Effects of Mometasone Furoate/Formoterol Combination Versus Formoterol and Mometasone Furoate Alone in COPD (Study P04229AM4)(COMPLETED)

• Sponsor: Organon and Co (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00383435
• Collaborator: Novartis (Industry)
• Enrollment: 1,055
• Arms: 5
• Duration (Months): 45

Study Details

Study Description

Brief Summary

This is a randomized, placebo-controlled, parallel-group, multi-site, double-blind study evaluating the efficacy of mometasone furoate/formoterol fumarate (MF/F) metered dose inhaler (MDI) 400/10 mcg twice daily (BID) and MF/F MDI 200/10 mcg BID compared with MF 400 mcg BID and F 10 mcg BID in adults at least 40 years of age, with moderate to severe chronic obstructive pulmonary disease (COPD). All placebo-treated subjects and active-treated

subjects who will not participate in the safety extension will be discontinued

and will have their Final Visit at Week 26. Subjects who continue into the

26-week safety extension will have their Final Visit at Week 52. Efficacy will be measured by the mean change from Baseline to Week 13 in area under the forced expiratory volume in one second concentration time curve from 0 to 12 hours (FEV1 AUC[0-12hr]) and change from Baseline to Week 13 in AM predose FEV1.

Condition or Disease	Intervention/Treatment	Phase
Chronic Obstructive Pulmonary Disease (COPD)	Drug: Mometasone furoate/formoterol (MF/F) combination; Drug: Mometasone furoate/formoterol (MF/F) combination; Drug: Mometasone furoate MDI (MF MDI); Drug: Formoterol MDI; Drug: Placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 1055 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Randomized, 26-Week, Placebo-Controlled Efficacy and Safety Study With a 26-Week Long-Term Safety Extension, of High- and Medium-Dose Inhaled Mometasone Furoate/Formoterol Fixed-Dose Combination Formulation Compared With Formoterol and High-Dose Inhaled Mometasone Furoate Monotherapy in Subjects With Moderate to Severe COPD
• Study Start Date: Oct 1, 2006
• Actual Primary Completion Date: Jul 1, 2010
• Actual Study Completion Date: Jul 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: MF/F MDI 400/10 mcg BID	Drug: Mometasone furoate/formoterol (MF/F) combination; MF/F 400/10 mcg via a metered dose inhaler (MDI) twice daily for 52 weeks; Other Names: SCH 418131
Experimental: MF/F MDI 200/10 mcg BID	Drug: Mometasone furoate/formoterol (MF/F) combination; MF/F 200/10 mcg via a metered dose inhaler (MDI) twice daily for 52 weeks; Other Names: SCH 418131
Experimental: MF MDI 400 mcg BID	Drug: Mometasone furoate MDI (MF MDI); MF 400 mcg via metered dose inhaler twice daily for 52 weeks; Other Names: SCH 32088
Active Comparator: Formoterol MDI 10 mcg BID	Drug: Formoterol MDI; Formoterol 10 mcg via metered dose inhaler twice a day for 52 weeks; Other Names: Foradil
Placebo Comparator: Placebo MDI BID	Drug: Placebo; Placebo MDI twice a day for 26 weeks

Outcome Measures

Primary Outcome Measures

1. Mean Area Under the Time Curve From 0 to 12 Hours (AUC(0-12 Hours)) of Change From Baseline to Week 13 in Forced Expiratory Volume (Liters) in 1 Second (FEV1) [Baseline to Endpoint (13 weeks)]

   FEV1 AUC was standardized to liters. Endpoint was the last post-baseline non-missing result through Week 13 carried forward.

2. Mean Change From Baseline to Week 13 Endpoint in AM Predose FEV1 [Baseline to Endpoint (13 weeks)]

   Endpoint was the last post-baseline non-missing result through Week 13 carried forward.

Secondary Outcome Measures

1. Change From Baseline to Endpoint in St George's Respiratory Questionaire (SGRQ) Total Score [Baseline to Endpoint (26 weeks)]

   SGRQ consisted of 76 items aggregated into 3 component scores: symptoms (frequency/severity), activity (cause or limited by breathlessness), impact (social functioning, psychological disturbances from airway disease), & total score. Best health scores have a low numeric value. All component scores & total score range from 0-100, with a higher score indicating greater disease burden. A 4-point increase over placebo (and Baseline) was considered the minimum clinically important difference. Endpoint is the last post-baseline non-missing result through the 26 week evaluation carried forward.

2. Change From Baseline in Proportion of Chronic Obstructive Pulmonary Disease (COPD) Symptom-Free Nights (AM Diary Symptoms) [Baseline to Endpoint (26 weeks)]

   Prior to the use of study drug rescue medication (in the morning upon awakening) the participant evaluated the COPD symptoms of wheezing, cough, and difficulty breathing. A symptom-free night was defined as a combined score of 0 (no symptoms) across all three COPD symptoms evaluated the following morning. Proportion for Baseline included data from the last week before the first dose. Proportion for Endpoint included data across the entire 26-week treatment period.

