Albuterol DPI (A006) Clinical Study-B2: Efficacy, Dose-Ranging and Initial Safety Evaluation

A Randomized, Double- or Evaluator-blind, Active- and Placebo-controlled, Single Dose, Seven-arm, Crossover Dose-ranging Study of A006 in Adult Asthma Patients

The main objective of this study is to evaluate the efficacy, dose-ranging and initial safety profiles of A006, an Albuterol dry powder inhaler (DPI), in the dose range of 25 to 180 mcg per dosing in comparison to a DPI Placebo Control and an Albuterol metered dose inhaler (MDI) Active Control.

This study will be conducted in male and female adult patients who have mild-to-moderate persistent asthma for at least 6 months, but are otherwise generally healthy.

Study Overview

• Status: Completed
• Conditions: Asthma
• Intervention / Treatment: Drug: Placebo DPI; Drug: Albuterol DPI 25 mcg/inh; Drug: Albuterol DPI 90 mcg/inh; Drug: Albuterol MDI 90 mcg/inh

Detailed Description

The main objective of this study is to evaluate the efficacy, dose-ranging and initial safety profiles of A006, an Albuterol dry powder inhaler (DPI), in the dose range of 25 to 180 mcg per dose in comparison to the DPI Placebo Control and the Active (Reference) Control. The study results of this study together with that of A006-B study will be utilized to determine the optimum final dose range of A006 for further clinical studies.

The study will be conducted in male and female adult patients who have mild-to-moderate persistent asthma but are otherwise generally healthy.

• Study Type: Interventional
• Enrollment (Actual): 23
• 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 a beta-agonist(s) inhaler
• Demonstrate a Forced Expiratory Volume (FEV1) at 50-85 percent of predicted normal during screening baseline measurement
• Demonstrate an airway reversibility of greater than or equal to 15 percent within 30 minutes of inhaling 2 inhalations of Proventil MDI during screening visit
• Demonstrate Peak Inspiratory Flow Rate (PIF) within 80-150 L/min (after training), at least 2 times consecutively
• Demonstrate ability to use a DPI and MDI inhaler properly after training
• Females must be not pregnant, not lactating, and using a clinically acceptable form of birth control
• Properly agree to participate in the trial

Exclusion Criteria:

• A smoking history of more than or equal to 10 years or having smoked within 6 months of screening visit
• Upper respiratory tract infections within 2 weeks or lower respiratory tract infection within 4 weeks prior to screening visit
• Asthma exacerbations that required emergency care or a hospital stay within 4 weeks prior to screening visit
• Any current or recent respiratory tract infections that might affect the response to the study drug as determined by the investigator, including cystic fibrosis, bronchiectasis, tuberculosis, emphysema and other significant respiratory diseases besides asthma
• Current clinically significant cardiovascular, hematological, renal, neurologic, hepatic, endocrine, psychiatric, malignant or other illnesses that could impact the study as determined by the investigator
• Known intolerance or hypersensitivity to any ingredients of the study drug DPI or Proventil MDI (i.e.: Albuterol, sulfate, lactose, milk protein, HFA-134a, oleic acid and ethanol)

Study Plan

How is the study designed?

Design Details

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

Number of Arms

7

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: T1; Two inhalations, one of Albuterol DPI 25 mcg/inh and one of Placebo DPI; Total Albuterol dose of 25 mcg	Drug: Placebo DPI; Placebo DPI with 0 mcg Albuterol/inhalation; Drug: Albuterol DPI 25 mcg/inh; Albuterol DPI with 25 mcg Albuterol/inhalation
Experimental: T2; Two inhalations of Albuterol DPI 25 mcg/inh; Total Albuterol dose of 50 mcg	Drug: Albuterol DPI 25 mcg/inh; Albuterol DPI with 25 mcg Albuterol/inhalation
Experimental: T3; Two inhalations, one of Albuterol DPI 90 mcg/inh and one of Placebo DPI; Total Albuterol dose of 90 mcg	Drug: Placebo DPI; Placebo DPI with 0 mcg Albuterol/inhalation; Drug: Albuterol DPI 90 mcg/inh; Albuterol DPI with 90 mcg Albuterol/inhalation
Experimental: T4; Two inhalations of Albuterol DPI 90 mcg/inh; Total Albuterol dose of 180 mcg	Drug: Albuterol DPI 90 mcg/inh; Albuterol DPI with 90 mcg Albuterol/inhalation
Placebo Comparator: P; Two inhalations Placebo DPI; Total Albuterol dose of 0 mcg	Drug: Placebo DPI; Placebo DPI with 0 mcg Albuterol/inhalation
Active Comparator: R1; One inhalation of Albuterol MDI 90 mcg/inh; Total Albuterol dose of 90 mcg	Drug: Albuterol MDI 90 mcg/inh; Albuterol MDI with 90 mcg Albtuerol/inhalation
Active Comparator: R2; Two inhalations of Albuterol MDI 90 mcg/inh; Total Albuterol dose of 180 mcg	Drug: Albuterol MDI 90 mcg/inh; Albuterol MDI with 90 mcg Albtuerol/inhalation

