Assessment of the Safety, Efficacy, PK, and Extrapulmonary Pharmacodynamics (PD) of Albuterol Sulfate Pressurized Inhalation Suspension (Hereafter Referred to as AS MDI) Compared to Proventil as an Active Control in Subjects With Asthma

• Sponsor: AstraZeneca (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03371459
• Collaborator: (none)
• Enrollment: 46
• Locations: 5
• Arms: 2
• Actual Duration (Months): 2.9
• Patients Per Site: 9.2
• Patients Per Site Per Month: 3.2

Study Details

Study Description

Brief Summary

This is a randomized, cumulative dose, open-label, 2-period crossover, multi-center study to assess the safety, efficacy, PK, and extrapulmonary PD of cumulative doses of AS MDI compared to cumulative doses of Proventil as an active control in subjects with mild to moderate asthma

Condition or Disease	Intervention/Treatment	Phase
Asthma	Drug: AS MDI; Drug: Proventil	Phase 2

Detailed Description

This is a randomized, cumulative dose, open-label, 2-period crossover, multi-center study to assess the safety, efficacy, PK, and extrapulmonary pharmacodynamics (PD) of cumulative doses of Albuterol Sulfate Pressurized Inhalation Suspension (hereafter referred to as AS MDI) compared to cumulative doses of Proventil® hydrofluoroalkane (HFA; hereafter referred to as Proventil) as an active control in subjects with mild to moderate asthma.

Study Design

• Study Type: Interventional
• Actual Enrollment: 46 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Randomized, Cumulative Dose, Open-label, 2-period Crossover, Multi-center Study to Assess the Safety, Efficacy, PK, and Extrapulmonary Pharmacodynamics (PD) of Cumulative Doses of Albuterol Sulfate Pressurized Inhalation Suspension (Hereafter Referred to as AS MDI) Compared to Cumulative Doses of Proventil® Hydrofluoroalkane (HFA; Hereafter Referred to as Proventil) as an Active Control in Subjects With Mild to Moderate Asthma (ASPEN)
• Actual Study Start Date: Dec 29, 2017
• Actual Primary Completion Date: Mar 26, 2018
• Actual Study Completion Date: Mar 26, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: AS MDI AS MDI 1+1+2+4+8 inhalations of 90 μg per inhalation	Drug: AS MDI; AS MDI 1+1+2+4+8 inhalations of 90 μg per inhalation
Active Comparator: Proventil Proventil 1+1+2+4+8 inhalations of 90 μg per inhalation	Drug: Proventil; Proventil 1+1+2+4+8 inhalations of 90 μg per inhalation

Outcome Measures

Primary Outcome Measures

1. Baseline-adjusted FEV1 30 Minutes After Each Cumulative Dose [At the two study treatment visits, FEV1 (forced expiratory volume in 1 second) will be measured prior to drug administration and 5 times, once at 30 minutes after each of the 5 doses]

   Forced expiratory volume in 1 second (FEV1) is the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation

Secondary Outcome Measures

1. Baseline-adjusted FEV1 AUC0-6 After the Last Cumulative Dose [Over 6 hours post dose on Day 1]

   The baseline-adjusted FEV1 AUC0-6 is the area under the curve for change from baseline calculated using the trapezoidal rule and normalized by dividing the AUC by the length of follow up post the last cumulative dose (typically 6 hours) (spirometry will be obtained at 5, 15, 30, 45, 60, 120, 180, and 240 minutes post-dose) normalized for length of follow up).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 45 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Have stable (for 6 months) physician-diagnosed asthma with historical documentation of the diagnosis

• Must be receiving 1 of the following required inhaled asthma therapies listed below for at least the last 30 days; Only SABA, which is used as needed for rescue, or Low to medium doses of ICS (alone or in combination with LABA), used regularly as maintenance asthma therapy

