Efficacy and Safety Study to Compare Formoterol Fumerate in the Pressair DPI to the Foradil Aerolizer in Patient with Mild to Moderate Asthma

Study identifier:LAC-MD-21

ClinicalTrials.gov identifier:NCT01641081

EudraCT identifier:N/A

CTIS identifier:N/A

Study Complete

Official Title

Phase II, Randomized, Placebo-controlled, Double-blind, Double-dummy, 5-period Complete Crossover study of the Bronchodilator Effects of Formoterol Fumarate Inhalation Powder in Patients with Mild to Moderate Asthma.

Medical condition

asthma

Phase

Phase 2

Healthy volunteers

Study drug

Formoterol Fumarate in the Pressair DPI, Low Dose, Formoterol Fumarate in the Pressair DPI, High Dose, Foradil Aerolizer, Low Dose, Foradil Aerolizer, High Dose, Placebo

Sex

All

Actual Enrollment

174

Study type

Interventional

Age

18 Years +

Date

Study Start Date: 01 Jun 2012

Primary Completion Date: 01 Feb 2013

Study Completion Date: 01 Feb 2013

Study design

Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Crossover Assignment
Masking: Double Blind
Primary Purpose: Treatment

Verification:

Verified 01 Jan 2017 by AstraZeneca Pharmaceuticals

Collaborators

Inclusion and exclusion criteria

Location

Forest Investigative Site 909

Phoenix, AZ, United States, 85006

Location

Forest Investigative Site 1134

Canton, OH, United States, 44718

Location

Forest Investigative Site 1137

Colorado Springs, CO, United States, 80907

Location

Forest Investigative Site 1153

Raleigh, NC, United States, 27607

Location

Forest Investigative Site 1155

Dallas, TX, United States, 75231

Location

Forest Investigative Site 1176

Oklahoma City, OK, United States, 73120

Location

Forest Investigative Site 1332

El Paso, TX, United States, 79903

Location

Forest Investigative Site 1333

Baltimore, MD, United States, 21236

Arms	Assigned Interventions
Experimental: Experimental 1 Formoterol Fumarate in the Pressair Pressair Dry Powder Inhaler (DPI), Low Dose	Drug: Formoterol Fumarate in the Pressair DPI, Low Dose Formoterol Fumarate in the Pressair DPI 6 micrograms, twice a day for 14 days
Experimental: Experimental 2 Formoterol fumarate in the Pressair Dry Powder Inhaler (DPI), High Dose	Drug: Formoterol Fumarate in the Pressair DPI, High Dose Formoterol Fumarate in the Pressair DPI 12 micrograms, twice a day for 14 days
Active Comparator: Active Comparator 1 Foradil Aerolizer, Low Dose	Drug: Foradil Aerolizer, Low Dose Foradil Aerolizer 12 micrograms, twice a day for 14 days Other Name: Formoterol
Active Comparator: Active Comparator 2 Foradil Aerolizer, High Dose	Drug: Foradil Aerolizer, High Dose Foradil Aerolizer 24 micrograms, twice per day for 14 days Other Name: Formoterol
Placebo Comparator: Placebo Dose matched placebo	Drug: Placebo Placebo in the Pressair for 14 days

Participant Flow

Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
The study was conducted in 29 study centers in the United States First patient visit was in June 2012 and last patient visit was in February 2013

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
A total of 408 patients were screened; there were 234 screen failures, primarily (225/234) because inclusion/exclusion criteria were not met

Reporting Groups

	Description
Sequence 1	24 μg Foradil Aerolizer; 12 μg Foradil Aerolizer; Placebo Pressair; Formoterol 12 μg Pressair; Formoterol 6 μg Pressair
Sequence 2	12 μg Foradil Aerolizer; Formoterol 12 μg Pressair; 24 μg Foradil Aerolizer; Formoterol 6 μg Pressair; Placebo Pressair
Sequence 3	Formoterol 12 μg Pressair; Formoterol 6 μg Pressair; 12 μg Foradil Aerolizer; Placebo Pressair; 24 μg Foradil Aerolizer
Sequence 4	Formoterol 6 μg Pressair; Placebo Pressair; Formoterol 12 μg Pressair; 24 μg Foradil Aerolizer; 12 μg Foradil Aerolizer
Sequence 5	Placebo Pressair; 24 μg Foradil Aerolizer; Formoterol 6 μg Pressair; 12 μg Foradil Aerolizer; Formoterol 12 μg Pressair
Sequence 6	Formoterol 6 μg Pressair; Formoterol 12 μg Pressair; Placebo Pressair; 12 μg Foradil Aerolizer; 24 μg Foradil Aerolizer
Sequence 7	Placebo Pressair; Formoterol 6 μg Pressair; 24 μg Foradil Aerolizer; Formoterol 12 μg Pressair; 12 μg Foradil Aerolizer
Sequence 8	24 μg Foradil Aerolizer; Placebo Pressair; 12 μg Foradil Aerolizer; Formoterol 6 μg Pressair; Formoterol 12 μg Pressair
Sequence 9	12 μg Foradil Aerolizer; 24 μg Foradil Aerolizer; Formoterol 12 μg Pressair; Placebo Pressair; Formoterol 6 μg Pressair
Sequence 10	Formoterol 12 μg Pressair; 12 μg Foradil Aerolizer; Formoterol 6 μg Pressair; 24 μg Foradil Aerolizer; Placebo Pressair

