SIENA: Steroids In Eosinophil Negative Asthma

• Sponsor: Milton S. Hershey Medical Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT02066298
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI) (NIH)
• Enrollment: 295
• Locations: 25
• Arms: 6
• Actual Duration (Months): 46
• Patients Per Site: 11.8
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

Because approximately half of all mild-moderately-severe asthma is persistently non-eosinophilic, it is important to determine prospectively if patients who are persistently non-eosinophilic differ in their benefit from inhaled corticosteroid treatment compared to patients who are not persistently non-eosinophilic.

Condition or Disease	Intervention/Treatment	Phase
Asthma	Drug: Mometasone 220mcg BID; Drug: Tiotropium Respimat 5mcg QD; Drug: Placebo	Phase 3

Detailed Description

SIENA is a 42-week randomized, stratified, 3-period double-blind placebo-controlled crossover study of patients with symptomatic mild-to-moderate asthma, not already taking an inhaled corticosteroid, in whom the effect of "medium-dose" inhaled corticosteroid (ICS) will be compared with the effect of placebo and with a long-acting muscarinic antagonist (LMA).

Study Design

• Study Type: Interventional
• Actual Enrollment: 295 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Steroids In Eosinophil Negative Asthma
• Actual Study Start Date: Jul 1, 2014
• Actual Primary Completion Date: May 1, 2018
• Actual Study Completion Date: May 1, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Mometasone then Tiotropium then Placebo Mometasone 220mcg BID, followed by Tiotropium Respimat 5mcg QD, followed by Placebo	Drug: Mometasone 220mcg BID; Mometasone is an ICS; Other Names: Asmanex ; Drug: Tiotropium Respimat 5mcg QD; Tiotropium is a LMA; Drug: Placebo
Experimental: Mometasone then Placebo then Tiotropium Mometasone 220mcg BID, followed by Placebo, followed by Tiotropium Respimat 5mcg QD	Drug: Mometasone 220mcg BID; Mometasone is an ICS; Other Names: Asmanex ; Drug: Tiotropium Respimat 5mcg QD; Tiotropium is a LMA; Drug: Placebo
Experimental: Placebo then Mometasone then Tiotropium Placebo, followed by Mometasone 220mcg BID, followed by Tiotropium Respimat 5mcg QD	Drug: Mometasone 220mcg BID; Mometasone is an ICS; Other Names: Asmanex ; Drug: Tiotropium Respimat 5mcg QD; Tiotropium is a LMA; Drug: Placebo
Experimental: Placebo then Tiotropium then Mometasone Placebo, followed by Tiotropium Respimat 5mcg QD, followed by Mometasone 220mcg BID	Drug: Mometasone 220mcg BID; Mometasone is an ICS; Other Names: Asmanex ; Drug: Tiotropium Respimat 5mcg QD; Tiotropium is a LMA; Drug: Placebo
Experimental: Tiotropium then Placebo then Mometasone Tiotropium Respimat 5mcg QD, followed by Placebo, followed by Mometasone 220mcg BID	Drug: Mometasone 220mcg BID; Mometasone is an ICS; Other Names: Asmanex ; Drug: Tiotropium Respimat 5mcg QD; Tiotropium is a LMA; Drug: Placebo
Experimental: Tiotropium then Mometasone then Placebo Tiotropium Respimat 5mcg QD, followed by Mometasone 220mcg BID, followed by Placebo	Drug: Mometasone 220mcg BID; Mometasone is an ICS; Other Names: Asmanex ; Drug: Tiotropium Respimat 5mcg QD; Tiotropium is a LMA; Drug: Placebo

Outcome Measures

Primary Outcome Measures

1. Pairwise Comparison of Treatments Based on Composite Measure Using Treatment Failures, Asthma Control Days, and Percent Predicted FEV1. [End of 12-week treatment period]

   This composite outcome uses a hierarchical method to ascertain differences in asthma control. For each participant, treatments are first compared to see if they differ in terms of treatment failures. If one treatment results in no treatment failures and another treatment does, it is deemed the superior treatment and no further comparisons are made. If treatment superiority cannot be assigned by treatment failures, then they are compared by asthma control days (ACDs). If one treatment yields at least 31 annualized ACDs more than another, it is deemed the superior treatment. If treatment superiority still cannot be assigned by ACDs, then they are compared by percent predicted FEV1 at the end of a treatment period. If one treatment yields at least 5% greater FEV1 than another, it is deemed the superior treatment. If treatment superiority cannot be assigned by exacerbations, ACDs or FEV1, then that participant is classified as having no differential response.

