Official Title: “Randomized, Double-Blind, Controlled, Single-Dose, Three-Treatment, Cross-Over Study of The Protective Effects Of Albuterol-HFA In Preventing Exercise-Induced Bronchoconstriction In Adolescent And Adult Asthmatic Patients”

This clinical study will evaluate and establish the protective effects of Amphastar's Albuterol Sulfate HFA Inhalation Aerosol (Albuterol-HFA), in preventing exercise-induced bronchoconstriction (EIB) in adolescent and adult asthmatic patients, in comparison with (1) Proventil®-HFA (Reference drug and Active Control ), and (2) Placebo-HFA control (HFA propellant only). Safety of the test drug, Albuterol-HFA, will also be evaluated in comparison to the Active and Placebo Controls. Analyses will be performed to determine if the Armstrong's Albuterol-HFA has resulted in a significant bronchoprotective effect, with attenuated Max % Fall in FEV1, in comparison to the Placebo-HFA control.

Study Type: Interventional

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

Study Primary Completion Date: May 2008

The prevalence of exercise-induced bronchoconstriction (EIB) has been reported to be around 70% to 75% among patients with clinically established asthma. Airway cooling and drying are thought to cause the release of inflammatory mediators, such as histamine and leukotrienes, which then mediate clinical EIB symptoms. Pretreatment with a variety of medications will ameliorate EIB. Albuterol has been found to be more effective in minimizing EIB than theophylline, ipratropiom, cromoglycate, etc. Tested using a treadmill exercise challenge, the newer formulations of albuterol MDI with HFA as propellant have been demonstrated to be as effective as those with CFC as propellant in protecting asthma patients from EIB in children and adults.

As a part of the Amphastar Pharmaceuticals' clinical development plan, the current study examines the clinical efficacy of A004, Armstrong Pharmaceuticals' Albuterol HFA oral inhalation MDI, in preventing EIB in adolescent and adult asthmatic patients.

This is a randomized, double-blind, active and placebo-controlled, three-treatment, cross-over study, to be conducted in adolescent and adult patients with mild to moderate asthma and demonstrable EIB.

All subjects will be screened against the inclusion/exclusion criteria for enrollment. A computer-generated randomization code will be created by the Amphastar Pharmaceuticals' IT Department, so that each enrolled subject will receive all three double-blinded treatments in randomized sequence. Each treatment is followed by a standardized exercise challenge and a series of FEV1 measurements during the 90 min post-exercise period. The three crossover Treatment Arms are: - Treatment T (Armstrong's Test Drug: Albuterol-HFA); - Treatment R (Reference Drug and Active Control: Proventil®-HFA); - Treatment P (Placebo-HFA).

By the definition of the crossover design, the three Treatment Arms are expected to consist comparably of 24 evaluable subjects. The consecutive study sessions will be separated by an interval of 1-14 days.

Intervention(s) in this Clinical Trial

• Drug: albuterol (Armstrong Albuterol HFA)
  • 2 inhalations of 108 mcg albuterol sulfate prior to exercise, single dose
• Drug: Albuterol Sulfate (Provenetil-HFA)
  • 2 inhalations of Proventil-HFA, 108 mcg/inhalation prior to exercise
• Drug: Placebo-HFA
  • Placebo containing HFA propellant without active drug substance

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: T
  • Armstrong Albuterol HFA Inhalation Aerosol
• Active Comparator: R
  • 2 inhalations Proventil-HFA Albuterol Sulfate, 108 mcg, prior to exercise
• Placebo Comparator: P
  • Placebo-HFA

Primary Measures

• The maximum percentage fall in FEV1, from the Pre-Exercise FEV1, between Albuterol-HFA and Placebo-HFA.
  • Time Frame: 90 minutes post exercise
    Safety Issue?: No

