Effects of Mometasone Furoate Dry Powder Inhaler, Fluticasone Propionate, and Montelukast on Bone Mineral Density in Asthmatics (Study P03418)

• Sponsor: Organon and Co (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00394355
• Collaborator: (none)
• Enrollment: 566
• Arms: 4
• Duration (Months): 37

Study Details

Study Description

Brief Summary

This is a randomized, multi-center, parallel-group, active-controlled, double-blind study evaluating the effects of mometasone furoate (MF) dry powder inhaler (DPI) on bone mineral density (BMD) in subjects with asthma. The mean percent change in lumbar spine BMD from the averaged baseline value (the average of the two scan results prior to treatment) to the endpoint of treatment time point (the average of the last two valid post-baseline scan results during treatment) for the comparison of MF DPI 400 mcg daily in the evening versus montelukast (ML) 10 mg daily in the evening.

Condition or Disease	Intervention/Treatment	Phase
Asthma	Drug: mometasone furoate dry powder inhaler; Drug: mometasone furoate dry powder inhaler; Drug: fluticasone propionate hydrofluoroalkane (HFA); Drug: montelukast	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 566 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: Comparative Study of the Effect of Two Doses of Mometasone Furoate Dry Powder Inhaler 200 mcg and 400 mcg QD PM, Fluticasone Propionate 250 mcg BID, and Montelukast 10 mg QD PM, on Bone Mineral Density in Adults With Asthma
• Study Start Date: Sep 1, 2006
• Actual Primary Completion Date: Oct 1, 2009
• Actual Study Completion Date: Oct 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Group 1 MF DPI 400 mcg once a day (QD) in the evening (PM)	Drug: mometasone furoate dry powder inhaler; 400 mcg MF DPI via a breath-actuated, dry-powder inhaler and a placebo tablet given by mouth once daily in the evening for 1 year.; Other Names: Asmanex
Experimental: Group 2 MF DPI 200 mcg QD PM	Drug: mometasone furoate dry powder inhaler; 200 mcg MF DPI via a breath-actuated, dry-powder inhaler and a placebo tablet given by mouth once daily in the evening for 1 year.; Other Names: Asmanex
Active Comparator: Group 3 Fluticasone propionate (FP) metered dose inhaler (MDI) 250 mcg twice a day (BID)	Drug: fluticasone propionate hydrofluoroalkane (HFA); 250 mcg FP HFA given twice a day via a metered-dose inhaler and a placebo tablet given once daily in the evening for 1 year; Other Names: Flovent HFA
Active Comparator: Group 4 ML 10 mg QD PM	Drug: montelukast; 10 mg given once daily in the evening by mouth for 1 year.; Other Names: Singulair

Outcome Measures

Primary Outcome Measures

1. Mean Percent Change in Lumbar Spine Bone Mineral Density (BMD) From the Averaged Baseline Value to the Endpoint of Treatment Time Point [Baseline and up to ~ one year of treatment]

   The averaged baseline value is the average of the two scan results prior to treatment. The endpoint of treatment time point is the average of the last two valid post baseline BMD scans during the treatment period carried forward.

Secondary Outcome Measures

1. Mean Percent Change in the Left Total Femur From the Averaged Baseline Value to the Averaged Value at the Endpoint of Treatment Time Point [Baseline and up to ~ one year of treatment]

   The averaged baseline value is the average of the two scan results prior to treatment. The endpoint of treatment time point is the average of the last two valid post baseline BMD scans during the treatment period carried forward.

2. Mean Percent Change in the Femoral Neck BMD From the Averaged Baseline Value to the Averaged Value at the Endpoint of Treatment Time Point [Baseline and up to ~ one year of treatment]

   The averaged baseline value is the average of the two scan results prior to treatment. The endpoint of treatment time point is the average of the last two valid post baseline BMD scans during the treatment period carried forward.

3. Summary of Change From Baseline to Endpoint in FEV1 (Forced Expiratory Volume in One Second). [Baseline and up to ~ one year of treatment]

   Mean percent change from Baseline (the last non-missing value prior to treatment) in pulmonary function test FEV1 from in-office visits and at Endpoint (last non-missing postbaseline value carried forward)

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 50 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Informed consent, adhere to schedules.

• Inform usual treating medical doctor (MD) of study participation.

• Female 18 to 40, male 18 to 50, any race.

• =3-month asthma history.

