Formoterol Dose Ranging Study (ACHIEVE Duaklir USA Phase IIb)

• Sponsor: AstraZeneca (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02796651
• Collaborator: Parexel (Industry)
• Enrollment: 132
• Locations: 20
• Arms: 6
• Actual Duration (Months): 5.3
• Patients Per Site: 6.6
• Patients Per Site Per Month: 1.3

Study Details

Study Description

Brief Summary

To assess the bronchodilation of three doses of formoterol fumarate (6 μg, 12 μg and 24 μg) twice daily (BID) administered via Pressair® compared to placebo and to open-label nebulized formoterol fumarate (20 μg and 40 μg).

Condition or Disease	Intervention/Treatment	Phase
Chronic Obstructive Pulmonary Disease - COPD	Drug: Formoterol fumarate (6 μg); Drug: Formoterol furmarate (20 μg); Drug: Placebo for formoterol fumarate; Drug: Formoterol fumarate (12 μg); Drug: Formoterol fumarate (40 μg)	Phase 2

Detailed Description

This is a prospective, randomized, double-blind, 5-period incomplete unbalanced crossover, placebo and active comparator (open-label) controlled, multicenter clinical trial to assess the efficacy and safety of three doses of formoterol fumarate (6 μg, 12 μg and 24 μg) BID administered via Pressair® compared to placebo and to open-label formoterol fumarate (20 μg BID and 40 μg single dose) administered as an inhalation solution via a standard jet nebulizer (with a mouthpiece) connected to an air compressor (Perforomist® Inhalation Solution). The drug product is an inhalation powder comprising of micronized aclidinium bromide and micronized formoterol fumarate with α-lactose monohydrate as the carrier, presented in a breathactuated device-metered dry-powder inhaler (DPI). It has been approved under the trademarks of Genuair® and/or Pressair® in some territories.

Study Design

• Study Type: Interventional
• Actual Enrollment: 132 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-blind, Placebo-controlled, Incomplete Unbalanced, Crossover Study to Assess the Efficacy and Safety of Three Doses of Formoterol Fumarate in Pressair® Compared With Perforomist® Inhalation Solution (20 and 40 μg Open-label) in Moderate to Severe COPD Patients With Reversible Airway Disease.
• Actual Study Start Date: Jun 30, 2016
• Actual Primary Completion Date: Dec 7, 2016
• Actual Study Completion Date: Dec 7, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Formoterol 6 μg Participants received formoterol fumarate 6 μg administered via Pressair twice daily (BID).	Drug: Formoterol fumarate (6 μg); Oral Inhalation (by Pressair® Dry Powder Inhaler, DPI); Other Names: Formoterol (Pressair®)
Experimental: Formoterol 12 μg Participants received formoterol fumarate 12 μg administered via Pressair BID.	Drug: Formoterol fumarate (12 μg); Oral Inhalation (by Pressair® Dry Powder Inhaler, DPI); Other Names: Formoterol (Pressair®)
Experimental: Formoterol 24 μg Participants received formoterol fumarate 24 μg administered via Pressair BID.	Drug: Formoterol fumarate (12 μg); Oral Inhalation (by Pressair® Dry Powder Inhaler, DPI); Other Names: Formoterol (Pressair®)
Placebo Comparator: Placebo Participants received placebo to formoterol fumarate administered via Pressair BID.	Drug: Placebo for formoterol fumarate; Oral Inhalation (by Pressair® Dry Powder Inhaler, DPI); Other Names: Placebo (Pressair®)
Experimental: Formoterol 20 μg Participants received Perforomist inhalation solution and were instructed to take one puff from each of the two Pressair inhalers or to inhale one vial from the Perforomist 20 μg inhalation solution BID for 7 ± 1 consecutive days.	Drug: Formoterol furmarate (20 μg); Oral Inhalation (via a standard jet nebulizer connected to an air compressor.; Other Names: Perforomist® Inhalation Solution
Experimental: Formoterol 40 μg Participants received Perforomist 40 μg (2 vials of Performist 20 μg) as a single dose of administration.	Drug: Formoterol fumarate (40 μg); Oral Inhalation (via a standard jet nebulizer connected to an air compressor.; Other Names: Perforomist® Inhalation Solution

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in Normalized Forced Expiratory Volume in 1 Second (FEV1) Area Under the Curve (AUC) Over the 12 h Period Immediately After Morning Study Drug Administration, AUC0-12/12h at Day 7 on Treatment [Day 7: 30 min, 1 to 4 hours, 6 hours, 9 hours and 12 hours post-dose]

   To assess the bronchodilation of 3 doses of formoterol fumarate (6 μg, 12 μg and 24 μg) twice daily (BID administered via Pressair® compared to placebo and to open-label nebulised formoterol fumarate(20 μg). Pre-dose spirometry was performed before the morning daily dose at Day 1 and Day 7 of each treatment period. Two sets of measurements were performed during the hour preceding the scheduled morning study drug administration, allowing approximately 30 minutes between them. Note: Perforomist® 40 μg treatment periods lasted for 1 day only. Hence, was not included in the calculation.

