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

• Sponsor: Teva Branded Pharmaceutical Products R&D, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01899144
• Collaborator: (none)
• Enrollment: 61
• Locations: 22
• Arms: 5
• Duration (Months): 3
• Patients Per Site: 2.8
• Patients Per Site Per Month: 0.9

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Asthma	Drug: Albuterol Spiromax; Drug: ProAir HFA; Drug: Placebo	Phase 2

Detailed Description

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 61 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: 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
• Study Start Date: Jul 1, 2013
• Actual Primary Completion Date: Oct 1, 2013
• Actual Study Completion Date: Oct 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Albuterol Spiromax 90 mcg 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; 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.; Other Names: Spiromax® albuterol ; Drug: Placebo; Single dose MDIs and DPIs containing placebo taken as a single orally-inhaled actuation each.
Experimental: Albuterol Spiromax 180 mcg 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; 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.; Other Names: Spiromax® albuterol ; Drug: Placebo; Single dose MDIs and DPIs containing placebo taken as a single orally-inhaled actuation each.
Active Comparator: ProAir HFA 90 mcg 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; 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.; Other Names: ProAir® ; Drug: Placebo; Single dose MDIs and DPIs containing placebo taken as a single orally-inhaled actuation each.
Active Comparator: ProAir HFA 180 mcg 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; 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.; Other Names: ProAir® ; Drug: Placebo; Single dose MDIs and DPIs containing placebo taken as a single orally-inhaled actuation each.
Placebo Comparator: Placebo 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; Single dose MDIs and DPIs containing placebo taken as a single orally-inhaled actuation each.

Outcome Measures

Primary Outcome Measures

1. Baseline-Adjusted Area-Under-The-Percent-Predicted Forced Expiratory Volume In 1 Second (FEV1) Versus Time Curve Over 6 Hours Post-Dose [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]

   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.

Secondary Outcome Measures

1. Baseline-Adjusted Area-Under-The- Forced Expiratory Volume In 1 Second (FEV1) Versus Time Curve Over 6 Hours Post-Dose (FEV1 AUC0-6) [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]

   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.

2. Participants With Treatment-Emergent Adverse Events [Day 1 up to Day 35]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 4 Years to 11 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Written informed consent/assent signed and dated by the patient and/or parent/caregiver/legal guardian (as appropriate) before conducting any study related procedure

2. Male or pre-menarchal female 4-11 years of age, inclusive, as of the screening visit

3. 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)

4. Has the ability to self-perform spirometry reproducibly per American Thoracic Society (ATS) guidelines

5. 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.

1. 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

2. 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

3. Can self-perform peak expiratory flow rate (PEF) measurements with a handheld peak flow meter

4. 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:

1. Known hypersensitivity to albuterol or any of the excipients in the inhaler formulations (lactose, ethanol, etc.)

2. 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

3. History of severe milk protein allergy

4. 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

5. 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.

6. 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

7. Use of any prohibited concomitant medications within the washout period prescribed per protocol prior to the screening visit.

8. Use of any medication for asthma or allergic rhinitis that is prohibited per the protocol

9. The dosage of any required intranasal corticosteroid and/or cromone has not been stable for at least 2 weeks prior to the screening visit.

10. Treated with oral or injectable corticosteroids within the 6 weeks before the screening visit.

11. 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Teva Investigational Site 10598	Birmingham	Alabama	United States
2	Teva Investigational Site 10593	Little Rock	Alaska	United States
3	Teva Investigational Site 10610	Costa Mesa	California	United States
4	Teva Investigational Site 10582	Huntington Beach	California	United States
5	Teva Investigational Site 10606	Orange	California	United States
6	Teva Investigational Site 10597	San Jose	California	United States
7	Teva Investigational Site 10596	Jacksonville	Florida	United States
8	Teva Investigational Site 10599	Lawrenceville	Georgia	United States
9	Teva Investigational Site 10580	Savannah	Georgia	United States
10	Teva Investigational Site 10592	Normal	Illinois	United States
11	Teva Investigational Site 10602	Missoula	Montana	United States
12	Teva Investigational Site 10578	Raleigh	North Carolina	United States
13	Teva Investigational Site 10577	Oklahoma City	Oklahoma	United States
14	Teva Investigational Site 10589	Medford	Oregon	United States
15	Teva Investigational Site 10604	Portland	Oregon	United States
16	Teva Investigational Site 10591	Charleston	South Carolina	United States
17	Teva Investigational Site 10609	Orangeburg	South Carolina	United States
18	Teva Investigational Site 10579	Spartanburg	South Carolina	United States
19	Teva Investigational Site 10588	Boerne	Texas	United States
20	Teva Investigational Site 10605	New Braunfels	Texas	United States
21	Teva Investigational Site 10583	San Antonio	Texas	United States
22	Teva Investigational Site 10576	Waco	Texas	United States

