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

• ClinicalTrials.gov Identifier: NCT01189396
• Recruitment Status: Completed
• First Posted: August 26, 2010
• Last Update Posted: July 2, 2017
• Sponsor: Amphastar Pharmaceuticals, Inc.
• Information provided by (Responsible Party): Amphastar Pharmaceuticals, Inc.

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Asthma; Bronchospasm; Chronic Obstructive Pulmonary Disease (COPD)	Drug: A006; Drug: Placebo DPI; Drug: Proventil-HFA	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 27 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double- or Evaluator-blinded, Active- and Placebo-controlled, Cumulative-dose, Dose-escalating, Three-arm, Cross-over Study, in 24 Asthma Patients
• Study Start Date: July 2010
• Actual Primary Completion Date: December 2010
• Actual Study Completion Date: January 2011

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. Bronchodilatory efficacy after the escalating and cumulative-doses, up to 1,440 mcg. [ Time Frame: -15 min predose, 15 min post dose 1, 2 and 3 and 15, 45, 90, 120, 180, 240, 360 min post dose 4 ]
   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.

Secondary Outcome Measures :

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

Eligibility Criteria

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

Criteria

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.

Contacts and Locations

Locations

United States, Oregon

Amphastar Site 0025

Medford, Oregon, United States, 97504

Amphastar Site 0026

Portland, Oregon, United States, 97213

United States, Texas

Amphastar Site 0032

San Antonio, Texas, United States, 78229

United States, Washington

Amphastar Site 0034

Seattle, Washington, United States, 98105

Sponsors and Collaborators

Amphastar Pharmaceuticals, Inc.

Investigators

• Study Director: Safety Monitor; Amphastar Pharmaceuticals, Inc.

More Information

Publications:

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.

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.

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.

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.

• Responsible Party: Amphastar Pharmaceuticals, Inc.
• ClinicalTrials.gov Identifier: NCT01189396
• Other Study ID Numbers: API-A006-CL-C
• First Posted: August 26, 2010
• Last Update Posted: July 2, 2017
• Last Verified: June 2017

Keywords provided by Amphastar Pharmaceuticals, Inc.:

asthma; bronchospasm; COPD; reversibility; efficacy

Additional relevant MeSH terms:

Asthma; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive; Bronchial Spasm; Bronchial Diseases; Respiratory Tract Diseases; Lung Diseases; Respiratory Hypersensitivity; Hypersensitivity, Immediate; Hypersensitivity; Immune System Diseases; Albuterol; Bronchodilator Agents; Autonomic Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Anti-Asthmatic Agents; Respiratory System Agents; Tocolytic Agents; Reproductive Control Agents; Adrenergic beta-2 Receptor Agonists; Adrenergic beta-Agonists; Adrenergic Agonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action