• Demonstrate acceptable spirometry performance (ie, meet American Thoracic Society [ATS]/European Respiratory Society [ERS] acceptability/repeatability criteria

• Pre-bronchodilator FEV1 of ≥50 to <80% predicted normal value after withholding SABA ≥6 hours

• Confirmed FEV1 reversibility to Ventolin, defined as a post-Ventolin increase in FEV1 of ≥15%

• Only 2 reversibility testing attempts are allowed

Exclusion Criteria:

• Chronic obstructive pulmonary disease or other significant lung disease (eg, chronic bronchitis, emphysema, bronchiectasis with the need of treatment, cystic fibrosis, or bronchopulmonary dysplasia)

• Oral corticosteroid use (any dose) within 6 weeks

• Received any marketed (eg, omalizumab, mepolizumab, reslizumab) or investigational biologic within 3 months or 5 half-lives, whichever is longer, or any other medication specifically prohibited by the protocol

• Current smokers, former smokers with >10 pack-years history, or former smokers who stopped smoking <6 months (including all forms of tobacco, e-cigarettes [vaping], and marijuana)

• Life-threatening asthma as defined as any history of significant asthma episode(s) requiring intubation associated with hypercapnia, respiratory arrest, hypoxic seizures, or asthma-related syncopal episode(s)

• Historical or current evidence of a clinically significant disease

• Cancer not in complete remission for at least 5 years

• Hospitalized for psychiatric disorder or attempted suicide within 1 year

• Unable to abstain from protocol-defined prohibited medications during the study

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Winter Park	Florida	United States	32789
2	Research Site	North Dartmouth	Massachusetts	United States	02747
3	Research Site	Saint Louis	Missouri	United States	63141
4	Research Site	Raleigh	North Carolina	United States	27607
5	Research Site	Medford	Oregon	United States	97504

Sponsors and Collaborators

• AstraZeneca

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Mar 15, 2018
• Statistical Analysis Plan - Mar 30, 2018

More Information

Additional Information:

• Protocol
• Statistical Analysis Plan (SAP)

Publications

None provided.

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT03371459
• Other Study ID Numbers: D6930C00002
• First Posted: Dec 13, 2017
• Last Update Posted: Jul 23, 2019
• Last Verified: Jun 1, 2019

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes
• Additional relevant MeSH terms: Asthma; Albuterol

Study Results

Participant Flow

Pre-assignment Detail	Subjects who met all screening and randomization requirements were eligible for rand to Tx Period, comprised of Visits 2 and 3 . Eligible subj were rand via IWRS to receive 2 cumulative-dose Tx's in one of 2 possible Tx sequences: AS MDI, given as 1+1+2+4+8 actuations of AS MDI 90 μg, Proventil, given as 1+1+2+4+8 actuations of Proventil 90 μg

Arm/Group Title	Treatment Sequence A	Treatment Sequence B
Arm/Group Description	AS MDI 90 ug then Proventil 90 ug	Proventil 90 ug then AS MDI 90 ug
Period Title: Period 1
STARTED	23	23
COMPLETED	23	23
NOT COMPLETED	0	0
Period Title: Period 1
STARTED	23	23
COMPLETED	23	22
NOT COMPLETED	0	1
Period Title: Period 1
STARTED	23	22
COMPLETED	23	22
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	mITT Population
Arm/Group Description	The mITT Analysis Set is defined as a subset of the ITT Analysis Set including subjects who received treatment and had post-treatment efficacy data from both Treatment Periods. Data judged to be impacted by major protocol deviations are determined prior to database lock in a blinded fashion and excluded per the statistical protocol deviation plan. Statistical tabulations and analyses are by randomized treatment, but data obtained after subjects received an incorrect treatment are excluded from the affected periods
Overall Participants	46
Age (Years) [Least Squares Mean (Standard Deviation) ]
Least Squares Mean (Standard Deviation) [Years]	34.2 (7.4)
Sex: Female, Male (Count of Participants)
Female	22 47.8%
Male	23 50%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	7 15.2%
Not Hispanic or Latino	38 82.6%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	11 23.9%
White	34 73.9%
More than one race	0 0%
Unknown or Not Reported	0 0%