• Never treated with inhaled corticosteroids (ICS) for asthma or not have taken ICS for ≥3 months prior to Screening.

• Prebronchodilator forced expiratory volume (liters) in 1 second (FEV1) >=60% & <=90% predicted at both Screening & Baseline, when all restricted medications withheld.

• Prior to randomization, demonstrate increase in absolute FEV1 of >=12%, with absolute volume increase of >=200 mL, after reversibility testing.

• Lab tests normal/acceptable to investigator/sponsor. Electrocardiogram (ECG) performed at screening or <30 days of screening normal/acceptable to investigator. Chest x-ray performed at screening or <12 months of screening normal/acceptable to investigator.

• 25-hydroxy vitamin D level >=15 ng/mL. If <15, re-tested after taking calcium plus vitamin D for 4 weeks.

• Free of significant disease (other than asthma) known to affect bone mineral metabolism including renal disease, unstable hyperthyroidism or other endocrinopathies, Paget's disease, osteoporosis, malabsorption, or others that could interfere with study evaluations (eg scoliosis, metal pins, calcification in spine/femur).

• Women of childbearing potential must use birth control. Includes: hormonal contraceptive, intra-uterine device (IUD); condom in combination with spermicide; monogamous relationship with male who had vasectomy or is using condom. Started method ≥3 months prior to Screening (exception condom), & agree to continue for duration. Women who are not currently sexually active must agree/consent to using double-barrier method if become active. Females must have negative serum pregnancy test at Screening.

• 2 valid scans, as confirmed by local dual energy x-ray absorptiometry (DXA) center, for lumbar spine, left total femur, & femoral neck prior to randomization. Valid scans will be 2 scans of same region, performed on same day, that agree within 5% & scans are technically satisfactory (eg correct scan mode, no artifacts present, correct region).

Exclusion Criteria:

• 12 inhalations/day of salbutamol on 2 consecutive days between Screening & Baseline.

• Increase/decrease in FEV1 of >=20% between Screening & Baseline.

• Treated with methotrexate, cyclosporin, gold, or other cytotoxic agents, for asthma or concurrent condition within last 3 months.

• Pipe/cigar smoking history.

• Smoker/ex-smoker who smoked within previous year or has smoking history ≥10 pack-years.

• Upper/lower respiratory tract infection within 2 weeks prior to Screening & Baseline. Can be rescheduled.

• 14 days of oral steroids within previous 12 months or required burst of systemic steroids within previous month.

• Ever required ventilator support for respiratory failure secondary to asthma.

• Treated in emergency room (ER) for asthma exacerbation or admitted to hospital for management of airway obstruction on 1 occasion in last 3 months or on >=2 occasions within last 6 months.

• Chronic bronchitis, bronchiectasis, emphysema or cystic fibrosis.

• Participated in study within last 30 days.

• Allergic to/intolerant of ICS, beta-agonists, or drugs/excipients in study.

• Average of 2 lumbar spine (L1-L4) scans at Screening is >2 standard deviations below normal.

• Condition that might affect ability to ambulate normally, (ie major surgical procedure). Condition that may interfere with BMD measurement.

• History of renal, hepatic, cardiovascular, metabolic, neurologic, hematologic, respiratory, gastrointestinal, cerebrovascular, or other which could interfere with study or require treatment which might interfere (eg calcium urolithiasis or absorptive hypercalcuria, insulin dependent diabetes, cancer within last 10 years (except basal cell carcinoma), active hepatitis, coronary artery disease, stroke, rheumatoid arthritis, human immunodeficiency virus (HIV), or respiratory conditions such as chronic obstructive pulmonary disease (COPD), chronic bronchitis, cystic fibrosis. Others which are well-controlled & stable (eg hypertension, arrhythmia, subjects on stable thyroid hormone replacement for at least 3 months whose thyroid stimulating hormone (TSH) levels are normal) may be allowed.

• Treated within last year with drug known to interfere with bone metabolism including: bisphosphonates, estrogens such as depot injectables (estrogens used in oral combined hormonal contraceptives are allowed if dose is stable throughout), high-dose fluoride, & thyroid replacement hormones (if not stabilized).

• History &/or presence of intraocular pressure in either eye >=22 mm Hg, glaucoma, &/or posterior subcapsular cataracts. History &/or presence of nuclear cataract or undergone bilateral lens extraction may be eligible.

