Asthma Clinical Research Network (ACRN) Trial - Tiotropium Bromide as an Alternative to Increased Inhaled Corticosteroid in Patients Inadequately Controlled on a Lower Dose of Inhaled Corticosteroid (TALC)

• Sponsor: Milton S. Hershey Medical Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT00565266
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI) (NIH)
• Enrollment: 210
• Locations: 10
• Arms: 6
• Duration (Months): 24
• Patients Per Site: 21
• Patients Per Site Per Month: 0.9

Study Details

Study Description

Brief Summary

Typically, people with asthma are initially prescribed a low dose of inhaled corticosteroid (ICS) medication to control asthma symptoms. If a low dose of ICS is ineffective at controlling symptoms, the addition of a second controller medication is recommended. This study will examine the effectiveness of the medication tiotropium bromide combined with a low dose of ICS at maintaining asthma control in people with moderately severe asthma.

Condition or Disease	Intervention/Treatment	Phase
Asthma	Drug: tiotropium bromide; Drug: salmeterol xinafoate; Drug: beclomethasone dipropionate	Phase 3

Detailed Description

National and international asthma treatment guidelines recommend ICS as the initial controller therapy for people with asthma who are in need of daily treatment with a controller medication. If treatment with low to moderate doses of ICS is not sufficient to gain and maintain asthma control, current guidelines recommend adding a second controller medication rather than increasing the dose of ICS. Current options for the second medication include a long-acting beta-agonist, a leukotriene modifier, or theophylline. It is possible that other medications, not yet tested, could fill the role of the second controller medication. Tiotropium bromide is a medication that is used to treat chronic obstructive pulmonary disease (COPD). It works by relaxing and opening the air passages to the lungs to make breathing easier. For people with asthma, the addition of tiotropium bromide may be a good option as a second controller medication. The purpose of this study is to determine if combining tiotropium bromide with a low dose of ICS is more effective than doubling the dose of ICS in people with moderately severe asthma. This study will also examine whether the addition of tiotropium bromide to low dose ICS is as effective as the addition of a long-acting beta-agonist at maintaining asthma control.

This study will begin with a 4-week run-in period during which participants will be monitored while they use an inhaler containing a low dose of ICS medication. Next, participants will be assigned to take part in either the TALC study or the Best Adjustment Strategy for Asthma in Long Term (BASALT) study, which is a separate Asthma Clinical Research Network (ACRN) study.

All TALC participants will then undergo three 16-week treatment periods, which will include the following:

• tiotropium bromide inhalation powder 18 mcg once daily (Tio) plus beclomethasone dipropionate 80 mcg twice daily (1xICS)

• salmeterol xinafoate inhalation powder 50 mcg twice daily (LABA) plus beclomethasone dipropionate 80 mcg twice daily (1xICS)

• beclomethasone dipropionate 160 mcg twice daily (2xICS)

The order in which the three treatment periods will occur will be randomly assigned for each participant. Each of the three 16-week treatment periods will consist of 14 weeks of treatment followed by a 2-week washout period, in which participants will receive a single does of ICS. Study visits will occur at baseline and Weeks 2 and 4 of the 4-week run-in period, and at Weeks 4, 9, 14, and 16 of each 16-week treatment period. Spirometry tests to measure lung function will occur at each study visit and exhaled nitric oxide testing and questionnaires to assess asthma control and symptoms will occur at most visits. During study visits at Week 4 of the run-in period and Week 14 of each treatment period, lung function measurements, sputum collection, questionnaires to assess asthma quality-of-life, and measurements of sleep and daytime alertness will all occur. Participants will also record asthma symptoms, peak flow measurements, and medication usage in a daily diary.

