A Dose-ranging Study to Evaluate Albuterol and Hydrofluoroalkane in Subjects Ages 12 and Older With Persistent Asthma

• Sponsor: Teva Branded Pharmaceutical Products R&D, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01058863
• Collaborator: (none)
• Enrollment: 72
• Locations: 13
• Arms: 5
• Duration (Months): 3.9
• Patients Per Site: 5.5
• Patients Per Site Per Month: 1.4

Study Details

Study Description

Brief Summary

This study is examining how well a dry powder inhaler (DPI) of albuterol medication works to help adult and adolescent subjects 12 years of age and older with persistent asthma to improve lung function.

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 72 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: A Double-blind, Randomized, Placebo-controlled, 5-way Crossover, Multicenter, Single-dose, Dose-ranging Study to Compare the Efficacy and Safety of Albuterol Spiromax® and ProAir® HFA in Adult and Adolescent Subjects Ages 12 and Older With Persistent Asthma
• Study Start Date: Feb 1, 2010
• Actual Primary Completion Date: Jun 1, 2010
• Actual Study Completion Date: Jun 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Albuterol Spiromax® 90 mcg A single dose of albuterol 90 mcg delivered with Spiromax®, an inhalation-driven, multi-dose dry powder inhaler. Placebo inhalers used to maintain the blind.	Drug: Albuterol Spiromax®; Albuterol Spiromax® delivers 90 mcg albuterol per inhalation. Doses of 180 mcg require two inhalations. Intervention given as double-blind medication on 2 of 5 treatment days, once at 90 mcg and once at 180 mcg.; Other Names: ProAir® RespiClick, Albuterol multi-dose dry powder inhaler (MDPI) ; Other: Placebo Inhaler; Placebo delivered in both the Spiromax® and HFA inhalers to maintain the blind and also to support the placebo treatment arm.
Experimental: Albuterol Spiromax® 180 mcg A single dose of albuterol 180 mcg delivered with Spiromax®, an inhalation-driven, multi-dose dry powder inhaler (2 inhalations). Placebo inhalers used to maintain the blind.	Drug: Albuterol Spiromax®; Albuterol Spiromax® delivers 90 mcg albuterol per inhalation. Doses of 180 mcg require two inhalations. Intervention given as double-blind medication on 2 of 5 treatment days, once at 90 mcg and once at 180 mcg.; Other Names: ProAir® RespiClick, Albuterol multi-dose dry powder inhaler (MDPI) ; Other: Placebo Inhaler; Placebo delivered in both the Spiromax® and HFA inhalers to maintain the blind and also to support the placebo treatment arm.
Active Comparator: ProAir® HFA 90 mcg A single dose of albuterol 90 mcg delivered with ProAir®, a 'press-and-breathe', metered-dose, aerosol inhaler. Placebo inhalers used to maintain the blind.	Drug: ProAir® HFA; ProAir® HFA delivers 90 mcg of albuterol per inhalation. Doses of 180 mcg require two inhalations. Intervention given as double-blind medication on 2 of 5 treatment days, once at 90 mcg and once at 180 mcg.; Other Names: albuterol HFA-MDI ; Other: Placebo Inhaler; Placebo delivered in both the Spiromax® and HFA inhalers to maintain the blind and also to support the placebo treatment arm.
Active Comparator: ProAir® HFA 180 mcg A single dose of albuterol 180 mcg delivered with ProAir®, a 'press-and-breathe', metered-dose, aerosol inhaler (2 inhalations). Placebo inhalers used to maintain the blind.	Drug: ProAir® HFA; ProAir® HFA delivers 90 mcg of albuterol per inhalation. Doses of 180 mcg require two inhalations. Intervention given as double-blind medication on 2 of 5 treatment days, once at 90 mcg and once at 180 mcg.; Other Names: albuterol HFA-MDI ; Other: Placebo Inhaler; Placebo delivered in both the Spiromax® and HFA inhalers to maintain the blind and also to support the placebo treatment arm.
Placebo Comparator: Placebo Inhaler Placebo delivered with Spiromax®, an inhalation-driven, multi-dose dry powder inhaler, and with ProAir®, a 'press-and-breathe', metered-dose, aerosol inhaler. Placebo inhalers used to maintain the blind.	Other: Placebo Inhaler; Placebo delivered in both the Spiromax® and HFA inhalers to maintain the blind and also to support the placebo treatment arm.