Outcome Measures

1. Primary Outcome

Title	Baseline-adjusted FEV1 30 Minutes After Each Cumulative Dose
Description	Forced expiratory volume in 1 second (FEV1) is the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation
Time Frame	At the two study treatment visits, FEV1 (forced expiratory volume in 1 second) will be measured prior to drug administration and 5 times, once at 30 minutes after each of the 5 doses

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	AS MDI	Proventil
Arm/Group Description	AS MDI 90 μg 1+1+2+4+8 inhalations of 90 μg per inhalation	Proventil 1+1+2+4+8 inhalations of 90 μg per inhalation
Measure Participants	45	45
Dose 1 - 90 μg	0.421	0.488
Cumulative Dose - 180 μg	0.548	0.586
Cumulative Dose - 360 μg	0.619	0.647
Cumulative Dose - 720 μg	0.659	0.690
Cumulative Dose - 1440 μg	0.721	0.805

2. Secondary Outcome

Title	Baseline-adjusted FEV1 AUC0-6 After the Last Cumulative Dose
Description	The baseline-adjusted FEV1 AUC0-6 is the area under the curve for change from baseline calculated using the trapezoidal rule and normalized by dividing the AUC by the length of follow up post the last cumulative dose (typically 6 hours) (spirometry will be obtained at 5, 15, 30, 45, 60, 120, 180, and 240 minutes post-dose) normalized for length of follow up).
Time Frame	Over 6 hours post dose on Day 1

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	AS MDI	Proventil
Arm/Group Description	AS MDI 90 μg 1+1+2+4+8 inhalations of 90 μg per inhalation	Proventil 1+1+2+4+8 inhalations of 90 μg per inhalation
Measure Participants	45	45
Least Squares Mean (95% Confidence Interval) [Liter]	0.561	0.602

Adverse Events

Time Frame	Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug
Adverse Event Reporting Description	Serious Adverse Events were collected from the time the subject signed informed consent until study completion for a maximum of 44 days. This reporting time frame includes the screening period, the two active treatment periods, and the follow up period (i.e. 3-7 days after last dose of study drug).
Arm/Group Title	AS MDI		Proventil
Arm/Group Description	AS MDI 90 μg 1+1+2+4+8 inhalations of 90 μg per inhalation		Proventil 1+1+2+4+8 inhalations of 90 μg per inhalation
All Cause Mortality
	AS MDI		Proventil
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/45 (0%)		0/46 (0%)
Serious Adverse Events
	AS MDI		Proventil
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/45 (0%)		0/46 (0%)
Other (Not Including Serious) Adverse Events
	AS MDI		Proventil
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/45 (17.8%)		10/46 (21.7%)
Gastrointestinal disorders
Vomiting	1/45 (2.2%)	1	0/46 (0%)	0
General disorders
Feeling Jittery	3/45 (6.7%)	3	6/46 (13%)	6
Investigations
Blood Potassium decreased	0/45 (0%)	0	1/46 (2.2%)	1
Nervous system disorders
Tremor	2/45 (4.4%)	2	2/46 (4.3%)	2
Headache	2/45 (4.4%)	2	0/46 (0%)	0
Dizziness	1/45 (2.2%)	1	0/46 (0%)	0
Respiratory, thoracic and mediastinal disorders
Epistaxis	0/45 (0%)	0	1/46 (2.2%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

Drafts of any and all publications or presentations of this study must be submitted at least 30 days prior to submission for publication or presentation to Pearl Therapeutics for review, approval, and to ensure consistency. Pearl Therapeutics has the right to request appropriate modification to correct facts and to represent it's opinions, or the opinions of the publication committee, if these differ with the proposed publication.