3. Number of Participants With Partly Stable COPD [Endpoint (26 weeks)]

   Partly stable COPD was a composite measure that included the following COPD outcomes: (1) No oral steroid rescue medication; (2) No AM or PM COPD weekly average symptom score greater than 2 during at least 7 of 8 weeks; (3) No moderate or severe exacerbations; (4) No unscheduled visits due to COPD worsenings; (5) No study discontinuation due to treatment failure or treatment-related adverse event as determined by the investigator.

4. Number of Participants With Mild, Moderate, or Severe COPD Exacerbations [Endpoint (26 weeks)]

   Mild = 12 or more inhalations/day of inhaled rescue medication or 2 or more nebulized treatments/day of inhaled rescue medication. Moderate = treatment with antibiotics or oral steroids. Severe = emergency room treatment or hospitalizations of survival curves. If an event was composed of multiple criteria, the most severe criteria was assigned to the event.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 40 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Moderate to severe COPD based on prebronchodilator FEV1/forced vital capacity (FVC) ratio of <=70%.

• At Screening, postbronchodilator FEV1 must be <=60% predicted normal & >=25% predicted normal.

• COPD symptoms for >=24 months.

• Ex- or current smoker with smoking history >=10 pack years.

• Only albuterol/salbutamol for relief for at least 2 weeks prior to randomization.

• Withdraw from parenteral & oral steroids, anticholinergics, & antibiotics at least 4 weeks prior to Screening.

• No harm in changing current COPD therapy, willing to discontinue his/her anticholinergics, inhaled corticosteroids (ICS) or ICS/long-acting beta agonists (LABA) at Screening, & transferred to albuterol/salbutamol for relief for 2 weeks prior to randomization.

• Lab tests conducted at Screening must be acceptable to investigator. Electrocardiogram (ECG) performed at Screening Visit or within 30 days prior to Screening must be acceptable to investigator. Chest x-ray performed at Screening or within 12 months prior to Screening must be acceptable to investigator.

• Women who have

been surgically sterilized or are at least 1 year postmenopausal are not

considered to be of childbearing potential. A female subject of childbearing

potential must have a negative serum pregnancy test at Screening in order to

be considered eligible for enrollment. Female of childbearing potential must use birth control. Includes: hormonal contraceptives, intra-uterine device (IUD), condom in combination with spermicide, monogamous relationship with male partner who had vasectomy. Started birth control at least 3 months prior to Screening (exception condom), & agree to continue. Female who is not currently sexually active must agree/consent to use a method should she become sexually active. Women surgically sterilized or are at least 1 year postmenopausal are not considered to be of childbearing potential. Female must have negative serum pregnancy test at Screening.

Exclusion Criteria:

• Evidence (upon visual inspection) of oropharyngeal candidiasis at Baseline with or without treatment. If there is evidence at Screening, may be treated as appropriate & visit can be scheduled upon resolution. If there is evidence at Baseline Visit, may be treated as appropriate & visit can be rescheduled upon resolution.

• History of renal, hepatic, cardiovascular, metabolic, neurologic, hematologic, ophthalmological, respiratory, gastrointestinal, cerebrovascular, or other which could interfere with study or require treatment which might interfere with study. Examples include (but are not limited to) hypertension being treated with beta-blockers, active hepatitis, coronary artery disease, arrhythmia, significant QTc prolongation (ie QTcF or QTcB [Fridericia or Bazett corrections, respectively >500 milliseconds (msecs)]), stroke, severe rheumatoid arthritis, chronic open-angle glaucoma or posterior subcapsular cataracts, acquired immune deficiency syndrome (AIDS), or conditions that may interfere with respiratory function such as asthma, bronchiectasis, cystic fibrosis. Others which are well-controlled & stable (eg hypertension not requiring beta-blockers) will not prohibit participation if deemed appropriate per investigator.

• Allergy/sensitivity to glucocorticosteroids, beta-2 agonists, study drug/excipients.

• Female who is breast-feeding, pregnant, or intends to become pregnant.

• Illicit drug user.

• Human immunodeficiency virus (HIV) positive (testing not conducted).

• Unable to correctly use oral MDI.

• Taking any restricted medications prior to Screening without meeting washout.

• Cannot adhere to permitted concomitant & prohibited medications.

• May not participate in this same study at another investigational site. Cannot participate in different investigational study at any site, during same time of study.

• Not be randomized into study more than once.

• No person directly associated with administration of study may participate.

• Previously participated in MF/F trial.

• Increase in absolute volume of >=400 milliliters (mL) at Screening or prior to Baseline within 30 minutes after administration of 4 inhalations of albuterol/salbutamol (total dose of 360 to 400 mcg), or nebulized 2.5 mg albuterol/salbutamol.

• Asthma.

• Blood eosinophil count greater than 0.57 x 10^3/microliter (uL).

• Lobectomy, pneumonectomy or lung volume reduction surgery.