• The subject has undergone incisional or intraocular surgery in which the natural lens is still present in the eye.

• The subject has a history of penetrating trauma to both eyes.

• The subject has one or more of the following lens opacities classification system version III (LOCS III) grades at screening: nuclear opalescence (NO) >=3.0, nuclear color (NC) >=3.0, cortical (C) >=2.0, posterior (P) >=0.5.

• Pregnant, breast-feeding, or postmenopausal women. Amenorrhea >6 months will be excluded (exception hysterectomy). Bilateral oophorectomy excluded.

• Relevant abnormal Baseline vital sign.

• Body mass index (BMI) >35 kg/m2.

• HIV positive (testing not performed).

• Alcoholic or illicit drug abuser.

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

• Normal sleep/wake cycle is inverted (eg night shift workers).

• Taken restricted medications prior to Screening.

• Cannot adhere to prohibited & permitted concomitant medications.

• No subject may participate in this same study at another site or simultaneously in any other study.

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

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Organon and Co

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Organon and Co
• ClinicalTrials.gov Identifier: NCT00394355
• Other Study ID Numbers: P03418; Doc ID: 3387777;; EUDRACT No: 2004-002930-21
• First Posted: Nov 1, 2006
• Last Update Posted: Feb 22, 2022
• Last Verified: Feb 1, 2022

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Additional relevant MeSH terms: Asthma; Fluticasone; Xhance; Mometasone Furoate; Montelukast

Study Results

Participant Flow

Arm/Group Title	MF DPI 200 mcg QD PM	MF DPI 400 mcg QD PM	FP MDI 250 mcg BID	ML 10 mg QD PM
Arm/Group Description	Mometasone furoate (MF) dry powder inhaler (DPI) 200 mcg once daily (QD) in the evening (PM) for 1 year	MF DPI 400 mcg QD PM for 1 year	Fluticasone proprionate (FP) metered dose inhaler (MDI) 250 mcg twice daily (BID) for 1 year	Montelukast (ML) 10 mg QD PM for 1 year
Period Title: Overall Study
STARTED	140	137	147	142
COMPLETED	105	103	109	111
NOT COMPLETED	35	34	38	31

Baseline Characteristics

Arm/Group Title	MF DPI 200 mcg QD PM	MF DPI 400 mcg QD PM	FP MDI 250 mcg BID	ML 10 mg QD PM	Total
Arm/Group Description	Mometasone furoate (MF) dry powder inhaler (DPI) 200 mcg once daily (QD) in the evening (PM) for 1 year	MF DPI 400 mcg QD PM for 1 year	Fluticasone proprionate (FP) metered dose inhaler (MDI) 250 mcg twice daily (BID) for 1 year	Montelukast (ML) 10 mg QD PM for 1 year	Total of all reporting groups
Overall Participants	140	137	147	142	566
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	29.7 (7.8)	29.8 (8.1)	28.2 (6.9)	28.2 (7.1)	29.0 (7.5)
Sex: Female, Male (Count of Participants)
Female	91 65%	90 65.7%	90 61.2%	88 62%	359 63.4%
Male	49 35%	47 34.3%	57 38.8%	54 38%	207 36.6%

Outcome Measures

1. Primary Outcome

Title	Mean Percent Change in Lumbar Spine Bone Mineral Density (BMD) From the Averaged Baseline Value to the Endpoint of Treatment Time Point
Description	The averaged baseline value is the average of the two scan results prior to treatment. The endpoint of treatment time point is the average of the last two valid post baseline BMD scans during the treatment period carried forward.
Time Frame	Baseline and up to ~ one year of treatment

