Official Title: “Randomized, Placebo-Controlled, Parallel, Multi-Center, 12-Week Study to Evaluate the Efficacy and Safety of Albuterol HFA Versus the Active Control, Proventil(R)-HFA in Adult and Adolescent Asthmatic Patients”

This 12-week clinical study evaluates the safety and efficacy of Albuterol Sulfate HFA Inhalation Aerosol (Albuterol-HFA, or: A004), Armstrong's proposed HFA formulation of metered dose inhaler (MDI) of Albuterol (Treatment T), in comparison with:

1. Placebo control: (HFA propellant only, Treatment P); and

2. Active control: 3M/Key's Proventil-HFA (Treatment R).

The treatments will be given as self-administered oral inhalations in adult and adolescent patients with mild-to-moderate asthma, for 12-weeks. Dosing regimen throughout the 12-week study is two actuations four times daily (QID).

Study Type: Interventional

Study Design: Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Parallel Assignment, Safety/Efficacy Study

Study Primary Completion Date: May 2008

This is a randomized, parallel, multicenter, 12-week study in adolescent and adult patients with mild-to-moderate asthma, to evaluate the efficacy and safety of Armstrong's Albuterol-HFA MDI, in comparison to a Placebo Control and an Active Control of Proventil-HFA.

While Albuterol-HFA (Treatment T) and Placebo (Treatment P) will be double-blinded to both the subjects and investigational staff, the active comparator drug, Proventil-HFA (Treatment R), can only be evaluator-blinded, due to: (1) its physical appearance differing from that of the T and P devices; and (2) unavailability of a Proventil-HFA placebo which would otherwise be used for a double-dummy design. All study medications will have the canisters and all product-identifying text or graphics (e.g., molded text on actuator) masked so that the treatments cannot be identified. No subject in any study arm will be given any information that could reveal the nature of the treatment given. All study subjects will be instructed not to reveal or discuss the study medications to the study staff or other subjects. The designated study evaluator(s), who conduct the clinical visits and safety and efficacy evaluations and perform the data recording and transcription, will be blinded to the study medications.

All subjects will be screened for enrollment, and will be randomized into the following three treatment groups in a double-blinded (for Treatments T and P) or evaluator-blinded (for Treatment R) manner:

Treatment T (Albuterol-HFA, N=200): 216 mcg albuterol sulfate (equivalent to 180 mcg albuterol base), QID; Treatment R (Proventil-HFA, N=50): 216 mcg albuterol sulfate (equivalent to 180 mcg albuterol base), QID; Treatment P (Placebo-HFA, N=50): two actuations of placebo, QID.

Randomization is achieved with blocks of six (6), with four (4) patients receiving Albuterol-HFA for every one (1) patient receiving Proventil-HFA and every one (1) receiving the Placebo-HFA. At each Clinical Visit that takes place every 3 weeks, the double-blinded (T, P) or evaluator-blinded (R) study drugs will be distributed in resealable masking pouches to the subjects of each arm.

An additional aim of the study is to evaluate the effect of weekly cleaning on the Albuterol-HFA MDI device clinical performance throughout the four, 3-week life-of-device treatment cycles, in conformance with the FDA's specific requirements.

Arms:

All subjects will be screened for enrollment, and will be randomized into the following three treatment groups in a double-blinded (for Treatments T and P) or evaluator-blinded (for Treatment R) manner:

Treatment T (Albuterol-HFA, N=200): 216 mcg albuterol sulfate (equivalent to 180 mcg albuterol base), QID; Treatment R (Proventil-HFA, N=50): 216 mcg albuterol sulfate (equivalent to 180 mcg albuterol base), QID; Treatment P (Placebo-HFA, N=50): two actuations of placebo, QID.

Intervention(s) in this Clinical Trial

• Drug: albuterol HFA (Armstrong's)
  • 180 mcg QID 12 weeks
• Drug: albuterol HFA (Proventil HFA)
  • 180 mcg QID 12 weeks
• Drug: HFA placebo
  • 2 actuations QID 12 weeks or until use of rescue drug

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: T
  • albuterol HFA 180 mcg QID
• Active Comparator: R
  • 180 mcg QID 12 weeks
• Placebo Comparator: P
  • 2 actuations QID 12 weeks or until use of rescue drug

Primary Measures

• The primary endpoint is the bronchodilator effect expressed as the mean area under the curve (AUC) of FEV1 (% change from Same-Day Baseline FEV1) versus time.
  • Time Frame: Concurent with each visit
    Safety Issue?: No