• Lung cancer.

• Requires long-term administration of oxygen (>15 hours per day).

• A subject who experiences an exacerbation of COPD requiring medical

intervention within 4 weeks prior to randomization, beta-blocking agents, or

treatment with additional excluded medication (other than short-acting beta agonists (SABA)/short-acting

anticholinergic to be used as rescue medication).

• alpha-1-antitrypsin deficiency.

• Cataract extractions on both eyes.

• A history and/or presence of intraocular pressure in either eye >=22 millimeters of mercury (mm Hg), glaucoma, and/or posterior subcapsular cataracts. A subject who has undergone incisional or intraocular surgery in which the natural lens is still present in the eye. A subject with a history of penetrating trauma to both eyes. A subject with one or more of the following Lens Opacities Classification System (LOCS) III grades at screening:

nuclear opalescence (NO): >=3.0,

nuclear color (NC): >=3.0,

cortical cataract (C): >=2.0,

posterior subcapsular (P): >=0.5.

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Organon and Co
• Novartis

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Organon and Co
• ClinicalTrials.gov Identifier: NCT00383435
• Other Study ID Numbers: P04229; Doc ID: 3227334;; Eudract No: 2006-002308-32
• First Posted: Oct 3, 2006
• Last Update Posted: Feb 15, 2022
• Last Verified: Feb 1, 2022

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Additional relevant MeSH terms: Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive; Mometasone Furoate; Formoterol Fumarate

Study Results

Participant Flow

Pre-assignment Detail	At Week 26, all participants randomized to placebo were to be discontinued, while 75% of participants randomized to an active treatment were randomly selected to participate in the 26-week Treatment Safety Extension. Several placebo-treated participants continued in error into the Treatment Safety Extension.

Arm/Group Title	MF/F MDI 400/10 mcg BID	MF/F MDI 200/10 mcg BID	MF MDI 400 mcg BID	F MDI 10 mcg BID	Placebo
Arm/Group Description	Mometasone furoate/formoterol fumarate (MF/F) 400/10 mcg via a metered dose inhaler (MDI) twice daily (BID) for 52 weeks	MF/F 200/10 mcg via a MDI BID for 52 weeks	Mometasone furoate (MF) 400 mcg via a MDI BID for 52 weeks	Formoterol fumarate (F) 10 mcg via a MDI BID for 52 weeks	Placebo MDI BID for 26 weeks
Period Title: 26-Week Double-Blind Treatment Period
STARTED	217	207	210	209	212
COMPLETED	176	169	164	172	159
NOT COMPLETED	41	38	46	37	53
Period Title: 26-Week Double-Blind Treatment Period
STARTED	131	130	124	131	13
COMPLETED	117	121	108	116	10
NOT COMPLETED	14	9	16	15	3

Baseline Characteristics

Arm/Group Title	MF/F MDI 400/10 mcg BID	MF/F MDI 200/10 mcg BID	MF MDI 400 mcg BID	F MDI 10 mcg BID	Placebo	Total
Arm/Group Description	Mometasone furoate/formoterol fumarate (MF/F) 400/10 mcg via a metered dose inhaler (MDI) twice daily (BID) for 52 weeks	MF/F 200/10 mcg via a MDI BID for 52 weeks	Mometasone furoate (MF) 400 mcg via a MDI BID for 52 weeks	Formoterol fumarate (F) 10 mcg via a MDI BID for 52 weeks	Placebo MDI BID for 26 weeks	Total of all reporting groups
Overall Participants	217	207	210	209	212	1055
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	59.7 (9.1)	60.9 (8.1)	59.8 (8.9)	59.6 (8.5)	58.8 (8.7)	59.8 (8.7)
Sex: Female, Male (Count of Participants)
Female	46 21.2%	46 22.2%	46 21.9%	57 27.3%	42 19.8%	237 22.5%
Male	171 78.8%	161 77.8%	164 78.1%	152 72.7%	170 80.2%	818 77.5%

Outcome Measures

1. Primary Outcome

Title	Mean Area Under the Time Curve From 0 to 12 Hours (AUC(0-12 Hours)) of Change From Baseline to Week 13 in Forced Expiratory Volume (Liters) in 1 Second (FEV1)
Description	FEV1 AUC was standardized to liters. Endpoint was the last post-baseline non-missing result through Week 13 carried forward.
Time Frame	Baseline to Endpoint (13 weeks)

