4-Week Study of Efficacy, Safety and PK of Albuterol-HFA Versus Proventil-HFA in Pediatric Asthma
4-Week Study of Efficacy, Safety and PK of Albuterol-HFA Versus Proventil-HFA in Pediatric Asthma
This 4-week clinical study evaluates the efficacy and safety of Albuterol Sulfate HFA
 Inhalation Aerosol in comparison with the Active Control, Proventil-HFA (3M Pharmaceuticals,
 Inc) in pediatric patients (4-11 years old) with mild-to-moderate asthma. In addition,
 pharmacokinetic profile in this population will be evaluated using a population PK approach
 with sparse blood samples.
This study consists of two periods:

 1. Run-in Period (7-14 days): During the Run-in Period, subjects will maintain their
 current inhaled short-acting B2-agonist and inhaled corticosteroid therapies. All
 long-acting b-agonists (LABA) will be prohibited and replaced with a short-acting
 B2-agonist (Ventolin-HFA) and an inhaled corticosteroid, for a minimum of 7 days. Such
 LABA replacement therapy is not considered as violation of the asthma stability. The
 current orally inhaled corticosteroids may be maintained at the prescribed dosing
 regimen. All concomitant medications must be compliant or adjusted to the restrictions
 and washout time limits per Appendix II. Subjects will document their daily asthma
 symptom scores, treatment regimens, concomitant medications, PEF records, and adverse
 events if any.

 2. Study Period (4 wk): During the 4-week Study Period, subjects will be randomized into
 one of the following 2 double-blinded treatment groups:

 -  Treatment T (Albuterol-HFA, N=24): 216 mcg albuterol sulfate (equivalent to 180 mcg
 albuterol base), oral inhalation, QID;

 -  Treatment R (Proventil-HFA, N=24): 216 mcg albuterol sulfate (equivalent to 180 mcg
 albuterol base), oral inhalation, QID.

 During the Study Period, subjects will document their daily asthma symptom scores, treatment
 regimens, concomitant medications, PEF records, and adverse events if any. Three Clinical
 Visits are to be conducted, for measurement of treatment efficacy with serial spirometry (at
 Clinical Visit 1 and 3); for monitoring safety and compliance (at Clinical Visit 1, 2 and 3);
 and for evaluating pharmacokinetic profiles in part of the study population (greater than or
 equal to 6 subjects per Arm) using a population PK approach (PPK) with a sparse blood
 sampling regimen (at Clinical Visit 3).

 STUDY POPULATION

 Sufficient enrollment will be planned to obtain 48 subjects as "Per protocol population",
 with 24 in Albuterol-HFA (Arm T) and 24 in the Proventil-HFA (Arm R). Qualified subjects
 should be:

 1. Male and female patients aged 4 - 11 years (upon screening), and female patients being
 premenarchal upon Visit-1.

 2. With documented mild-to-moderate asthma for at least 6 months prior to screening;

 3. Being able to reliably perform spirometric FEV1 test;

 4. Consent, under supervision of a parent or a legal guardian, to participate in the study;

 5. Having a baseline forced expiratory volume in 1 second (FEV1) that is 50.0%-100.0% of
 predicted values at screening (Screening Baseline FEV1);

 6. Demonstrating a greater than or equal to 12.0% FEV1 reversibility in the Reversibility
 Test, at 30 min after inhaling 180 mcg of Ventolin-HFA;

 7. Satisfying the criterion of asthma stability, defined as no significant changes in
 asthma therapy and no asthma-related hospitalization or emergency visits, over 4 weeks
 prior to the screening;

 8. Satisfying the Run-in Period requirements;

 9. Satisfying all other inclusion/exclusion criteria, as specified in Section 4.2.

 TREATMENT REGIMENS

 Enrolled subjects will be randomized to receive one of the 2 double-blinded treatments:
 Albuterol-HFA (Treatment T) or Proventil-HFA (Treatment R).

 CLINICAL VISITS:

 The entire study consists of a Screening Period, a Run-in Period, and a Study Period which
 consists of three (3) Clinical Visits. The three (3) Clinical Visits are scheduled with 14±3
 days intervals, as Visit 1 (Day 0 of treatment), Visit 2 (Day 14), and Visit 3 (Day 28). The
 Clinical Visit 1 will be held within 7-14 days after Screening Visit. Serial FEV1 are
 performed at Visit 1 and 3. Safety and compliance are evaluated at all 3 Visits. Population
 PK (PPK) blood sampling is conducted at Visit 3.

 METHODOLOGIES AND SPECIFIC MEASUREMENTS

 1. Forced Expiratory Volume at 1st Second (FEV1)

 Spirometry is to be used to determine Forced Expiratory Volume in the 1st second (FEV1).
 Patient may choose either a standing or a sitting position for FEV1. The position, once
 chosen, should be kept consistent for the entire study. Nose clips will be worn for the
 FEV1 measurements.

 Each FEV1 is measured in triplicate at a given test or a given time point. The highest
 FEV1 volume, from the triplicate attempts, is used as the representative value. The
 highest and second highest FEV1 attempts should not differ by greater than 0.2 L. Up to
 2 additional attempts may be measured if necessary, with a total of 3-5 attempts allowed
 for a given test. The accepted attempts have to be technically conforming to the current
 spirometry standards from the American Thoracic Society (ATS). The current clinical
 normative lung volumes in conformity with the ATS guidelines will be used for
 calculating the predicted percentage.

