A 12-week Study to Compare the Efficacy and Safety of Albuterol Spiromax® Versus a Placebo in People 12 Years and Older With Persistent Asthma

• Sponsor: Teva Branded Pharmaceutical Products R&D, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01424813
• Collaborator: (none)
• Enrollment: 158
• Locations: 38
• Arms: 2
• Duration (Months): 11
• Patients Per Site: 4.2
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

The study will measure the change in lung function in subjects with asthma after inhaling from either of two inhalers: Albuterol Spiromax® or placebo.

Condition or Disease	Intervention/Treatment	Phase
Asthma	Drug: Placebo MDPI; Drug: Albuterol MDPI	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 158 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A 12-week Comparison of the Efficacy and Safety of Albuterol Spiromax® Versus Placebo in Subjects 12 Years and Older With Persistent Asthma
• Study Start Date: Dec 1, 2012
• Actual Primary Completion Date: Oct 1, 2013
• Actual Study Completion Date: Nov 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo MDPI Placebo multi-dose dry powder inhaler (MDPI) administered as 2 inhalations four times a day for 12 weeks.	Drug: Placebo MDPI; Placebo MDPI administered as 2 inhalations 4 times a day (QID) (at approximately 7:00 AM, 12 noon, 5:00 PM, and bedtime) for 12 weeks.; Other Names: Placebo Spiromax®
Experimental: Albuterol MDPI Albuterol multi-dose dry powder inhaler (MDPI) at a dose of 720 micrograms per day administered as 2 inhalations of 90 mcg /inhalation four times a day for 12 weeks.	Drug: Albuterol MDPI; Albuterol MDPI administered as 2 inhalations 4 times a day (QID) (at approximately 7:00 AM, 12 noon, 5:00 PM, and bedtime) for 12 weeks.; Other Names: ProAir® RespiClick, Albuterol Spiromax®

Outcome Measures

Primary Outcome Measures

1. Baseline-adjusted Forced Expiratory Volume in 1 Second (FEV1) Area Under the Curve (AUC 0-6) Over the 12-week Treatment Period [Day 1, Day 8 and Day 85]

   FEV1 AUC 0-6 is the area under the effect-time curve from time 0 (pre-dose) up to 6 hours post-dose. It represents the weighted average (by the trapezoidal rule) of FEV1 AUC 0-6 measures adjusted for the baseline measure (i.e., change from baseline at each timepoint) recorded on days 1, 8 and 85 of the treatment period. The baseline for each study day was the average of the 2 pre-dose FEV1 measurements on that study day. FEV1 was measured using spirometry. Spirometry assessments were obtained predose at -30 ± 5, and - 5 minutes, then post dose at 5 ± 2, 15 ± 5, 30 ± 5, 45 ± 5 minutes, and at 1hr ± 5 min, 2hr ± 5 min, 3hr ± 5 min, 4hr ± 5 min, 5hr ± 5 min, and 6hr ± 5 min.

Secondary Outcome Measures

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

   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 was the average of the 2 pre-dose FEV1 measurements on that study day. The baseline-adjustment refers to change from baseline at each post dose timepoint recorded on Day 1. FEV1 was measured using spirometry. Spirometry assessments were obtained predose at -30 ± 5, and - 5 minutes, then post dose at 5 ± 2, 15 ± 5, 30 ± 5, 45 ± 5 minutes, and at 1hr ± 5 min, 2hr ± 5 min, 3hr ± 5 min, 4hr ± 5 min, 5hr ± 5 min, and 6hr ± 5 min.

2. Baseline-adjusted Forced Expiratory Volume in 1 Second (FEV1) Area Under the Curve (AUC 0-6) on Day 8 [Day 8]

   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 was the average of the 2 pre-dose FEV1 measurements on that study day. The baseline-adjustment refers to change from baseline at each post dose timepoint recorded on Day 8. FEV1 was measured using spirometry. Spirometry assessments were obtained predose at -30 ± 5, and - 5 minutes, then post dose at 5 ± 2, 15 ± 5, 30 ± 5, 45 ± 5 minutes, and at 1hr ± 5 min, 2hr ± 5 min, 3hr ± 5 min, 4hr ± 5 min, 5hr ± 5 min, and 6hr ± 5 min.