Outcome Measures

Primary Outcome Measures

1. Baseline-adjusted Forced Expiratory Volume in 1 Second (FEV1) Area Under the Curve (AUC 0-6) [Day 1 up to Day 30]

   FEV1 AUC 0-6 is the area under the effect-time curve from time 0 (pre-dose) up to 6 hours post-dose. The baseline for each study day was the average of the 2 pre-dose FEV1 measurements on that study day. The first baseline spirometry was obtained between 6-11 AM. The highest FEV1 value from two acceptable values was captured for calculation of the efficacy endpoints. Assessments were obtained at approximately 0.5 hours and immediately before dosing, and 5 minutes, 0.25, 0.50, 0.75, 1, 2, 3, 4, 5 and 6 hours after completion of dosing.

Secondary Outcome Measures

1. Baseline-adjusted Percent-Predicted Forced Expiratory Volume in 1 Second (PPFEV1) Area Under the Curve (AUC 0-6) [Day 1 up to Day 30]

   Percent-predicted FEV1 AUC 0-6 is the area under the effect-time curve from time 0 (pre-dose) up to 6 hours post-dose. Percent-predicted FEV1 is the expected FEV1 taking into account age, height, gender and race, as per the National Health and Nutrition Examination Survey III (NHANES III) reference values. The first baseline spirometry was obtained between 6-11 AM. The highest FEV1 value from two acceptable values was captured for calculation of the efficacy endpoints. Assessments were obtained at approximately 0.5 hours and immediately before dosing, and 5 minutes, 0.25, 0.50, 0.75, 1, 2, 3, 4, 5 and 6 hours after completion of dosing.

2. Participants With Treatment-Emergent Adverse Events [Day 1 up to Day 37]

   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. 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: 12 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Must provide written informed consent,

• Be between 12 years of age and older,

• Male or Female, females of non-child bearing potential or using reliable contraception

• Asthma for at least 6 months, FEV1 (forced expiratory volume in 1 second) between 50-80% of predicted value, and reversibility greater than or equal to 15% following 180 mcg albuterol

• Stable low dose of Inhaled Corticosteroids

• Non-smoker, 12 months smoking-free and <=10-pack years history

• Otherwise healthy

• Other criteria apply

Exclusion Criteria:

• Pregnant

• Allergic to albuterol or severe milk protein allergy

• Must not be on another trial for 30days.

• Other criteria apply

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Teva Clinical Study Site	Huntington Beach	California	United States	92647
2	Teva Clinical Study Site	Rolling Hills Est.	California	United States	90274
3	Teva Clinical Study Site	San Diego	California	United States	92123
4	Teva Clinical Study Site	Colorado Springs	Colorado	United States	080907
5	Teva Clinical Study Site	Margate	Florida	United States	33036
6	Teva Clinical Study Site	Miami	Florida	United States	33173
7	Teva Clinical Study Site	Saint Louis	Missouri	United States	63141
8	Teva Clinical Study Site	Skillman	New Jersey	United States	08558
9	Teva Clinical Study Site	Raleigh	North Carolina	United States	27607
10	Teva Clinical Study Site	Cincinnati	Ohio	United States	45231
11	Teva Clinical Study Site	Dayton	Ohio	United States	45406
12	Teva Clinical Study Site	Medford	Oregon	United States	97504
13	Teva Clinical Study Site	Portland	Oregon	United States	97213

Sponsors and Collaborators

• Teva Branded Pharmaceutical Products R&D, Inc.

Investigators

• Study Director: Teva Study Leader, Teva Branded Pharmaceutical Products R&D, Inc.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Teva Branded Pharmaceutical Products R&D, Inc.
• ClinicalTrials.gov Identifier: NCT01058863
• Other Study ID Numbers: ABS-AS-201
• First Posted: Jan 29, 2010
• Last Update Posted: Nov 9, 2021
• Last Verified: Nov 1, 2021

• Additional relevant MeSH terms: Asthma; Albuterol; Procaterol

Study Results

Participant Flow

Pre-assignment Detail	A total of 163 patients were screened and 72 patients were randomized. Most screening failures did not qualify for the study based on reversibility or spirometry criteria.

