Effects of Mometasone Furoate/Formoterol Combination Versus Formoterol and Mometasone Furoate Alone in Chronic Obstructive Pulmonary Disease (COPD) (Study P04230AM4)(COMPLETED)

• Sponsor: Organon and Co (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00383721
• Collaborator: Novartis (Industry)
• Enrollment: 1,196
• Arms: 5
• Duration (Months): 46

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: 1196 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: Sep 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 ranged 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 was 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 & Baseline, postbronchodilator FEV1 must be >= 60% predicted normal &

=25% predicted normal.

• COPD symptoms for >=24 months.

• =2 COPD exacerbations requiring course of oral corticosteroid &/or antibiotics within 2-12 months before screening.

• 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 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 or within 30 days prior to Screening must be acceptable to investigator. Chest X-ray or computerized tomography (CT) scan is acceptable within 12 months prior to Screening must be acceptable to investigator.

• 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), & must agree to continue. Female who is not currently sexually active must agree/consent to using a method should she become sexually active. Women who have been 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, 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 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 appropriate to 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.

• 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.

• Lobectomy, pneumonectomy or lung volume reduction surgery.

• Lung cancer.

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

• Alpha-1-antitrypsin deficiency.

• 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: NCT00383721
• Other Study ID Numbers: P04230; Doc ID: 3227335,; Eudract No: 2006-002309-30,
• 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; 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	225	239	253	243	236
COMPLETED	190	202	202	193	169
NOT COMPLETED	35	37	51	50	67
Period Title: 26-Week Double-Blind Treatment Period
STARTED	145	153	149	148	8
COMPLETED	126	136	126	131	8
NOT COMPLETED	19	17	23	17	0

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	225	239	253	243	236	1196
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	59.2 (9.1)	60.1 (9.0)	60.5 (8.5)	59.7 (8.7)	58.8 (9.5)	59.7 (9.0)
Sex: Female, Male (Count of Participants)
Female	57 25.3%	64 26.8%	56 22.1%	61 25.1%	58 24.6%	296 24.7%
Male	168 74.7%	175 73.2%	197 77.9%	182 74.9%	178 75.4%	900 75.3%

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	216	230	246	236	225
Baseline	1.189 (0.408)	1.195 (0.408)	1.260 (0.408)	1.176 (0.408)	1.205 (0.408)
Endpoint (Change from Baseline)	0.179 (0.274)	0.139 (0.274)	0.053 (0.274)	0.092 (0.274)	0.018 (0.274)

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	<0.001
	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	215	228	245	235	224
Baseline	1.188 (0.408)	1.194 (0.408)	1.255 (0.408)	1.175 (0.408)	1.205 (0.408)
Endpoint (Change from Baseline)	0.098 (0.280)	0.063 (0.280)	0.028 (0.280)	0.049 (0.280)	-0.003 (0.280)

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	0.062
	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	0.583
	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 ranged 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 was 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	211	227	240	231	216
Baseline	48.22 (17.49)	47.29 (17.49)	48.27 (17.49)	46.27 (17.49)	46.59 (17.49)
Endpoint (Change from Baseline)	-6.04 (13.95)	-7.99 (13.95)	-5.87 (13.95)	-4.93 (13.95)	-2.88 (13.95)

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	0.020
	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	<0.001
	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	228	242	234	224
Baseline	0.24 (0.334)	0.22 (0.334)	0.24 (0.334)	0.25 (0.334)	0.24 (0.334)
Endpoint (Change from Baseline)	0.13 (0.29)	0.17 (0.29)	0.16 (0.29)	0.13 (0.29)	0.12 (0.29)

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	221	235	249	239	232
Number [Participants]	91 40.4%	101 42.3%	92 36.4%	98 40.3%	87 36.9%

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	221	235	249	239	232
Mild	56 24.9%	53 22.2%	49 19.4%	61 25.1%	64 27.1%
Moderate	24 10.7%	20 8.4%	29 11.5%	33 13.6%	38 16.1%
Severe	3 1.3%	3 1.3%	5 2%	2 0.8%	4 1.7%