Study Design

• Study Type: Interventional
• Actual Enrollment: 210 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Asthma Clinical Research Network (ACRN) Trial - Tiotropium Bromide as an Alternative to Increased Inhaled Corticosteroid in Patients Inadequately Controlled on a Lower Dose of Inhaled Corticosteroid (TALC)
• Study Start Date: May 1, 2008
• Actual Primary Completion Date: May 1, 2010
• Actual Study Completion Date: May 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Tio + 1xICS || LABA + 1xICS || 2xICS Participants will take part in three 16-week treatment periods, which will occur in the following order: tiotropium bromide inhalation powder 18 mcg once daily (Tio) plus beclomethasone dipropionate 80 mcg twice daily (1xICS) salmeterol xinafoate inhalation powder 50 mcg twice daily (LABA) plus beclomethasone dipropionate 80 mcg twice daily (1xICS) beclomethasone dipropionate 160 mcg twice daily (2xICS) Each of the three 16-week treatment periods will consist of 14 weeks of treatment followed by a 2-week washout period, in which participants will receive beclomethasone dipropionate 80 mcg twice daily (1xICS).	Drug: tiotropium bromide; tiotropium bromide inhalation powder 18 mcg once daily; Other Names: SPIRIVA® HandiHaler® ; Drug: salmeterol xinafoate; salmeterol xinafoate inhalation powder 50 mcg twice daily; Other Names: Serevent® Diskus® ; Drug: beclomethasone dipropionate; beclomethasone dipropionate 80 mcg twice daily (1xICS) or 160 mcg twice daily (2xICS); Other Names: QVAR® Inhalation Aerosol
Experimental: TIO + 1xICS || 2xICS || LABA + 1xICS Participants will take part in three 16-week treatment periods, which will occur in the following order: tiotropium bromide inhalation powder 18 mcg once daily (Tio) plus beclomethasone dipropionate 80 mcg twice daily (1xICS) beclomethasone dipropionate 160 mcg twice daily (2xICS) salmeterol xinafoate inhalation powder 50 mcg twice daily (LABA) plus beclomethasone dipropionate 80 mcg twice daily (1xICS) Each of the three 16-week treatment periods will consist of 14 weeks of treatment followed by a 2-week washout period, in which participants will receive beclomethasone dipropionate 80 mcg twice daily (1xICS).	Drug: tiotropium bromide; tiotropium bromide inhalation powder 18 mcg once daily; Other Names: SPIRIVA® HandiHaler® ; Drug: salmeterol xinafoate; salmeterol xinafoate inhalation powder 50 mcg twice daily; Other Names: Serevent® Diskus® ; Drug: beclomethasone dipropionate; beclomethasone dipropionate 80 mcg twice daily (1xICS) or 160 mcg twice daily (2xICS); Other Names: QVAR® Inhalation Aerosol
Experimental: LABA + 1xICS || Tio + 1xICS || 2xICS Participants will take part in three 16-week treatment periods, which will occur in the following order: salmeterol xinafoate inhalation powder 50 mcg twice daily (LABA) plus beclomethasone dipropionate 80 mcg twice daily (1xICS) tiotropium bromide inhalation powder 18 mcg once daily (Tio) plus beclomethasone dipropionate 80 mcg twice daily (1xICS) beclomethasone dipropionate 160 mcg twice daily (2xICS) Each of the three 16-week treatment periods will consist of 14 weeks of treatment followed by a 2-week washout period, in which participants will receive beclomethasone dipropionate 80 mcg twice daily (1xICS).	Drug: tiotropium bromide; tiotropium bromide inhalation powder 18 mcg once daily; Other Names: SPIRIVA® HandiHaler® ; Drug: salmeterol xinafoate; salmeterol xinafoate inhalation powder 50 mcg twice daily; Other Names: Serevent® Diskus® ; Drug: beclomethasone dipropionate; beclomethasone dipropionate 80 mcg twice daily (1xICS) or 160 mcg twice daily (2xICS); Other Names: QVAR® Inhalation Aerosol
Experimental: LABA + 1xICS || 2xICS || Tio + 1xICS Participants will take part in three 16-week treatment periods, which will occur in the following order: salmeterol xinafoate inhalation powder 50 mcg twice daily (LABA) plus beclomethasone dipropionate 80 mcg twice daily (1xICS) beclomethasone dipropionate 160 mcg twice daily (2xICS) tiotropium bromide inhalation powder 18 mcg once daily (Tio) plus beclomethasone dipropionate 80 mcg twice daily (1xICS) Each of the three 16-week treatment periods will consist of 14 weeks of treatment followed by a 2-week washout period, in which participants will receive beclomethasone dipropionate 80 mcg twice daily (1xICS).	Drug: tiotropium bromide; tiotropium bromide inhalation powder 18 mcg once daily; Other Names: SPIRIVA® HandiHaler® ; Drug: salmeterol xinafoate; salmeterol xinafoate inhalation powder 50 mcg twice daily; Other Names: Serevent® Diskus® ; Drug: beclomethasone dipropionate; beclomethasone dipropionate 80 mcg twice daily (1xICS) or 160 mcg twice daily (2xICS); Other Names: QVAR® Inhalation Aerosol
Experimental: 2xICS || Tio + 1xICS| || LABA + 1xICS Participants will take part in three 16-week treatment periods, which will occur in the following order: beclomethasone dipropionate 160 mcg twice daily (2xICS) tiotropium bromide inhalation powder 18 mcg once daily (Tio) plus beclomethasone dipropionate 80 mcg twice daily (1xICS) salmeterol xinafoate inhalation powder 50 mcg twice daily (LABA) plus beclomethasone dipropionate 80 mcg twice daily (1xICS) Each of the three 16-week treatment periods will consist of 14 weeks of treatment followed by a 2-week washout period, in which participants will receive beclomethasone dipropionate 80 mcg twice daily (1xICS).	Drug: tiotropium bromide; tiotropium bromide inhalation powder 18 mcg once daily; Other Names: SPIRIVA® HandiHaler® ; Drug: salmeterol xinafoate; salmeterol xinafoate inhalation powder 50 mcg twice daily; Other Names: Serevent® Diskus® ; Drug: beclomethasone dipropionate; beclomethasone dipropionate 80 mcg twice daily (1xICS) or 160 mcg twice daily (2xICS); Other Names: QVAR® Inhalation Aerosol
Experimental: 2xICS || LABA + 1xICS || Tio + 1xICS Participants will take part in three 16-week treatment periods, which will occur in the following order: beclomethasone dipropionate 160 mcg twice daily (2xICS) salmeterol xinafoate inhalation powder 50 mcg twice daily (LABA) plus beclomethasone dipropionate 80 mcg twice daily (1xICS) tiotropium bromide inhalation powder 18 mcg once daily (Tio) plus beclomethasone dipropionate 80 mcg twice daily (1xICS) Each of the three 16-week treatment periods will consist of 14 weeks of treatment followed by a 2-week washout period, in which participants will receive beclomethasone dipropionate 80 mcg twice daily (1xICS).	Drug: tiotropium bromide; tiotropium bromide inhalation powder 18 mcg once daily; Other Names: SPIRIVA® HandiHaler® ; Drug: salmeterol xinafoate; salmeterol xinafoate inhalation powder 50 mcg twice daily; Other Names: Serevent® Diskus® ; Drug: beclomethasone dipropionate; beclomethasone dipropionate 80 mcg twice daily (1xICS) or 160 mcg twice daily (2xICS); Other Names: QVAR® Inhalation Aerosol