Secondary Outcome Measures

1. Treatment Failure [End of 12-week treatment period]

   Treatment Failure includes: Awakening from asthma three or more times in a two-week period or on two consecutive nights, or Using albuterol for relief of symptoms four or more times/day for two or more consecutive days, or Albuterol has been relieving symptoms for less than four hours after each treatment over a 12-hour period, or Using albuterol for relief of symptoms daily for seven days, and this use exceeds two times the weekly use of albuterol in the baseline period, or exercise induces unusual breathlessness

2. Annualized Asthma Control Days [End of 12-week treatment period]

   Asthma Control Days (ACD) are based on patient completed electronic daily diaries, and are defined as: A day with no rescue albuterol use (pre-exercise albuterol will not be counted), no non-study asthma medications, no daytime asthma symptoms (shortness of breath, wheezing, chest tightness, phlegm/mucus rated as mild, moderate or severe, or cough rated as moderate or severe), no nighttime asthma symptoms, no unscheduled healthcare visits for asthma, and no PEF < 80% of predetermined baseline. Annualized ACD are calculated as the proportion of ACD during the treatment period multiplied by 365.

3. Forced Expiratory Volume at One Second (FEV1) Percent of Predicted [End of 12-week treatment period]

   FEV1, expressed as percent of predicted FEV1 based on age, sex, race, and height.

4. Peak Expiratory Flow Rate [End of 12-week treatment period]

   Peak expiratory flow rate is a person's maximum speed of expiration. It measures the airflow through the bronchi and thus the degree of obstruction in the airways.

5. Asthma Exacerbations [End of 12-week treatment period]

   Asthma exacerbations are more severe episodes of acute worsening, defined by meeting one or more of the following: FEV1 <50% of baseline on 2 consecutive measurements FEV1 <40% of predicted on 2 consecutive measurements Use of ≥ 16 puffs of "as needed" β-agonist per 24 hours for a period of 48 hours Use of oral/parenteral corticosteroid due to asthma

Eligibility Criteria

Criteria

• Ages Eligible for Study: 12 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Physician-diagnosed asthma for at least previous 12 months.

• Able to perform reproducible spirometry.

• Baseline FEV1≥70% of predicted.

• Asthma confirmed either by:

• Beta-agonist reversibility to 4 puffs albuterol ≥ 12% OR

• Methacholine PC20 ≤ 16 mg/ml

• At least 1 of the following indications for chronic controller therapy:

• Asthma Symptoms > 2 days/week OR

• Nocturnal Asthma Symptoms > 2 nights/month OR

• Short-acting beta-agonist use for symptom control > 2 days/week

• For participants ≥18 years of age: Ability to provide informed consent. For participants under 18 years of age: Ability to provide verbal or written assent and ability of parent to provide informed consent.

• Willingness, if female and able to conceive, to utilize one medically-acceptable form of contraception.

Exclusion Criteria:

• Chronic inhaled or oral corticosteroid therapy.

• Use of inhaled or oral corticosteroid therapy within 6 weeks.

• New allergen immunotherapy within the past 3 months or anticipated changes to an ongoing immunotherapy regimen.

• Use of omalizumab within 3 months.

• History of:

• bladder-neck obstruction, urinary retention or benign prostatic hyperplasia

• narrow angle glaucoma

• significant cardiovascular disorders and arrhythmias

• life-threatening asthma requiring treatment with intubation or mechanical ventilation within the past 5 years

• Respiratory tract infection within past 6 weeks.

• History of smoking within the past 1 year, or > 10 pack-years total if ≥ 18 years of age, or > 5 pack-years total if < 18 years of age.