3. Baseline-adjusted Forced Expiratory Volume in 1 Second (FEV1) Area Under the Curve (AUC 0-6) on Day 85 [Day 85]

   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 was the average of the 2 pre-dose FEV1 measurements on that study day. The baseline-adjustment refers to change from baseline at each post dose timepoint recorded on Day 85. FEV1 was measured using spirometry. Spirometry assessments were obtained predose at -30 ± 5, and - 5 minutes, then post dose at 5 ± 2, 15 ± 5, 30 ± 5, 45 ± 5 minutes, and at 1hr ± 5 min, 2hr ± 5 min, 3hr ± 5 min, 4hr ± 5 min, 5hr ± 5 min, and 6hr ± 5 min.

4. Participants With Adverse Events [Day 1 to Day 92]

   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 on a scale of mild, moderate and severe, with severe= an AE which prevents normal daily 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.

5. Physical Examination Findings Shifts From Baseline to Endpoint by Treatment Group [Day 1 (Baseline), Day 85]

   Physical exam was recorded as normal or abnormal based on physician assessment. Format for results is: Test Baseline/Endpoint HEENT = head, eyes, ears, nose, throat

6. Participants With Clinically Significant Vital Sign Assessments [Day 8, Day 85]

   For both standard and serial vital signs, participants were seated for at least 5 minutes before vital signs were assessed. Heart rate was obtained prior to the blood pressure measurement. Serial heart rate and blood pressure were conducted in the sitting position prior to the spirometry assessment; baseline measures were taken pre-dose at -30 ± 5 and -5 minutes on Day 1. Day 85 serial vital sign measures were taken in the sitting position prior to spirometry assessments pre-dose at -30 ± 5 and -5 minutes, then post-dose at 30 (±5) minutes, 1hr (± 10 min), 2hr (± 10 min), 3hr (± 10 min), 4hr (± 10 min), 5hr (± 10 min) and 6 hr (± 10 min). Serial heart rate and blood pressure measurements that were elevated to the following criteria were considered clinically significant: Systolic blood pressure: > 160 beats/minute Diastolic blood pressure: >100 beats/minute Heart rate: >120 beats/minute

Other Outcome Measures

1. Percent Change From Baseline in FEV1 AUC 0-6 Over the 12-week Treatment Period [Day 1, Day 8, Day 85]

2. Percent Change From Baseline in FEV1 AUC 0-6 [Day 1]

3. Percent Change From Baseline in FEV1 AUC [Day 8]

4. Percent Change From Baseline in FEV1 AUC [Day 85]

5. Maximum Percent Change From Baseline in FEV1 Within 2 Hours Post Dose Over the 12-week Treatment Period [Day 1, Day 8, Day 85]

6. Maximum Percent Change From Baseline in FEV1 Within 2 Hours Post Dose on Day 1 [Day 1]

7. Maximum Percent Change From Baseline in FEV1 Within 2 Hours Post Dose on Day 8 [Day 8]

8. Maximum Percent Change From Baseline in FEV1 Within 2 Hours Post Dose on Day 85 [Day 85]

9. Time to Onset of Effect (Change in FEV1 of 12% From Baseline Within 30 Minutes Postdose) [Day 1, Day 8, Day 85]

10. Duration of Response Measured From the Time Post-dosing to the First Time After the Response Onset (Increase ≥12% Above Baseline) When the FEV1 Decreases to Less Than 12% Above Baseline (Within 6 Hours After Dosing) for Those Who Responded in 30 Minutes [Day 1, Day 8, Day 85]

11. Time to Onset of Effect (Change in FEV1 of 15% From Baseline Within 30 Minutes Postdose)for Those Who Responded in 30 Minutes [Day 1, Day 8, Day 85]

12. Duration of Response on Days 1, 8 and 85 [Day 1, Day 8, Day 85]

    Duration of response measured from the time post-dosing to the first time after the response onset (increase ≥15% above baseline) when the FEV1 decreases to less than 15% above baseline (within 6 hours after dosing) for those who responded within 30 minutes

13. Percent of Symptom Free Days on the Patient Diary [Treatment days 1 through 85]

14. Percent of Rescue Medication Free Days in the Patient Diary [Treatment days 1 through 85]

15. Morning Peak Expiratory Flow Reading Reported on Patient Diary [Treatment days 1 through 85]

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Written informed consent/assent

• General good health

• Persistent asthma, with an FEV1 50-80% predicted.