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) population

Arm/Group Title	MF/F MDI 400/10 mcg BID	MF/F MDI 200/10 mcg BID	MF MDI 400 mcg BID	F MDI 10 mcg BID	Placebo
Arm/Group Description	Mometasone furoate/formoterol fumarate (MF/F) 400/10 mcg via a metered dose inhaler (MDI) twice daily (BID) for 52 weeks	MF/F 200/10 mcg via a MDI BID for 52 weeks	Mometasone furoate (MF) 400 mcg via a MDI BID for 52 weeks	Formoterol fumarate (F) 10 mcg via a MDI BID for 52 weeks	Placebo MDI BID for 26 weeks
Measure Participants	214	207	207	208	207
Baseline	1.186 (0.418)	1.227 (0.418)	1.255 (0.418)	1.252 (0.418)	1.227 (0.418)
Endpoint (Change from Baseline)	0.166 (0.258)	0.126 (0.258)	0.057 (0.258)	0.077 (0.258)	0.003 (0.258)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	MF/F MDI 400/10 mcg BID, MF MDI 400 mcg BID
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	ANCOVA
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	MF/F MDI 200/10 mcg BID, MF MDI 400 mcg BID
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.007
	Comments
	Method	ANCOVA
	Comments

2. Primary Outcome

Title	Mean Change From Baseline to Week 13 Endpoint in AM Predose FEV1
Description	Endpoint was the last post-baseline non-missing result through Week 13 carried forward.
Time Frame	Baseline to Endpoint (13 weeks)

Outcome Measure Data

Analysis Population Description

ITT population

Arm/Group Title	MF/F MDI 400/10 mcg BID	MF/F MDI 200/10 mcg BID	MF MDI 400 mcg BID	F MDI 10 mcg BID	Placebo
Arm/Group Description	Mometasone furoate/formoterol fumarate (MF/F) 400/10 mcg via a metered dose inhaler (MDI) twice daily (BID) for 52 weeks	MF/F 200/10 mcg via a MDI BID for 52 weeks	Mometasone furoate (MF) 400 mcg via a MDI BID for 52 weeks	Formoterol fumarate (F) 10 mcg via a MDI BID for 52 weeks	Placebo MDI BID for 26 weeks
Measure Participants	213	203	206	208	204
Baseline	1.191 (0.424)	1.223 (0.424)	1.258 (0.424)	1.252 (0.424)	1.230 (0.424)
Endpoint (Change from Baseline)	0.111 (0.270)	0.058 (0.270)	0.027 (0.270)	0 (0.270)	-0.017 (0.270)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	MF/F MDI 400/10 mcg BID, F MDI 10 mcg BID
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	ANCOVA
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	MF/F MDI 200/10 mcg BID, F MDI 10 mcg BID
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.029
	Comments
	Method	ANCOVA
	Comments

3. Secondary Outcome

Title	Change From Baseline to Endpoint in St George's Respiratory Questionaire (SGRQ) Total Score
Description	SGRQ consisted of 76 items aggregated into 3 component scores: symptoms (frequency/severity), activity (cause or limited by breathlessness), impact (social functioning, psychological disturbances from airway disease), & total score. Best health scores have a low numeric value. All component scores & total score range from 0-100, with a higher score indicating greater disease burden. A 4-point increase over placebo (and Baseline) was considered the minimum clinically important difference. Endpoint is the last post-baseline non-missing result through the 26 week evaluation carried forward.
Time Frame	Baseline to Endpoint (26 weeks)

Outcome Measure Data

Analysis Population Description

ITT population

Arm/Group Title	MF/F MDI 400/10 mcg BID	MF/F MDI 200/10 mcg BID	MF MDI 400 mcg BID	F MDI 10 mcg BID	Placebo
Arm/Group Description	Mometasone furoate/formoterol fumarate (MF/F) 400/10 mcg via a metered dose inhaler (MDI) twice daily (BID) for 52 weeks	MF/F 200/10 mcg via a MDI BID for 52 weeks	Mometasone furoate (MF) 400 mcg via a MDI BID for 52 weeks	Formoterol fumarate (F) 10 mcg via a MDI BID for 52 weeks	Placebo MDI BID for 26 weeks
Measure Participants	207	196	193	201	198
Baseline	45.05 (18.48)	45.89 (18.48)	47.00 (18.48)	44.87 (18.48)	44.60 (18.48)
Endpoint (Change from Baseline)	-7.43 (14.72)	-5.69 (14.72)	-6.99 (14.72)	-6.18 (14.72)	-2.87 (14.72)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	MF/F MDI 400/10 mcg BID, Placebo
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.002
	Comments
	Method	ANCOVA
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	MF/F MDI 200/10 mcg BID, Placebo
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.059
	Comments
	Method	ANCOVA
	Comments

4. Secondary Outcome

Title	Change From Baseline in Proportion of Chronic Obstructive Pulmonary Disease (COPD) Symptom-Free Nights (AM Diary Symptoms)
Description	Prior to the use of study drug rescue medication (in the morning upon awakening) the participant evaluated the COPD symptoms of wheezing, cough, and difficulty breathing. A symptom-free night was defined as a combined score of 0 (no symptoms) across all three COPD symptoms evaluated the following morning. Proportion for Baseline included data from the last week before the first dose. Proportion for Endpoint included data across the entire 26-week treatment period.
Time Frame	Baseline to Endpoint (26 weeks)

Outcome Measure Data

Analysis Population Description

ITT population.