Outcome Measures

Primary Outcome Measures

1. Change Between Week 14 and Week 0 in the Morning (AM) Peak Expiratory Flow (PEF) [AM PEF was measured daily during each of the three 14-week treatment periods. The primary analysis constructed the change between week 14 and week 0.]

Secondary Outcome Measures

1. Change Between Week 14 and Week 0 in the Forced Expiratory Volume in One Second (FEV1) [FEV1 was measured on four occasions during each of the three 14-week treatment periods. The primary analysis constructed the change between week 14 and week 0.]

2. Change Between Week 14 and Week 0 in Asthma Symptoms [Asthma symptoms were measured daily during each of the three 14-week treatment periods. The primary analysis constructed the change between week 14 and week 0.]

   Asthma symptoms were recorded as 0 (absent = no symptom ) (mild = symptom was minimally troublesome, i.e. not sufficient to interfere with normal daily activity or sleep) (moderate = symptom was sufficiently troublesome to interfere with normal daily activity or sleep) (severe = symptom was so severe as to prevent normal activity and/or sleep )

3. Change Between Week 14 and Week 0 in the Asthma Quality-of-life Questionnaire Score [The asthma quality-of-life questionnaire score was measured on four occasions during each of the three 14-week treatment periods. The primary analysis constructed the change between week 14 and week 0.]

   Scores on the Asthma Quality-of-Life Questionnaire range from 1 to 7, with a higher score indicating a better quality of life.

4. Change Between Week 14 and Week 0 in the Asthma Control Questionnaire Score [The asthma control questionnaire score was measured on four occasions during each of the three 14-week treatment periods. The primary analysis constructed the change between week 14 and week 0.]

   Scores on the Asthma Control Questionnaire range from 0 to 6, with a higher score indicating worse asthma control.

5. Change Between Week 14 and Week 0 in the Albuterol Rescue Puffs Per Day [Albuterol rescue puffs were measured daily during each of the three 14-week treatment periods. The primary analysis constructed the change between week 14 and week 0.]