Sponsors and Collaborators

• Teva Branded Pharmaceutical Products R&D, Inc.

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Teva Branded Pharmaceutical Products R&D, Inc.
• ClinicalTrials.gov Identifier: NCT01899144
• Other Study ID Numbers: ABS-AS-202
• First Posted: Jul 15, 2013
• Last Update Posted: Jan 26, 2022
• Last Verified: Jan 1, 2022

• Keywords provided by Teva Branded Pharmaceutical Products R&D, Inc.: Albuterol Spiromax; ProAir HFA; albuterol sulfate
• Additional relevant MeSH terms: Asthma; Albuterol; Procaterol

Study Results

Participant Flow

Recruitment Details	Of the 102 patients screened, 61 patients at 14 centers in the US met entry criteria and were considered to be eligible for enrollment into the study. 41 patients were not enrolled: 33 were excluded due to inclusion criteria, 1 patient withdrew consent, 3 patients were lost to follow-up before the baseline visit, and 4 patients for other reasons.
Pre-assignment Detail	Participants were randomized in a 1:1:1:1:1:1:1:1:1:1 fashion into 10 treatment sequences with 6 participants in 9 of the sequences and 7 participants in the remaining sequence.

Arm/Group Title	All Participants
Arm/Group Description	Participants were assigned to 1 of 10 possible treatment sequences for five treatments, separated by 2-7 days. Treatments were single inhalations of Albuterol MDPI 90 mcg, Albuterol MDPI 180 mcg, ProAir HFA MDI 90 mcg, ProAir HFA MDI 180 mcg, and placebo.
Period Title: Treatment Period 1
STARTED	61
COMPLETED	61
NOT COMPLETED	0
Period Title: Treatment Period 1
STARTED	61
COMPLETED	60
NOT COMPLETED	1
Period Title: Treatment Period 1
STARTED	60
COMPLETED	58
NOT COMPLETED	2
Period Title: Treatment Period 1
STARTED	58
COMPLETED	58
NOT COMPLETED	0
Period Title: Treatment Period 1
STARTED	58
COMPLETED	57
NOT COMPLETED	1

Baseline Characteristics

Arm/Group Title	All Participants
Arm/Group Description	Participants were assigned to 1 of 10 possible treatment sequences for five treatments, separated by 2-7 days. Treatments were single inhalations of Albuterol MDPI 90 mcg, Albuterol MDPI 180 mcg, ProAir HFA MDI 90 mcg, ProAir HFA MDI 180 mcg, and placebo.
Overall Participants	61
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	9.0 (1.6)
Sex: Female, Male (Count of Participants)
Female	23 37.7%
Male	38 62.3%
Race/Ethnicity, Customized (participants) [Number]
White	28 45.9%
Black	29 47.5%
Other	4 6.6%
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	38.2 (12.8)
Height (cm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cm]	138.7 (10.2)
Body Mass Index (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	19.5 (4.35)
Duration of Asthma (participants) [Number]
None	0 0%
<3 months	0 0%
3 to <6 months	0 0%
6 months to <1 year	1 1.6%
1 to <5 years	22 36.1%
5 to <10 years	30 49.2%
10 to <15 years	8 13.1%
Duration of Previous Dry-Powder Inhaler (DPI) Experience (participants) [Number]
None	46 75.4%
<3 months	2 3.3%
3 to <6 months	1 1.6%
6 months to <1 year	3 4.9%
1 to <5 years	9 14.8%
5 to <10 years	0 0%
10 to <15 years	0 0%
Duration of Previous Metered-Dose Inhaler (MDI) Experience (participants) [Number]
None	1 1.6%
<3 months	1 1.6%
3 to <6 months	0 0%
6 months to <1 year	3 4.9%
1 to <5 years	34 55.7%
5 to <10 years	19 31.1%
10 to <15 years	3 4.9%