Outcome Measure Data

Analysis Population Description

All randomized participants

Arm/Group Title	MF DPI 200 mcg QD PM	MF DPI 400 mcg QD PM	FP MDI 250 mcg BID	ML 10 mg QD PM
Arm/Group Description	Mometasone furoate (MF) dry powder inhaler (DPI) 200 mcg once daily (QD) in the evening (PM) for 1 year	MF DPI 400 mcg QD PM for 1 year	Fluticasone proprionate (FP) metered dose inhaler (MDI) 250 mcg twice daily (BID) for 1 year	Montelukast (ML) 10 mg QD PM for 1 year
Measure Participants	117	121	131	127
Mean (Standard Deviation) [percentage of BMD]	0.7 (2.56)	0.9 (2.56)	1.1 (2.56)	1.2 (2.56)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	MF DPI 400 mcg QD PM, ML 10 mg QD PM
	Comments	Least squares mean percent changes were obtained from the two-way analysis of variance (ANOVA) model with treatment and BMD scan center effects. Results shown use percent change as a response. Pooled Standard deviation from the ANOVA model with treatment effects.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.261
	Comments
	Method	ANOVA
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	FP MDI 250 mcg BID, ML 10 mg QD PM
	Comments	Least squares mean percent changes were obtained from the two-way ANOVA model with treatment and BMD scan center effects. Results shown use percent change as a response. Pooled Standard deviation from the ANOVA model with treatment effects.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.644
	Comments
	Method	ANOVA
	Comments

2. Secondary Outcome

Title	Mean Percent Change in the Left Total Femur From the Averaged Baseline Value to the Averaged Value at the Endpoint of Treatment Time Point
Description	The averaged baseline value is the average of the two scan results prior to treatment. The endpoint of treatment time point is the average of the last two valid post baseline BMD scans during the treatment period carried forward.
Time Frame	Baseline and up to ~ one year of treatment

Outcome Measure Data

Analysis Population Description

All randomized participants

Arm/Group Title	MF DPI 200 mcg QD PM	MF DPI 400 mcg QD PM	FP MDI 250 mcg BID	ML 10 mg QD PM
Arm/Group Description	Mometasone furoate (MF) dry powder inhaler (DPI) 200 mcg once daily (QD) in the evening (PM) for 1 year	MF DPI 400 mcg QD PM for 1 year	Fluticasone proprionate (FP) metered dose inhaler (MDI) 250 mcg twice daily (BID) for 1 year	Montelukast (ML) 10 mg QD PM for 1 year
Measure Participants	117	121	130	127
Mean (Standard Deviation) [percentage of BMD]	0.3 (2.00)	0.2 (2.00)	0.2 (2.00)	0.5 (2.00)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	MF DPI 400 mcg QD PM, ML 10 mg QD PM
	Comments	Least squares mean percent changes were obtained from the two-way ANOVA model with treatment and BMD scan center effects. Results shown use percent change as a response. Pooled Standard deviation from the ANOVA model with treatment effects.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.359
	Comments
	Method	ANOVA
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	FP MDI 250 mcg BID, ML 10 mg QD PM
	Comments	Least squares mean percent changes were obtained from the two-way ANOVA model with treatment and BMD scan center effects. Results shown use percent change as a response. Pooled Standard deviation from the ANOVA model with treatment effects.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.390
	Comments
	Method	ANOVA
	Comments

3. Secondary Outcome

Title	Mean Percent Change in the Femoral Neck BMD From the Averaged Baseline Value to the Averaged Value at the Endpoint of Treatment Time Point
Description	The averaged baseline value is the average of the two scan results prior to treatment. The endpoint of treatment time point is the average of the last two valid post baseline BMD scans during the treatment period carried forward.
Time Frame	Baseline and up to ~ one year of treatment

Outcome Measure Data

Analysis Population Description

All randomized participants

Arm/Group Title	MF DPI 200 mcg QD PM	MF DPI 400 mcg QD PM	FP MDI 250 mcg BID	ML 10 mg QD PM
Arm/Group Description	Mometasone furoate (MF) dry powder inhaler (DPI) 200 mcg once daily (QD) in the evening (PM) for 1 year	MF DPI 400 mcg QD PM for 1 year	Fluticasone proprionate (FP) metered dose inhaler (MDI) 250 mcg twice daily (BID) for 1 year	Montelukast (ML) 10 mg QD PM for 1 year
Measure Participants	117	121	130	127
Mean (Standard Deviation) [percentage of BMD]	-0.2 (3.17)	0.4 (3.17)	-0.4 (3.17)	-0.2 (3.17)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	MF DPI 400 mcg QD PM, ML 10 mg QD PM
	Comments	Least squares mean percent changes were obtained from the two-way ANOVA model with treatment and BMD scan center effects. Results shown use percent change as a response. Pooled Standard deviation from the ANOVA model with treatment effects.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.169
	Comments
	Method	ANOVA
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	FP MDI 250 mcg BID, ML 10 mg QD PM
	Comments	Least squares mean percent changes were obtained from the two-way ANOVA model with treatment and BMD scan center effects. Results shown use percent change as a response. Pooled Standard deviation from the ANOVA model with treatment effects.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.526
	Comments
	Method	ANOVA
	Comments

