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

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

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.

Study Overview

• Status: Completed
• Conditions: Asthma; Chronic Obstructive Pulmonary Disease (COPD); Bronchospasm
• Intervention / Treatment: Drug: A006; Drug: Proventil-HFA; Drug: Placebo DPI

• Study Type: Interventional
• Enrollment (Actual): 27
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Oregon
    • Medford, Oregon, United States, 97504
      • Amphastar Site 0025
    • Portland, Oregon, United States, 97213
      • Amphastar Site 0026
  • Texas
    • San Antonio, Texas, United States, 78229
      • Amphastar Site 0032
  • Washington
    • Seattle, Washington, United States, 98105
      • Amphastar Site 0034

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 53 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: T; 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; Albuterol DPI with 180 mcg Albuterol/inhalation
Active Comparator: R; 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; Albuterol MDI with 90 mcg Albuterol/inhalation
Placebo Comparator: P; 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; Placebo DPI with 0 mcg Albuterol/inhalation

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Amphastar Pharmaceuticals, 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.
• 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.
• Miller MR, Crapo R, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, Enright P, van der Grinten CP, Gustafsson P, Jensen R, Johnson DC, MacIntyre N, McKay R, Navajas D, Pedersen OF, Pellegrino R, Viegi G, Wanger J; ATS/ERS Task Force. General considerations for lung function testing. Eur Respir J. 2005 Jul;26(1):153-61. doi: 10.1183/09031936.05.00034505. No abstract available.

Study record dates

Study Major Dates

• Study Start: July 1, 2010
• Primary Completion (Actual): December 1, 2010
• Study Completion (Actual): January 1, 2011

Study Registration Dates

• First Submitted: August 24, 2010
• First Submitted That Met QC Criteria: August 25, 2010
• First Posted (Estimate): August 26, 2010

Study Record Updates

• Last Update Posted (Actual): July 2, 2017
• Last Update Submitted That Met QC Criteria: June 27, 2017
• Last Verified: June 1, 2017

More Information

Terms related to this study

• Keywords: COPD; asthma; efficacy; bronchospasm; reversibility
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Immune System Diseases; Lung Diseases; Hypersensitivity, Immediate; Bronchial Diseases; Respiratory Hypersensitivity; Hypersensitivity; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive; Asthma; Bronchial Spasm; 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-C