Outcome Measures

1. Primary Outcome

Title	Baseline-Adjusted Area-Under-The-Percent-Predicted Forced Expiratory Volume In 1 Second (FEV1) Versus Time Curve Over 6 Hours Post-Dose
Description	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.
Time Frame	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

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) included all participants in the ITT population who received at least 1 dose of study medication, had a baseline assessment, and had at least 1 post baseline assessment.

Arm/Group Title	Albuterol Spiromax 90 mcg	Albuterol Spiromax 180 mcg	ProAir HFA 90 mcg	ProAir HFA 180 mcg	Placebo
Arm/Group Description	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.	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.	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.	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.	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.
Measure Participants	58	59	59	59	59
Mean (Standard Error) [%predicted FEV1*hour]	46.6 (6.27)	48.0 (6.24)	37.9 (6.25)	49.1 (6.26)	25.4 (6.25)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Albuterol Spiromax 180 mcg, Placebo
	Comments	The mean difference between each active group and placebo was tested in a sequential manner: Albuterol MDPI 180 mcg to placebo Albuterol MDPI 90 mcg to placebo ProAir HFA 180 mcg to placebo ProAir HFA 90 mcg to placebo Each test was 2 sided and done at the 0.05 level of significance. However, if a test was not significant at this level, no further tests were done. This sequential process assured that the overall alpha level for the entire series was not greater than 0.05.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANOVA
	Comments	Mixed effect analysis of variance with fixed effects of sequence, treatment group, and period, and random effect for the patient within sequence
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	22.6
	Confidence Interval	(2-Sided) 95%; 13.00 to 32.20
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 4.87
	Estimation Comments	Active - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Albuterol Spiromax 90 mcg, Placebo
	Comments	The mean difference between each active group and placebo was tested in a sequential manner: Albuterol MDPI 180 mcg to placebo Albuterol MDPI 90 mcg to placebo ProAir HFA 180 mcg to placebo ProAir HFA 90 mcg to placebo Each test was 2 sided and done at the 0.05 level of significance. However, if a test was not significant at this level, no further tests were done. This sequential process assured that the overall alpha level for the entire series was not greater than 0.05.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANOVA
	Comments	Mixed effect analysis of variance with fixed effects of sequence, treatment group, and period, and random effect for the patient within sequence
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	21.2
	Confidence Interval	(2-Sided) 95%; 11.6 to 30.81
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 4.87
	Estimation Comments	Active - Placebo

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	ProAir HFA 180 mcg, Placebo
	Comments	The mean difference between each active group and placebo was tested in a sequential manner: Albuterol MDPI 180 mcg to placebo Albuterol MDPI 90 mcg to placebo ProAir HFA 180 mcg to placebo ProAir HFA 90 mcg to placebo Each test was 2 sided and done at the 0.05 level of significance. However, if a test was not significant at this level, no further tests were done. This sequential process assured that the overall alpha level for the entire series was not greater than 0.05.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANOVA
	Comments	Mixed effect analysis of variance with fixed effects of sequence, treatment group, and period, and random effect for the patient within sequence
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	23.7
	Confidence Interval	(2-Sided) 95%; 14.13 to 33.23
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 4.85
	Estimation Comments	Active - Placebo

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	ProAir HFA 90 mcg, Placebo
	Comments	The mean difference between each active group and placebo was tested in a sequential manner: Albuterol MDPI 180 mcg to placebo Albuterol MDPI 90 mcg to placebo ProAir HFA 180 mcg to placebo ProAir HFA 90 mcg to placebo Each test was 2 sided and done at the 0.05 level of significance. However, if a test was not significant at this level, no further tests were done. This sequential process assured that the overall alpha level for the entire series was not greater than 0.05.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.0107
	Comments
	Method	ANOVA
	Comments	Mixed effect analysis of variance with fixed effects of sequence, treatment group, and period, and random effect for the patient within sequence
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	12.5
	Confidence Interval	(2-Sided) 95%; 2.93 to 22.05
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 4.85
	Estimation Comments	Active - Placebo