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 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.
All Cause Mortality
	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
	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 400/10 mcg BID		MF/F MDI 200/10 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	26/225 (11.6%)		28/239 (11.7%)		33/253 (13%)		25/243 (10.3%)		21/236 (8.9%)
Cardiac disorders
Acute coronary syndrome	0/225 (0%)	0	0/239 (0%)	0	1/253 (0.4%)	1	0/243 (0%)	0	0/236 (0%)	0
Acute myocardial infarction	0/225 (0%)	0	0/239 (0%)	0	0/253 (0%)	0	1/243 (0.4%)	1	0/236 (0%)	0
Angina unstable	0/225 (0%)	0	1/239 (0.4%)	1	0/253 (0%)	0	0/243 (0%)	0	0/236 (0%)	0
Atrial fibrillation	0/225 (0%)	0	1/239 (0.4%)	1	0/253 (0%)	0	0/243 (0%)	0	0/236 (0%)	0
Atrial flutter	0/225 (0%)	0	1/239 (0.4%)	1	0/253 (0%)	0	0/243 (0%)	0	0/236 (0%)	0
Atrioventricular block complete	0/225 (0%)	0	1/239 (0.4%)	1	0/253 (0%)	0	0/243 (0%)	0	0/236 (0%)	0
Cardiac failure	0/225 (0%)	0	0/239 (0%)	0	0/253 (0%)	0	0/243 (0%)	0	1/236 (0.4%)	1
Cardio failure acute	0/225 (0%)	0	0/239 (0%)	0	1/253 (0.4%)	1	0/243 (0%)	0	0/236 (0%)	0
Cardiac failure congestive	0/225 (0%)	0	0/239 (0%)	0	1/253 (0.4%)	1	0/243 (0%)	0	0/236 (0%)	0
Cardiomyopathy	0/225 (0%)	0	0/239 (0%)	0	0/253 (0%)	0	1/243 (0.4%)	1	0/236 (0%)	0
Cor pulmonale	1/225 (0.4%)	1	0/239 (0%)	0	0/253 (0%)	0	1/243 (0.4%)	1	0/236 (0%)	0
Coronary artery disease	0/225 (0%)	0	0/239 (0%)	0	0/253 (0%)	0	1/243 (0.4%)	1	0/236 (0%)	0
Myocardial infarction	0/225 (0%)	0	3/239 (1.3%)	3	2/253 (0.8%)	2	2/243 (0.8%)	2	0/236 (0%)	0
Myocardial ischaemia	0/225 (0%)	0	1/239 (0.4%)	1	0/253 (0%)	0	0/243 (0%)	0	0/236 (0%)	0
Supraventricular extrasystoles	1/225 (0.4%)	1	0/239 (0%)	0	0/253 (0%)	0	0/243 (0%)	0	0/236 (0%)	0
Ventricular fibrillation	1/225 (0.4%)	1	0/239 (0%)	0	0/253 (0%)	0	0/243 (0%)	0	0/236 (0%)	0
Endocrine disorders
Hyperparathyroidism primary	0/225 (0%)	0	0/239 (0%)	0	0/253 (0%)	0	1/243 (0.4%)	1	0/236 (0%)	0
Eye disorders
Cataract	0/225 (0%)	0	2/239 (0.8%)	2	3/253 (1.2%)	3	0/243 (0%)	0	1/236 (0.4%)	1
Cataract nuclear	0/225 (0%)	0	1/239 (0.4%)	1	1/253 (0.4%)	1	0/243 (0%)	0	0/236 (0%)	0
Cataract subcapsular	0/225 (0%)	0	1/239 (0.4%)	1	1/253 (0.4%)	1	0/243 (0%)	0	0/236 (0%)	0