• Chronic diseases or medical conditions (other than asthma) that could put the participant at risk by participation, e.g. chronic diseases of the lung (other than asthma), heart, liver, kidney, endocrine or nervous system, or immunodeficiency.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Arizona College of Medicine	Tucson	Arizona	United States	85724
2	UCSF Benioff Children's Hospital	San Francisco	California	United States	94143
3	University of California at San Francisco	San Francisco	California	United States	94143
4	National Jewish Health	Denver	Colorado	United States	80206
5	Nemours Children's Clinic	Jacksonville	Florida	United States	32207
6	Nemours Children's Clinic	Orlando	Florida	United States	32827
7	Emory University	Atlanta	Georgia	United States	30322
8	Northwestern Memorial Hospital	Chicago	Illinois	United States	60611
9	Rush University Medical Center	Chicago	Illinois	United States	60612
10	University of Illinois at Chicago	Chicago	Illinois	United States	60612
11	Ann and Robert H. Lurie Children's Hospital	Chicago	Illinois	United States	60614
12	University of Chicago	Chicago	Illinois	United States	60637
13	Brigham and Women's Hospital	Boston	Massachusetts	United States	02115
14	Children's Hospital Boston	Boston	Massachusetts	United States	02115
15	St. Louis Children's Hospital	Saint Louis	Missouri	United States	63110
16	Washington University	Saint Louis	Missouri	United States	63110
17	Columbia University Medical Center	New York	New York	United States	10032
18	Duke University School of Medicine	Durham	North Carolina	United States	27110
19	North Carolina Clinical Research	Raleigh	North Carolina	United States	27607
20	Wake Forest University Health Sciences	Winston-Salem	North Carolina	United States	27157
21	Rainbow Babies and Children's Hospital, Case Western Reserve University	Cleveland	Ohio	United States	44106
22	Allegheny General Hospital	Pittsburgh	Pennsylvania	United States	15212
23	University of Pittsburgh	Pittsburgh	Pennsylvania	United States	15213
24	Children's Hospital of Pittsburgh of UPMC	Pittsburgh	Pennsylvania	United States	15224
25	University of Wisconsin-Madison	Madison	Wisconsin	United States	53792

Sponsors and Collaborators

• Milton S. Hershey Medical Center
• National Heart, Lung, and Blood Institute (NHLBI)

Investigators

• Study Chair: William Busse, M.D., University of Wisconsin, Madison

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Nov 12, 2015

More Information

Additional Information:

• AsthmaNet

Publications

None provided.

• Responsible Party: dave mauger, Principal Investigator, AsthmaNet Data Coordinating Center, Milton S. Hershey Medical Center
• ClinicalTrials.gov Identifier: NCT02066298
• Other Study ID Numbers: AsthmaNet 007; 1U10HL098115
• First Posted: Feb 19, 2014
• Last Update Posted: May 29, 2019
• Last Verified: May 1, 2019

• Keywords provided by dave mauger, Principal Investigator, AsthmaNet Data Coordinating Center, Milton S. Hershey Medical Center: Asthma; Mometasone; Tiotropium
• Additional relevant MeSH terms: Asthma; Mometasone Furoate; Tiotropium Bromide