• Ability to perform spirometry in an acceptable manner as per protocol guidelines.

• Ability to perform PEFR with a handheld peak flow meter.

• Demonstration of reversible bronchoconstriction as verified by a 15% or greater increase from baseline FEV1.

• Taking inhaled corticosteroids at a stable dose for at least 4 weeks prior to the Screening Visit.

• Non-smokers.

• Capable of understanding the requirements, risks, and benefits of study participation.

• Other inclusion criteria apply.

Exclusion Criteria:

• Participation in any investigational drug trial within the 30 days preceding the Screening Visit (SV).

• A known hypersensitivity to albuterol or any of the excipients in the formulations.

• History of severe milk protein allergy.

• History of a respiratory infection or disorder that has not resolved within the 2 weeks preceding the Screening Visit (SV).

• Currently requires treatment with β2-adrenergic receptor antagonists or non-selective β-receptor blocking agents.

• History of life-threatening asthma that is defined for this protocol as an asthma episode that required intubation.

• Any asthma exacerbation requiring oral corticosteroids within 3 months of the Screening Visit (SV). A subject must not have had any hospitalization for asthma within 6 months prior to the Screening Visit (SV).

• Historical or current evidence of any clinically significant non-asthmatic acute or chronic condition including.

• Other exclusion criteria apply.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Teva Investigational Site 10077	Birmingham	Alabama	United States
2	Teva Investigational Site 10079	Phoenix	Arizona	United States
3	Teva Investigational Site 10569	Costa Mesa	California	United States
4	Teva Investigational Site 10053	Fountain Valley	California	United States
5	Teva Investigational Site 10065	Huntington Beach	California	United States
6	Teva Investigational Site 10572	Huntington Beach	California	United States
7	Teva Investigational Site 10075	Los Angeles	California	United States
8	Teva Investigational Site 10061	Roseville	California	United States
9	Teva Investigational Site 10066	San Diego	California	United States
10	Teva Investigational Site 10068	Denver	Colorado	United States
11	Teva Investigational Site 10069	Denver	Colorado	United States
12	Teva Investigational Site 10058	Miami	Florida	United States
13	Teva Investigational Site 10060	Miami	Florida	United States
14	Teva Investigational Site 10064	Ormond Beach	Florida	United States
15	Teva Investigational Site 10071	Savannah	Georgia	United States
16	Teva Investigational Site 10073	Wichita	Kansas	United States
17	Teva Investigational Site 10070	Owensboro	Kentucky	United States
18	Teva Investigational Site 10063	Bethesda	Maryland	United States
19	Teva Investigational Site 10571	Gaithersburg	Maryland	United States
20	Teva Investigational Site 10067	Wheaton	Maryland	United States
21	Teva Investigational Site 10072	St. Louis	Missouri	United States
22	Teva Investigational Site 10050	Missoula	Montana	United States
23	Teva Investigational Site 10057	Raleigh	North Carolina	United States
24	Teva Investigational Site 10051	Cincinnati	Ohio	United States
25	Teva Investigational Site 10078	Sylvania	Ohio	United States
26	Teva Investigational Site 10054	Oklahoma City	Oklahoma	United States
27	Teva Investigational Site 10568	Oklahoma City	Oklahoma	United States
28	Teva Investigational Site 10055	Tulsa	Oklahoma	United States
29	Teva Investigational Site 10056	Medford	Oregon	United States
30	Teva Investigational Site 10076	Medford	Oregon	United States
31	Teva Investigational Site 10684	Charleston	South Carolina	United States
32	Teva Investigational Site 10570	Spartanburg	South Carolina	United States
33	Teva Investigational Site 10049	Live Oak	Texas	United States
34	Teva Investigational Site 10052	San Antonio	Texas	United States
35	Teva Investigational Site 10685	Waco	Texas	United States
36	Teva Investigational Site 10059	Fairfax	Virginia	United States
37	Teva Investigational Site 10074	Puyallup	Washington	United States
38	Teva Investigational Site 10062	Tacoma	Washington	United States

Sponsors and Collaborators

• Teva Branded Pharmaceutical Products R&D, Inc.

