Efficacy of Inhaled Albuterol Spiromax® in Subjects With Persistent Asthma With Steady State Pharmacokinetics

A 12-week Comparison of the Efficacy and Safety and Steady-State Pharmacokinetics of Albuterol Spiromax® Versus Placebo in Subjects 12 Years and Older With Persistent Asthma

The primary objective of this study is to evaluate the efficacy of Albuterol Spiromax® versus placebo in subjects with persistent asthma.

Study Overview

• Status: Completed
• Conditions: Asthma
• Intervention / Treatment: Drug: Placebo MDPI; Drug: Albuterol MDPI

• Study Type: Interventional
• Enrollment (Actual): 160
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • California
    • Costa Mesa, California, United States
      • Teva Investigational Site 10225
    • Encinitas, California, United States
      • Teva Investigational Site 10250
    • Huntington Beach, California, United States
      • Teva Investigational Site 10230
    • Palmdale, California, United States
      • Teva Investigational Site 10255
    • Rancho Mirage, California, United States
      • Teva Investigational Site 10231
    • Riverside, California, United States
      • Teva Investigational Site 10252
    • Rolling Hills Estates, California, United States
      • Teva Investigational Site 10242
    • San Diego, California, United States
      • Teva Investigational Site 10238
    • San Jose, California, United States
      • Teva Investigational Site 10243
  • Florida
    • Miami Lakes, Florida, United States
      • Teva Investigational Site 10247
    • Tallahassee, Florida, United States
      • Teva Investigational Site 10239
    • Tampa, Florida, United States
      • Teva Investigational Site 10234
  • Maine
    • Bangor, Maine, United States
      • Teva Investigational Site 10253
  • Maryland
    • Baltimore, Maryland, United States
      • Teva Investigational Site 10257
    • White Marsh, Maryland, United States
      • Teva Investigational Site 10254
  • Massachusetts
    • Fall River, Massachusetts, United States
      • Teva Investigational Site 10235
    • North Dartmouth, Massachusetts, United States
      • Teva Investigational Site 10236
  • Minnesota
    • Minneapolis, Minnesota, United States
      • Teva Investigational Site 10226
    • Minneapolis, Minnesota, United States
      • Teva Investigational Site 10233
  • Missouri
    • St. Louis, Missouri, United States
      • Teva Investigational Site 10241
  • Nebraska
    • Bellevue, Nebraska, United States
      • Teva Investigational Site 10229
  • New York
    • Rochester, New York, United States
      • Teva Investigational Site 10227
  • North Carolina
    • Charlotte, North Carolina, United States
      • Teva Investigational Site 10244
  • Ohio
    • Cincinnati, Ohio, United States
      • Teva Investigational Site 10248
  • Oklahoma
    • Oklahoma City, Oklahoma, United States
      • Teva Investigational Site 10249
  • Oregon
    • Eugene, Oregon, United States
      • Teva Investigational Site 10232
    • Medford, Oregon, United States
      • Teva Investigational Site 10259
    • Portland, Oregon, United States
      • Teva Investigational Site 10237
  • Pennsylvania
    • Bethlehem, Pennsylvania, United States
      • Teva Investigational Site 10240
    • Pittsburgh, Pennsylvania, United States
      • Teva Investigational Site 10246
    • Pittsburgh, Pennsylvania, United States
      • Teva Investigational Site 10256
  • South Carolina
    • Rock Hill, South Carolina, United States
      • Teva Investigational Site 10251
    • Spartanburg, South Carolina, United States
      • Teva Investigational Site 10228
  • Texas
    • San Antonio, Texas, United States
      • Teva Investigational Site 10258
  • Washington
    • Seattle, Washington, United States
      • Teva Investigational Site 10245

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Written informed consent/assent
• At least 12 years of age at screening
• General good health
• Persistent asthma for ≥3 months, with an FEV1 50-80% predicted and ≥15% reversibility
• Taking inhaled corticosteroids at a stable dose (≤ equivalent of 500mcg of fluticasone propionate/day) for at least 4 weeks prior to the Screening Visit.
• Ability to perform spirometry in an acceptable manner as per protocol guidelines
• Other inclusion criteria apply

Exclusion Criteria:

• A known hypersensitivity to albuterol or any of the excipients in the formulations.
• History of a respiratory infection or disorder that has not resolved within 1 week preceding the Screening Visit (SV).
• History of life-threatening asthma that is defined for this protocol as an asthma episode that required intubation.
• Any asthma exacerbation requiring oral corticosteroids within 3 months of the SV. A subject must not have had any hospitalization for asthma within 6 months prior to the SV.
• Hospitalization due to asthma exacerbation 2 or more times in the past year
• Initiation of immunotherapy or dose escalation during the study period
• Other exclusion criteria apply.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo MDPI; Placebo multi-dose dry powder inhaler (MDPI) administered as 2 inhalations four times a day for 12 weeks.	Drug: Placebo MDPI; Placebo MDPI administered as 2 inhalations 4 times a day (QID) (at approximately 7:00 AM, 12 noon, 5:00 PM, and bedtime) for 12 weeks.; Other Names: Placebo Spiromax®
Experimental: Albuterol MDPI; Albuterol multi-dose dry powder inhaler (MDPI) at a dose of 720 micrograms per day administered as 2 inhalations of 90 mcg /inhalation four times a day for 12 weeks.	Drug: Albuterol MDPI; Albuterol MDPI administered as 2 inhalations 4 times a day (QID) (at approximately 7:00 AM, 12 noon, 5:00 PM, and bedtime) for 12 weeks.; Other Names: ProAir® RespiClick, Albuterol Spiromax®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Baseline-adjusted Forced Expiratory Volume in 1 Second (FEV1) Area Under the Curve (AUC 0-6) Over the 12-week Treatment Period	FEV1 AUC 0-6 is the area under the effect-time curve from time 0 (pre-dose) up to 6 hours post-dose. It represents the weighted average (by the trapezoidal rule) over six hours of the FEV1 AUC 0-6 measures adjusted for the baseline measure (i.e., change from baseline at each timepoint) recorded on days 1, 8 and 85 of the treatment period. The baseline for each study day was the average of the 2 pre-dose FEV1 measurements on that study day. FEV1 was measured using spirometry. Spirometry assessments were obtained predose at -30 ± 5, and - 5 minutes, then post dose at 5 ± 2, 15 ± 5, 30 ± 5, 45 ± 5 minutes, and at 1hr ± 5 min, 2hr ± 5 min, 3hr ± 5 min, 4hr ± 5 min, 5hr ± 5 min, and 6hr ± 5 min.	Day 1, Day 8 and Day 85