Arm/Group Title	MF/F MDI 400/10 mcg BID	MF/F MDI 200/10 mcg BID	MF MDI 400 mcg BID	F MDI 10 mcg BID	Placebo
Arm/Group Description	Mometasone furoate/formoterol fumarate (MF/F) 400/10 mcg via a metered dose inhaler (MDI) twice daily (BID) for 52 weeks	MF/F 200/10 mcg via a MDI BID for 52 weeks	Mometasone furoate (MF) 400 mcg via a MDI BID for 52 weeks	Formoterol fumarate (F) 10 mcg via a MDI BID for 52 weeks	Placebo MDI BID for 26 weeks
Measure Participants	213	198	204	206	205
Baseline	0.31 (0.345)	0.29 (0.345)	0.33 (0.345)	0.35 (0.345)	0.31 (0.345)
Endpoint (Change from Baseline)	0.15 (0.27)	0.07 (0.27)	0.11 (0.27)	0.14 (0.27)	0.06 (0.27)

5. Secondary Outcome

Title	Number of Participants With Partly Stable COPD
Description	Partly stable COPD was a composite measure that included the following COPD outcomes: (1) No oral steroid rescue medication; (2) No AM or PM COPD weekly average symptom score greater than 2 during at least 7 of 8 weeks; (3) No moderate or severe exacerbations; (4) No unscheduled visits due to COPD worsenings; (5) No study discontinuation due to treatment failure or treatment-related adverse event as determined by the investigator.
Time Frame	Endpoint (26 weeks)

Outcome Measure Data

Analysis Population Description

ITT population

Arm/Group Title	MF/F MDI 400/10 mcg BID	MF/F MDI 200/10 mcg BID	MF MDI 400 mcg BID	F MDI 10 mcg BID	Placebo
Arm/Group Description	Mometasone furoate/formoterol fumarate (MF/F) 400/10 mcg via a metered dose inhaler (MDI) twice daily (BID) for 52 weeks	MF/F 200/10 mcg via a MDI BID for 52 weeks	Mometasone furoate (MF) 400 mcg via a MDI BID for 52 weeks	Formoterol fumarate (F) 10 mcg via a MDI BID for 52 weeks	Placebo MDI BID for 26 weeks
Measure Participants	217	207	210	209	212
Number [Participants]	82 37.8%	95 45.9%	83 39.5%	90 43.1%	85 40.1%

6. Secondary Outcome

Title	Number of Participants With Mild, Moderate, or Severe COPD Exacerbations
Description	Mild = 12 or more inhalations/day of inhaled rescue medication or 2 or more nebulized treatments/day of inhaled rescue medication. Moderate = treatment with antibiotics or oral steroids. Severe = emergency room treatment or hospitalizations of survival curves. If an event was composed of multiple criteria, the most severe criteria was assigned to the event.
Time Frame	Endpoint (26 weeks)

Outcome Measure Data

Analysis Population Description

ITT population

Arm/Group Title	MF/F MDI 400/10 mcg BID	MF/F MDI 200/10 mcg BID	MF MDI 400 mcg BID	F MDI 10 mcg BID	Placebo
Arm/Group Description	Mometasone furoate/formoterol fumarate (MF/F) 400/10 mcg via a metered dose inhaler (MDI) twice daily (BID) for 52 weeks	MF/F 200/10 mcg via a MDI BID for 52 weeks	Mometasone furoate (MF) 400 mcg via a MDI BID for 52 weeks	Formoterol fumarate (F) 10 mcg via a MDI BID for 52 weeks	Placebo MDI BID for 26 weeks
Measure Participants	217	207	210	209	212
Mild	41 18.9%	48 23.2%	41 19.5%	45 21.5%	41 19.3%
Moderate	14 6.5%	23 11.1%	30 14.3%	30 14.4%	25 11.8%
Severe	1 0.5%	0 0%	1 0.5%	4 1.9%	3 1.4%