Investigators

• Study Director: Clinical Project Leader, Teva Respiratory R&D

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Teva Branded Pharmaceutical Products R&D, Inc.
• ClinicalTrials.gov Identifier: NCT01424813
• Other Study ID Numbers: ABS-AS-301
• First Posted: Aug 29, 2011
• Last Update Posted: Jun 26, 2015
• Last Verified: May 1, 2015

• Keywords provided by Teva Branded Pharmaceutical Products R&D, Inc.: Asthma; dry powder inhaler; short-acting beta2-agonist; SABA; bronchoconstriction; bronchodilation; bronchodilator; metered dose inhaler
• Additional relevant MeSH terms: Asthma; Albuterol

Study Results

Participant Flow

Pre-assignment Detail	384 patients screened; 180 patients were excluded on the basis of inclusion criteria, 4 due to exclusion criteria, 21 patients withdrew consent, 1 patient was lost to follow-up before the baseline visit, 6 patients had other reasons, and 14 patients failed to meet randomization criteria at the end of the run-in period.

Arm/Group Title	Placebo MDPI	Albuterol MDPI
Arm/Group Description	Placebo multi-dose dry powder inhaler (MDPI) administered as 2 inhalations four times a day for 12 weeks.	Albuterol multi-dose dry powder inhaler (MDPI) at a dose of 720 micrograms per day administered as 2 inhalations of 90 mcg /inhalation four times a day for 12 weeks.
Period Title: Overall Study
STARTED	79	79
Treated	79	78
COMPLETED	74	77
NOT COMPLETED	5	2

Baseline Characteristics

Arm/Group Title	Placebo MDPI	Albuterol MDPI	Total
Arm/Group Description	Placebo multi-dose dry powder inhaler (MDPI) administered as 2 inhalations four times a day for 12 weeks.	Albuterol multi-dose dry powder inhaler (MDPI) at a dose of 720 micrograms per day administered as 2 inhalations of 90 mcg /inhalation four times a day for 12 weeks.	Total of all reporting groups
Overall Participants	79	79	158
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	40.3 (16.84)	37.3 (16.89)	38.8 (16.88)
Age, Customized (participants) [Number]
12-17 years	14 17.7%	16 20.3%	30 19%
18-64 years	63 79.7%	60 75.9%	123 77.8%
65+ years	2 2.5%	3 3.8%	5 3.2%
Sex: Female, Male (Count of Participants)
Female	47 59.5%	44 55.7%	91 57.6%
Male	32 40.5%	35 44.3%	67 42.4%
Race/Ethnicity, Customized (participants) [Number]
White	59 74.7%	55 69.6%	114 72.2%
Black	18 22.8%	21 26.6%	39 24.7%
Asian	2 2.5%	0 0%	2 1.3%
American Indian or Alaskan Native	0 0%	0 0%	0 0%
Pacific Islander	0 0%	0 0%	0 0%
Other	0 0%	3 3.8%	3 1.9%
Race/Ethnicity, Customized (participants) [Number]
Hispanic or Latino	3 3.8%	6 7.6%	9 5.7%
Not Hispanic or Latino	76 96.2%	73 92.4%	149 94.3%
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	82.4 (21.34)	83.4 (24.20)	82.9 (22.75)
Height (cm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cm]	169.5 (9.47)	168.9 (9.27)	169.2 (9.35)
Body Mass Index (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	28.6 (6.92)	29.2 (8.22)	28.9 (7.58)

Outcome Measures

1. Primary Outcome

Title	Baseline-adjusted Forced Expiratory Volume in 1 Second (FEV1) Area Under the Curve (AUC 0-6) Over the 12-week Treatment Period
Description	FEV1 AUC 0-6 is the area under the effect-time curve from time 0 (pre-dose) up to 6 hours post-dose. It represents the weighted average (by the trapezoidal rule) of FEV1 AUC 0-6 measures adjusted for the baseline measure (i.e., change from baseline at each timepoint) recorded on days 1, 8 and 85 of the treatment period. The baseline for each study day was the average of the 2 pre-dose FEV1 measurements on that study day. FEV1 was measured using spirometry. Spirometry assessments were obtained predose at -30 ± 5, and - 5 minutes, then post dose at 5 ± 2, 15 ± 5, 30 ± 5, 45 ± 5 minutes, and at 1hr ± 5 min, 2hr ± 5 min, 3hr ± 5 min, 4hr ± 5 min, 5hr ± 5 min, and 6hr ± 5 min.
Time Frame	Day 1, Day 8 and Day 85

Outcome Measure Data

Analysis Population Description

Full analysis set which includes all participants in the intent-to-treat (ITT) population who received at least 1 dose of study medication and had at least 1 post-baseline assessment.

