Efficacy and Safety Comparison of Albuterol Spiromax® and ProAir® Hydrofluoroalkane (HFA) in Pediatric Patients

Study Overview
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Brief Summary
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This is a multicenter, randomized, double-blind, double-dummy, placebo-controlled, single-dose, 5-treatment, 5-period, 5-way crossover study in pediatric patients with persistent asthma. The primary purpose of this study is to compare the efficacy and safety of Albuterol Spiromax with that of ProAir HFA in pediatric asthma patients at 2 delivered dose levels equivalent to 90 mcg and 180 mcg of albuterol base.

Detailed Description
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The study consists of a screening visit (SV) followed by up to 16 days by a treatment period comprising 5 visits (TV1-TV5). The treatment period visits will each be separated by a washout period lasting 2-7 days. During each treatment period visit, the forced expiratory volume in 1 second (FEV1) will be determined at 30 minutes and again immediately prior to the commencement of study medication administration, and 5, 15, 30, 45, 60, 120, 180, 240, 300, and 360 minutes after completion of study medication administration.

Official Title
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A Single-Dose, Multicenter, Randomized, Double-Blind, Double-Dummy, Placebo-Controlled, Five-Period Crossover, Dose-Ranging Efficacy and Safety Comparison of Albuterol Spiromax® and ProAir® HFA in Pediatric Patients With Persistent Asthma

Conditions
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Asthma

Intervention / Treatment
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* Drug: Albuterol Spiromax
* Drug: ProAir HFA
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent/assent signed and dated by the patient and/or parent/caregiver/legal guardian (as appropriate) before conducting any study related procedure Male or pre-menarchal female 4-11 years of age, inclusive, as of the screening visit Has a documented physician diagnosis of persistent asthma of a minimum of 6 months duration that has been stable for at least 4 weeks prior to the screening visit. The asthma diagnosis must be in accordance with the National Asthma Education and Prevention Program Guidelines Expert Panel Report 3 (EPR3) Has the ability to self-perform spirometry reproducibly per American Thoracic Society (ATS) guidelines Has forced expiratory volume in 1 second (FEV1) 60-90% predicted for age, height, and gender at the screening visit based on the pediatric population standards as per protocol. Notes: (1) Predicted values of 59.50-59.99% may be rounded up to 60% and 90.01-90.49% rounded down to 90%. (2) Patients who at the screening visit fail to meet the predicted spirometry values for study entry may be allowed a single attempt to re-qualify on another day, but they must re-qualify no later than 16 days following the first attempt. Demonstrates reversible bronchoconstriction as verified by a 15% or greater increase in baseline FEV1 within 30 minutes following inhalation of 180 mcg of albuterol to 200 mcg of fluticasone propionate per day or equivalent), leukotriene modifiers (LTM), inhaled cromones, or on β2-agonists alone as needed. The Inhaled corticosteroid (ICS), LTM, and cromone doses must have been stable for at least 4 weeks prior to the screening visit and are expected to be maintained for the duration of the study Is maintained on low-dose inhaled corticosteroids ([ICS], less than or equal to 200 mcg of fluticasone propionate per day or equivalent), leukotriene modifiers (LTM), inhaled cromones, or on β2-agonists alone as needed. The ICS, LTM, and cromone doses must have been stable for at least 4 weeks prior to the screening visit and are expected to be maintained for the duration of the study Can self-perform peak expiratory flow rate (PEF) measurements with a handheld peak flow meter Has the ability to demonstrate acceptable and reproducible inhalation technique with the Spiromax and metered dose inhaler (MDI) devices Other inclusion criteria apply. Exclusion Criteria: Known hypersensitivity to albuterol or any of the excipients in the inhaler formulations (lactose, ethanol, etc.) Participation (receiving study medication) in any investigational drug trial within the 30 days preceding the screening visit or planned participation in another investigational drug trial at any time during this trial History of severe milk protein allergy History of a respiratory infection or disorder (including, but not limited to bronchitis, pneumonia, acute or chronic sinusitis, otitis media, influenza, etc.) that has not resolved within 4 weeks preceding the screening visit Any asthma exacerbation requiring oral corticosteroids within 3 months of the screening visit. A patient must not have had any hospitalization for asthma within 6 months prior to the screening visit. History of life-threatening asthma that is defined for this protocol as an asthma episode that required intubation and/or was associated with hypercapnea, respiratory arrest, or hypoxic seizures Use of any prohibited concomitant medications within the washout period prescribed per protocol prior to the screening visit. Use of any medication for asthma or allergic rhinitis that is prohibited per the protocol The dosage of any required intranasal corticosteroid and/or cromone has not been stable for at least 2 weeks prior to the screening visit. Treated with oral or injectable corticosteroids within the 6 weeks before the screening visit. Initiation of immunotherapy during the study period or dose escalation during the study period. Patients being treated with immunotherapy prior to the screening visit must be using a stable (maintenance) dose (90 days or more) to be considered for inclusion.