Secondary Outcome Measures

1. Change From Baseline in FEV1 AUC0-6/6h at Day 1 on Treatment [Day 1: zero time to 6 hours post-dose]

   To assess the bronchodilation of 3 doses of formoterol fumarate (6 μg, 12 μg and 24 μg) BID administered via Pressair® compared to placebo and to open-label nebulised formoterol fumarate (20 μg and 40 μg). 6-hour serial spirometry was performed at Day 1 of each treatment period: spirometry was performed post-dose at 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours and 6 hours post-dose.

2. Change From Baseline in FEV1 AUC0-6/6h at Day 7 on Treatment [Day 7: zero time to 6 hours post-dose]

   To assess the bronchodilation of 3 doses of formoterol fumarate (6 μg, 12 μg and 24 μg) BID administered via Pressair® compared to placebo and to open-label nebulised formoterol fumarate (20 μg). 6-hour serial spirometry was performed at Day 7 of each treatment period: spirometry was performed post-dose at 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours and 6 hours post-dose Note: Perforomist® 40 μg treatment periods lasted for 1 day only. Hence, was not included in the calculation

3. Change From Baseline in Morning Pre-dose (Trough) FEV1 at Day 7 on Treatment [At baseline and Day 7]

   To assess the bronchodilation of 3 doses of formoterol fumarate (6 μg, 12 μg and 24 μg) BID administered via Pressair® compared to placebo and to open-label nebulised formoterol fumarate (20 μg). Trough value was defined as the mean of the 2 pre-dose measurements on Day 7. If 1 of the 2 measurements was missing, the non-missing measurement was used as the trough value. Note: Perforomist® 40 μg treatment periods lasted for 1 day only. Hence, was not included in the calculation.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 40 Years to 130 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Adult male or non-pregnant, non-lactating female patients aged ≥40.

• Patients with a diagnosis of COPD (GOLD guidelines, 2016) for a period of at least 6 months prior to Visit 1.

• Patients with moderate to severe stable COPD: post-bronchodilator FEV1 ≥ 30% and <80% of the predicted normal and post-bronchodilator FEV1/FVC < 70% at Visit 1.

• Patients with reversible airway obstruction defined as an increase in FEV1 of at least 12% and 200 mL over the baseline value after four inhalations of albuterol sulfate 108 µg via a pMDI at Visit 1.

• Current or former-smokers, with a smoking history of ≥ 10 pack-years.

• Patients able to perform acceptable and repeatable pulmonary function testing for FEV1 according to the American Thoracic Society (ATS)/European Respiratory Society (ERS) 2005 criteria at Visit 1.

• Patients eligible and able to participate in the study and who had signed an Informed Consent Form prior to initiation of any study-related procedures.

Exclusion Criteria:

• Patients with asthma.

• Any respiratory tract infection (including the upper respiratory tract) or COPD exacerbation (including the mild COPD exacerbation) within 6 weeks prior to Visit 1 or during the run-in period.

• Patients hospitalized for a COPD exacerbation (an emergency room visit for longer than 24 hours is considered a hospitalization) within 3 months prior to Visit 1.

• Clinically significant respiratory conditions other than COPD.

• Patients who in the investigator's opinion may need to start a pulmonary rehabilitation program during the study and/or patients who started/finished it within 3 months prior to Visit 1.

• Use of long-term oxygen therapy (≥ 15 hours/day).

• Patients who do not maintain regular day/night, waking/sleeping cycles including night shift workers.

• Clinically significant cardiovascular conditions.

• Patients with uncontrolled Type I or Type II diabetes, uncontrolled hypo-or hyperthyroidism, hypokalaemia, or hyperadrenergic state, uncontrolled hypertension.

• Patients with history of long QT syndrome or whose QTc (calculated according to Fridericia's Formula QTc=QT/RR1/3) > 470 ms as indicated in the centralized reading report assessed at Visit 1.

• Patients with clinically significant abnormalities in the laboratory tests, ECG parameters (other than QTc) or in the physical examination at Visit 1 that might compromise patient safety.

• Patients with a history of hypersensitivity reaction to an inhaled medication or any component thereof, including paradoxical bronchospasm.

• Patients with known narrow-angle glaucoma, symptomatic bladder neck obstruction, acute urinary retention or symptomatic unstable prostate hypertrophy.

• History of malignancy of any organ system (including lung cancer), treated or untreated, within the past 5 years other than basal or squamous cell skin cancer.

• Patients with any other serious or uncontrolled physical or mental dysfunction.

• Patients with a history (within 2 years prior to screening) of drug and/or alcohol abuse that may prevent study compliance based on the Investigator judgment.

• Patients unlikely to be cooperative or who cannot comply with the study procedures.

• Patients treated with any investigational drug within 30 days (or 6 half-lives, whichever is longer) prior to Visit 1.