Study Results

Participant Flow

Arm/Group Title	Mometasone Then Tiotropium Then Placebo	Mometasone Then Placebo Then Tiotropium	Placebo Then Mometasone Then Tiotropium	Placebo Then Tiotropium Then Mometasone	Tiotropium Then Placebo Then Mometasone	Tiotropium Then Mometasone Then Placebo
Arm/Group Description	Mometasone 220mcg BID, followed by Tiotropium Respimat 5mcg QD, followed by Placebo Mometasone 220mcg BID: Mometasone is an ICS Tiotropium Respimat 5mcg QD: Tiotropium is a LMA Placebo	Mometasone 220mcg BID, followed by Placebo, followed by Tiotropium Respimat 5mcg QD Mometasone 220mcg BID: Mometasone is an ICS Tiotropium Respimat 5mcg QD: Tiotropium is a LMA Placebo	Placebo, followed by Mometasone 220mcg BID, followed by Tiotropium Respimat 5mcg QD Mometasone 220mcg BID: Mometasone is an ICS Tiotropium Respimat 5mcg QD: Tiotropium is a LMA Placebo	Placebo, followed by Tiotropium Respimat 5mcg QD, followed by Mometasone 220mcg BID Mometasone 220mcg BID: Mometasone is an ICS Tiotropium Respimat 5mcg QD: Tiotropium is a LMA Placebo	Tiotropium Respimat 5mcg QD, followed by Placebo, followed by Mometasone 220mcg BID Mometasone 220mcg BID: Mometasone is an ICS Tiotropium Respimat 5mcg QD: Tiotropium is a LMA Placebo	Tiotropium Respimat 5mcg QD, followed by Mometasone 220mcg BID, followed by Placebo Mometasone 220mcg BID: Mometasone is an ICS Tiotropium Respimat 5mcg QD: Tiotropium is a LMA Placebo
Period Title: Overall Study
STARTED	49	48	50	51	47	50
Completed 1st Period	44	47	45	48	46	45
Completed 2nd Period	41	41	41	46	42	41
Completed 3rd Period	40	40	40	45	38	38
COMPLETED	40	40	40	45	38	38
NOT COMPLETED	9	8	10	6	9	12

Baseline Characteristics

Arm/Group Title	Mometasone Then Tiotropium Then Placebo	Mometasone Then Placebo Then Tiotropium	Placebo Then Mometasone Then Tiotropium	Placebo Then Tiotropium Then Mometasone	Tiotropium Then Placebo Then Mometasone	Tiotropium Then Mometasone Then Placebo	Total
Arm/Group Description	Mometasone 220mcg BID, followed by Tiotropium Respimat 5mcg QD, followed by Placebo Mometasone 220mcg BID: Mometasone is an ICS Tiotropium Respimat 5mcg QD: Tiotropium is a LMA Placebo	Mometasone 220mcg BID, followed by Placebo, followed by Tiotropium Respimat 5mcg QD Mometasone 220mcg BID: Mometasone is an ICS Tiotropium Respimat 5mcg QD: Tiotropium is a LMA Placebo	Placebo, followed by Mometasone 220mcg BID, followed by Tiotropium Respimat 5mcg QD Mometasone 220mcg BID: Mometasone is an ICS Tiotropium Respimat 5mcg QD: Tiotropium is a LMA Placebo	Placebo, followed by Tiotropium Respimat 5mcg QD, followed by Mometasone 220mcg BID Mometasone 220mcg BID: Mometasone is an ICS Tiotropium Respimat 5mcg QD: Tiotropium is a LMA Placebo	Tiotropium Respimat 5mcg QD, followed by Placebo, followed by Mometasone 220mcg BID Mometasone 220mcg BID: Mometasone is an ICS Tiotropium Respimat 5mcg QD: Tiotropium is a LMA Placebo	Tiotropium Respimat 5mcg QD, followed by Mometasone 220mcg BID, followed by Placebo Mometasone 220mcg BID: Mometasone is an ICS Tiotropium Respimat 5mcg QD: Tiotropium is a LMA Placebo	Total of all reporting groups
Overall Participants	49	48	50	51	47	50	295
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	32.3 (15.3)	32.6 (13.8)	33.2 (13.9)	30.0 (14.8)	30.8 (12.5)	28.2 (12.9)	31.2 (13.9)
Sex: Female, Male (Count of Participants)
Female	29 59.2%	30 62.5%	32 64%	33 64.7%	27 57.4%	33 66%	184 62.4%
Male	20 40.8%	18 37.5%	18 36%	18 35.3%	20 42.6%	17 34%	111 37.6%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	6 12.2%	4 8.3%	4 8%	7 13.7%	7 14.9%	7 14%	35 11.9%
Not Hispanic or Latino	43 87.8%	44 91.7%	46 92%	44 86.3%	40 85.1%	43 86%	260 88.1%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Asian	2 4.1%	2 4.2%	2 4%	3 5.9%	0 0%	2 4%	11 3.7%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	13 26.5%	14 29.2%	15 30%	16 31.4%	14 29.8%	16 32%	88 29.8%
White	34 69.4%	32 66.7%	33 66%	31 60.8%	32 68.1%	30 60%	192 65.1%
More than one race	0 0%	0 0%	0 0%	1 2%	1 2.1%	2 4%	4 1.4%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	49 100%	48 100%	50 100%	51 100%	47 100%	50 100%	295 100%
Forced expiratory volume at one second (FEV1) Percent of Predicted (percentage of predicted FEV1) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [percentage of predicted FEV1]	90.6 (11.5)	91.5 (11.2)	92.0 (11.8)	93.8 (12.4)	91.7 (13.6)	91.6 (12.5)	91.9 (12.1)
Asthma Control Test (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	21.3 (2.3)	21.2 (2.5)	21.1 (2.7)	20.9 (2.2)	20.9 (2.8)	21.1 (2.5)	21.1 (2.5)
Sputum differential count - Percent eosinophils (percentage of cells) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [percentage of cells]	0.1	0.4	0.4	0.2	0.2	0.2	0.2
Blood differential count - Percent eosinophils (percentage of cells) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [percentage of cells]	2.3	4.0	3.0	3.2	3.0	2.8	3.0