   Total number of puffs from the albuterol (rescue) inhaler during the previous 24 hours (excluding those puffs for preventive use).

6. Change Between Week 14 and Week 0 in the Proportion of Asthma Control Days [An asthma control day was determined daily during each of the three 14-week treatment periods. The primary analysis constructed the change between week 14 and week 0.]

   An asthma control day was defined as a day in which there were no symptoms and no albuterol (rescue) puffs.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria for TALC and BASALT Studies:

• Clinical history consistent with asthma

• Forced expiratory volume in one second (FEV1) greater than 40% of predicted value

• Asthma confirmed by one of the following two criteria:

1. Beta-agonist reversibility to 4 puffs albuterol of at least 12% OR

2. Methacholine provocative concentration at 20% (PC20) of 8 milligrams per milliliter (mg/mL) or less when not on an inhaled corticosteroid (ICS), or 16 mg/mL or less when on an ICS

• Need for daily controller therapy (i.e., ICS, leukotriene modifiers, and/or long-acting beta-agonists) based on one or more of the following criteria:

1. Received prescription for or used asthma controller within the 12 months prior to study entry OR

2. Experienced symptoms for more than twice a week and not on asthma controller

• If on inhaled steroids (any drug at any dose not exceeding the equivalent of 1000 micrograms (mcg) of fluticasone daily), participant must have been on a stable dose for at least 2 weeks prior to study entry

• Non-smoker (i.e., total lifetime smoking history less than 10 pack-years; no smoking for at least 1 year prior to study entry)

• Willing to use an effective form of birth control throughout the study

Inclusion Criteria for TALC Study:

• Ability to measure morning (AM) peak expiratory flow (PEF) on schedule using electronic peak flow meter (EPFM) and to complete the study diary correctly at least 75% of the time during the interval between Weeks 2 and 4 of the run-in period

• Adherence with study medication dosing at least 75% of the time during the interval between Weeks 2 and 4 of the run-in period

• No asthma exacerbation requiring use of oral corticosteroids or additional asthma medications (including an increased dose of ICS) during the run-in period

• FEV1 greater than 40% of the predicted value

Exclusion Criteria for BASALT and TALC Studies:

• Lung disease other than asthma, including chronic obstructive pulmonary disease (COPD) and chronic bronchitis

• Established or suspected diagnosis of vocal cord dysfunction

• Significant medical illness other than asthma

• History of respiratory tract infection within the 4 weeks prior to study entry

• History of a significant asthma exacerbation within the 4 weeks prior to study entry

• History of life-threatening asthma requiring treatment with intubation and mechanical ventilation in the 5 years prior to study entry

• Hyposensitization therapy other than an established maintenance regimen

• Inability to coordinate use of the delivery devices used in the study, based on the opinion of the investigator or clinical coordinator

• Pregnant

Exclusion Criteria for TALC Study:

• Inability to coordinate use of the medication delivery devices used in the study, based on the opinion of the investigator or clinical coordinator

• Presence at Week 4 of the run-in period of any of the exclusion criteria stipulated for Week 0 of the run-in period (Note: Respiratory tract infections that do not cause the participant to meet exacerbation criteria are not considered exclusionary.)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of California, San Diego	San Diego	California	United States	92093
2	University of California, San Francisco	San Francisco	California	United States	94143
3	National Jewish Medical and Research Center	Denver	Colorado	United States	80206
4	Brigham & Women's Hospital	Boston	Massachusetts	United States	02115
5	Washington University, St. Louis	Saint Louis	Missouri	United States	63130
6	Columbia University Health Sciences	New York	New York	United States	10032
7	Duke University Medical Center	Durham	North Carolina	United States	27710
8	Wake Forest University Health Sciences	Winston-Salem	North Carolina	United States	27157
9	University of Texas Medical Branch	Galveston	Texas	United States	77555
10	University of Wisconsin, Madison	Madison	Wisconsin	United States	53706

Sponsors and Collaborators

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

Investigators

• Principal Investigator: Homer A. Boushey, MD, University of California, San Francisco
• Principal Investigator: Richard J. Martin, MD, National Jewish Health
• Principal Investigator: Elliot Israel, MD, Brigham and Women's Hospital
• Principal Investigator: Stephen I. Wasserman, MD, University of California, San Diego
• Principal Investigator: Mario Castro, MD, Washington University School of Medicine
• Principal Investigator: Emily A. DiMango, MD, Columbia University
• Principal Investigator: Stephen P. Peters, MD, PhD, Wake Forest University Health Sciences
• Principal Investigator: Monica Kraft, MD, Duke University
• Principal Investigator: William J. Calhoun, MD, University of Texas
• Principal Investigator: Robert F. Lemanske, MD, University of Wisconsin, Madison
• Study Chair: Reuben M. Cherniack, MD, National Jewish Health

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Click here for the Asthma Clinical Research Network Web site

Publications

None provided.