• Patients who intended to use any concomitant medication not permitted by this protocol or who had not undergone the required washout period for a particular prohibited medication.

• Patients unable to give consent, or patients of consenting age but under guardianship, or vulnerable patients.

• Any other conditions that, in the investigator's opinion, might render the patient to be unsuitable for the study.

• Involvement in the planning and/or conduct of the study (applies to AstraZeneca staff and/or site staff), or patients employed by or relatives of the employees of the site or sponsor.

• Previous randomization in the present study D6571C00002.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Glendale	Arizona	United States	85306
2	Research Site	Phoenix	Arizona	United States	85006
3	Research Site	Tempe	Arizona	United States	85283
4	Research Site	Celebration	Florida	United States	34747
5	Research Site	Clearwater	Florida	United States	33756
6	Research Site	DeLand	Florida	United States	32720
7	Research Site	Orlando	Florida	United States	32825
8	Research Site	Lawrenceville	Georgia	United States	30046
9	Research Site	Saint Louis	Missouri	United States	63141
10	Research Site	Las Vegas	Nevada	United States	89102
11	Research Site	Charlotte	North Carolina	United States	28207
12	Research Site	Gastonia	North Carolina	United States	28054
13	Research Site	Medford	Oregon	United States	97504
14	Research Site	Portland	Oregon	United States	97202
15	Research Site	Easley	South Carolina	United States	29640
16	Research Site	Greenville	South Carolina	United States	29615
17	Research Site	Rock Hill	South Carolina	United States	29372
18	Research Site	Spartanburg	South Carolina	United States	29303
19	Research Site	Boerne	Texas	United States	78006
20	Research Site	Killeen	Texas	United States	76543

Sponsors and Collaborators

• AstraZeneca
• Parexel

Investigators

• Principal Investigator: Mark H. Gotfried, MD, 1112 East McDowell Road, Phoenix, AZ 85006, United States.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT02796651
• Other Study ID Numbers: D6571C00002
• First Posted: Jun 13, 2016
• Last Update Posted: Feb 7, 2018
• Last Verified: Jan 1, 2018

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by AstraZeneca: Perforomist; Pressair; COPD; Cigarette smoking; Formoterol fumarate; long-acting β2-adrenergic agonists (LABA); long-acting muscarinic antagonists (LAMA)
• Additional relevant MeSH terms: Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive; Pharmaceutical Solutions; Formoterol Fumarate

Study Results

Participant Flow

Recruitment Details	This study was carried on 132 participants with moderate to severe chronic obstructive pulmonary disease (COPD) & reversible airway disease in the United States of America (USA; 21 sites) & were randomized to one of treatment sequences (each with 5 periods of different treatment, separated by wash-out period of 7 (+/1) days after treatment period).
Pre-assignment Detail	After signature of the informed consent, participants who were taking prohibited medication performed a wash-out period and were given Atrovent (2 puffs 4 times/day) before Screening and during the run-in period. All participants were provided with rescue drug (albuterol) and Atrovent to be taken during the wash-out between treatment periods.

Arm/Group Title	Total Participants
Arm/Group Description	All patients were randomized in a treatment sequence containing 5 treatment periods. All patients received FF12 and Perforomist 20 mcg, 90% received FF6, FF24 and Perforomist 40 mcg, and only 30% received placebo. Treatment was double blind for FF in Pressair, and open label for Perforomist. If treatment was FF6, FF12, FF24 or placebo, patients received two identical Pressair dry powder inhalers (DPI) and were instructed to take 1 puff from each of the inhalers in the morning and in the evening for 7 days. If treatment was Perforomist 20 mcg, patients were instructed to take 1 vial in the morning and 1 vial in the evening for 7 days. Treatment with Perforomist 40 mcg was a single dose administration. Note: 132 participants were randomized. But, one participant was excluded from the ITT analysis set as the participant did not have a post-baseline forced expiratory volume in 1 second (FEV1) measurement.
Period Title: Overall Study
STARTED	132
Formoterol Fumarate (FF) 6 μg	107
Formoterol Fumarate (FF) 12 μg	121
Formoterol Fumarate (FF) 24 μg	105
Perforomist 20 μg	118
Perforomist 40 μg	108
Placebo (Lactose Monohydrate)	38
COMPLETED	106
NOT COMPLETED	26