4. Secondary Outcome

Title	Summary of Change From Baseline to Endpoint in FEV1 (Forced Expiratory Volume in One Second).
Description	Mean percent change from Baseline (the last non-missing value prior to treatment) in pulmonary function test FEV1 from in-office visits and at Endpoint (last non-missing postbaseline value carried forward)
Time Frame	Baseline and up to ~ one year of treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	MF DPI 200 mcg QD PM	MF DPI 400 mcg QD PM	FP MDI 250 mcg BID	ML 10 mg QD PM
Arm/Group Description	Mometasone furoate (MF) dry powder inhaler (DPI) 200 mcg once daily (QD) in the evening (PM) for 1 year	MF DPI 400 mcg QD PM for 1 year	Fluticasone proprionate (FP) metered dose inhaler (MDI) 250 mcg twice daily (BID) for 1 year	Montelukast (ML) 10 mg QD PM for 1 year
Measure Participants	140	136	146	141
Mean (Standard Deviation) [percentage of FEV1]	0.29 (0.43)	0.38 (0.43)	0.31 (0.43)	0.19 (0.43)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	MF DPI 400 mcg QD PM, ML 10 mg QD PM
	Comments	Least square means and Pstd (pooled standard deviations) are obtained from the ANOVA model with treatment effects.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	ANOVA
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	FP MDI 250 mcg BID, ML 10 mg QD PM
	Comments	Least square means and Pstd (pooled standard deviations) are obtained from the ANOVA model with treatment effects.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.023
	Comments
	Method	ANOVA
	Comments

