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

Asthma Clinical Trial

— A006-B3  

Official title:

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02210806
• Other study ID #: API-A006-CL-B3
• Status: Completed
• Phase: Phase 2
• First received: August 4, 2014
• Last updated: April 17, 2017
• Start date: July 2014
• Est. completion date: October 2014

Study information

• Verified date: April 2017
• Source: Amphastar Pharmaceuticals, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 22
• Est. completion date: October 2014
• Est. primary completion date: September 2014
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 55 Years

Eligibility

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 ß-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.

Related Conditions & MeSH terms

• Asthma

Intervention

Drug:
• A006 DPI
Single dose 110 mcg, 1 inhalation
• A006 DPI
Single dose 220 mcg, 1 inhalation

Other:
• Placebo DPI
Placebo, 1 inhalation

Drug:
• Proventil® MDI
Single dose 90 mcg, 1 inhalation
• Proventil® MDI
Single dose 90 mcg, 2 inhalations

Locations

Country	Name	City	State
United States	Amphastar Site 0025	Medford	Oregon
United States	Amphastar Site 0030	New Braunfels	Texas
United States	Amphastar Site 0032	San Antonio	Texas
United States	Amphastar Site 0001	San Jose	California

Sponsors (1)

Lead Sponsor	Collaborator
Amphastar Pharmaceuticals, Inc.

Country where clinical trial is conducted

United States, 

References & Publications (7)

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. Review. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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
Other	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
Other	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
Other	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
Other	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
Other	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
Other	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
Other	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
Other	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
Other	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)
Other	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
Other	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)
Other	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
Other	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)
Other	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
Other	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)
Other	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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