Arm/Group Title	Placebo MDPI	Albuterol MDPI
Arm/Group Description	Placebo multi-dose dry powder inhaler (MDPI) administered as 2 inhalations four times a day for 12 weeks.	Albuterol multi-dose dry powder inhaler (MDPI) at a dose of 720 micrograms per day administered as 2 inhalations of 90 mcg /inhalation four times a day for 12 weeks.
Measure Participants	79	78
Mean (Standard Error) [L*hr]	0.28 (0.091)	1.11 (0.092)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo MDPI, Albuterol MDPI
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Significance at the 0.05 level.
	Method	mixed-model repeated-measures (MMRM)
	Comments	Fixed effects- pooled center, treatment group, study day, and study day by drug interaction, with baseline measured at each study day as covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.83
	Confidence Interval	(2-Sided) 95%; 0.57 to 1.08
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.128
	Estimation Comments

2. Secondary Outcome

Title	Baseline-adjusted Forced Expiratory Volume in 1 Second (FEV1) Area Under the Curve (AUC 0-6) on Day 1
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 was the average of the 2 pre-dose FEV1 measurements on that study day. The baseline-adjustment refers to change from baseline at each post dose timepoint recorded on Day 1. FEV1 was measured using spirometry. Spirometry assessments were obtained predose at -30 ± 5, and - 5 minutes, then post dose at 5 ± 2, 15 ± 5, 30 ± 5, 45 ± 5 minutes, and at 1hr ± 5 min, 2hr ± 5 min, 3hr ± 5 min, 4hr ± 5 min, 5hr ± 5 min, and 6hr ± 5 min.
Time Frame	Day 1

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	Placebo MDPI	Albuterol MDPI
Arm/Group Description	Placebo multi-dose dry powder inhaler (MDPI) administered as 2 inhalations four times a day for 12 weeks.	Albuterol multi-dose dry powder inhaler (MDPI) at a dose of 720 micrograms per day administered as 2 inhalations of 90 mcg /inhalation four times a day for 12 weeks.
Measure Participants	79	78
Mean (95% Confidence Interval) [L*hr]	0.52	1.58

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo MDPI, Albuterol MDPI
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	To adjust for multiplicity, so that the overall alpha level for all tests was controlled at the 0.05 level, tests were done sequentially [day 1, then day 8, then day 85] and terminated if individual results were not significant at the 0.05 level.
	Method	mixed model repeated measures (MMRM)
	Comments	Fixed effects- pooled center, treatment group, study day, and study day by drug interaction, with baseline measured at each study day as covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.07
	Confidence Interval	(2-Sided) 95%; 0.68 to 1.46
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.198
	Estimation Comments

3. Other Pre-specified Outcome

Title	Percent Change From Baseline in FEV1 AUC 0-6 Over the 12-week Treatment Period
Time Frame	Day 1, Day 8, Day 85

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

4. Other Pre-specified Outcome

Title	Percent Change From Baseline in FEV1 AUC 0-6
Time Frame	Day 1

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

5. Other Pre-specified Outcome

Title	Percent Change From Baseline in FEV1 AUC
Time Frame	Day 8

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

6. Other Pre-specified Outcome

Title	Percent Change From Baseline in FEV1 AUC
Time Frame	Day 85

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

7. Other Pre-specified Outcome

Title	Maximum Percent Change From Baseline in FEV1 Within 2 Hours Post Dose Over the 12-week Treatment Period
Time Frame	Day 1, Day 8, Day 85

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

8. Other Pre-specified Outcome

Title	Maximum Percent Change From Baseline in FEV1 Within 2 Hours Post Dose on Day 1
Time Frame	Day 1