Ages Eligible for Study
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Minimum Age: 4 Years
Maximum Age: 11 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Albuterol Spiromax 90 mcg<br>At each treatment visit, participants receive 1 actuation from each of 4 pre-arranged device combinations comprising 2 dry powder inhalers (DPIs) and 2 metered-dose inhalers (MDIs) in order to maintain the study blind. In this arm, one of the DPIs contains Albuterol Spiromax 90 mcg; the other three devices contained placebo. | Drug: Albuterol Spiromax<br>* Albuterol Spiromax® Inhalation Aerosol contains 90 mcg albuterol per actuation orally inhaled in a single dose dry powder inhaler (DPI). Participants took doses at either the 90 or 180 mcg levels. If the higher level, two DPIs filled with Albuterol Spiromax® were used.<br>* Other names: albuterol;Drug: Placebo<br>* Single dose MDIs and DPIs containing placebo taken as a single orally-inhaled actuation each.<br>|
| Experimental: Albuterol Spiromax 180 mcg<br>At each treatment visit, participants receive 1 actuation from each of 4 pre-arranged device combinations comprising 2 dry powder inhalers (DPIs) and 2 metered-dose inhalers (MDIs) in order to maintain the study blind. In this arm, both of the DPIs contain Albuterol Spiromax 90 mcg for a total dose of 180 mcg; the MDIs contained placebo. | Drug: Albuterol Spiromax<br>* Albuterol Spiromax® Inhalation Aerosol contains 90 mcg albuterol per actuation orally inhaled in a single dose dry powder inhaler (DPI). Participants took doses at either the 90 or 180 mcg levels. If the higher level, two DPIs filled with Albuterol Spiromax® were used.<br>* Other names: albuterol;Drug: Placebo<br>* Single dose MDIs and DPIs containing placebo taken as a single orally-inhaled actuation each.<br>|
| Active Comparator: ProAir HFA 90 mcg<br>At each treatment visit, participants receive 1 actuation from each of 4 pre-arranged device combinations comprising 2 dry powder inhalers (DPIs) and 2 metered-dose inhalers (MDIs) in order to maintain the study blind. In this arm, one of the MDIs contains ProAir HFA 90 mcg; the other three devices contained placebo. | Drug: ProAir HFA<br>* ProAir® HFA Inhalation Aerosol contains 90 mcg albuterol per actuation orally inhaled in a single dose metered dose inhaler (MDI). Participants took doses at either the 90 or 180 mcg levels. If the higher level, two MDIs filled with ProAir HFA were used.<br>* Other names: ProAir®;Drug: Placebo<br>* Single dose MDIs and DPIs containing placebo taken as a single orally-inhaled actuation each.<br>|
| Active Comparator: ProAir HFA 180 mcg<br>At each treatment visit, participants receive 1 actuation from each of 4 pre-arranged device combinations comprising 2 dry powder inhalers (DPIs) and 2 metered-dose inhalers (MDIs) in order to maintain the study blind. In this arm, both of the MDIs contain ProAir HFA 90 mcg for a total dose of 180 mcg; the DPIs contained placebo. | Drug: ProAir HFA<br>* ProAir® HFA Inhalation Aerosol contains 90 mcg albuterol per actuation orally inhaled in a single dose metered dose inhaler (MDI). Participants took doses at either the 90 or 180 mcg levels. If the higher level, two MDIs filled with ProAir HFA were used.<br>* Other names: ProAir®;Drug: Placebo<br>* Single dose MDIs and DPIs containing placebo taken as a single orally-inhaled actuation each.<br>|
| Placebo Comparator: Placebo<br>At each treatment visit, participants receive 1 actuation from each of 4 pre-arranged device combinations comprising 2 dry powder inhalers (DPIs) and 2 metered-dose inhalers (MDIs) in order to maintain the study blind. In this arm, all devices contain placebo. | Drug: Placebo<br>* Single dose MDIs and DPIs containing placebo taken as a single orally-inhaled actuation each.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Baseline-Adjusted Area-Under-The-Percent-Predicted Forced Expiratory Volume In 1 Second (FEV1) Versus Time Curve Over 6 Hours Post-Dose | Percent predicted FEV1: measured FEV1 as a percent of the predicted values for the patients of similar characteristics. Predicted FEV1 values were computed and adjusted for age, height, and gender for patients aged 4-5 years (Eigen et al 2001) and for patients aged 6-11 years (Quanjer et al 1995) using ATS/European Thoracic Society (ERS) criteria applicable to pediatric patients (ATS/ERS 2007). The percent predicted FEV1 (PPFEV1) area under the curve (AUC)0-6 was calculated using the linear trapezoidal rule, and baseline adjustment was made by subtracting the average of the 2 pre-dose PPFEV1 values from each post-dose PPFEV1 determination. | Treatment visits 1-5 (approximately days 1, 6, 11, 16, and 21); -35 and -5 minutes prior to dosing and 5 (±2), 15 (±5), 30 (±5), 45 (±5), 60 (±5), 120 (±5), 180 (±5), 240 (±5), 300 (±5), and 360 (±5) minutes after the completion of study drug administrati | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Baseline-Adjusted Area-Under-The- Forced Expiratory Volume In 1 Second (FEV1) Versus Time Curve Over 6 Hours Post-Dose (FEV1 AUC0-6) | FEV1 AUC0-6 was calculated using the linear trapezoidal rule, and baseline adjustment was made by subtracting the average of the 2 pre-dose FEV1 values from each post-dose FEV1 determination. | Treatment visits 1-5 (approximately days 1, 6, 11, 16, and 21); -35 and -5 minutes prior to dosing and 5 (±2), 15 (±5), 30 (±5), 45 (±5), 60 (±5), 120 (±5), 180 (±5), 240 (±5), 300 (±5), and 360 (±5) minutes after the completion of study drug administrati | 
| Participants With Treatment-Emergent 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 as mild (no limitation of usual activities), moderate, or severe (inability to carry out usual 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 up to Day 35 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Albuterol Spiromax, ProAir HFA, albuterol sulfate