Baseline Characteristics

Arm/Group Title	Overall Study Total
Arm/Group Description	All patients were randomized in a treatment sequence containing 5 treatment periods. All patients received FF12 and Perforomist 20 mcg, 90% received FF6, FF24 and Perforomist 40 mcg, and only 30% received placebo. Treatment was double blind for FF in Pressair, and open label for Perforomist. If treatment was FF6, FF12, FF24 or placebo, patients received two identical Pressair DPI and were instructed to take 1 puff from each of the inhalers in the morning and in the evening for 7 days. If treatment was Perforomist 20 mcg, patients were instructed to take 1 vial in the morning and 1 vial in the evening for 7 days. Treatment with Perforomist 40 mcg was a single dose administration. Note: 132 participants were randomized. But, one participant was excluded from the ITT analysis set as the participant did not have a post-baseline forced expiratory volume in 1 second (FEV1) measurement.
Overall Participants	131
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	62.3 (7.5)
Age, Customized (Number) [Number]
<50 years	5 3.8%
≥50 to <65 years	78 59.5%
≥65 years	48 36.6%
Sex: Female, Male (Count of Participants)
Female	66 50.4%
Male	65 49.6%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Normalized Forced Expiratory Volume in 1 Second (FEV1) Area Under the Curve (AUC) Over the 12 h Period Immediately After Morning Study Drug Administration, AUC0-12/12h at Day 7 on Treatment
Description	To assess the bronchodilation of 3 doses of formoterol fumarate (6 μg, 12 μg and 24 μg) twice daily (BID administered via Pressair® compared to placebo and to open-label nebulised formoterol fumarate(20 μg). Pre-dose spirometry was performed before the morning daily dose at Day 1 and Day 7 of each treatment period. Two sets of measurements were performed during the hour preceding the scheduled morning study drug administration, allowing approximately 30 minutes between them. Note: Perforomist® 40 μg treatment periods lasted for 1 day only. Hence, was not included in the calculation.
Time Frame	Day 7: 30 min, 1 to 4 hours, 6 hours, 9 hours and 12 hours post-dose

Outcome Measure Data

Analysis Population Description

The ITT analysis set consisted of all randomized participants who received at least 1 dose of investigational product (IP) and had a baseline FEV1 value and at least 1 post-baseline FEV1 measurement, regardless of a participant's adherence to the randomized treatment.

Arm/Group Title	Formoterol Fumarate 6 μg	Formoterol Fumarate (FF) 12 μg	Formoterol Fumarate (FF) 24 μg	Perforomist 20 μg	Placebo (Lactose Monohydrate)
Arm/Group Description	Randomized participants received 2 puffs of Formoterol Fumarate 6 μg oral inhalation powder using Pressair® dry powder inhaler (DPI) in the morning and evening for 7 (±1) days	Randomized participants received two identical Pressair dry powder inhaler (DPI; FF 12 μg and placebo) and were instructed to take one puff from each of the two Pressair DPI in the morning and in the evening for 7 days	Randomized participants received two identical Pressair dry powder inhaler (DPI; FF 24 μg and placebo) and were instructed to take one puff from each of the two Pressair DPI in the morning and in the evening for 7 days	Randomized participants received 1 vial of Perforomist 20 μg oral nebulization solution via a jet nebulizer in the morning and evening for 7 (±1) days	Randomized participants received two identical Pressair dry powder inhaler (DPI; FF 6/12/24 μg and placebo) and were instructed to take one puff from each of the two Pressair DPI in the morning and in the evening for 7 days
Measure Participants	105	118	104	116	35
Least Squares Mean (95% Confidence Interval) [Litre/Hour]	0.108	0.117	0.161	0.122	0.000

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Formoterol Fumarate 6 μg, Placebo (Lactose Monohydrate)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LSMean difference
	Estimated Value	0.108
	Confidence Interval	(2-Sided) 95%; 0.055 to 0.161
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Formoterol Fumarate (FF) 12 μg, Placebo (Lactose Monohydrate)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LSMean difference
	Estimated Value	0.117
	Confidence Interval	(2-Sided) 95%; 0.064 to 0.171
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Formoterol Fumarate (FF) 24 μg, Placebo (Lactose Monohydrate)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LSMean difference
	Estimated Value	0.162
	Confidence Interval	(2-Sided) 95%; 0.107 to 0.216
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Perforomist 20 μg, Placebo (Lactose Monohydrate)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LSMean difference
	Estimated Value	0.122
	Confidence Interval	(2-Sided) 95%; 0.069 to 0.175
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Formoterol Fumarate 6 μg, Formoterol Fumarate (FF) 12 μg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.556
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LSMean difference
	Estimated Value	0.009
	Confidence Interval	(2-Sided) 95%; -0.021 to 0.039
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Formoterol Fumarate 6 μg, Formoterol Fumarate (FF) 24 μg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LSMean difference
	Estimated Value	0.053
	Confidence Interval	(2-Sided) 95%; 0.021 to 0.085
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Formoterol Fumarate 6 μg, Perforomist 20 μg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.365
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LSMean difference
	Estimated Value	0.014
	Confidence Interval	(2-Sided) 95%; -0.016 to 0.044
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Formoterol Fumarate (FF) 12 μg, Formoterol Fumarate (FF) 24 μg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.006
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LSMean difference
	Estimated Value	0.044
	Confidence Interval	(2-Sided) 95%; 0.013 to 0.076
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Formoterol Fumarate (FF) 12 μg, Perforomist 20 μg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.756
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LSMean difference
	Estimated Value	0.005
	Confidence Interval	(2-Sided) 95%; -0.026 to 0.036
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Formoterol Fumarate (FF) 24 μg, Perforomist 20 μg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.014
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LSMean difference
	Estimated Value	-0.039
	Confidence Interval	(2-Sided) 95%; -0.071 to -0.008
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Change From Baseline in FEV1 AUC0-6/6h at Day 1 on Treatment
Description	To assess the bronchodilation of 3 doses of formoterol fumarate (6 μg, 12 μg and 24 μg) BID administered via Pressair® compared to placebo and to open-label nebulised formoterol fumarate (20 μg and 40 μg). 6-hour serial spirometry was performed at Day 1 of each treatment period: spirometry was performed post-dose at 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours and 6 hours post-dose.
Time Frame	Day 1: zero time to 6 hours post-dose