Outcome Measures

1. Primary Outcome

Title	Pairwise Comparison of Treatments Based on Composite Measure Using Treatment Failures, Asthma Control Days, and Percent Predicted FEV1.
Description	This composite outcome uses a hierarchical method to ascertain differences in asthma control. For each participant, treatments are first compared to see if they differ in terms of treatment failures. If one treatment results in no treatment failures and another treatment does, it is deemed the superior treatment and no further comparisons are made. If treatment superiority cannot be assigned by treatment failures, then they are compared by asthma control days (ACDs). If one treatment yields at least 31 annualized ACDs more than another, it is deemed the superior treatment. If treatment superiority still cannot be assigned by ACDs, then they are compared by percent predicted FEV1 at the end of a treatment period. If one treatment yields at least 5% greater FEV1 than another, it is deemed the superior treatment. If treatment superiority cannot be assigned by exacerbations, ACDs or FEV1, then that participant is classified as having no differential response.
Time Frame	End of 12-week treatment period

Outcome Measure Data

Analysis Population Description

For each pairwise comparison (mometasone vs. placebo and tiotropium vs. placebo), participants were required to complete both of the relevant treatment periods in order to be included in the analysis.

Arm/Group Title	Eosinophil Low	Eosinophil High
Arm/Group Description	Participants with sputum eosinophils < 2% at study entry	Participants with sputum eosinophils >= 2% at study entry
Measure Participants	184	67
Mometesone superior to placebo	74 151%	35 72.9%
Placebo superior to mometasone	56 114.3%	12 25%
Mometesone equal to placebo	46 93.9%	20 41.7%
Tiotropium superior to placebo	80 163.3%	25 52.1%
Placebo superior to tiotropium	52 106.1%	19 39.6%
Tiotropium equal to placebo	49 100%	18 37.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Eosinophil Low
	Comments	The null hypothesis was that, among those participants for which either mometasone is not equal to placebo, the proportion for which mometasone is superior to placebo is equal to the proportion for which placebo is superior to mometasone. The trial was designed to provide power of 0.85 for a 0.20 difference between the proportions being compared at a significance level of 0.025.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.14
	Comments
	Method	exact binomial test
	Comments	a priori threshold for significance was 0.025