Participant Flow for 5 periods

Period 1: Period 1

	Sequence 1	Sequence 2	Sequence 3	Sequence 4	Sequence 5	Sequence 6	Sequence 7	Sequence 8	Sequence 9	Sequence 10
STARTED	18	18	15	22	17	19	19	17	15	14
COMPLETED	17	18	15	22	16	19	18	14	15	14
NOT COMPLETED	1	0	0	0	1	0	1	3	0	0
Sponsor request (potential unblinding)	0	0	0	0	0	0	1	0	0	0
Protocol Violation	0	0	0	0	1	0	0	1	0	0
Adverse Event	1	0	0	0	0	0	0	2	0	0

Period 2: Period 2

	Sequence 1	Sequence 2	Sequence 3	Sequence 4	Sequence 5	Sequence 6	Sequence 7	Sequence 8	Sequence 9	Sequence 10
STARTED	17	18	15	22	16	19	18	14	15	14
COMPLETED	16	18	15	21	16	18	16	14	15	14
NOT COMPLETED	1	0	0	1	0	1	2	0	0	0
Adverse Event	0	0	0	0	0	1	0	0	0	0
Withdrawal by Subject	0	0	0	1	0	0	2	0	0	0
Protocol Violation	1	0	0	0	0	0	0	0	0	0

Period 3: Period 3

	Sequence 1	Sequence 2	Sequence 3	Sequence 4	Sequence 5	Sequence 6	Sequence 7	Sequence 8	Sequence 9	Sequence 10
STARTED	16	18	15	21	16	18	16	14	15	14
COMPLETED	16	18	14	21	16	18	16	14	14	14
NOT COMPLETED	0	0	1	0	0	0	0	0	1	0
Adverse Event	0	0	1	0	0	0	0	0	0	0
Withdrawal by Subject	0	0	0	0	0	0	0	0	1	0

Period 4: Period 4

	Sequence 1	Sequence 2	Sequence 3	Sequence 4	Sequence 5	Sequence 6	Sequence 7	Sequence 8	Sequence 9	Sequence 10
STARTED	16	18	14	21	16	18	16	14	14	14
COMPLETED	16	17	14	20	16	18	16	14	14	14
NOT COMPLETED	0	1	0	1	0	0	0	0	0	0
Adverse Event	0	1	0	1	0	0	0	0	0	0

Period 5: Period 5

	Sequence 1	Sequence 2	Sequence 3	Sequence 4	Sequence 5	Sequence 6	Sequence 7	Sequence 8	Sequence 9	Sequence 10
STARTED	16	17	14	20	16	18	16	14	14	14
COMPLETED	16	17	12	20	16	18	16	14	14	14
NOT COMPLETED	0	0	2	0	0	0	0	0	0	0
Adverse Event	0	0	2	0	0	0	0	0	0	0

Baseline Characteristics

Analysis Population Description -- Explanation of how the number of participants for analysis was determined.

Reporting Groups

	Description
Overall study population	All patients participating in the crossover study

Baseline Measures

	Overall study population
Number of Participants [units: Participants]	174
Age Continuous [units: Years] Mean ± Standard Deviation	45.4 ± 13.2
Gender, Male/Female [units: Participants]
Female	91
Male	83

Outcome Measures

1. Primary Outcome Measure: Change from baseline in normalized forced expiratory volume in one second (FEV1) AUC0-6 after the morning dose (Day 14) [ Time Frame: Baseline and up to 6 hrs post-dose (±15 min) on Day 14 of treatment ]