Adverse Events

Adverse Event Reporting Description	Treatment period for adverse events was 52 weeks for MF/F MDI 400/10 mcg BID, MF/F MDI 200/10 mcg BID, MF MDI 400 mcg BID, and F MDI 10 mcg BID and 26 weeks for placebo.
Arm/Group Title	MF/F MDI 200/10 MCG BID		MF/F MDI 400/10 MCG BID		MF MDI 400 MCG BID		F MDI 10 MCG BID		PLACEBO
Arm/Group Description
All Cause Mortality
	MF/F MDI 200/10 MCG BID		MF/F MDI 400/10 MCG BID		MF MDI 400 MCG BID		F MDI 10 MCG BID		PLACEBO
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	MF/F MDI 200/10 MCG BID		MF/F MDI 400/10 MCG BID		MF MDI 400 MCG BID		F MDI 10 MCG BID		PLACEBO
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	13/207 (6.3%)		29/217 (13.4%)		22/210 (10.5%)		29/209 (13.9%)		13/212 (6.1%)
Cardiac disorders
ACUTE MYOCARDIAL INFARCTION	0/207 (0%)	0	0/217 (0%)	0	1/210 (0.5%)	1	1/209 (0.5%)	1	0/212 (0%)	0
ANGINA PECTORIS	0/207 (0%)	0	2/217 (0.9%)	2	0/210 (0%)	0	0/209 (0%)	0	0/212 (0%)	0
ANGINA UNSTABLE	0/207 (0%)	0	1/217 (0.5%)	1	0/210 (0%)	0	1/209 (0.5%)	1	1/212 (0.5%)	1
ATRIAL FIBRILLATION	0/207 (0%)	0	1/217 (0.5%)	1	1/210 (0.5%)	1	0/209 (0%)	0	0/212 (0%)	0
BRADYCARDIA	0/207 (0%)	0	0/217 (0%)	0	1/210 (0.5%)	1	0/209 (0%)	0	0/212 (0%)	0
CARDIAC FAILURE CONGESTIVE	0/207 (0%)	0	1/217 (0.5%)	1	0/210 (0%)	0	0/209 (0%)	0	0/212 (0%)	0
COR PULMONALE CHRONIC	0/207 (0%)	0	0/217 (0%)	0	0/210 (0%)	0	1/209 (0.5%)	1	0/212 (0%)	0
CORONARY ARTERY DISEASE	0/207 (0%)	0	0/217 (0%)	0	1/210 (0.5%)	1	0/209 (0%)	0	0/212 (0%)	0
MYOCARDIAL INFARCTION	0/207 (0%)	0	0/217 (0%)	0	1/210 (0.5%)	1	0/209 (0%)	0	1/212 (0.5%)	1
PALPITATIONS	0/207 (0%)	0	0/217 (0%)	0	0/210 (0%)	0	0/209 (0%)	0	1/212 (0.5%)	1
Endocrine disorders
GOITRE	1/207 (0.5%)	1	0/217 (0%)	0	0/210 (0%)	0	0/209 (0%)	0	0/212 (0%)	0
Eye disorders
CATARACT	1/207 (0.5%)	1	3/217 (1.4%)	4	2/210 (1%)	2	0/209 (0%)	0	1/212 (0.5%)	1
CATARACT NUCLEAR	1/207 (0.5%)	1	0/217 (0%)	0	1/210 (0.5%)	1	0/209 (0%)	0	0/212 (0%)	0
GLAUCOMA	0/207 (0%)	0	0/217 (0%)	0	0/210 (0%)	0	1/209 (0.5%)	1	0/212 (0%)	0
LENTICULAR OPACITIES	1/207 (0.5%)	1	1/217 (0.5%)	1	2/210 (1%)	2	1/209 (0.5%)	1	1/212 (0.5%)	1
Gastrointestinal disorders
DIARRHOEA HAEMORRHAGIC	0/207 (0%)	0	0/217 (0%)	0	0/210 (0%)	0	1/209 (0.5%)	1	0/212 (0%)	0
EROSIVE OESOPHAGITIS	0/207 (0%)	0	0/217 (0%)	0	0/210 (0%)	0	0/209 (0%)	0	1/212 (0.5%)	1
GASTRIC ULCER	0/207 (0%)	0	0/217 (0%)	0	0/210 (0%)	0	2/209 (1%)	2	0/212 (0%)	0
GASTRITIS	0/207 (0%)	0	1/217 (0.5%)	1	0/210 (0%)	0	0/209 (0%)	0	0/212 (0%)	0
GASTROINTESTINAL HAEMORRHAGE	0/207 (0%)	0	0/217 (0%)	0	0/210 (0%)	0	1/209 (0.5%)	2	0/212 (0%)	0
HERNIAL EVENTRATION	1/207 (0.5%)	1	0/217 (0%)	0	0/210 (0%)	0	0/209 (0%)	0	0/212 (0%)	0
OESOPHAGEAL FOOD IMPACTION	0/207 (0%)	0	1/217 (0.5%)	1	0/210 (0%)	0	0/209 (0%)	0	0/212 (0%)	0
OESOPHAGEAL RUPTURE	1/207 (0.5%)	1	0/217 (0%)	0	0/210 (0%)	0	0/209 (0%)	0	0/212 (0%)	0
PEPTIC ULCER PERFORATION	0/207 (0%)	0	1/217 (0.5%)	1	0/210 (0%)	0	0/209 (0%)	0	0/212 (0%)	0