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Eosinophil Low
	Comments	The null hypothesis was that, among those participants for which either tiotropium is not equal to placebo, the proportion for which tiotropium is superior to placebo is equal to the proportion for which placebo is superior to tiotropium. The trial was designed to provide power of 0.85 for a 0.20 difference between the proportions being compared at a significance level of 0.025.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.029
	Comments	a priori threshold for significance was 0.025
	Method	exact binomial test
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Eosinophil High
	Comments	The null hypothesis was that, among those participants for which either mometasone is not equal to placebo, the proportion for which mometasone is superior to placebo is equal to the proportion for which placebo is superior to mometasone. This was an exploratory analysis and there were no power considerations.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.001
	Comments	this analysis is considered exploratory
	Method	exact binomial test
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Eosinophil High
	Comments	The null hypothesis was that, among those participants for which either tiotropium is not equal to placebo, the proportion for which tiotropium is superior to placebo is equal to the proportion for which placebo is superior to tiotropium. This was an exploratory analysis and there were no power considerations.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.45
	Comments	this analysis is considered exploratory
	Method	exact binomial test
	Comments

2. Secondary Outcome

Title	Treatment Failure
Description	Treatment Failure includes: Awakening from asthma three or more times in a two-week period or on two consecutive nights, or Using albuterol for relief of symptoms four or more times/day for two or more consecutive days, or Albuterol has been relieving symptoms for less than four hours after each treatment over a 12-hour period, or Using albuterol for relief of symptoms daily for seven days, and this use exceeds two times the weekly use of albuterol in the baseline period, or exercise induces unusual breathlessness
Time Frame	End of 12-week treatment period

Outcome Measure Data

Analysis Population Description

participants who completed the treatment period with data to evaluate treatment failure outcome

Arm/Group Title	Placebo	Mometasone 220mcg BID	Tiotropium Respimat 5mcg QD
Arm/Group Description	The placebo treatment period for all participants.	The mometasone treatment period for all participants. Mometasone administered 220mcg BID	The tiotropium treatment period for all participants. Tiotropium administered 5mcg QD
Measure Participants	254	255	258
Count of Participants [Participants]	29 59.2%	29 60.4%	35 70%

3. Secondary Outcome

Title	Annualized Asthma Control Days
Description	Asthma Control Days (ACD) are based on patient completed electronic daily diaries, and are defined as: A day with no rescue albuterol use (pre-exercise albuterol will not be counted), no non-study asthma medications, no daytime asthma symptoms (shortness of breath, wheezing, chest tightness, phlegm/mucus rated as mild, moderate or severe, or cough rated as moderate or severe), no nighttime asthma symptoms, no unscheduled healthcare visits for asthma, and no PEF < 80% of predetermined baseline. Annualized ACD are calculated as the proportion of ACD during the treatment period multiplied by 365.
Time Frame	End of 12-week treatment period

Outcome Measure Data

Analysis Population Description

participants who completed the treatment period with data to evaluate asthma control days

Arm/Group Title	Placebo	Mometasone 220mcg BID	Tiotropium Respimat 5mcg QD
Arm/Group Description	The placebo treatment period for all participants	The mometasone treatment period for all participants. Mometasone administered 220mcg BID	The tiotropium treatment period for all participants. Tiotropium administered 5mcg QD
Measure Participants	216	225	228
Mean (Standard Deviation) [days]	179 (137)	186 (141)	176 (139)

4. Secondary Outcome

Title	Forced Expiratory Volume at One Second (FEV1) Percent of Predicted
Description	FEV1, expressed as percent of predicted FEV1 based on age, sex, race, and height.
Time Frame	End of 12-week treatment period

Outcome Measure Data

Analysis Population Description

participants who completed the treatment period and were able to provide FEV1 measurements

Arm/Group Title	Eosinophil Low - Placebo	Mometasone 220mcg BID	Tiotropium Respimat 5mcg QD
Arm/Group Description	The placebo treatment period for all participants	The mometasone treatment period for all participants. Mometasone administered 220mcg BID	The tiotropium treatment period for all participants. Tiotropium administered 5mcg QD
Measure Participants	254	247	252
Mean (Standard Deviation) [percentage of predicted FEV1]	92 (14)	94 (13)	95 (14)

5. Secondary Outcome

Title	Peak Expiratory Flow Rate
Description	Peak expiratory flow rate is a person's maximum speed of expiration. It measures the airflow through the bronchi and thus the degree of obstruction in the airways.
Time Frame	End of 12-week treatment period