Secondary Measures

• The comparative analysis of AUC of FEV1 (% change from the Same-Day Baseline) versus time, for bronchodilator effect (between Albuterol-HFA and Proventil-HFA).
  • Time Frame: End of Study
    Safety Issue?: No
• AUC of FEV1-time curve (changes of actual volumes from the Same-Day Baseline).
  • Time Frame: End of Study
    Safety Issue?: No
• Time to onset of bronchodilator effect, determined by linear interpolation as the time point where FEV1 first reaches 12% over Same-Day Baseline.
  • Time Frame: End of Study
    Safety Issue?: No
• The peak bronchodilator response, defined as the maximum FEV1 (% change from Same-Day Baseline) post-dose.
  • Time Frame: end of study
    Safety Issue?: No
• The time to peak FEV1 effect, measured as the time point of peak response, as defined (4) above.
  • Time Frame: End of Study
    Safety Issue?: No
• Duration of bronchodilator effect, defined as the total length of time when FEV1 is maintained 12% above the respective Same-Day Baseline values (time points calculated with linear interpolation).
  • Time Frame: Concurrent with each visit
    Safety Issue?: No
• Percentage of positive responders including those whose FEV1 exceed the Same-Day Baseline by 12% within 30 minutes post-dose (quick responders), and during the entire 6 hr post-dose (overall responders).
  • Time Frame: Concurrent with visit
    Safety Issue?: No
• Number of inhalations of the rescue inhalers taken.
  • Time Frame: Concurrent with each visit
    Safety Issue?: No
• Global assessment of Overall Asthma Control Scores by investigators.
  • Time Frame: End of Study
    Safety Issue?: No
• Total daytime asthma symptom scores.
  • Time Frame: End of Study
    Safety Issue?: No
• Nighttime sleep disturbance scores.
  • Time Frame: End of Study
    Safety Issue?: No
• Morning pre-dose Peak Expiratory Flow Rate (PEF).
  • Time Frame: Concurrent with each visit
    Safety Issue?: No
• The clinical performances of the Albuterol-HFA MDI at the representative first, middle and last one third of the usable life stage, are compared with each other, and are also compared to those of the active control, Proventil-HFA.
  • Time Frame: End of Study
    Safety Issue?: No
• The in vitro performance of the Albuterol-HFA MDI will be evaluated.
  • Time Frame: Concurrent with each visit
    Safety Issue?: No
• Vital signs (SBP/DBP, and heart rate) will be monitored at Clinical Visit 1, 3 and 5, at baseline (within 30 minutes prior to dosing), and 90+/-15 min, and 360+/-30 min, post-dose.
  • Time Frame: concurrent with study visits as noted
    Safety Issue?: Yes
• A 12-lead ECG (for HR, QT and QTc intervals) will be recorded at Screening Visit, and at baseline (within 30 min) pre-dose and at 90+/-15 min post-dose (predicted time of peak effect).
  • Time Frame: Clinical Visits 1 and 5
    Safety Issue?: Yes
• Data for CBC, blood chemistry panel (8-hr fasted), and urinalysis.
  • Time Frame: Screening and end-of-study
    Safety Issue?: Yes
• Study compliance and diaries will be reviewed
  • Time Frame: at all cliniical visits
    Safety Issue?: Yes
• Concomitant medications will be reviewed and recorded
  • Time Frame: each study visit
    Safety Issue?: Yes
• Adverse events/side effects whether observed by investigators or reported by subjects, will be documented, evaluated, followed up, and treated if deemed necessary.
  • Time Frame: concurrent with each study visit
    Safety Issue?: Yes

Inclusion Criteria:

• Male and female asthma patients aged 12 - 75 years, in general good health.
• A documented history of mild to moderate asthma, for at-least 6-months prior to Screening, requiring inhaled B2-adrenergic agonists, with or without orally inhaled corticosteroids, for asthma treatment.
• Satisfying criteria of asthma stability, defined as no asthma-related hospitalization or emergency visits, and no significant changes in asthma therapy, over 4 weeks prior to Screening (with exception for switching from long- to short-acting B2-agonists).
• Can tolerate withholding treatment with inhaled bronchodilators and other allowed medications for the minimum washout periods indicated in Appendix II prior to the Screening Baseline FEV1 testing.
• Having a Screening Baseline FEV1 test that falls within 50-90% of the predicted values.
• Airway Reversibility PFT at screening should demonstrate a greater than 12% increase in FEV1 at 30 minutes of inhaling 2 actuations of Ventolin-HFA (180 mcg albuterol base).
• Demonstrating satisfactory techniques in the use of metered-dose inhaler (MDIs) and a hand held peak flow meter.
• Female patients of child-bearing potential being non-pregnant and non-lactating at
• Screening and throughout the study, and using an acceptable method of contraception during the study.
• Has properly consented to participate in this study.

Exclusion Criteria:

• Male and female asthma patients aged 12 - 75 years, in general good health.
• A documented history of mild to moderate asthma, for at-least 6-months prior to Screening, requiring inhaled B2-adrenergic agonists, with or without orally inhaled corticosteroids, for asthma treatment.
• Satisfying criteria of asthma stability, defined as no asthma-related hospitalization or emergency visits, and no significant changes in asthma therapy, over 4 weeks prior to Screening (with exception for switching from long- to short-acting B2-agonists).
• Can tolerate withholding treatment with inhaled bronchodilators and other allowed medications for the minimum washout periods indicated in Appendix II prior to the Screening Baseline FEV1 testing.
• Having a Screening Baseline FEV1 test that falls within 50-90% of the predicted values.
• Airway Reversibility PFT at screening should demonstrate a greater than12% increase in FEV1 at 30 minutes of inhaling 2 actuations of Ventolin-HFA (180 mcg albuterol base).
• Demonstrating satisfactory techniques in the use of metered-dose inhaler (MDIs) and a hand held peak flow meter.
• Female patients of child-bearing potential being non-pregnant and non-lactating at
• Screening and throughout the study, and using an acceptable method of contraception during the study.
• Has properly consented to participate in this study.

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 12 Years

Maximum Age for this Clinical Trial: 75 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: Amphastar Pharmaceuitcals, Inc.

Information obtained from ClinicalTrials.gov on October 10, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00635505

Study ID Number: API-A004-CLN-C

ClinicalTrials.gov Identifier: NCT00635505

Health Authority: United States: Food and Drug Administration