VOMITING	0/207 (0%)	0	0/217 (0%)	0	0/210 (0%)	0	1/209 (0.5%)	1	1/212 (0.5%)	1
General disorders
MULTI-ORGAN FAILURE	0/207 (0%)	0	1/217 (0.5%)	1	0/210 (0%)	0	0/209 (0%)	0	0/212 (0%)	0
SUDDEN DEATH	0/207 (0%)	0	0/217 (0%)	0	2/210 (1%)	2	1/209 (0.5%)	1	0/212 (0%)	0
Hepatobiliary disorders
CHOLECYSTITIS	1/207 (0.5%)	1	0/217 (0%)	0	0/210 (0%)	0	0/209 (0%)	0	0/212 (0%)	0
CHOLELITHIASIS	0/207 (0%)	0	0/217 (0%)	0	0/210 (0%)	0	1/209 (0.5%)	1	0/212 (0%)	0
CHRONIC HEPATIC FAILURE	1/207 (0.5%)	1	0/217 (0%)	0	0/210 (0%)	0	0/209 (0%)	0	0/212 (0%)	0
Infections and infestations
ABSCESS LIMB	0/207 (0%)	0	1/217 (0.5%)	1	0/210 (0%)	0	0/209 (0%)	0	0/212 (0%)	0
APPENDICITIS	0/207 (0%)	0	1/217 (0.5%)	1	0/210 (0%)	0	0/209 (0%)	0	0/212 (0%)	0
ARTHRITIS BACTERIAL	0/207 (0%)	0	1/217 (0.5%)	1	0/210 (0%)	0	0/209 (0%)	0	0/212 (0%)	0
BRONCHITIS	0/207 (0%)	0	0/217 (0%)	0	0/210 (0%)	0	0/209 (0%)	0	1/212 (0.5%)	1
CELLULITIS	0/207 (0%)	0	2/217 (0.9%)	2	0/210 (0%)	0	0/209 (0%)	0	0/212 (0%)	0
DIVERTICULITIS	0/207 (0%)	0	0/217 (0%)	0	1/210 (0.5%)	1	0/209 (0%)	0	0/212 (0%)	0
OESOPHAGEAL CANDIDIASIS	0/207 (0%)	0	0/217 (0%)	0	0/210 (0%)	0	0/209 (0%)	0	1/212 (0.5%)	1
PNEUMONIA	1/207 (0.5%)	1	3/217 (1.4%)	3	1/210 (0.5%)	1	2/209 (1%)	2	1/212 (0.5%)	1
PULMONARY TUBERCULOSIS	0/207 (0%)	0	1/217 (0.5%)	1	0/210 (0%)	0	0/209 (0%)	0	0/212 (0%)	0
VIRAL INFECTION	1/207 (0.5%)	1	0/217 (0%)	0	0/210 (0%)	0	0/209 (0%)	0	1/212 (0.5%)	1
Injury, poisoning and procedural complications
SKIN LACERATION	0/207 (0%)	0	1/217 (0.5%)	1	0/210 (0%)	0	0/209 (0%)	0	0/212 (0%)	0
SPINAL COMPRESSION FRACTURE	0/207 (0%)	0	1/217 (0.5%)	1	0/210 (0%)	0	0/209 (0%)	0	0/212 (0%)	0
Metabolism and nutrition disorders
DEHYDRATION	0/207 (0%)	0	0/217 (0%)	0	0/210 (0%)	0	0/209 (0%)	0	1/212 (0.5%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
ADENOCARCINOMA	0/207 (0%)	0	0/217 (0%)	0	1/210 (0.5%)	1	0/209 (0%)	0	0/212 (0%)	0
COLON NEOPLASM	0/207 (0%)	0	0/217 (0%)	0	0/210 (0%)	0	1/209 (0.5%)	1	0/212 (0%)	0
EXTRANODAL MARGINAL ZONE B-CELL LYMPHOMA (MALT TYPE)	0/207 (0%)	0	0/217 (0%)	0	0/210 (0%)	0	1/209 (0.5%)	1	0/212 (0%)	0
LARYNGEAL CANCER	0/207 (0%)	0	0/217 (0%)	0	0/210 (0%)	0	0/209 (0%)	0	1/212 (0.5%)	1
LUNG CANCER METASTATIC	0/207 (0%)	0	1/217 (0.5%)	1	0/210 (0%)	0	0/209 (0%)	0	0/212 (0%)	0
LUNG NEOPLASM MALIGNANT	0/207 (0%)	0	0/217 (0%)	0	0/210 (0%)	0	1/209 (0.5%)	1	0/212 (0%)	0
MALIGNANT PALATE NEOPLASM	0/207 (0%)	0	1/217 (0.5%)	1	0/210 (0%)	0	0/209 (0%)	0	0/212 (0%)	0
NON-HODGKIN'S LYMPHOMA	0/207 (0%)	0	0/217 (0%)	0	0/210 (0%)	0	1/209 (0.5%)	1	0/212 (0%)	0
Nervous system disorders
CEREBRAL INFARCTION	0/207 (0%)	0	0/217 (0%)	0	1/210 (0.5%)	1	0/209 (0%)	0	0/212 (0%)	0
CEREBRAL ISCHAEMIA	0/207 (0%)	0	0/217 (0%)	0	1/210 (0.5%)	1	0/209 (0%)	0	0/212 (0%)	0
CEREBROVASCULAR ACCIDENT	0/207 (0%)	0	0/217 (0%)	0	1/210 (0.5%)	1	0/209 (0%)	0	0/212 (0%)	0
CEREBROVASCULAR DISORDER	0/207 (0%)	0	0/217 (0%)	0	0/210 (0%)	0	2/209 (1%)	2	0/212 (0%)	0