Arm/Group Title	All Randomized Participants
Arm/Group Description	Participants were randomized to one of ten treatment sequences, which indicated the order of the 5 single-dose treatments administered in this 5-way crossover study.
Period Title: Overall Study
STARTED	72
Safety and ITT Populations	71
Treated With Albuterol Spiromax® 90 mcg	68
Treated With Albuterol Spiromax® 180 mcg	68
Treated With ProAir® HFA 90 mcg	70
Treated With ProAir® HFA 180 mcg	68
Treated With Placebo Inhaler	69
COMPLETED	68
NOT COMPLETED	4

Baseline Characteristics

Arm/Group Title	Randomized Treated Participants
Arm/Group Description	Participants were randomized to one of ten treatment sequences, which indicated the order of the 5 single-dose treatments administered in this 5-way crossover study.
Overall Participants	71
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	43.3 (14.78)
Age, Customized (participants) [Number]
12 to <18 years	3 4.2%
18 to 65 years	64 90.1%
>65 years	4 5.6%
Sex: Female, Male (Count of Participants)
Female	41 57.7%
Male	30 42.3%
Race/Ethnicity, Customized (participants) [Number]
White	54 76.1%
Black or African American	16 22.5%
Asian	1 1.4%
Race/Ethnicity, Customized (participants) [Number]
Not Latino or Hispanic	67 94.4%
Latino or Hispanic	4 5.6%
Height (cm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cm]	169.1 (9.49)
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	89.6 (22.77)

Outcome Measures

1. Primary Outcome

Title	Baseline-adjusted Forced Expiratory Volume in 1 Second (FEV1) Area Under the Curve (AUC 0-6)
Description	FEV1 AUC 0-6 is the area under the effect-time curve from time 0 (pre-dose) up to 6 hours post-dose. The baseline for each study day was the average of the 2 pre-dose FEV1 measurements on that study day. The first baseline spirometry was obtained between 6-11 AM. The highest FEV1 value from two acceptable values was captured for calculation of the efficacy endpoints. Assessments were obtained at approximately 0.5 hours and immediately before dosing, and 5 minutes, 0.25, 0.50, 0.75, 1, 2, 3, 4, 5 and 6 hours after completion of dosing.
Time Frame	Day 1 up to Day 30