Outcome Measure Data

Analysis Population Description

The ITT analysis set consisted of all randomized participants who received at least 1 dose of investigational product (IP) and had a baseline FEV1 value and at least 1 post-baseline FEV1 measurement, regardless of a participant's adherence to the randomized treatment.

Arm/Group Title	Formoterol Fumarate 6 μg	Formoterol Fumarate (FF) 12 μg	Formoterol Fumarate (FF) 24 μg	Perforomist 20 μg	Perforomist 40 μg	Placebo (Lactose Monohydrate)
Arm/Group Description	Randomized participants received 2 puffs of Formoterol Fumarate 6 μg oral inhalation powder using Pressair® dry powder inhaler (DPI) in the morning and evening for 7 (±1) days	Randomized participants received two identical Pressair dry powder inhaler (DPI; FF 12 μg and placebo) and were instructed to take one puff from each of the two Pressair DPI in the morning and in the evening for 7 days	Randomized participants received two identical Pressair dry powder inhaler (DPI; FF 24 μg and placebo) and were instructed to take one puff from each of the two Pressair DPI in the morning and in the evening for 7 days	Randomized participants received 1 vial of Perforomist 20 μg oral nebulization solution via a jet nebulizer in the morning and evening for 7 (±1) days	Randomized participants received single dose of 2 vials of Perforomist 20 μg oral nebulization solution via a jet nebulizer in the morning of Day 1 of assigned treatment period.	Randomized participants received two identical Pressair dry powder inhaler (DPI; FF 6/12/24 μg and placebo) and were instructed to take one puff from each of the two Pressair DPI in the morning and in the evening for 7 days
Measure Participants	106	121	104	118	108	38
Least Squares Mean (95% Confidence Interval) [Litre/Hour]	0.111	0.148	0.205	0.195	0.246	-0.019

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Formoterol Fumarate 6 μg, Placebo (Lactose Monohydrate)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LSMean difference
	Estimated Value	0.130
	Confidence Interval	(2-Sided) 95%; 0.091 to 0.169
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Formoterol Fumarate (FF) 12 μg, Placebo (Lactose Monohydrate)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LSMean difference
	Estimated Value	0.167
	Confidence Interval	(2-Sided) 95%; 0.128 to 0.206
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Formoterol Fumarate (FF) 24 μg, Placebo (Lactose Monohydrate)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LSMean difference
	Estimated Value	0.224
	Confidence Interval	(2-Sided) 95%; 0.184 to 0.263
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Perforomist 20 μg, Placebo (Lactose Monohydrate)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LSMean difference
	Estimated Value	0.214
	Confidence Interval	(2-Sided) 95%; 0.176 to 0.253
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo (Lactose Monohydrate), Placebo (Lactose Monohydrate)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LSMean difference
	Estimated Value	0.265
	Confidence Interval	(2-Sided) 95%; 0.226 to 0.304
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Formoterol Fumarate 6 μg, Formoterol Fumarate (FF) 12 μg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.004
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LSMean difference
	Estimated Value	0.037
	Confidence Interval	(2-Sided) 95%; 0.012 to 0.062
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Formoterol Fumarate 6 μg, Formoterol Fumarate (FF) 24 μg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LSMean difference
	Estimated Value	0.094
	Confidence Interval	(2-Sided) 95%; 0.068 to 0.119
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Formoterol Fumarate 6 μg, Perforomist 20 μg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LSMean difference
	Estimated Value	0.084
	Confidence Interval	(2-Sided) 95%; 0.059 to 0.110
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Formoterol Fumarate 6 μg, Placebo (Lactose Monohydrate)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LSMean difference
	Estimated Value	0.135
	Confidence Interval	(2-Sided) 95%; 0.109 to 0.161
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Formoterol Fumarate (FF) 12 μg, Formoterol Fumarate (FF) 24 μg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LSMean difference
	Estimated Value	0.057
	Confidence Interval	(2-Sided) 95%; 0.031 to 0.082
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Formoterol Fumarate (FF) 12 μg, Perforomist 20 μg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LSMean difference
	Estimated Value	0.047
	Confidence Interval	(2-Sided) 95%; 0.023 to 0.071
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Formoterol Fumarate (FF) 12 μg, Placebo (Lactose Monohydrate)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LSMean difference
	Estimated Value	0.098
	Confidence Interval	(2-Sided) 95%; 0.073 to 0.123
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 13