SUBARACHNOID HAEMORRHAGE	0/207 (0%)	0	0/217 (0%)	0	1/210 (0.5%)	1	0/209 (0%)	0	0/212 (0%)	0
TREMOR	0/207 (0%)	0	0/217 (0%)	0	0/210 (0%)	0	0/209 (0%)	0	1/212 (0.5%)	1
VASCULAR HEADACHE	0/207 (0%)	0	0/217 (0%)	0	0/210 (0%)	0	1/209 (0.5%)	1	0/212 (0%)	0
Renal and urinary disorders
RENAL FAILURE ACUTE	0/207 (0%)	0	1/217 (0.5%)	1	0/210 (0%)	0	0/209 (0%)	0	1/212 (0.5%)	1
Respiratory, thoracic and mediastinal disorders
ACUTE RESPIRATORY FAILURE	0/207 (0%)	0	2/217 (0.9%)	2	0/210 (0%)	0	0/209 (0%)	0	2/212 (0.9%)	2
CHRONIC OBSTRUCTIVE PULMONARY DISEASE	4/207 (1.9%)	4	13/217 (6%)	14	6/210 (2.9%)	6	10/209 (4.8%)	10	7/212 (3.3%)	8
COUGH	0/207 (0%)	0	0/217 (0%)	0	0/210 (0%)	0	0/209 (0%)	0	1/212 (0.5%)	1
DYSPNOEA	0/207 (0%)	0	1/217 (0.5%)	1	0/210 (0%)	0	0/209 (0%)	0	0/212 (0%)	0
HICCUPS	0/207 (0%)	0	0/217 (0%)	0	0/210 (0%)	0	0/209 (0%)	0	1/212 (0.5%)	1
HYPOXIA	0/207 (0%)	0	0/217 (0%)	0	0/210 (0%)	0	0/209 (0%)	0	1/212 (0.5%)	1
PNEUMOMEDIASTINUM	1/207 (0.5%)	1	0/217 (0%)	0	0/210 (0%)	0	0/209 (0%)	0	0/212 (0%)	0
PNEUMOTHORAX	0/207 (0%)	0	0/217 (0%)	0	0/210 (0%)	0	1/209 (0.5%)	2	0/212 (0%)	0
PULMONARY AMYLOIDOSIS	0/207 (0%)	0	1/217 (0.5%)	1	0/210 (0%)	0	0/209 (0%)	0	0/212 (0%)	0
PULMONARY EMBOLISM	0/207 (0%)	0	2/217 (0.9%)	2	0/210 (0%)	0	1/209 (0.5%)	1	0/212 (0%)	0
RESPIRATORY FAILURE	1/207 (0.5%)	1	0/217 (0%)	0	0/210 (0%)	0	1/209 (0.5%)	1	0/212 (0%)	0
Surgical and medical procedures
CAROTID ENDARTERECTOMY	1/207 (0.5%)	1	0/217 (0%)	0	0/210 (0%)	0	0/209 (0%)	0	0/212 (0%)	0
INCISIONAL HERNIA REPAIR	0/207 (0%)	0	1/217 (0.5%)	1	0/210 (0%)	0	0/209 (0%)	0	0/212 (0%)	0
Vascular disorders
FEMORAL ARTERIAL STENOSIS	0/207 (0%)	0	0/217 (0%)	0	0/210 (0%)	0	1/209 (0.5%)	1	0/212 (0%)	0
PERIPHERAL ARTERY ANEURYSM	0/207 (0%)	0	0/217 (0%)	0	0/210 (0%)	0	1/209 (0.5%)	1	0/212 (0%)	0
POOR PERIPHERAL CIRCULATION	1/207 (0.5%)	1	0/217 (0%)	0	0/210 (0%)	0	0/209 (0%)	0	0/212 (0%)	0
Other (Not Including Serious) Adverse Events
	MF/F MDI 200/10 MCG BID		MF/F MDI 400/10 MCG BID		MF MDI 400 MCG BID		F MDI 10 MCG BID		PLACEBO
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/207 (3.9%)		10/217 (4.6%)		9/210 (4.3%)		11/209 (5.3%)		11/212 (5.2%)
Nervous system disorders
HEADACHE	8/207 (3.9%)	11	10/217 (4.6%)	15	9/210 (4.3%)	21	11/209 (5.3%)	18	11/212 (5.2%)	22

Limitations/Caveats

[Not Specified]

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Certain Agreements

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

The investigator has the right to publish or publicly present results. The investigator agrees not to publish or publicly present any interim results without prior written consent of the sponsor. The investigator agrees to provide to the sponsor 45 days before submission for publication that report results of the study. The sponsor shall have the right to review & comment with respect to publications, abstracts, slides, & manuscripts & the right to review & comment on the data & presentation.