Glaucoma	0/225 (0%)	0	0/239 (0%)	0	1/253 (0.4%)	1	0/243 (0%)	0	0/236 (0%)	0
Lenticular opacities	1/225 (0.4%)	1	2/239 (0.8%)	2	2/253 (0.8%)	2	1/243 (0.4%)	2	1/236 (0.4%)	2
Gastrointestinal disorders
Abdominal hernia	0/225 (0%)	0	0/239 (0%)	0	0/253 (0%)	0	1/243 (0.4%)	1	0/236 (0%)	0
Duodenal ulcer perforation	0/225 (0%)	0	0/239 (0%)	0	0/253 (0%)	0	0/243 (0%)	0	1/236 (0.4%)	1
Gastric ulcer perforation	0/225 (0%)	0	1/239 (0.4%)	1	0/253 (0%)	0	0/243 (0%)	0	0/236 (0%)	0
Gastric atrophic	0/225 (0%)	0	0/239 (0%)	0	0/253 (0%)	0	1/243 (0.4%)	1	0/236 (0%)	0
Gastritis erosive	0/225 (0%)	0	0/239 (0%)	0	0/253 (0%)	0	1/243 (0.4%)	1	0/236 (0%)	0
Gastrointestinal haemorrhage	0/225 (0%)	0	0/239 (0%)	0	0/253 (0%)	0	1/243 (0.4%)	1	0/236 (0%)	0
Peptic ulcer	0/225 (0%)	0	0/239 (0%)	0	0/253 (0%)	0	0/243 (0%)	0	1/236 (0.4%)	1
Peritonitis	0/225 (0%)	0	0/239 (0%)	0	0/253 (0%)	0	0/243 (0%)	0	1/236 (0.4%)	1
Umbilical hernia	0/225 (0%)	0	0/239 (0%)	0	0/253 (0%)	0	1/243 (0.4%)	1	0/236 (0%)	0
General disorders
Death	0/225 (0%)	0	0/239 (0%)	0	1/253 (0.4%)	1	0/243 (0%)	0	0/236 (0%)	0
Sudden death	1/225 (0.4%)	1	0/239 (0%)	0	0/253 (0%)	0	0/243 (0%)	0	0/236 (0%)	0
Hepatobiliary disorders
Cholecystitis	0/225 (0%)	0	1/239 (0.4%)	1	0/253 (0%)	0	0/243 (0%)	0	0/236 (0%)	0
Cholelithiasis	0/225 (0%)	0	0/239 (0%)	0	0/253 (0%)	0	1/243 (0.4%)	1	0/236 (0%)	0
Infections and infestations
Amoebic dysentery	0/225 (0%)	0	0/239 (0%)	0	0/253 (0%)	0	0/243 (0%)	0	1/236 (0.4%)	1
Diarrhoea infectious	0/225 (0%)	0	0/239 (0%)	0	0/253 (0%)	0	1/243 (0.4%)	1	0/236 (0%)	0
Gastroenteritis	0/225 (0%)	0	0/239 (0%)	0	0/253 (0%)	0	1/243 (0.4%)	1	0/236 (0%)	0
H1N1 influenza	1/225 (0.4%)	1	0/239 (0%)	0	0/253 (0%)	0	0/243 (0%)	0	0/236 (0%)	0
Lobar pneumonia	1/225 (0.4%)	1	1/239 (0.4%)	1	0/253 (0%)	0	0/243 (0%)	0	0/236 (0%)	0
Pneumonia	5/225 (2.2%)	6	1/239 (0.4%)	1	4/253 (1.6%)	5	4/243 (1.6%)	5	1/236 (0.4%)	1
Pumonary tuberculosis	0/225 (0%)	0	0/239 (0%)	0	0/253 (0%)	0	0/243 (0%)	0	1/236 (0.4%)	1
Rectal abcess	0/225 (0%)	0	0/239 (0%)	0	1/253 (0.4%)	1	0/243 (0%)	0	0/236 (0%)	0
Sepsis	1/225 (0.4%)	1	0/239 (0%)	0	0/253 (0%)	0	0/243 (0%)	0	0/236 (0%)	0
Subcutaneous abscess	0/225 (0%)	0	1/239 (0.4%)	1	0/253 (0%)	0	0/243 (0%)	0	0/236 (0%)	0