Measure Type	Primary
Measure Name	Change from baseline in normalized forced expiratory volume in one second (FEV1) AUC0-6 after the morning dose (Day 14)
Measure Description	AUC0-6 is area under the curve from time 0 to 6 hours Serial spirometry was performed at -60 min predose, at 5 (+5) and 30 (±5) min post-dose, and at 1, 2, 3, 4, and 6 hrs post-dose (±15 min) Change from baseline was baseline of each treatment period The normalized FEV1 AUC0-6 was calculated by means of the trapezoidal method, dividing the area under the curve by the corresponding time intervals
Time Frame	Baseline and up to 6 hrs post-dose (±15 min) on Day 14 of treatment
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Intent to treat (ITT) Population defined as all patients in the Safety Population who had a baseline and at least 1 post-baseline FEV1 assessment

Reporting Groups

	Description
Foradil 24 μg	Administered via Aerolizer
Foradil 12 μg	Administered via Aerolizer
Formoterol 12 μg	Administered via Pressair
Formoterol 6 μg	Administered via Pressair
Placebo	Administered via Pressair

Measured Values

	Foradil 24 μg	Foradil 12 μg	Formoterol 12 μg	Formoterol 6 μg	Placebo
Number of Participants Analyzed [units:participants]	155	151	155	159	154
Change from baseline in normalized forced expiratory volume in one second (FEV1) AUC0-6 after the morning dose (Day 14) [units: Liters] Least Squares Mean (Standard Error)	0.3196 (0.0382)	0.3076 (0.0382)	0.2795 (0.0382)	0.2726 (0.0381)	0.0552 (0.0382)

Statistical Analysis 1 for Change from baseline in normalized forced expiratory volume in one second (FEV1) AUC0-6 after the morning dose (Day 14)

Groups^[1]	Foradil 24 μg, Placebo
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	Mixed Models Analysis
P-Value^[4]	<0.0001
Other^[5]	0.2644
Standard Error of the mean	± 0.0148
95% Confidence Interval	( 0.2353 to 0.2934 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Treatment and period as fixed effects, and baseline FEV1 values at each period as a covariate
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 2 for Change from baseline in normalized forced expiratory volume in one second (FEV1) AUC0-6 after the morning dose (Day 14)

Groups^[1]	Foradil 12 μg, Placebo
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	Mixed Models Analysis
P-Value^[4]	<0.0001
Other^[5]	0.2524
Standard Error of the mean	± 0.0156
95% Confidence Interval	( 0.2218 to 0.2830 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Treatment and period as fixed effects, and baseline FEV1 values at each period as a covariate
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 3 for Change from baseline in normalized forced expiratory volume in one second (FEV1) AUC0-6 after the morning dose (Day 14)

Groups^[1]	Formoterol 12 μg, Placebo
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	Mixed Models Analysis
P-Value^[4]	<0.0001
Other^[5]	0.2242
Standard Error of the mean	± 0.0153
95% Confidence Interval	( 0.1941 to 0.2544 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Treatment and period as fixed effects, and baseline FEV1 values at each period as a covariate
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 4 for Change from baseline in normalized forced expiratory volume in one second (FEV1) AUC0-6 after the morning dose (Day 14)

Groups^[1]	Formoterol 6 μg, Placebo
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	Mixed Models Analysis
P-Value^[4]	<0.0001
Other^[5]	0.2174
Standard Error of the mean	± 0.0146
95% Confidence Interval	( 0.1887 to 0.2461 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Treatment and period as fixed effects, and baseline FEV1 values at each period as a covariate
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

2. Secondary Outcome Measure: Change from baseline in normalized FEV1 AUC0-6 after the morning dose (Day 1) [ Time Frame: Baseline and up to 6 hrs post-dose (±15 min) on Day 1 of treatment ]

Measure Type	Secondary
Measure Name	Change from baseline in normalized FEV1 AUC0-6 after the morning dose (Day 1)
Measure Description	AUC0-6 is area under the curve from time 0 to 6 hours Serial spirometry was performed at -60 min predose, at 5 (+5) and 30 (±5) min post-dose, and at 1, 2, 3, 4, and 6 hrs post-dose (±15 min) Change from baseline was baseline of Period 1 The time-normalized FEV1 AUC0-6 was calculated by means of the trapezoidal method, dividing the area under the curve by the corresponding time intervals
Time Frame	Baseline and up to 6 hrs post-dose (±15 min) on Day 1 of treatment
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Intent to treat (ITT) Population defined as all patients in the Safety Population who had a baseline and at least 1 post-baseline FEV1 assessment