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Baseline-adjusted Forced Expiratory Volume in 1 Second (FEV1) Area Under the Curve (AUC 0-6) on Day 1	FEV1 AUC 0-6 is the area under the effect-time curve from time 0 (pre-dose) up to 6 hours post-dose. It represents the weighted average over six hours of the FEV1 AUC 0-6 measures adjusted for the baseline measure. The baseline was the average of the 2 pre-dose FEV1 measurements on that study day. FEV1 was measured using spirometry. Spirometry assessments were obtained predose at -30 ± 5, and - 5 minutes, then post dose at 5 ± 2, 15 ± 5, 30 ± 5, 45 ± 5 minutes, and at 1hr ± 5 min, 2hr ± 5 min, 3hr ± 5 min, 4hr ± 5 min, 5hr ± 5 min, and 6hr ± 5 min.	Day 1
Baseline-adjusted Forced Expiratory Volume in 1 Second (FEV1) Area Under the Curve (AUC 0-6) on Day 8	FEV1 AUC 0-6 is the area under the effect-time curve from time 0 (pre-dose) up to 6 hours post-dose. It represents the weighted average over six hours of the FEV1 AUC 0-6 measures adjusted for the baseline measure. The baseline was the average of the 2 pre-dose FEV1 measurements on that study day. FEV1 was measured using spirometry. Spirometry assessments were obtained predose at -30 ± 5, and - 5 minutes, then post dose at 5 ± 2, 15 ± 5, 30 ± 5, 45 ± 5 minutes, and at 1hr ± 5 min, 2hr ± 5 min, 3hr ± 5 min, 4hr ± 5 min, 5hr ± 5 min, and 6hr ± 5 min.	Day 8
Baseline-adjusted Forced Expiratory Volume in 1 Second (FEV1) Area Under the Curve (AUC 0-6) on Day 85	FEV1 AUC 0-6 is the area under the effect-time curve from time 0 (pre-dose) up to 6 hours post-dose. It represents the weighted average over six hours of the FEV1 AUC 0-6 measures adjusted for the baseline measure. The baseline was the average of the 2 pre-dose FEV1 measurements on that study day. FEV1 was measured using spirometry. Spirometry assessments were obtained predose at -30 ± 5, and - 5 minutes, then post dose at 5 ± 2, 15 ± 5, 30 ± 5, 45 ± 5 minutes, and at 1hr ± 5 min, 2hr ± 5 min, 3hr ± 5 min, 4hr ± 5 min, 5hr ± 5 min, and 6hr ± 5 min.	Day 85
Participants With Adverse Events	Adverse events (AEs) summarized in this table are those that began or worsened after treatment with study drug (treatment-emergent AEs). An adverse event was defined in the protocol as any untoward medical occurrence that develops or worsens in severity during the conduct of a clinical study and does not necessarily have a causal relationship to the study drug. Severity was rated by the investigator on a scale of mild, moderate and severe, with severe= an AE which prevents normal daily activities. Relation of AE to treatment was determined by the investigator. Serious AEs include death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, OR an important medical event that jeopardized the patient and required medical intervention to prevent the previously listed serious outcomes.	Day 1 to Day 93
Physical Examination Findings Shifts From Baseline to Endpoint by Treatment Group	Physical exam was recorded as normal or abnormal based on physician assessment. Format for results is: Test Baseline/Endpoint. HEENT = head, eyes, ears, nose, throat.	Day 1 (Baseline), Day 85
Participants With Clinically Significant Vital Sign Assessments	For both standard and serial vital signs, participants were seated for at least 5 minutes before vital signs were assessed. Heart rate was obtained prior to the blood pressure measurement. Serial heart rate and blood pressure were conducted in the sitting position prior to the spirometry assessment; baseline measures were taken pre-dose at -30 ± 5 and -5 minutes on Day 1. Day 85 serial vital sign measures were taken in the sitting position prior to spirometry assessments pre-dose at -30 ± 5 and -5 minutes, then post-dose at 30 (±5) minutes, 1hr (± 10 min), 2hr (± 10 min), 3hr (± 10 min), 4hr (± 10 min), 5hr (± 10 min) and 6 hr (± 10 min). Serial heart rate and blood pressure measurements that were elevated to the following criteria were considered clinically significant: Systolic blood pressure: > 160 beats/minute Diastolic blood pressure: >100 beats/minute Heart rate: >120 beats/minute	Days 8 and 85
Maximum Observed Plasma Drug Concentration (Cmax) for Albuterol on Days 1 and 8	Pharmacokinetic parameters of albuterol were determined on Day 1 after the first dose administration and at steady-state on Day 8. Day 1 serial (10-hr) blood samples for pharmacokinetics pre-dose (within 30 minutes prior to dosing), and post-dose at the following times: 15 (±5) min, 30 (±5) min, and 1, 2, 3, 4, 5, 6, 8 and 10 hours (±10 minutes). Day 8 serial (6-hr) blood samples for pharmacokinetics pre-dose (within 30 min prior to dosing), and post-dose at the following times: 15 (±5) min, 30 (±5) min, and 1, 2, 3, 4, 5 and 6 hr (±10 min).	Days 1 and 8