Urinary tract infection	0/225 (0%)	0	0/239 (0%)	0	0/253 (0%)	0	0/243 (0%)	0	1/236 (0.4%)	1
Viral infection	1/225 (0.4%)	1	0/239 (0%)	0	0/253 (0%)	0	0/243 (0%)	0	0/236 (0%)	0
Injury, poisoning and procedural complications
Collapse of lung	1/225 (0.4%)	1	0/239 (0%)	0	0/253 (0%)	0	0/243 (0%)	0	0/236 (0%)	0
Femoral neck fracture	0/225 (0%)	0	1/239 (0.4%)	1	0/253 (0%)	0	0/243 (0%)	0	0/236 (0%)	0
Humerus fracture	0/225 (0%)	0	0/239 (0%)	0	1/253 (0.4%)	1	0/243 (0%)	0	1/236 (0.4%)	1
Injury	0/225 (0%)	0	0/239 (0%)	0	0/253 (0%)	0	1/243 (0.4%)	1	0/236 (0%)	0
Multiple injuries	1/225 (0.4%)	1	0/239 (0%)	0	0/253 (0%)	0	0/243 (0%)	0	0/236 (0%)	0
Subdural haematoma	0/225 (0%)	0	0/239 (0%)	0	1/253 (0.4%)	1	0/243 (0%)	0	0/236 (0%)	0
Traumatic brain injury	1/225 (0.4%)	1	0/239 (0%)	0	0/253 (0%)	0	0/243 (0%)	0	0/236 (0%)	0
Upper limb fracture	0/225 (0%)	0	1/239 (0.4%)	1	0/253 (0%)	0	0/243 (0%)	0	0/236 (0%)	0
Investigations
Intraocular pressure increased	1/225 (0.4%)	1	0/239 (0%)	0	0/253 (0%)	0	0/243 (0%)	0	0/236 (0%)	0
Metabolism and nutrition disorders
Type 2 diabetes mellitus	1/225 (0.4%)	1	0/239 (0%)	0	0/253 (0%)	0	0/243 (0%)	0	0/236 (0%)	0
Musculoskeletal and connective tissue disorders
Intervertebral disc disorder	0/225 (0%)	0	0/239 (0%)	0	0/253 (0%)	0	0/243 (0%)	0	1/236 (0.4%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Lip neoplasm malignant stage unspecified	0/225 (0%)	0	0/239 (0%)	0	1/253 (0.4%)	1	0/243 (0%)	0	0/236 (0%)	0
Malignant palate neoplasm	1/225 (0.4%)	1	0/239 (0%)	0	0/253 (0%)	0	0/243 (0%)	0	0/236 (0%)	0
Uterine leiomyoma	1/225 (0.4%)	1	0/239 (0%)	0	0/253 (0%)	0	0/243 (0%)	0	0/236 (0%)	0
Nervous system disorders
Amnesia	1/225 (0.4%)	1	0/239 (0%)	0	0/253 (0%)	0	0/243 (0%)	0	0/236 (0%)	0
Cerebral infarction	0/225 (0%)	0	0/239 (0%)	0	1/253 (0.4%)	1	0/243 (0%)	0	0/236 (0%)	0
Cerebral ischaemia	0/225 (0%)	0	0/239 (0%)	0	0/253 (0%)	0	1/243 (0.4%)	1	0/236 (0%)	0
Cerebrovascular accident	0/225 (0%)	0	1/239 (0.4%)	1	1/253 (0.4%)	1	1/243 (0.4%)	1	0/236 (0%)	0
Cognitive disorder	0/225 (0%)	0	0/239 (0%)	0	0/253 (0%)	0	1/243 (0.4%)	1	0/236 (0%)	0
Hypoxic encephalopathy	1/225 (0.4%)	1	0/239 (0%)	0	0/253 (0%)	0	0/243 (0%)	0	0/236 (0%)	0