Outcome Measure Data

Analysis Population Description

Intent to treat population: randomized participants who received at least 1 dose of randomized study medication 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 Inhaler
Arm/Group Description	A single dose of albuterol 90 mcg delivered with Spiromax®, an inhalation-driven, multi-dose dry powder inhaler. Placebo inhalers used to maintain the blind.	A single dose of albuterol 180 mcg delivered with Spiromax®, an inhalation-driven, multi-dose dry powder inhaler (2 inhalations). Placebo inhalers used to maintain the blind.	A single dose of albuterol 90 mcg delivered with ProAir®, a 'press-and-breathe', metered-dose, aerosol inhaler. Placebo inhalers used to maintain the blind.	A single dose of albuterol 180 mcg delivered with ProAir®, a 'press-and-breathe', metered-dose, aerosol inhaler (2 inhalations). Placebo inhalers used to maintain the blind.	Placebo delivered with Spiromax®, an inhalation-driven, multi-dose dry powder inhaler, and with ProAir®, a 'press-and-breathe', metered-dose, aerosol inhaler. Placebo inhalers used to maintain the blind.
Measure Participants	68	68	70	68	69
Mean (Standard Error) [L*hour]	1.21 (0.224)	1.39 (0.224)	1.12 (0.223)	1.33 (0.224)	0.24 (0.224)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Albuterol Spiromax® 180 mcg, Placebo Inhaler
	Comments	Of interest was the mean difference between each active group and placebo at each dose level. Analyses were performed at the 2-sided 0.05 significance level in this sequence: Albuterol Spiromax 180 mcg versus placebo; Albuterol Spiromax 90 mcg versus placebo, ProAir HFA 180 mcg versus placebo, and ProAir HFA 90 mcg versus placebo. If a test was not significant, no further tests were done. This sequential procedure preserved the error rate for the family of tests at the 0.05 level.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Significance at the 0.05 level.
	Method	ANOVA
	Comments	Fixed effects of baseline FEV1 as a covariate, sequence, treatment group, period, and center, and random effect for subject within sequence.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.15
	Confidence Interval	(2-Sided) 95%; 0.88 to 1.42
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.136
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Albuterol Spiromax® 90 mcg, Placebo Inhaler
	Comments	Of interest was the mean difference between each active group and placebo at each dose level. Analyses were performed at the 2-sided 0.05 significance level in this sequence: Albuterol Spiromax 180 mcg versus placebo; Albuterol Spiromax 90 mcg versus placebo, ProAir HFA 180 mcg versus placebo, and ProAir HFA 90 mcg versus placebo. If a test was not significant, no further tests were done. This sequential procedure preserved the error rate for the family of tests at the 0.05 level.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Significance at the 0.05 level.
	Method	ANOVA
	Comments	Fixed effects of baseline FEV1 as a covariate, sequence, treatment group, period, and center, and random effect for subject within sequence.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.97
	Confidence Interval	(2-Sided) 95%; 0.70 to 1.24
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.136
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	ProAir® HFA 180 mcg, Placebo Inhaler
	Comments	Of interest was the mean difference between each active group and placebo at each dose level. Analyses were performed at the 2-sided 0.05 significance level in this sequence: Albuterol Spiromax 180 mcg versus placebo; Albuterol Spiromax 90 mcg versus placebo, ProAir HFA 180 mcg versus placebo, and ProAir HFA 90 mcg versus placebo. If a test was not significant, no further tests were done. This sequential procedure preserved the error rate for the family of tests at the 0.05 level..
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Significance at the 0.05 level.
	Method	ANOVA
	Comments	Fixed effects of baseline FEV1 as a covariate, sequence, treatment group, period, and center, and random effect for subject within sequence.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.08
	Confidence Interval	(2-Sided) 95%; 0.81 to 1.35
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.136
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	ProAir® HFA 90 mcg, Placebo Inhaler
	Comments	Of interest was the mean difference between each active group and placebo at each dose level. Analyses were performed at the 2-sided 0.05 significance level in this sequence: Albuterol Spiromax 180 mcg versus placebo; Albuterol Spiromax 90 mcg versus placebo, ProAir HFA 180 mcg versus placebo, and ProAir HFA 90 mcg versus placebo. If a test was not significant, no further tests were done. This sequential procedure preserved the error rate for the family of tests at the 0.05 level.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Significance at the 0.05 level.
	Method	ANOVA
	Comments	Fixed effects of baseline FEV1 as a covariate, sequence, treatment group, period, and center, and random effect for subject within sequence.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.88
	Confidence Interval	(2-Sided) 95%; 0.61 to 1.15
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.136
	Estimation Comments

2. Secondary Outcome

Title	Baseline-adjusted Percent-Predicted Forced Expiratory Volume in 1 Second (PPFEV1) Area Under the Curve (AUC 0-6)
Description	Percent-predicted FEV1 AUC 0-6 is the area under the effect-time curve from time 0 (pre-dose) up to 6 hours post-dose. Percent-predicted FEV1 is the expected FEV1 taking into account age, height, gender and race, as per the National Health and Nutrition Examination Survey III (NHANES III) reference values. The first baseline spirometry was obtained between 6-11 AM. The highest FEV1 value from two acceptable values was captured for calculation of the efficacy endpoints. Assessments were obtained at approximately 0.5 hours and immediately before dosing, and 5 minutes, 0.25, 0.50, 0.75, 1, 2, 3, 4, 5 and 6 hours after completion of dosing.
Time Frame	Day 1 up to Day 30