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Albuterol Spiromax 90 mcg, Albuterol Spiromax 180 mcg
	Comments	Pre-specified, exploratory analysis
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.7772
	Comments	0.05 level of significance
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.4
	Confidence Interval	(2-Sided) 95%; -11.00 to 8.23
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 4.88
	Estimation Comments	90 mcg - 180 mcg

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	ProAir HFA 90 mcg, ProAir HFA 180 mcg
	Comments	Pre-specified, exploratory analysis
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.0226
	Comments	0.05 level of significance
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-11.2
	Confidence Interval	(2-Sided) 95%; -20.80 to -1.59
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 4.87
	Estimation Comments	90 mcg - 180 mcg

2. Secondary Outcome

Title	Baseline-Adjusted Area-Under-The- Forced Expiratory Volume In 1 Second (FEV1) Versus Time Curve Over 6 Hours Post-Dose (FEV1 AUC0-6)
Description	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.
Time Frame	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

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	Albuterol Spiromax 90 mcg	Albuterol Spiromax 180 mcg	ProAir HFA 90 mcg	ProAir HFA 180 mcg	Placebo
Arm/Group Description	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.	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.	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.	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.	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.
Measure Participants	58	59	59	59	59
Mean (Standard Error) [L*hour]	0.88 (0.14)	0.93 (0.14)	0.74 (0.14)	0.93 (0.14)	0.48 (0.14)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Albuterol Spiromax 180 mcg, Placebo
	Comments	The mean difference between each active group and placebo was tested in a sequential manner: Albuterol MDPI 180 mcg to placebo Albuterol MDPI 90 mcg to placebo ProAir HFA 180 mcg to placebo ProAir HFA 90 mcg to placebo Each test was 2 sided and done at the 0.05 level of significance. However, if a test was not significant at this level, no further tests were done. This sequential process assured that the overall alpha level for the entire series was not greater than 0.05.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANOVA
	Comments	Mixed effect analysis of variance with fixed effects of sequence, treatment group, and period, and random effect for the patient within sequence
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.45
	Confidence Interval	(2-Sided) 95%; 0.26 to 0.64
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.10
	Estimation Comments	Active - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Albuterol Spiromax 90 mcg, Placebo
	Comments	The mean difference between each active group and placebo was tested in a sequential manner: Albuterol MDPI 180 mcg to placebo Albuterol MDPI 90 mcg to placebo ProAir HFA 180 mcg to placebo ProAir HFA 90 mcg to placebo Each test was 2 sided and done at the 0.05 level of significance. However, if a test was not significant at this level, no further tests were done. This sequential process assured that the overall alpha level for the entire series was not greater than 0.05.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANOVA
	Comments	Mixed effect analysis of variance with fixed effects of sequence, treatment group, and period, and random effect for the patient within sequence
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.40
	Confidence Interval	(2-Sided) 95%; 0.21 to 0.59
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.10
	Estimation Comments	Active - Placebo

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	ProAir HFA 180 mcg, Placebo
	Comments	The mean difference between each active group and placebo was tested in a sequential manner: Albuterol MDPI 180 mcg to placebo Albuterol MDPI 90 mcg to placebo ProAir HFA 180 mcg to placebo ProAir HFA 90 mcg to placebo Each test was 2 sided and done at the 0.05 level of significance. However, if a test was not significant at this level, no further tests were done. This sequential process assured that the overall alpha level for the entire series was not greater than 0.05.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANOVA
	Comments	Mixed effect analysis of variance with fixed effects of sequence, treatment group, and period, and random effect for the patient within sequence
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.45
	Confidence Interval	(2-Sided) 95%; 0.26 to 0.64
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.10
	Estimation Comments	Active - Placebo