Time to Observed Peak Plasma Concentration (Tmax) for Albuterol on Days 1 and 8	Pharmacokinetic parameters of albuterol were determined on Day 1 after the first dose administration and at steady-state on Day 8. Day 1 serial (10-hr) blood samples for pharmacokinetics pre-dose (within 30 minutes prior to dosing), and post-dose at the following times: 15 (±5) min, 30 (±5) min, and 1, 2, 3, 4, 5, 6, 8 and 10 hours (±10 minutes). Day 8 serial (6-hr) blood samples for pharmacokinetics pre-dose (within 30 min prior to dosing), and post-dose at the following times: 15 (±5) min, 30 (±5) min, and 1, 2, 3, 4, 5 and 6 hr (±10 min).	Days 1 and 8
Area Under the Concentration-time Curve From Time 0 (Pre-dose) up to 6 Hours Post-dose (AUC0-6) for Albuterol on Days 1 and 8	Pharmacokinetic parameters of albuterol were determined on Day 1 after the first dose administration and at steady-state on Day 8. Day 1 serial (10-hr) blood samples for pharmacokinetics pre-dose (within 30 minutes prior to dosing), and post-dose at the following times: 15 (±5) min, 30 (±5) min, and 1, 2, 3, 4, 5, 6, 8 and 10 hours (±10 minutes). Day 8 serial (6-hr) blood samples for pharmacokinetics pre-dose (within 30 min prior to dosing), and post-dose at the following times: 15 (±5) min, 30 (±5) min, and 1, 2, 3, 4, 5 and 6 hr (±10 min). AUC0-6 on Day 8 is not from pre-dose but at steady state.	Days 1 and 8
Area Under the Concentration-time Curve From Time 0 (Pre-dose) to Last Time of Quantifiable Concentration (AUC0-t) for Albuterol on Days 1 and 8	Pharmacokinetic parameters of albuterol were determined on Day 1 after the first dose administration and at steady-state on Day 8. Day 1 serial (10-hr) blood samples for pharmacokinetics pre-dose (within 30 minutes prior to dosing), and post-dose at the following times: 15 (±5) min, 30 (±5) min, and 1, 2, 3, 4, 5, 6, 8 and 10 hours (±10 minutes). Day 8 serial (6-hr) blood samples for pharmacokinetics pre-dose (within 30 min prior to dosing), and post-dose at the following times: 15 (±5) min, 30 (±5) min, and 1, 2, 3, 4, 5 and 6 hr (±10 min). AUC0-t on Day 8 is not from pre-dose but at steady state.	Days 1 and 8
Area Under the Concentration-time Curve From Time 0 (Pre-dose) to Infinity Post-dose(AUC0-inf) for Albuterol on Day 1	Pharmacokinetic parameters of albuterol were determined on Day 1 after the first dose administration and at steady-state on Day 8. Day 1 serial (10-hr) blood samples for pharmacokinetics pre-dose (within 30 minutes prior to dosing), and post-dose at the following times: 15 (±5) min, 30 (±5) min, and 1, 2, 3, 4, 5, 6, 8 and 10 hours (±10 minutes). Day 8 serial (6-hr) blood samples for pharmacokinetics pre-dose (within 30 min prior to dosing), and post-dose at the following times: 15 (±5) min, 30 (±5) min, and 1, 2, 3, 4, 5 and 6 hr (±10 min).	Day 1
Area Under the Concentration-time Curve From Time 0 (Pre-dose) to 24 Hours Post-dose(AUC0-24) for Albuterol on Day 8	Pharmacokinetic parameters of albuterol were determined on Day 1 after the first dose administration and at steady-state on Day 8. Day 1 serial (10-hr) blood samples for pharmacokinetics pre-dose (within 30 minutes prior to dosing), and post-dose at the following times: 15 (±5) min, 30 (±5) min, and 1, 2, 3, 4, 5, 6, 8 and 10 hours (±10 minutes). Day 8 serial (6-hr) blood samples for pharmacokinetics pre-dose (within 30 min prior to dosing), and post-dose at the following times: 15 (±5) min, 30 (±5) min, and 1, 2, 3, 4, 5 and 6 hr (±10 min).	Day 8
Terminal Plasma Half-life (t1/2) for Albuterol on Days 1 and 8	Pharmacokinetic parameters of albuterol were determined on Day 1 after the first dose administration and at steady-state on Day 8. Day 1 serial (10-hr) blood samples for pharmacokinetics pre-dose (within 30 minutes prior to dosing), and post-dose at the following times: 15 (±5) min, 30 (±5) min, and 1, 2, 3, 4, 5, 6, 8 and 10 hours (±10 minutes). Day 8 serial (6-hr) blood samples for pharmacokinetics pre-dose (within 30 min prior to dosing), and post-dose at the following times: 15 (±5) min, 30 (±5) min, and 1, 2, 3, 4, 5 and 6 hr (±10 min).	Days 1 and 8

Collaborators and Investigators

• Sponsor: Teva Branded Pharmaceutical Products R&D, Inc.

Publications and helpful links

General Publications

• Raphael G, Taveras H, Iverson H, O'Brien C, Miller D. Twelve- and 52-week safety of albuterol multidose dry powder inhaler in patients with persistent asthma. J Asthma. 2016;53(2):187-93. doi: 10.3109/02770903.2015.1070862. Epub 2015 Sep 15.

Study record dates

Study Major Dates

• Study Start: December 1, 2012
• Primary Completion (Actual): October 1, 2013
• Study Completion (Actual): November 1, 2013

Study Registration Dates

• First Submitted: December 7, 2012
• First Submitted That Met QC Criteria: December 7, 2012
• First Posted (Estimate): December 11, 2012

Study Record Updates

• Last Update Posted (Estimate): June 26, 2015
• Last Update Submitted That Met QC Criteria: May 28, 2015
• Last Verified: May 1, 2015

More Information

Terms related to this study

• Keywords: Asthma; dry powder inhaler; short-acting beta2-agonist; SABA; bronchoconstriction; bronchodilation; bronchodilator; metered dose inhaler; Albuterol Spiromax®
• 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: ABS-AS-304