Outcome Measure Data

Analysis Population Description

Intent to treat population: randomized participants who received at least 1 dose of randomized study medication 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 Inhaler
Arm/Group Description	A single dose of albuterol 90 mcg delivered with Spiromax®, an inhalation-driven, multi-dose dry powder inhaler. Placebo inhalers used to maintain the blind.	A single dose of albuterol 180 mcg delivered with Spiromax®, an inhalation-driven, multi-dose dry powder inhaler (2 inhalations). Placebo inhalers used to maintain the blind.	A single dose of albuterol 90 mcg delivered with ProAir®, a 'press-and-breathe', metered-dose, aerosol inhaler. Placebo inhalers used to maintain the blind.	A single dose of albuterol 180 mcg delivered with ProAir®, a 'press-and-breathe', metered-dose, aerosol inhaler (2 inhalations). Placebo inhalers used to maintain the blind.	Placebo delivered with Spiromax®, an inhalation-driven, multi-dose dry powder inhaler, and with ProAir®, a 'press-and-breathe', metered-dose, aerosol inhaler. Placebo inhalers used to maintain the blind.
Measure Participants	68	68	70	68	69
Mean (Standard Error) [% predicted * hour]	35.31 (4.497)	41.05 (4.495)	33.19 (4.461)	40.68 (4.496)	7.58 (4.482)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Albuterol Spiromax® 180 mcg, Placebo Inhaler
	Comments	Of interest was the mean difference between each active group and placebo at each dose level. Analyses were performed at the 2-sided 0.05 significance level in this sequence: Albuterol Spiromax 180 mcg versus placebo; Albuterol Spiromax 90 mcg versus placebo, ProAir HFA 180 mcg versus placebo, and ProAir HFA 90 mcg versus placebo. If a test was not significant, no further tests were done. This sequential procedure preserved the error rate for the family of tests at the 0.05 level.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Significance at the 0.05 level.
	Method	ANOVA
	Comments	Fixed effects of baseline PPFEV1 as a covariate, sequence, treatment group, period, and center, and random effect for subject within sequence.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	33.47
	Confidence Interval	(2-Sided) 95%; 26.21 to 40.74
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.690
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Albuterol Spiromax® 90 mcg, Placebo Inhaler
	Comments	Of interest was the mean difference between each active group and placebo at each dose level. Analyses were performed at the 2-sided 0.05 significance level in this sequence: Albuterol Spiromax 180 mcg versus placebo; Albuterol Spiromax 90 mcg versus placebo, ProAir HFA 180 mcg versus placebo, and ProAir HFA 90 mcg versus placebo. If a test was not significant, no further tests were done. This sequential procedure preserved the error rate for the family of tests at the 0.05 level.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Significance at the 0.05 level.
	Method	ANOVA
	Comments	Fixed effects of baseline PPFEV1 as a covariate, sequence, treatment group, period, and center, and random effect for subject within sequence.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	27.73
	Confidence Interval	(2-Sided) 95%; 20.47 to 34.99
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.686
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	ProAir® HFA 180 mcg, Placebo Inhaler
	Comments	Of interest was the mean difference between each active group and placebo at each dose level. Analyses were performed at the 2-sided 0.05 significance level in this sequence: Albuterol Spiromax 180 mcg versus placebo; Albuterol Spiromax 90 mcg versus placebo, ProAir HFA 180 mcg versus placebo, and ProAir HFA 90 mcg versus placebo. If a test was not significant, no further tests were done. This sequential procedure preserved the error rate for the family of tests at the 0.05 level.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Significance at the 0.05 level.
	Method	ANOVA
	Comments	Fixed effects of baseline PPFEV1 as a covariate, sequence, treatment group, period, and center, and random effect for subject within sequence.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	33.10
	Confidence Interval	(2-Sided) 95%; 25.84 to 40.35
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.686
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	ProAir® HFA 90 mcg, Placebo Inhaler
	Comments	Of interest was the mean difference between each active group and placebo at each dose level. Analyses were performed at the 2-sided 0.05 significance level in this sequence: Albuterol Spiromax 180 mcg versus placebo; Albuterol Spiromax 90 mcg versus placebo, ProAir HFA 180 mcg versus placebo, and ProAir HFA 90 mcg versus placebo. If a test was not significant, no further tests were done. This sequential procedure preserved the error rate for the family of tests at the 0.05 level.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Significance at the 0.05 level.
	Method	ANOVA
	Comments	Fixed effects of baseline PPFEV1 as a covariate, sequence, treatment group, period, and center, and random effect for subject within sequence.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	25.61
	Confidence Interval	(2-Sided) 95%; 18.36 to 32.85
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.680
	Estimation Comments

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. 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 37

Outcome Measure Data

Analysis Population Description

Safety population of all randomized participants who received at least one dose of randomized study medication.