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

9. Other Pre-specified Outcome

Title	Maximum Percent Change From Baseline in FEV1 Within 2 Hours Post Dose on Day 8
Time Frame	Day 8

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

10. Other Pre-specified Outcome

Title	Maximum Percent Change From Baseline in FEV1 Within 2 Hours Post Dose on Day 85
Time Frame	Day 85

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

11. Other Pre-specified Outcome

Title	Time to Onset of Effect (Change in FEV1 of 12% From Baseline Within 30 Minutes Postdose)
Time Frame	Day 1, Day 8, Day 85

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

12. Other Pre-specified Outcome

Title	Duration of Response Measured From the Time Post-dosing to the First Time After the Response Onset (Increase ≥12% Above Baseline) When the FEV1 Decreases to Less Than 12% Above Baseline (Within 6 Hours After Dosing) for Those Who Responded in 30 Minutes
Time Frame	Day 1, Day 8, Day 85

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

13. Other Pre-specified Outcome

Title	Time to Onset of Effect (Change in FEV1 of 15% From Baseline Within 30 Minutes Postdose)for Those Who Responded in 30 Minutes
Time Frame	Day 1, Day 8, Day 85

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

14. Other Pre-specified Outcome

Title	Duration of Response on Days 1, 8 and 85
Description	Duration of response measured from the time post-dosing to the first time after the response onset (increase ≥15% above baseline) when the FEV1 decreases to less than 15% above baseline (within 6 hours after dosing) for those who responded within 30 minutes
Time Frame	Day 1, Day 8, Day 85

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

15. Other Pre-specified Outcome

Title	Percent of Symptom Free Days on the Patient Diary
Time Frame	Treatment days 1 through 85

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

16. Other Pre-specified Outcome

Title	Percent of Rescue Medication Free Days in the Patient Diary
Time Frame	Treatment days 1 through 85

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

17. Secondary Outcome

Title	Baseline-adjusted Forced Expiratory Volume in 1 Second (FEV1) Area Under the Curve (AUC 0-6) on Day 8
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 was the average of the 2 pre-dose FEV1 measurements on that study day. The baseline-adjustment refers to change from baseline at each post dose timepoint recorded on Day 8. FEV1 was measured using spirometry. Spirometry assessments were obtained predose at -30 ± 5, and - 5 minutes, then post dose at 5 ± 2, 15 ± 5, 30 ± 5, 45 ± 5 minutes, and at 1hr ± 5 min, 2hr ± 5 min, 3hr ± 5 min, 4hr ± 5 min, 5hr ± 5 min, and 6hr ± 5 min.
Time Frame	Day 8

Outcome Measure Data

Analysis Population Description

Full analysis set of participants with data at the time point

Arm/Group Title	Placebo MDPI	Albuterol MDPI
Arm/Group Description	Placebo multi-dose dry powder inhaler (MDPI) administered as 2 inhalations four times a day for 12 weeks.	Albuterol multi-dose dry powder inhaler (MDPI) at a dose of 720 micrograms per day administered as 2 inhalations of 90 mcg /inhalation four times a day for 12 weeks.
Measure Participants	78	78
Mean (95% Confidence Interval) [L*hr]	0.26	0.99

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo MDPI, Albuterol MDPI
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	To adjust for multiplicity, so that the overall alpha level for all tests was controlled at the 0.05 level, tests were done sequentially [day 1, then day 8, then day 85] and terminated if individual results were not significant at the 0.05 level.
	Method	mixed model repeated measures (MMRM)
	Comments	Fixed effects- pooled center, treatment group, study day, and study day by drug interaction, with baseline measured at each study day as covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.73
	Confidence Interval	(2-Sided) 95%; 0.41 to 1.06
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.164
	Estimation Comments

18. Secondary Outcome

Title	Baseline-adjusted Forced Expiratory Volume in 1 Second (FEV1) Area Under the Curve (AUC 0-6) on Day 85
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 was the average of the 2 pre-dose FEV1 measurements on that study day. The baseline-adjustment refers to change from baseline at each post dose timepoint recorded on Day 85. FEV1 was measured using spirometry. Spirometry assessments were obtained predose at -30 ± 5, and - 5 minutes, then post dose at 5 ± 2, 15 ± 5, 30 ± 5, 45 ± 5 minutes, and at 1hr ± 5 min, 2hr ± 5 min, 3hr ± 5 min, 4hr ± 5 min, 5hr ± 5 min, and 6hr ± 5 min.
Time Frame	Day 85