Statistical Analysis Overview	Comparison Group Selection	Formoterol Fumarate (FF) 24 μg, Perforomist 20 μg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.469
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LSMean difference
	Estimated Value	-0.009
	Confidence Interval	(2-Sided) 95%; -0.035 to 0.016
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 14

Statistical Analysis Overview	Comparison Group Selection	Formoterol Fumarate (FF) 24 μg, Placebo (Lactose Monohydrate)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.002
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LSMean difference
	Estimated Value	0.041
	Confidence Interval	(2-Sided) 95%; 0.015 to 0.068
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 15

Statistical Analysis Overview	Comparison Group Selection	Perforomist 20 μg, Placebo (Lactose Monohydrate)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LSMean difference
	Estimated Value	0.051
	Confidence Interval	(2-Sided) 95%; 0.025 to 0.076
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Change From Baseline in FEV1 AUC0-6/6h at Day 7 on Treatment
Description	To assess the bronchodilation of 3 doses of formoterol fumarate (6 μg, 12 μg and 24 μg) BID administered via Pressair® compared to placebo and to open-label nebulised formoterol fumarate (20 μg). 6-hour serial spirometry was performed at Day 7 of each treatment period: spirometry was performed post-dose at 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours and 6 hours post-dose Note: Perforomist® 40 μg treatment periods lasted for 1 day only. Hence, was not included in the calculation
Time Frame	Day 7: zero time to 6 hours post-dose

Outcome Measure Data

Analysis Population Description

The ITT analysis set consisted of all randomized participants who received at least 1 dose of investigational product (IP) and had a baseline FEV1 value and at least 1 post-baseline FEV1 measurement, regardless of a participant's adherence to the randomized treatment.

Arm/Group Title	Formoterol Fumarate 6 μg	Formoterol Fumarate (FF) 12 μg	Formoterol Fumarate (FF) 24 μg	Perforomist 20 μg	Placebo (Lactose Monohydrate)
Arm/Group Description	Randomized participants received 2 puffs of Formoterol Fumarate 6 μg oral inhalation powder using Pressair® dry powder inhaler (DPI) in the morning and evening for 7 (±1) days	Randomized participants received two identical Pressair dry powder inhaler (DPI; FF 12 μg and placebo) and were instructed to take one puff from each of the two Pressair DPI in the morning and in the evening for 7 days	Randomized participants received two identical Pressair dry powder inhaler (DPI; FF 24 μg and placebo) and were instructed to take one puff from each of the two Pressair DPI in the morning and in the evening for 7 days	Randomized participants received 1 vial of Perforomist 20 μg oral nebulization solution via a jet nebulizer in the morning and evening for 7 (±1) days	Randomized participants received two identical Pressair dry powder inhaler (DPI; FF 6/12/24 μg and placebo) and were instructed to take one puff from each of the two Pressair DPI in the morning and in the evening for 7 days
Measure Participants	105	119	104	117	36
Least Squares Mean (95% Confidence Interval) [Litre/Hour]	0.166	0.177	0.225	0.186	0.007

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Formoterol Fumarate 6 μg, Placebo (Lactose Monohydrate)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LSMean difference
	Estimated Value	0.159
	Confidence Interval	(2-Sided) 95%; 0.105 to 0.213
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Formoterol Fumarate (FF) 12 μg, Placebo (Lactose Monohydrate)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LSMean difference
	Estimated Value	0.170
	Confidence Interval	(2-Sided) 95%; 0.116 to 0.224
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Formoterol Fumarate (FF) 24 μg, Placebo (Lactose Monohydrate)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LSMean difference
	Estimated Value	0.219
	Confidence Interval	(2-Sided) 95%; 0.163 to 0.274
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Perforomist 20 μg, Placebo (Lactose Monohydrate)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LSMean difference
	Estimated Value	0.179
	Confidence Interval	(2-Sided) 95%; 0.125 to 0.233
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Formoterol Fumarate 6 μg, Formoterol Fumarate (FF) 12 μg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.488
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LSMean difference
	Estimated Value	0.011
	Confidence Interval	(2-Sided) 95%; -0.020 to 0.042
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Formoterol Fumarate 6 μg, Formoterol Fumarate (FF) 24 μg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LSMean difference
	Estimated Value	0.060
	Confidence Interval	(2-Sided) 95%; 0.027 to 0.092
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Formoterol Fumarate 6 μg, Perforomist 20 μg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.206
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LSMean difference
	Estimated Value	0.020
	Confidence Interval	(2-Sided) 95%; -0.011 to 0.051
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Formoterol Fumarate (FF) 12 μg, Formoterol Fumarate (FF) 24 μg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.004
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LSMean difference
	Estimated Value	0.049
	Confidence Interval	(2-Sided) 95%; 0.016 to 0.081
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Formoterol Fumarate (FF) 12 μg, Perforomist 20 μg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.567
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LSMean difference
	Estimated Value	0.009
	Confidence Interval	(2-Sided) 95%; -0.022 to 0.041
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Formoterol Fumarate (FF) 24 μg, Perforomist 20 μg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.017
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LSMean difference
	Estimated Value	-0.039
	Confidence Interval	(2-Sided) 95%; -0.072 to -0.007
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Change From Baseline in Morning Pre-dose (Trough) FEV1 at Day 7 on Treatment
Description	To assess the bronchodilation of 3 doses of formoterol fumarate (6 μg, 12 μg and 24 μg) BID administered via Pressair® compared to placebo and to open-label nebulised formoterol fumarate (20 μg). Trough value was defined as the mean of the 2 pre-dose measurements on Day 7. If 1 of the 2 measurements was missing, the non-missing measurement was used as the trough value. Note: Perforomist® 40 μg treatment periods lasted for 1 day only. Hence, was not included in the calculation.
Time Frame	At baseline and Day 7