Arm/Group Title	All Randomized Participants
Arm/Group Description	Participants were randomized to one of five treatment arms, which indicated the order of the 5 single-dose treatments administered in this 5-way crossover study.
Measure Participants	71
Any adverse event	9 12.7%
Treatment-related AE	0 0%
Withdrawn from study due to AEs	0 0%
Any serious AEs	0 0%
Treatment-related serious AE	0 0%
Onset treatment for AE: Placebo Inhaler	2 2.8%
Onset treatment for AE: Albuterol Spiromax 90mcg	3 4.2%
Onset treatment for AE: Albuterol Spiromax 180mcg	3 4.2%
Onset treatment for AE: ProAir HFA 90 mcg	0 0%
Onset treatment for AE: ProAir HFA 180 mcg	2 2.8%

Adverse Events

Time Frame	Day 1 to Day 37
Arm/Group Title	Albuterol Spiromax® 90 mcg		Albuterol Spiromax® 180 mcg		ProAir® HFA 90 mcg		ProAir® HFA 180 mcg		Placebo Inhaler
Arm/Group Description	A single dose of albuterol 90 mcg delivered with Spiromax®, an inhalation-driven, multi-dose dry powder inhaler. Placebo inhalers used to maintain the blind.		A single dose of albuterol 180 mcg delivered with Spiromax®, an inhalation-driven, multi-dose dry powder inhaler (2 inhalations). Placebo inhalers used to maintain the blind.		A single dose of albuterol 90 mcg delivered with ProAir®, a 'press-and-breathe', metered-dose, aerosol inhaler. Placebo inhalers used to maintain the blind.		A single dose of albuterol 180 mcg delivered with ProAir®, a 'press-and-breathe', metered-dose, aerosol inhaler (2 inhalations). Placebo inhalers used to maintain the blind.		Placebo delivered with Spiromax®, an inhalation-driven, multi-dose dry powder inhaler, and with ProAir®, a 'press-and-breathe', metered-dose, aerosol inhaler. Placebo inhalers used to maintain the blind.
All Cause Mortality
	Albuterol Spiromax® 90 mcg		Albuterol Spiromax® 180 mcg		ProAir® HFA 90 mcg		ProAir® HFA 180 mcg		Placebo Inhaler
	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 Inhaler
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/68 (0%)		0/68 (0%)		0/70 (0%)		0/68 (0%)		0/69 (0%)
Other (Not Including Serious) Adverse Events
	Albuterol Spiromax® 90 mcg		Albuterol Spiromax® 180 mcg		ProAir® HFA 90 mcg		ProAir® HFA 180 mcg		Placebo Inhaler
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/68 (4.4%)		3/68 (4.4%)		0/70 (0%)		2/68 (2.9%)		2/69 (2.9%)
General disorders
Cyst	1/68 (1.5%)		0/68 (0%)		0/70 (0%)		0/68 (0%)		0/69 (0%)
Immune system disorders
Hypersensitivity	0/68 (0%)		0/68 (0%)		0/70 (0%)		0/68 (0%)		1/69 (1.4%)
Food allergy	1/68 (1.5%)		0/68 (0%)		0/70 (0%)		0/68 (0%)		0/69 (0%)
Infections and infestations
Localized infection	0/68 (0%)		0/68 (0%)		0/70 (0%)		1/68 (1.5%)		0/69 (0%)
Upper respiratory tract infection	1/68 (1.5%)		0/68 (0%)		0/70 (0%)		0/68 (0%)		0/69 (0%)
Viral infection	0/68 (0%)		0/68 (0%)		0/70 (0%)		0/68 (0%)		1/69 (1.4%)
Injury, poisoning and procedural complications
Thermal burn	0/68 (0%)		1/68 (1.5%)		0/70 (0%)		0/68 (0%)		0/69 (0%)
Nervous system disorders
Migraine	0/68 (0%)		0/68 (0%)		0/70 (0%)		0/68 (0%)		1/69 (1.4%)
Respiratory, thoracic and mediastinal disorders
Cough	0/68 (0%)		1/68 (1.5%)		0/70 (0%)		0/68 (0%)		0/69 (0%)
Dysphonia	0/68 (0%)		0/68 (0%)		0/70 (0%)		1/68 (1.5%)		0/69 (0%)
Vascular disorders
Hypertension	0/68 (0%)		1/68 (1.5%)		0/70 (0%)		0/68 (0%)		0/69 (0%)

Limitations/Caveats

[Not Specified]

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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.