 2. Peak Expiratory Flow (PEF) Rate

 PEF will be measured as a means of monitoring safety and asthma control. PEF will be measured
 in triplicate, with additional attempts if necessary. The highest PEF volume is used as the
 representative value. Two measurements of PEF are made daily, once prior to the first AM dose
 and once prior to the last PM dose of the study drug. Subject will be standing for PEF
 measurements. No nose-clips will be needed for PEF.

 2) Screening Baseline FEV1

 Passing the Screening Baseline FEV1 test is one of the prerequisites for enrollment, and is
 to be conducted at the Screening Visit by all subjects. The Screening Baseline FEV1 should
 fall within 50.0%-100.0% of the predicted value to qualify the subject.

 3) Reversibility FEV1 Test

 Reversibility FEV1 Test will be performed at the Screening Visit. Within 30 min after the
 Screening Baseline FEV1 is obtained, the subject will self-administer 180 to 360 mcg
 Ventolin-HFA (2-4 inhalations). To qualify for the study, the subject needs to demonstrate an
 FEV1 reversibility of greater than or equal to 12.0%, from the (same-day) Screening Baseline
 FEV1, with 3 to 8 attempts, at 30 min after inhaling Ventolin-HFA. Reversibility is defined
 as:

 % Reversibility = [(FEV1 postdose ~ FEV1 predose)/FEV1 predose] x 100%

 Up to two-time re-tests of the Reversibility FEV1 Test will be allowed if the highest
 attempted reversibility value is less than 12.0% but greater than or equal to 6.0, if deemed
 necessary by the investigator, with screening period extendable to a total of 21 days.

 4) Serial FEV1 measurements of study drug efficacy

 Response to the study drugs (T and R) is examined by serial spirometric measurements of FEV1
 post-dose. Serial FEV1 will be conducted at each of the following time points during Study
 Visits 1 and 3:

 1. at baseline (within 30 minutes prior to study drug dosing).

 2. at 10, 30, 45, 60, 120, 180, 240, 300, and 360 minutes after dosing.

 POPULATION PHARMACOKINETIC (PPK) EVALUATION

 At clinical Visit 3, a sufficient number of patients will be subject to a population
 pharmacokinetic (PPK) study to obtain a minimum of 6 subjects per arm with complete and
 correct 4 PK samples. An indwelling IV catheter may be used, as an alternative to repeated
 venipunctures, for PPK samples. An appropriate anticoagulant may be used to maintain the
 catheter patency. Four blood samples (~5.0 mL each) will be taken from a hand or forearm vein
 of the subject, at pre-scheduled 4 time points: 2, 4, 6 and 8 hr post-dose (each with a ±15
 min window). No inhalation of the study drug or rescue medication should take place until
 completion of the 8-hr PK sampling, unless needed for rescue, at which point the subject will
 not be considered evaluable for the PK endpoint.
Inclusion Criteria:

 1. Generally healthy.

 2. Male and female mild-to-moderate asthma patients.

 3. Aged 4 - 11 yr (upon screening).

 4. Female patients must be premenarchal upon Visit-1, and those who become menarchal
 during the study must use an accepted method of contraception including abstinence.

 5. A documented history of asthma, for at-least 6-months prior to Screening, requiring
 inhaled B-adrenergic agonists, with or without inhaled corticosteroids for asthma
 symptom control.

 6. Satisfying asthma stability criterion, defined as no changes in asthma therapy and no
 asthma-related hospitalization or emergency room visits, over the 4 weeks prior to
 Screening.

 7. Being able to withhold treatment with inhaled bronchodilators and/or restricted
 medications for the minimum washout periods indicated in Appendix II, for the purpose
 of conducting clinical visits.

 8. Having a baseline forced expiratory volume in 1 second (FEV1), that is 50.0-100.0% of
 predicted values at the screening (Screening Baseline FEV1).

 9. Demonstrating a greater than or equal to 12.0% reversibility in the Reversibility
 Test, at 30 min after inhaling 2-4 puffs (180-360 mcg) of Ventolin-HFA.

 10. Demonstrating correct use of metered-dose inhaler (MDIs), and acceptable performance
 in the FEV1 measurements.

 11. Has properly consented, with a parent or a legal guardian, to participate in this
 study.

 Exclusion Criteria:

 1. Any current or past significant medical conditions that, according to the
 investigator, might affect pharmacodynamic response to the study drugs, such as
 significant systemic or respiratory diseases (e.g., cystic fibrosis, bronchiectasis,
 emphysema, nonreversible pulmonary diseases), other than asthma.

 2. Concurrent clinically significant cardiovascular, hematological, renal, neurological,
 hepatic, and endocrine disorders, or psychiatric diseases.

 3. Known intolerance or hypersensitivity to any component of the MDI formulation (e.g.,
 albuterol, HFA-134a, oleic acid, ethanol).

 4. Recent upper (within 2 weeks) or lower (within 4 weeks) respiratory tract infection
 before screening.

 5. Recent (within 4 weeks) use of systemic (or oral) corticosteroids and B-adrenergic
 bronchodilators; or recent (within 2 weeks) use of monoamine oxidase inhibitors
 (MAOIs), tricyclic antidepressants (TCAs), or B-blockers; before the Screening.

 6. Having been on other investigational drug/device studies in the last 30 days prior to
 screening.

 7. Known or reasonably suspected alcohol/drug abuses.

 8. Having smoked within the last 12 months.