Outcome Measure Data

Analysis Population Description

The ITT analysis set consisted of all randomized participants who received at least 1 dose of investigational product (IP) and had a baseline FEV1 value and at least 1 post-baseline FEV1 measurement, regardless of a participant's adherence to the randomized treatment.

Arm/Group Title	Formoterol Fumarate 6 μg	Formoterol Fumarate (FF) 12 μg	Formoterol Fumarate (FF) 24 μg	Perforomist 20 μg	Placebo (Lactose Monohydrate)
Arm/Group Description	Randomized participants received 2 puffs of Formoterol Fumarate 6 μg oral inhalation powder using Pressair® dry powder inhaler (DPI) in the morning and evening for 7 (±1) days	Randomized participants received two identical Pressair dry powder inhaler (DPI; FF 12 μg and placebo) and were instructed to take one puff from each of the two Pressair DPI in the morning and in the evening for 7 days	Randomized participants received two identical Pressair dry powder inhaler (DPI; FF 24 μg and placebo) and were instructed to take one puff from each of the two Pressair DPI in the morning and in the evening for 7 days	Randomized participants received 1 vial of Perforomist 20 μg oral nebulization solution via a jet nebulizer in the morning and evening for 7 (±1) days	Randomized participants received two identical Pressair dry powder inhaler (DPI; FF 6/12/24 μg and placebo) and were instructed to take one puff from each of the two Pressair DPI in the morning and in the evening for 7 days
Measure Participants	105	119	104	117	36
Least Squares Mean (95% Confidence Interval) [Litre]	0.077	0.067	0.102	0.061	0.002