Outcome Measure Data

Analysis Population Description

participants who completed the treatment period and were able to provide FEV1 measurements

Arm/Group Title	Placebo	Mometasone 220mcg BID	Tiotropium Respimat 5mcg QD
Arm/Group Description	The placebo treatment period for all participants	The mometasone treatment period for all participants. Mometasone administered 220mcg BID	The tiotropium treatment period for all participants. Tiotropium administered 5mcg QD
Measure Participants	253	249	256
Mean (Standard Deviation) [liters per minute]	476 (117)	485 (117)	497 (117)

6. Secondary Outcome

Title	Asthma Exacerbations
Description	Asthma exacerbations are more severe episodes of acute worsening, defined by meeting one or more of the following: FEV1 <50% of baseline on 2 consecutive measurements FEV1 <40% of predicted on 2 consecutive measurements Use of ≥ 16 puffs of "as needed" β-agonist per 24 hours for a period of 48 hours Use of oral/parenteral corticosteroid due to asthma
Time Frame	End of 12-week treatment period

Outcome Measure Data

Analysis Population Description

participants who completed the treatment period with data to evaluate exacerbations

Arm/Group Title	Placebo	Mometasone 220mcg BID	Tiotropium Respimat 5mcg QD
Arm/Group Description	The placebo treatment period for all participants	The mometasone treatment period for all participants. Mometasone administered 220mcg BID	The tiotropium treatment period for all participants. Tiotropium administered 5mcg QD
Measure Participants	254	255	258
Count of Participants [Participants]	1 2%	3 6.3%	5 10%

Adverse Events

Time Frame	Each participant was followed over the course of three 12-week treatment periods for a total of 36 weeks. The adverse events recorded below are reported at the treatment period level and represent 12 weeks of "at risk" exposure time.
Arm/Group Title	Placebo		Mometasone 220mcg BID		Tiotropium Respimat 5mcg QD
Arm/Group Description	The placebo treatment period for all participants		The mometasone treatment period for all participants. Mometasone administered 220mcg BID		The tiotropium treatment period for all participants. Tiotropium administered 5mcg QD
All Cause Mortality
	Placebo		Mometasone 220mcg BID		Tiotropium Respimat 5mcg QD
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/276 (0%)		0/275 (0%)		0/271 (0%)
Serious Adverse Events
	Placebo		Mometasone 220mcg BID		Tiotropium Respimat 5mcg QD
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/276 (0%)		6/275 (2.2%)		2/271 (0.7%)
Gastrointestinal disorders
Partial bowel obstruction.	/276 (NaN)		0/275 (0%)	0	1/271 (0.4%)	1
Acute appendicitis without mention of peritonitis	/276 (NaN)		1/275 (0.4%)	1	0/271 (0%)	0
Musculoskeletal and connective tissue disorders
closed fracture of lower end of humerus	/276 (NaN)		1/275 (0.4%)	1	0/271 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Hydatidiform mole	/276 (NaN)		0/275 (0%)	0	1/271 (0.4%)	1
malignant neoplasm of skin of other and unspecified parts of face	/276 (NaN)		1/275 (0.4%)	1	0/271 (0%)	0
Pregnancy, puerperium and perinatal conditions
pregnancy	/276 (NaN)		1/275 (0.4%)	1	0/271 (0%)	0
Psychiatric disorders
Unspecified nonpsychotic mental disorder	/276 (NaN)		1/275 (0.4%)	1	0/271 (0%)	0
Adjustment disorder with depressed mood	/276 (NaN)		1/275 (0.4%)	1	0/271 (0%)	0
Other (Not Including Serious) Adverse Events
	Placebo		Mometasone 220mcg BID		Tiotropium Respimat 5mcg QD
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	45/276 (16.3%)		47/275 (17.1%)		38/271 (14%)
Respiratory, thoracic and mediastinal disorders
Acute nasopharyngitis	37/276 (13.4%)	42	33/275 (12%)	38	29/271 (10.7%)	37
Acute URI not otherwise specified	8/276 (2.9%)	9	16/275 (5.8%)	18	11/271 (4.1%)	13

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.