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.

Tracking Information

• First Submitted Date: August 24, 2010
• First Posted Date: August 26, 2010
• Last Update Posted Date: July 2, 2017
• Study Start Date: July 2010
• Actual Primary Completion Date: December 2010 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 25, 2010)

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.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: June 27, 2017)

• 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.
• 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.
• 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.
• 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
• 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
• 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

Original Secondary Outcome Measures (submitted: August 25, 2010)

• 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.
• 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.
• 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.
• 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 Albuterol MDI may be expected with the use of Albuterol DPI
• 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
• 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

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Escalating and Cumulative-Dose Study of Pharmacokinetics (PK), Pharmacodynamics (PD) and Safety of A006
• 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
• 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.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Crossover Assignment; Masking: Triple (Participant, Investigator, Outcomes Assessor); Primary Purpose: Treatment

Condition

• Asthma
• Bronchospasm
• Chronic Obstructive Pulmonary Disease (COPD)

Intervention

• Drug: A006
  Albuterol DPI with 180 mcg Albuterol/inhalation
• Drug: Placebo DPI
  Placebo DPI with 0 mcg Albuterol/inhalation
• Drug: Proventil-HFA
  Albuterol MDI with 90 mcg Albuterol/inhalation

Study Arms

• 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.
  Intervention: Drug: A006
• 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.
  Intervention: Drug: Proventil-HFA
• 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.
  Intervention: Drug: Placebo DPI

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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: January 27, 2011): 27
• Original Estimated Enrollment (submitted: August 25, 2010): 24
• Actual Study Completion Date: January 2011
• Actual Primary Completion Date: December 2010 (Final data collection date for primary outcome measure)

Eligibility 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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 55 Years (Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT01189396
• Other Study ID Numbers: API-A006-CL-C
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Amphastar Pharmaceuticals, Inc.
• Original Responsible Party: Medical Director, Amphastar Pharmaceuticals, Inc.
• Current Study Sponsor: Amphastar Pharmaceuticals, Inc.
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

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

• PRS Account: Amphastar Pharmaceuticals, Inc.
• Verification Date: June 2017