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Formoterol Fumarate 6 μg, Placebo (Lactose Monohydrate)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.027
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LSMean difference
	Estimated Value	0.075
	Confidence Interval	(2-Sided) 95%; 0.008 to 0.141
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Formoterol Fumarate (FF) 12 μg, Placebo (Lactose Monohydrate)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.054
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LSMean difference
	Estimated Value	0.065
	Confidence Interval	(2-Sided) 95%; -0.001 to 0.131
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Formoterol Fumarate (FF) 24 μg, Placebo (Lactose Monohydrate)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.004
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LSMean difference
	Estimated Value	0.100
	Confidence Interval	(2-Sided) 95%; 0.032 to 0.168
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Perforomist 20 μg, Placebo (Lactose Monohydrate)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.075
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LSMean difference
	Estimated Value	0.059
	Confidence Interval	(2-Sided) 95%; -0.006 to 0.123
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Formoterol Fumarate 6 μg, Formoterol Fumarate (FF) 12 μg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.615
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LSMean difference
	Estimated Value	-0.010
	Confidence Interval	(2-Sided) 95%; -0.048 to 0.028
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Formoterol Fumarate 6 μg, Formoterol Fumarate (FF) 24 μg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.209
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LSMean difference
	Estimated Value	0.025
	Confidence Interval	(2-Sided) 95%; -0.014 to 0.065
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Formoterol Fumarate 6 μg, Perforomist 20 μg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.403
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LSMean difference
	Estimated Value	-0.016
	Confidence Interval	(2-Sided) 95%; -0.053 to 0.022
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Formoterol Fumarate (FF) 12 μg, Formoterol Fumarate (FF) 24 μg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.074
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LSMean difference
	Estimated Value	0.035
	Confidence Interval	(2-Sided) 95%; -0.003 to 0.074
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Formoterol Fumarate (FF) 12 μg, Perforomist 20 μg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.750
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LSMean difference
	Estimated Value	-0.006
	Confidence Interval	(2-Sided) 95%; -0.045 to 0.032
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Formoterol Fumarate (FF) 24 μg, Perforomist 20 μg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.035
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LSMean difference
	Estimated Value	-0.041
	Confidence Interval	(2-Sided) 95%; -0.080 to -0.003
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	From the time of signature of informed consent throughout the treatment period and including the follow-up period (i.e. 2 weeks after the last IP).
Adverse Event Reporting Description	Adverse event: The development of an undesirable medical condition or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product. An undesirable medical condition can be symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver) or the abnormal results of an investigation (e.g., laboratory findings, electrocardiogram)
Arm/Group Title	Formoterol Fumarate 6 μg		Formoterol Fumarate (FF) 12 μg		Formoterol Fumarate (FF) 24 μg		Perforomist 20 μg		Perforomist 40 μg		Placebo (Lactose Monohydrate)
Arm/Group Description	Randomized participants received 2 puffs of Formoterol Fumarate 6 μg oral inhalation powder using Pressair® dry powder inhaler (DPI) in the morning and evening for 7 (±1) days		Randomized participants received two identical Pressair dry powder inhaler (DPI; FF 12 μg and placebo) and were instructed to take one puff from each of the two Pressair DPI in the morning and in the evening for 7 days		Randomized participants received two identical Pressair dry powder inhaler (DPI; FF 24 μg and placebo) and were instructed to take one puff from each of the two Pressair DPI in the morning and in the evening for 7 days		Randomized participants received 1 vial of Perforomist 20 μg oral nebulization solution via a jet nebulizer in the morning and evening for 7 (±1) days		Randomized participants received single dose of 2 vials of Perforomist 20 μg oral nebulization solution via a jet nebulizer in the morning of Day 1 of assigned treatment period.		Randomized participants received two identical Pressair dry powder inhaler (DPI; FF 6/12/24 μg and placebo) and were instructed to take one puff from each of the two Pressair DPI in the morning and in the evening for 7 days
All Cause Mortality
	Formoterol Fumarate 6 μg		Formoterol Fumarate (FF) 12 μg		Formoterol Fumarate (FF) 24 μg		Perforomist 20 μg		Perforomist 40 μg		Placebo (Lactose Monohydrate)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/107 (0%)		1/121 (0.8%)		0/105 (0%)		0/118 (0%)		0/109 (0%)		0/38 (0%)
Serious Adverse Events
	Formoterol Fumarate 6 μg		Formoterol Fumarate (FF) 12 μg		Formoterol Fumarate (FF) 24 μg		Perforomist 20 μg		Perforomist 40 μg		Placebo (Lactose Monohydrate)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/107 (0.9%)		2/121 (1.7%)		0/105 (0%)		0/118 (0%)		1/109 (0.9%)		1/38 (2.6%)
Cardiac disorders
Myocardial infarction	0/107 (0%)		1/121 (0.8%)		0/105 (0%)		0/118 (0%)		0/109 (0%)		0/38 (0%)
General disorders
Vascular stent occlusion	0/107 (0%)		1/121 (0.8%)		0/105 (0%)		0/118 (0%)		0/109 (0%)		0/38 (0%)
Injury, poisoning and procedural complications
Multiple injuries	1/107 (0.9%)		0/121 (0%)		0/105 (0%)		0/118 (0%)		0/109 (0%)		0/38 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Squamous cell carcinoma of lung	0/107 (0%)		0/121 (0%)		0/105 (0%)		0/118 (0%)		1/109 (0.9%)		0/38 (0%)
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	0/107 (0%)		0/121 (0%)		0/105 (0%)		0/118 (0%)		0/109 (0%)		1/38 (2.6%)
Other (Not Including Serious) Adverse Events
	Formoterol Fumarate 6 μg		Formoterol Fumarate (FF) 12 μg		Formoterol Fumarate (FF) 24 μg		Perforomist 20 μg		Perforomist 40 μg		Placebo (Lactose Monohydrate)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/107 (2.8%)		4/121 (3.3%)		1/105 (1%)		7/118 (5.9%)		0/109 (0%)		3/38 (7.9%)
Infections and infestations
Upper respiratory tract infection	1/107 (0.9%)		0/121 (0%)		0/105 (0%)		2/118 (1.7%)		0/109 (0%)		0/38 (0%)
Urinary tract infection	2/107 (1.9%)		1/121 (0.8%)		0/105 (0%)		1/118 (0.8%)		0/109 (0%)		0/38 (0%)
Musculoskeletal and connective tissue disorders
Muscle spasms	0/107 (0%)		0/121 (0%)		0/105 (0%)		2/118 (1.7%)		0/109 (0%)		0/38 (0%)
Nervous system disorders
Headache	0/107 (0%)		3/121 (2.5%)		1/105 (1%)		2/118 (1.7%)		0/109 (0%)		0/38 (0%)
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	0/107 (0%)		0/121 (0%)		0/105 (0%)		0/118 (0%)		0/109 (0%)		3/38 (7.9%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

All clinical study findings and documents will be regarded as confidential. The investigator and members of his/her research team must not disclose such information without prior written approval from the sponsor.