Outcome Measure Data

Analysis Population Description

Full analysis set of participants with data at the time point

Arm/Group Title	Placebo MDPI	Albuterol MDPI
Arm/Group Description	Placebo multi-dose dry powder inhaler (MDPI) administered as 2 inhalations four times a day for 12 weeks.	Albuterol multi-dose dry powder inhaler (MDPI) at a dose of 720 micrograms per day administered as 2 inhalations of 90 mcg /inhalation four times a day for 12 weeks.
Measure Participants	77	77
Mean (95% Confidence Interval) [L*hr]	0.06	0.74

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo MDPI, Albuterol MDPI
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	To adjust for multiplicity, so that the overall alpha level for all tests was controlled at the 0.05 level, tests were done sequentially [day 1, then day 8, then day 85] and terminated if individual results were not significant at the 0.05 level.
	Method	mixed model repeated measures (MMRM)
	Comments	Fixed effects- pooled center, treatment group, study day, and study day by drug interaction, with baseline measured at each study day as covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.68
	Confidence Interval	(2-Sided) 95%; 0.38 to 0.99
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.154
	Estimation Comments

19. Secondary Outcome

Title	Participants With 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 on a scale of mild, moderate and severe, with severe= an AE which prevents normal daily 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 to Day 92

Outcome Measure Data

Analysis Population Description

Safety analysis set

Arm/Group Title	Placebo MDPI	Albuterol MDPI
Arm/Group Description	Placebo multi-dose dry powder inhaler (MDPI) administered as 2 inhalations four times a day for 12 weeks.	Albuterol multi-dose dry powder inhaler (MDPI) at a dose of 720 micrograms per day administered as 2 inhalations of 90 mcg /inhalation four times a day for 12 weeks.
Measure Participants	79	78
Any adverse event	25 31.6%	22 27.8%
Severe adverse events	1 1.3%	1 1.3%
Treatment-related AE	1 1.3%	1 1.3%
Deaths	0 0%	0 0%
Other serious AEs	0 0%	0 0%
Withdrawn from study due to AEs	0 0%	0 0%

20. Secondary Outcome

Title	Physical Examination Findings Shifts From Baseline to Endpoint by Treatment Group
Description	Physical exam was recorded as normal or abnormal based on physician assessment. Format for results is: Test Baseline/Endpoint HEENT = head, eyes, ears, nose, throat
Time Frame	Day 1 (Baseline), Day 85

Outcome Measure Data

Analysis Population Description

Safety population. Only participants with both baseline and endpoint physical examination findings are summarized. Two placebo participants were missing endpoint physical examinations.

Arm/Group Title	Placebo MDPI	Albuterol MDPI
Arm/Group Description	Placebo multi-dose dry powder inhaler (MDPI) administered as 2 inhalations four times a day for 12 weeks.	Albuterol multi-dose dry powder inhaler (MDPI) at a dose of 720 micrograms per day administered as 2 inhalations of 90 mcg /inhalation four times a day for 12 weeks.
Measure Participants	77	78
General appearance Normal/Normal	76 96.2%	76 96.2%
General appearance Normal/Abnormal	0 0%	0 0%
General appearance Abnormal/Normal	1 1.3%	1 1.3%
General appearance Abnormal/Abnormal	0 0%	1 1.3%
HEENT Normal/Normal	46 58.2%	50 63.3%
HEENT Normal/Abnormal	12 15.2%	5 6.3%
HEENT Abnormal/Normal	11 13.9%	12 15.2%
HEENT Abnormal/Abnormal	8 10.1%	11 13.9%
Chest and Lungs Normal/Normal	66 83.5%	67 84.8%
Chest and Lungs Normal/Abnormal	8 10.1%	4 5.1%
Chest and Lungs Abnormal/Normal	2 2.5%	7 8.9%
Chest and Lungs Abnormal/abnormal	1 1.3%	0 0%
Heart Normal/Normal	76 96.2%	77 97.5%
Heart Normal/Abnormal	0 0%	0 0%
Heart Abnormal/Normal	1 1.3%	1 1.3%
Heart Abnormal/Abnormal	0 0%	0 0%
Abdomen Normal/Normal	75 94.9%	77 97.5%
Abdomen Normal/Abnormal	1 1.3%	0 0%
Abdomen Abnormal/Normal	0 0%	1 1.3%
Abdomen Abnormal/Abnormal	1 1.3%	0 0%
Musculoskeletal Normal/Normal	74 93.7%	76 96.2%
Musculoskeletal Normal/Abnormal	0 0%	1 1.3%
Musculoskeletal Abnormal/Normal	3 3.8%	1 1.3%
Musculoskeletal Abnormal/Abnormal	0 0%	0 0%
Skin Normal/Normal	75 94.9%	73 92.4%
Skin Normal/Abnormal	0 0%	1 1.3%
Skin Abnormal/Normal	2 2.5%	4 5.1%
Skin Abnormal/Abnormal	0 0%	0 0%
Lymph nodes Normal/Normal	77 97.5%	78 98.7%
Lymph nodes Normal/Abnormal	0 0%	0 0%
Lymph nodes Abnormal/Normal	0 0%	0 0%
Lymph nodes Abnormal/Abnormal	0 0%	0 0%
Neurological Normal/Normal	76 96.2%	78 98.7%
Neurological Normal/Abnormal	1 1.3%	0 0%
Neurological Abnormal/Normal	0 0%	0 0%
Neurological Abnormal/Abnormal	0 0%	0 0%