Subarachnoid haemorrhage	0/225 (0%)	0	0/239 (0%)	0	0/253 (0%)	0	0/243 (0%)	0	1/236 (0.4%)	1
Psychiatric disorders
Completed suicide	0/225 (0%)	0	0/239 (0%)	0	1/253 (0.4%)	1	0/243 (0%)	0	0/236 (0%)	0
Depression	0/225 (0%)	0	1/239 (0.4%)	1	0/253 (0%)	0	0/243 (0%)	0	0/236 (0%)	0
Renal and urinary disorders
Nephrolithiasis	0/225 (0%)	0	0/239 (0%)	0	0/253 (0%)	0	1/243 (0.4%)	1	0/236 (0%)	0
Renal failure	1/225 (0.4%)	1	0/239 (0%)	0	0/253 (0%)	0	0/243 (0%)	0	0/236 (0%)	0
Renal failure acute	0/225 (0%)	0	0/239 (0%)	0	0/253 (0%)	0	1/243 (0.4%)	1	0/236 (0%)	0
Respiratory, thoracic and mediastinal disorders
Acute respiratory distress syndrome	0/225 (0%)	0	0/239 (0%)	0	0/253 (0%)	0	1/243 (0.4%)	1	0/236 (0%)	0
Acute respiratory failure	1/225 (0.4%)	1	0/239 (0%)	0	0/253 (0%)	0	0/243 (0%)	0	0/236 (0%)	0
Bronchospasm	1/225 (0.4%)	1	0/239 (0%)	0	0/253 (0%)	0	0/243 (0%)	0	0/236 (0%)	0
Chronic obstructive pulmonary disease	12/225 (5.3%)	12	8/239 (3.3%)	10	12/253 (4.7%)	14	9/243 (3.7%)	10	13/236 (5.5%)	14
Pneumonia aspiration	0/225 (0%)	0	0/239 (0%)	0	0/253 (0%)	0	1/243 (0.4%)	2	0/236 (0%)	0
Pneumothorax	2/225 (0.9%)	2	0/239 (0%)	0	0/253 (0%)	0	0/243 (0%)	0	0/236 (0%)	0
Pulmonary embolism	0/225 (0%)	0	0/239 (0%)	0	0/253 (0%)	0	1/243 (0.4%)	1	0/236 (0%)	0
Respiratory disorder	0/225 (0%)	0	0/239 (0%)	0	0/253 (0%)	0	1/243 (0.4%)	1	0/236 (0%)	0
Respiratory failure	1/225 (0.4%)	1	0/239 (0%)	0	0/253 (0%)	0	0/243 (0%)	0	0/236 (0%)	0
Skin and subcutaneous tissue disorders
Angioedema	0/225 (0%)	0	1/239 (0.4%)	1	0/253 (0%)	0	0/243 (0%)	0	0/236 (0%)	0
Other (Not Including Serious) Adverse Events
	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
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	37/225 (16.4%)		28/239 (11.7%)		34/253 (13.4%)		30/243 (12.3%)		34/236 (14.4%)
Infections and infestations
Nasopharyngitis	13/225 (5.8%)	16	9/239 (3.8%)	11	14/253 (5.5%)	21	12/243 (4.9%)	13	9/236 (3.8%)	11
Upper respiratory tract infection	18/225 (8%)	20	8/239 (3.3%)	12	8/253 (3.2%)	10	10/243 (4.1%)	13	11/236 (4.7%)	13
Nervous system disorders
Headache	9/225 (4%)	16	12/239 (5%)	24	16/253 (6.3%)	21	11/243 (4.5%)	29	14/236 (5.9%)	20

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.