Reporting Groups

	Description
Foradil 24 μg	Administered via Aerolizer
Foradil 12 μg	Administered via Aerolizer
Formoterol 12 μg	Administered via Pressair
Formoterol 6 μg	Administered via Pressair
Placebo	Administered via Pressair

Measured Values

	Foradil 24 μg	Foradil 12 μg	Formoterol 12 μg	Formoterol 6 μg	Placebo
Number of Participants Analyzed [units:participants]	163	155	159	158	154
Change from baseline in normalized FEV1 AUC0-6 after the morning dose (Day 1) [units: Liters] Least Squares Mean (Standard Error)	0.3544 (0.0196)	0.3068 (0.0198)	0.2712 (0.0197)	0.2204 (0.0197)	0.0306 (0.0198)

No statistical analysis provided for Change from baseline in normalized FEV1 AUC0-6 after the morning dose (Day 1)

Serious Adverse Events

Time Frame	Day 14±1 of the final treatment period (Period 5)
Additional Description	The Safety Population consisted of all patients screened, randomized to a treatment sequence, and who took at least one dose of double-blind investigational product The total number of patients in the Safety Population was 174; due to study drop-out and the crossover study design, not all patients received all treatments

Reporting Groups

	Description
Foradil 24 μg	Administered via Aerolizer
Foradil 12 μg	Administered via Aerolizer
Formoterol 12 μg	Administered via Pressair
Formoterol 6 μg	Administered via Pressair
Placebo	Administered via Pressair

Serious Adverse Events

Foradil 24 μg

Foradil 12 μg

Formoterol 12 μg

Formoterol 6 μg

Placebo

Total, serious adverse events

# participants affected / at risk

0/167 (0.00%)

2/163 (1.23%)

0/164 (0.00%)

0/166 (0.00%)

0/165 (0.00%)

Injury, poisoning and procedural complications

Ankle fracture¹,^†

# participants affected / at risk

0/167 (0.00%)

1/163 (0.61%)

0/164 (0.00%)

0/166 (0.00%)

0/165 (0.00%)

Musculoskeletal and connective tissue disorders

Osteoarthritis¹,^†

# participants affected / at risk

0/167 (0.00%)

1/163 (0.61%)

0/164 (0.00%)

0/166 (0.00%)

0/165 (0.00%)

†	Events were collected by systematic assessment
1	Term from vocabulary, MedDRA v 16.0

Other Adverse Events

Time Frame	Day 14±1 of the final treatment period (Period 5)
Additional Description	The Safety Population consisted of all patients screened, randomized to a treatment sequence, and who took at least one dose of double-blind investigational product The total number of patients in the Safety Population was 174; due to study drop-out and the crossover study design, not all patients received all treatments

Frequency Threshold

Threshold above which other adverse events are reported	5%

Reporting Groups

	Description
Foradil 24 μg	Administered via Aerolizer
Foradil 12 μg	Administered via Aerolizer
Formoterol 12 μg	Administered via Pressair
Formoterol 6 μg	Administered via Pressair
Placebo	Administered via Pressair

Other Adverse Events

Foradil 24 μg

Foradil 12 μg

Formoterol 12 μg

Formoterol 6 μg

Placebo

Total, other (not including serious) adverse events

# participants affected / at risk

10/167 (5.99%)

2/163 (1.23%)

2/164 (1.22%)

1/166 (0.60%)

0/165 (0.00%)

Nervous system disorders

Tremor¹,^†

# participants affected / at risk

10/167 (5.99%)

2/163 (1.23%)

2/164 (1.22%)

1/166 (0.60%)

0/165 (0.00%)

†	Events were collected by systematic assessment
1	Term from vocabulary, MedDRA v 16.0

Certain Agreements

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

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The agreement is:

	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days . The sponsor cannot require changes to the communication and cannot extend the embargo.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description: Publication of the results by the PI will be subject to mutual agreement between the PI and sponsor.

Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
No text entered.

Results Point of Contact

Name/Title:	Study Director
Organization:	AstraZeneca
E-mail:	[email protected]

Documents available

CSR Synopsis
Download
Trial Results Summaries
Available here

Contacts

Contact

AstraZeneca Clinical Study Information Center

1-877-240-9479

information.center@astrazeneca.com

Investigators

Principal Investigator

Esther Garcia

AstraZeneca

Sponsors

Collaborators

Forest Investigative Site 909

Forest Investigative Site 1134

Forest Investigative Site 1137

Forest Investigative Site 1153

Forest Investigative Site 1155

Forest Investigative Site 1176

Forest Investigative Site 1332

Forest Investigative Site 1333

CSR Synopsis

Trial Results Summaries