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	ProAir HFA 90 mcg, Placebo
	Comments	The mean difference between each active group and placebo was tested in a sequential manner: Albuterol MDPI 180 mcg to placebo Albuterol MDPI 90 mcg to placebo ProAir HFA 180 mcg to placebo ProAir HFA 90 mcg to placebo Each test was 2 sided and done at the 0.05 level of significance. However, if a test was not significant at this level, no further tests were done. This sequential process assured that the overall alpha level for the entire series was not greater than 0.05.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.0062
	Comments
	Method	ANOVA
	Comments	Mixed effect analysis of variance with fixed effects of sequence, treatment group, and period, and random effect for the patient within sequence
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.26
	Confidence Interval	(2-Sided) 95%; 0.08 to 0.45
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.10
	Estimation Comments	Active - Placebo

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Albuterol Spiromax 90 mcg, Albuterol Spiromax 180 mcg
	Comments	Pre-specified, exploratory analysis
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.6342
	Comments	0.05 level of significance
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.05
	Confidence Interval	(2-Sided) 95%; -0.23 to 0.14
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.10
	Estimation Comments	90 mcg - 180 mcg

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	ProAir HFA 90 mcg, ProAir HFA 180 mcg
	Comments	Pre-specified, exploratory analysis
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.0488
	Comments	0.05 level of significance
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.19
	Confidence Interval	(2-Sided) 95%; -0.38 to 0.00
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.10
	Estimation Comments	90 mcg - 180 mcg

3. Secondary Outcome

Title	Participants With Treatment-Emergent Adverse Events
Description	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.
Time Frame	Day 1 up to Day 35

Outcome Measure Data

Analysis Population Description

The safety population included all randomized patients who received at least 1 dose of randomized study medication. In this population, treatment was assigned based upon the treatment patients actually receive regardless of the treatment to which they were randomized.

Arm/Group Title	Albuterol Spiromax 90 mcg	Albuterol Spiromax 180 mcg	ProAir HFA 90 mcg	ProAir HFA 180 mcg	Placebo
Arm/Group Description	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.	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.	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.	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.	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.
Measure Participants	61	61	61	61	61
Treatment-related AE	0 0%	2 NaN	5 NaN	1 NaN	1 NaN
Severe TEAE	0 0%	0 NaN	0 NaN	0 NaN	0 NaN
Related TEAE	0 0%	0 NaN	0 NaN	0 NaN	0 NaN
Death	0 0%	0 NaN	0 NaN	0 NaN	0 NaN
Serious AE	0 0%	0 NaN	0 NaN	0 NaN	0 NaN
TEAE leading to withdrawal	0 0%	0 NaN	0 NaN	0 NaN	0 NaN

Adverse Events

Time Frame	Day 1 up to Day 35
Arm/Group Title	Albuterol Spiromax 90 mcg		Albuterol Spiromax 180 mcg		ProAir HFA 90 mcg		ProAir HFA 180 mcg		Placebo
Arm/Group Description	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.		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.		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.		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.		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.
All Cause Mortality
	Albuterol Spiromax 90 mcg		Albuterol Spiromax 180 mcg		ProAir HFA 90 mcg		ProAir HFA 180 mcg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Albuterol Spiromax 90 mcg		Albuterol Spiromax 180 mcg		ProAir HFA 90 mcg		ProAir HFA 180 mcg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/61 (0%)		0/61 (0%)		0/61 (0%)		0/61 (0%)		0/61 (0%)
Other (Not Including Serious) Adverse Events
	Albuterol Spiromax 90 mcg		Albuterol Spiromax 180 mcg		ProAir HFA 90 mcg		ProAir HFA 180 mcg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/61 (0%)		0/61 (0%)		3/61 (4.9%)		0/61 (0%)		0/61 (0%)
Nervous system disorders
Headache	0/61 (0%)		0/61 (0%)		3/61 (4.9%)		0/61 (0%)		0/61 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Sponsor has the right 60 days before submission for publication to review/provide comments. If the Sponsor's review shows that potentially patentable subject matter would be disclosed, publication or public disclosure shall be delayed for up to 90 additional days in order for the Sponsor, or Sponsor's designees, to file the necessary patent applications. In multicenter trials, each PI will postpone single center publications until after disclosure or publication of multicenter data.