Adverse Events

Arm/Group Title	MF DPI 200 mcg QD PM		MF DPI 400 mcg QD PM		FP MDI 250 mcg BID		ML 10 mg QD PM
Arm/Group Description	Mometasone furoate (MF) dry powder inhaler (DPI) 200 mcg once daily (QD) in the evening (PM) for 1 year		MF DPI 400 mcg QD PM for 1 year		Fluticasone proprionate (FP) metered dose inhaler (MDI) 250 mcg twice daily (BID) for 1 year		Montelukast (ML) 10 mg QD PM for 1 year
All Cause Mortality
	MF DPI 200 mcg QD PM		MF DPI 400 mcg QD PM		FP MDI 250 mcg BID		ML 10 mg QD PM
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	MF DPI 200 mcg QD PM		MF DPI 400 mcg QD PM		FP MDI 250 mcg BID		ML 10 mg QD PM
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/140 (3.6%)		2/137 (1.5%)		4/147 (2.7%)		8/142 (5.6%)
Eye disorders
Lenticular opacities	0/140 (0%)	0	1/137 (0.7%)	1	0/147 (0%)	0	0/142 (0%)	0
Gastrointestinal disorders
Gastritis	1/140 (0.7%)	1	0/137 (0%)	0	0/147 (0%)	0	0/142 (0%)	0
Hepatobiliary disorders
Cholelithiasis	1/140 (0.7%)	1	0/137 (0%)	0	0/147 (0%)	0	0/142 (0%)	0
Infections and infestations
Appendicitis	0/140 (0%)	0	0/137 (0%)	0	0/147 (0%)	0	1/142 (0.7%)	1
Bronchopneumonia	0/140 (0%)	0	0/137 (0%)	0	1/147 (0.7%)	1	0/142 (0%)	0
Herpes zoster	0/140 (0%)	0	0/137 (0%)	0	0/147 (0%)	0	1/142 (0.7%)	1
Keratitis herpetic	0/140 (0%)	0	0/137 (0%)	0	0/147 (0%)	0	1/142 (0.7%)	1
Pneumonia	0/140 (0%)	0	0/137 (0%)	0	0/147 (0%)	0	1/142 (0.7%)	1
Injury, poisoning and procedural complications
Drug exposure during pregnancy	2/140 (1.4%)	2	0/137 (0%)	0	1/147 (0.7%)	1	1/142 (0.7%)	1
Overdose	1/140 (0.7%)	1	0/137 (0%)	0	0/147 (0%)	0	0/142 (0%)	0
Pregnancy, puerperium and perinatal conditions
Abortion spontaneous	2/140 (1.4%)	2	0/137 (0%)	0	1/147 (0.7%)	1	1/142 (0.7%)	1
Ectopic pregnancy	0/140 (0%)	0	0/137 (0%)	0	1/147 (0.7%)	1	0/142 (0%)	0
Psychiatric disorders
Anxiety	1/140 (0.7%)	1	0/137 (0%)	0	0/147 (0%)	0	0/142 (0%)	0
Depression	1/140 (0.7%)	1	0/137 (0%)	0	0/147 (0%)	0	0/142 (0%)	0
Psychotic disorder	0/140 (0%)	0	0/137 (0%)	0	0/147 (0%)	0	1/142 (0.7%)	1
Suicidal ideation	1/140 (0.7%)	1	0/137 (0%)	0	0/147 (0%)	0	0/142 (0%)	0
Reproductive system and breast disorders
Vaginal haemorrhage	0/140 (0%)	0	0/137 (0%)	0	0/147 (0%)	0	1/142 (0.7%)	1
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure	1/140 (0.7%)	1	0/137 (0%)	0	0/147 (0%)	0	0/142 (0%)	0
Asthma	0/140 (0%)	0	0/137 (0%)	0	0/147 (0%)	0	1/142 (0.7%)	1
Asthmatic crisis	0/140 (0%)	0	1/137 (0.7%)	1	0/147 (0%)	0	0/142 (0%)	0
Nasal septum deviation	0/140 (0%)	0	0/137 (0%)	0	1/147 (0.7%)	1	0/142 (0%)	0
Pleural effusion	0/140 (0%)	0	0/137 (0%)	0	0/147 (0%)	0	1/142 (0.7%)	1
Sinus congestion	0/140 (0%)	0	0/137 (0%)	0	1/147 (0.7%)	1	0/142 (0%)	0
Social circumstances
Victim of homicide	0/140 (0%)	0	0/137 (0%)	0	0/147 (0%)	0	1/142 (0.7%)	1
Other (Not Including Serious) Adverse Events
	MF DPI 200 mcg QD PM		MF DPI 400 mcg QD PM		FP MDI 250 mcg BID		ML 10 mg QD PM
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	61/140 (43.6%)		69/137 (50.4%)		75/147 (51%)		64/142 (45.1%)
Gastrointestinal disorders
Abdominal pain	5/140 (3.6%)	6	4/137 (2.9%)	5	8/147 (5.4%)	28	6/142 (4.2%)	7
Dyspepsia	4/140 (2.9%)	12	7/137 (5.1%)	8	2/147 (1.4%)	3	2/142 (1.4%)	3
Infections and infestations
Bronchitis	3/140 (2.1%)	4	10/137 (7.3%)	12	7/147 (4.8%)	8	10/142 (7%)	13
Influenza	14/140 (10%)	16	10/137 (7.3%)	15	11/147 (7.5%)	13	13/142 (9.2%)	19
Nasopharyngitis	16/140 (11.4%)	29	27/137 (19.7%)	45	26/147 (17.7%)	40	23/142 (16.2%)	32
Pharyngitis	17/140 (12.1%)	19	14/137 (10.2%)	19	11/147 (7.5%)	15	12/142 (8.5%)	15
Rhinitis	3/140 (2.1%)	4	6/137 (4.4%)	28	3/147 (2%)	6	9/142 (6.3%)	21
Upper respiratory tract infection	6/140 (4.3%)	9	10/137 (7.3%)	15	7/147 (4.8%)	7	2/142 (1.4%)	2
Musculoskeletal and connective tissue disorders
Back pain	4/140 (2.9%)	4	10/137 (7.3%)	14	9/147 (6.1%)	11	4/142 (2.8%)	6
Nervous system disorders
Headache	22/140 (15.7%)	55	18/137 (13.1%)	38	19/147 (12.9%)	37	21/142 (14.8%)	93
Respiratory, thoracic and mediastinal disorders
Rhinitis allergic	7/140 (5%)	12	9/137 (6.6%)	14	11/147 (7.5%)	35	7/142 (4.9%)	15

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

Principal investigator (PI) agrees not to publish or publicly present any interim results of the study without prior written consent of the sponsor. The PI further agrees to provide to the sponsor, 30 days prior to submission, review copies for publication that report any study results. The sponsor has the right to review and comment. If the parties disagree, PI agrees to meet with the sponsor, prior to submission for publication, to discuss and resolve any such issues or disagreement.