21. Secondary Outcome

Title	Participants With Clinically Significant Vital Sign Assessments
Description	For both standard and serial vital signs, participants were seated for at least 5 minutes before vital signs were assessed. Heart rate was obtained prior to the blood pressure measurement. Serial heart rate and blood pressure were conducted in the sitting position prior to the spirometry assessment; baseline measures were taken pre-dose at -30 ± 5 and -5 minutes on Day 1. Day 85 serial vital sign measures were taken in the sitting position prior to spirometry assessments pre-dose at -30 ± 5 and -5 minutes, then post-dose at 30 (±5) minutes, 1hr (± 10 min), 2hr (± 10 min), 3hr (± 10 min), 4hr (± 10 min), 5hr (± 10 min) and 6 hr (± 10 min). Serial heart rate and blood pressure measurements that were elevated to the following criteria were considered clinically significant: Systolic blood pressure: > 160 beats/minute Diastolic blood pressure: >100 beats/minute Heart rate: >120 beats/minute
Time Frame	Day 8, Day 85

Outcome Measure Data

Analysis Population Description

Safety population

Arm/Group Title	Placebo MDPI	Albuterol MDPI
Arm/Group Description	Placebo multi-dose dry powder inhaler (MDPI) administered as 2 inhalations four times a day for 12 weeks.	Albuterol multi-dose dry powder inhaler (MDPI) at a dose of 720 micrograms per day administered as 2 inhalations of 90 mcg /inhalation four times a day for 12 weeks.
Measure Participants	79	78
Systolic blood pressure - high	3 3.8%	0 0%
Diastolic blood pressure - high	3 3.8%	1 1.3%
Heart rate - high	0 0%	1 1.3%

22. Other Pre-specified Outcome

Title	Morning Peak Expiratory Flow Reading Reported on Patient Diary
Time Frame	Treatment days 1 through 85

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	Day 1 to Day 92
Arm/Group Title	Albuterol MDPI		Placebo MDPI
Arm/Group Description	Albuterol multi-dose dry powder inhaler (MDPI) at a dose of 720 micrograms per day administered as 2 inhalations of 90 mcg /inhalation four times a day for 12 weeks.		Placebo multi-dose dry powder inhaler (MDPI) administered as 2 inhalations four times a day for 12 weeks.
All Cause Mortality
	Albuterol MDPI		Placebo MDPI
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Albuterol MDPI		Placebo MDPI
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/78 (0%)		0/79 (0%)
Other (Not Including Serious) Adverse Events
	Albuterol MDPI		Placebo MDPI
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/78 (7.7%)		9/79 (11.4%)
Infections and infestations
Upper respiratory tract infection	3/78 (3.8%)	3	5/79 (6.3%)	5
Nervous system disorders
Headache	3/78 (3.8%)	4	4/79 (5.1%)	5

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.