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in FEV1 Area Under the Curve (AUC) versus placebo	Serial FEV1 measurements to demonstrate the mean AUC change in percent FEV1 from same-day baseline of A006 versus placebo control	Visits 1-7, at baseline, 5, 20, 30, 60, 90, 120, 240, 360 minutes post-dose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Placebo AUC of adjusted FEV1 changes	Determination of change of FEV1 in placebo arm	Visits 1-7 at baseline, 5, 20, 30, 60, 90, 120, 180, 240 and 360 minutes post-dose
AUC of post-dose FEV1 volume changes from pre-dose baseline to Visit 7	Determination of FEV1 volume change from pre-dose baseline to post treatment at Visit 7	Visits 1-7 at baseline, 5, 20, 30, 60, 90, 120, 180, 240, 360 minutes post-dose
Time post-dose change in FEV1 percent first reaches greater than or equal to 12 percent over the Pre-dose Baseline	Time to onset of bronchodilator effect (Tonset), determined by linear interpolation as the point where post-dose change in FEV1 percent first reaches greater than or equal to 12 percent over the Pre-dose Baseline.	Visits 1-7, at 5, 20, 30, 60, 90, 120, 180, 240 and 360 minutes post-dose
Peak bronchodilator response (Fmax)	The peak bronchodilator response (Fmax), defined as the maximum post-dose change in FEV1 percent.	Visits 1-7 at 5, 20, 30, 60, 90, 120, 180, 240, 360 minutes post-dose
Time to peak FEV1 effect (tmax)	The time to peak FEV1 effect (tmax), defined as the time of Fmax.	Visits 1-7 at 5, 20, 30, 60, 90, 120, 180, 240 and 360 minutes post-dose
Duration of effect	Duration of effect, calculated as the total duration of bronchodilator effects when change in FEV1 percent is greater than or equal to 12 percent above baseline.	Visits 1-7 at 5, 20, 30, 60, 90, 120, 180 and 360 minutes post-dose
Bronchodilatory Response Rate (R percent)	Evaluation of Bronchodilatory Response Rate (R percent) of responders who demonstrate a greater than or equal to 12 percent increase for change in FEV1 percent during the initial 60 min post-dose.	Visits 1-7 at 60 minutes
Dose response curve: AUC of change in percent FEV1 versus Dose	Evaluation of change in FEV1 in relation to dose.	Visits 1-7
Vital Signs (i.e.: blood pressure and heart rate)	Vital signs, i.e. blood pressure (SBP/DBP) and heart rate (HR), at pre-dose baseline, and 3, 8, 15, 30, 90, and 360 min post-dose.	Visits 1-7 and EOS at baseline, 3, 8, 15, 30, 90 and 360 minutes post-dose
12-lead ECG (for routine and QT/QTc)	Measurement of 12-lead ECG (for routine and QT/QTc), at pre-dose baseline, and at 10, 50, and 360 min post-dose.	Visits 1-7 at baseline, 10, 50 and 360 minutes post-dose
Serum glucose	Determination of Serum glucose, at pre-dose baseline, and at 15, 35 and 120 min post-dose.	Visits 1-7 at baseline, 15, 35 and 120 minutes post-dose
Serum potassium	Determination of serum potassium levels, at pre-dose baseline, and at 15, 35 and 120 min post-dose.	Visits 1-7 at baseline, 15, 35 and 120 minutes post-dose
Asthma exacerbation incidents	Evaluation of asthma exacerbation incidents in all patients throughout the duration of the study.	Visits 1-7 and EOS
Asthma management/ rescue drug usage	Evaluation of asthma exacerbation incidents in all patients throughout the duration of the study.	Visits 1-7 and EOS
Physical examination	Physical examination of all subjects performed at screening and end-of-study visit to evaluate subject's general health.	Screening and End-of-Study Visit
CBC	Evaluation of CBC in all subjects at screening and end-of-study visit.	Screening and End-of-Study Visit
Comprehensive metabolic panel	Comprehensive metabolic panel performed on all subjects at screening and end-of-study visit.	Screening and End-of-Study Visit
Urinalysis	Urinalysis performed on all subjects at screening and end-of-study visit.	Screening and End-of-Study Visit
Pregnancy test	A pregnancy test for women of child bearing potential at screening and end-of-study visit.	Screening and End-of-Study Visit
Medication interactions	Evaluation of concomitant medications used by subjects throughout the study and their potential to affect the study	Screening, Visits 1-7 and End-of-Study Visit
Number of participants with adverse events as a measure of safety and tolerability	Adverse drug events whether observed by investigators or reported by subjects, will be documented, evaluated, followed up, and treated if deemed necessary.	Screening, Visits 1-7, End-of-Study Visit

Collaborators and Investigators

• Sponsor: Amphastar Pharmaceuticals, Inc.

Publications and helpful links

General Publications

• 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: April 1, 2012
• Primary Completion (Actual): July 1, 2012
• Study Completion (Actual): August 1, 2012

Study Registration Dates

• First Submitted: April 17, 2012
• First Submitted That Met QC Criteria: April 18, 2012
• First Posted (Estimate): April 20, 2012

Study Record Updates

• Last Update Posted (Actual): May 19, 2017
• Last Update Submitted That Met QC Criteria: May 18, 2017
• Last Verified: May 1, 2017

More Information

Terms related to this study

• Keywords: asthma; mild asthma; persistent asthma; moderate asthma; mild-to-moderate 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-B2