Secondary Measures

• Evaluation of relative broncho-protective efficacy of Albuterol-HFA, in comparison to the active comparator, Proventil®-HFA, using the Max % fall in Post-Exercise FEV1, from the Pre-exercise FEV1
  • Time Frame: 90 minutes post exercise
    Safety Issue?: Yes
• Pre-exercise FEV1 values (volume in Liters, recorded ), indicative of bronchodilator responsiveness.
  • Time Frame: 20-30 min post dose
    Safety Issue?: No
• Number and percentage of subjects who demonstrate a <20.0% fall in FEV1, from the Pre-exercise FEV1.
  • Time Frame: 90 min post-exercise
    Safety Issue?: No
• Area Under-the-Curve of percentage fall in FEV1, from the Pre-exercise FEV1.
  • Time Frame: 90 min post-exercise
    Safety Issue?: No
• Time to recovery, as the time point where FEV1 recovers from maximum percent fall in FEV1 to be within 5.0% of the Pre-Exercise FEV1 values.
  • Time Frame: concurrent with study visit
    Safety Issue?: No
• Number of subjects who cannot complete the exercise at specified intensity and length, due to asthma symptoms.
  • Time Frame: concurrent with study visit
    Safety Issue?: Yes
• Number of subjects requiring B2-agonist rescue inhalations during exercise, and during the 90 min post-exercise period.
  • Time Frame: 90 minutes post exercise
    Safety Issue?: No
• The following baseline and post-dose safety parameters before and after each exercise-challenge tests will be assessed: Vital signs: blood pressure (SBP/DBP) and heart rate (HR).
  • Time Frame: concurrent with study visit
    Safety Issue?: Yes
• 12-lead ECG: HR, QT and QTc intervals, before and after treatment with Albuterol-HFA, versus the active control, and placebo control.
  • Time Frame: concurrent with study visit
    Safety Issue?: Yes
• Pre-study (Screening) and End-of-Study laboratory tests for CBC, blood chemistry panel, urinalysis and urine pregnancy test.
  • Time Frame: Throughout study
    Safety Issue?: Yes
• Adverse events and side effects will be documented when observed by investigators or reported by subjects.
  • Time Frame: throughout study
    Safety Issue?: Yes

Inclusion Criteria:

• 1. Male and female subjects, aged 12 - 50 years, and in general good health.
• 2. A documented history of mild to moderate asthma, for at-least 6-months, requiring inhaled B-adrenergic agonists for symptom control.
• 3. Having a history of exercise-induced bronchoconstriction, that can be prevented or relieved by the use of an inhaled B-agonist.
• 4. Satisfying asthma stability requirement, such that over the 30 days prior to the screening, there are no significant changes in asthma therapy and no asthma-related hospitalization or emergency medical visits.
• 5. Being able to withhold treatment with inhaled bronchodilators and/or restricted medications for the minimum washout periods indicated in Appendix II prior to pulmonary function testing at Screening Visit and Clinical Visits 1, 2 and 3.
• 6. Having a baseline forced expiratory volume in the 1st second (FEV1) that is greater than nor equal to 65.0% of predicted normal values.
• 7. Demonstrating a greater than or equal to 20.0%, but <50.0%, fall in FEV1 during a Standard Exercise Challenge test per current ATS guidance, at Screening.
• 8. Demonstrating satisfactory techniques in the correct use of metered-dose inhaler (MDIs).
• 9. Female patients of child-bearing potential being non-pregnant and non-lactating, and using an acceptable method of contraception.
• 10. Willingness and ability to sign the informed consent and HIPPA forms to participate in this trial.

Exclusion Criteria:

• 1. A smoking history of ≥10 pack-years, or having smoked within the past 12 months prior to Screening.
• 2. Any current or past significant respiratory diseases that might significantly interfere with pharmacodynamic response to the study drugs, such as cystic fibrosis, bronchiectasis, emphysema, pulmonary malignancies, etc, other than asthma.
• 3. Clinically significant cardiovascular, hematological, renal, neurologic, hepatic, and endocrine disorders, or psychiatric diseases, or any other significant health conditions that in the opinion of the investigator might interfere with bronchodilator responses.
• 4. Recent upper or lower respiratory tract infection (within 4 weeks) prior to Screening.
• 5. Recent (per Appendix II, Part I) use of orally ingested or systemically administered corticosteroids, B-adrenergic bronchodilators, monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants (TCAs), B-blockers, or drugs that affect study drug performance.
• 6. Taking >1,000 mcg daily of inhaled beclomethasone dipropionate or budesonide, or >500 mcg daily of inhaled fluticasone propionate, or taking high doses of other orally inhaled corticosteroids that suggest severe asthma state, in the opinion of the investigator, within four weeks of Screening.
• 7. Demonstrating clinically significant abnormal 12-lead ECG results, upon Screening.
• 8. Any significant physical (e.g., musculoskeletal, overweight, etc) conditions that, in the opinion of the investigator, could limit the subject's ability to perform the exercise challenge test.
• 9. Known intolerance or hypersensitivity to any component of the MDI formulation (albuterol, HFA-134a, oleic acid and alcohol).
• 10. Known or reasonably suspected substance abuses.

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 12 Years

Maximum Age for this Clinical Trial: 50 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: Amphastar Pharmaceuitcals, Inc.

Information obtained from ClinicalTrials.gov on August 29, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00634829

Study ID Number: API-A004-CLN-D

ClinicalTrials.gov Identifier: NCT00634829

Health Authority: United States: Food and Drug Administration