 1 hour prior to dosing (baseline) to 6 hours post-dose
12-Lead ECG QT/QTc Intervals at Screening	12-Lead ECGs are performed to measure QT and QTc intervals prior to reversibility dosing during the Screening Visit.	Within 1 hour prior to reversibility dosing
12-Lead ECG QT/QTc Intervals	12-Lead ECGs are performed to measure QT and QTc intervals prior to dosing and at 30 minutes and 1, 2, and 6 hours post-dose during each treatment period.	Within 1 hour prior to dosing (baseline) to 6 hours post-dose
Number of Subjects with Incidents of Asthma Exacerbation	An asthma exacerbation incident is defined as significant worsening of clinical symptoms that cannot be adequately relieved by the rescue medication, or significant deterioration of FEV1 tests combined with clinical symptoms. Investigators monitor worsening of asthma symptoms during the treatment period and determine if subjects had experienced an asthma exacerbation.	Participants will be followed for the duration of the study, an expected average of 3 weeks
Number of Subjects that Used Rescue Drug	Rescue medication may be used to control worsening or exacerbations of asthma symptoms during the study visits when necessary, as determined by the investigator.	Within 30 minutes prior to dosing (baseline) to 6 hours post-dose
Complete Blood Count (CBC) at Screening	A CBC is performed as part of the subject safety evaluations with differentials including: red blood cell (RBC), hemoglobin, hematocrit, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), and white blood cell types (WBC).	Within 1 hour after reversibility dosing
Complete Blood Count (CBC) at End-of-Study	A CBC is performed as part of the subject safety evaluations with differentials including: red blood cell (RBC), hemoglobin, hematocrit, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), and white blood cell types (WBC).	120 minutes post-dose at Visit 5 (within 57 days after Visit 1)
Comprehensive Metabolic Panel (CMP) at Screening	A CMP is performed as part of the subject safety evaluations looking at levels for the following: total protein (albumin/globulin), sodium, chloride, potassium, glucose, calcium, carbon dioxide (CO2), blood urea nitrogen (BUN), creatinine, alkaline phosphate (ALP), alanine transaminase (ALT), aspartate transaminase (AST), and bilirubin.	Within 1 hour after reversibility dosing
Comprehensive Metabolic Panel (CMP) at End-of-Study	A CMP is performed as part of the subject safety evaluations looking at levels for the following: total protein (albumin/globulin), sodium, chloride, potassium, glucose, calcium, carbon dioxide (CO2), blood urea nitrogen (BUN), creatinine, alkaline phosphate (ALP), alanine transaminase (ALT), aspartate transaminase (AST), and bilirubin.	120 minutes post-dose at Visit 5 (within 57 days after Visit 1)
Urinalysis at Screening	Routine and microscopic urinalysis is performed as part of the subject safety evaluations to measure urine pH and specific gravity.	Within 1 hour after reversibility dosing
Urinalysis at End-of-Study	Routine and microscopic urinalysis is performed as part of the subject safety evaluations to measure urine pH and specific gravity.	120 minutes post-dose at Visit 5 (within 57 days after Visit 1)
Incidents of Pregnancy at Screening	A urinary pregnancy test was performed for women of child-bearing potential as a part of the Screening Visit evaluations to determine the eligibility of the subject for the study.	Within 1 hour prior to reversibility dosing
Incidents of Pregnancy at End-of-Study	A urinary pregnancy test was performed for women of child-bearing potential as a part of the End-of-Study safety evaluations to determine if a pregnancy had occurred during the study.	At or after 120 minutes post-dose at Visit 5 (within 57 days after Visit 1)
Concomitant Medication Usage	Concomitant medications used by subjects throughout the duration of the study, from 30 days prior to Screening to End-of-Study evaluations, are recorded by the investigators. The total number of times a specific concomitant medication is used during the study is summarized.	Participants will be followed for the duration of the study, an expected average of 3 weeks

Collaborators and Investigators

• Sponsor: Amphastar Pharmaceuticals, Inc.
• Investigators: Study Director: Safety Monitor, Amphastar Pharmeceuticals, Inc.

Publications and helpful links

General Publications

• Pellegrino R, Viegi G, Brusasco V, Crapo RO, Burgos F, Casaburi R, Coates A, van der Grinten CP, Gustafsson P, Hankinson J, Jensen R, Johnson DC, MacIntyre N, McKay R, Miller MR, Navajas D, Pedersen OF, Wanger J. Interpretative strategies for lung function tests. Eur Respir J. 2005 Nov;26(5):948-68. doi: 10.1183/09031936.05.00035205. No abstract available.
• Lipworth BJ, Clark DJ. Lung delivery of salbutamol given by breath activated pressurized aerosol and dry powder inhaler devices. Pulm Pharmacol Ther. 1997 Aug;10(4):211-4. doi: 10.1006/pupt.1997.0093.
• Ahrens RC. The role of the MDI and DPI in pediatric patients: "Children are not just miniature adults". Respir Care. 2005 Oct;50(10):1323-8; discussion 1328-30.
• Goldstein DA, Tan YK, Soldin SJ. Pharmacokinetics and absolute bioavailability of salbutamol in healthy adult volunteers. Eur J Clin Pharmacol. 1987;32(6):631-4. doi: 10.1007/BF02456001.
• Hindle M, Newton DA, Chrystyn H. Dry powder inhalers are bioequivalent to metered-dose inhalers. A study using a new urinary albuterol (salbutamol) assay technique. Chest. 1995 Mar;107(3):629-33. doi: 10.1378/chest.107.3.629.
• Crapo RO, Morris AH, Gardner RM. Reference spirometric values using techniques and equipment that meet ATS recommendations. Am Rev Respir Dis. 1981 Jun;123(6):659-64. doi: 10.1164/arrd.1981.123.6.659.
• Crapo RO, Morris AH, Clayton PD, Nixon CR. Lung volumes in healthy nonsmoking adults. Bull Eur Physiopathol Respir. 1982 May-Jun;18(3):419-25.

Study record dates

Study Major Dates

• Study Start: July 1, 2014
• Primary Completion (Actual): September 1, 2014
• Study Completion (Actual): October 1, 2014

Study Registration Dates

• First Submitted: August 4, 2014
• First Submitted That Met QC Criteria: August 5, 2014
• First Posted (Estimate): August 7, 2014

Study Record Updates

• Last Update Posted (Actual): April 19, 2017
• Last Update Submitted That Met QC Criteria: April 17, 2017
• Last Verified: April 1, 2017

More Information

Terms related to this study

• Keywords: Asthma; Mild asthma; Mild-to-moderate persistent asthma; Moderate asthma; Persistent asthma
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Immune System Diseases; Lung Diseases; Hypersensitivity, Immediate; Bronchial Diseases; Lung Diseases, Obstructive; Respiratory Hypersensitivity; Hypersensitivity; Asthma; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Adrenergic Agonists; Bronchodilator Agents; Anti-Asthmatic Agents; Respiratory System Agents; Reproductive Control Agents; Adrenergic beta-2 Receptor Agonists; Adrenergic beta-Agonists; Tocolytic Agents; Albuterol
• Other Study ID Numbers: API-A006-CL-B3