• Responsible Party: Vernon M. Chinchilli, PhD, Professor and Chair, Department of Public Health Sciences, Milton S. Hershey Medical Center
• ClinicalTrials.gov Identifier: NCT00565266
• Other Study ID Numbers: 547; U10HL074206; U10HL074208; U10HL074073; U10HL074227; U10HL074225; U10HL074204; U10HL074218; U10HL074212; U10HL074231
• First Posted: Nov 29, 2007
• Last Update Posted: Jul 2, 2018
• Last Verified: May 1, 2018

• Additional relevant MeSH terms: Asthma; Beclomethasone; Bromides; Tiotropium Bromide; Salmeterol Xinafoate

Study Results

Participant Flow

Arm/Group Title	All Participants
Arm/Group Description	All participants randomized into the six-sequence crossover study. All TALC participants underwent three 16-week treatment periods: tiotropium bromide inhalation powder 18 mcg once daily (Tio) plus beclomethasone dipropionate 80 mcg twice daily (1xICS) salmeterol xinafoate inhalation powder 50 mcg twice daily (LABA) plus beclomethasone dipropionate 80 mcg twice daily (1xICS) beclomethasone dipropionate 160 mcg twice daily (2xICS)
Period Title: Overall Study
STARTED	210
COMPLETED	174
NOT COMPLETED	36

Baseline Characteristics

Arm/Group Title	All Participants
Arm/Group Description	All participants randomized into the six-sequence crossover study
Overall Participants	210
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	207 98.6%
>=65 years	3 1.4%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	42.2 (12.3)
Sex: Female, Male (Count of Participants)
Female	141 67.1%
Male	69 32.9%
Region of Enrollment (participants) [Number]
United States	210 100%

Outcome Measures

1. Primary Outcome

Title	Change Between Week 14 and Week 0 in the Morning (AM) Peak Expiratory Flow (PEF)
Time Frame	AM PEF was measured daily during each of the three 14-week treatment periods. The primary analysis constructed the change between week 14 and week 0.

Outcome Measure Data

Analysis Population Description

All randomized participants were included in the linear mixed-effects model analysis

Arm/Group Title	Tio + 1xICS	LABA + 1xICS	2xICS
Arm/Group Description	tiotropium bromide inhalation powder 18 mcg once daily (Tio) plus beclomethasone dipropionate 80 mcg twice daily (1xICS)	salmeterol xinafoate inhalation powder 50 mcg twice daily (LABA) plus beclomethasone dipropionate 80 mcg twice daily (1xICS)	beclomethasone dipropionate 160 mcg twice daily (2xICS)
Measure Participants	210	210	210
Least Squares Mean (Standard Error) [Liters per minute]	24.4 (4.2)	18.0 (3.2)	-1.4 (3.5)

2. Secondary Outcome

Title	Change Between Week 14 and Week 0 in the Forced Expiratory Volume in One Second (FEV1)
Time Frame	FEV1 was measured on four occasions during each of the three 14-week treatment periods. The primary analysis constructed the change between week 14 and week 0.

Outcome Measure Data

Analysis Population Description

All randomized participants were included in the linear mixed-effects model analysis

Arm/Group Title	Tio + 1xICS	LABA + 1xICS	2xICS
Arm/Group Description	tiotropium bromide inhalation powder 18 mcg once daily (Tio) plus beclomethasone dipropionate 80 mcg twice daily (1xICS)	salmeterol xinafoate inhalation powder 50 mcg twice daily (LABA) plus beclomethasone dipropionate 80 mcg twice daily (1xICS)	beclomethasone dipropionate 160 mcg twice daily (2xICS)
Measure Participants	210	210	210
Least Squares Mean (Standard Error) [liters]	0.12 (0.025)	0.01 (0.025)	0.02 (0.025)

3. Secondary Outcome

Title	Change Between Week 14 and Week 0 in Asthma Symptoms
Description	Asthma symptoms were recorded as 0 (absent = no symptom ) (mild = symptom was minimally troublesome, i.e. not sufficient to interfere with normal daily activity or sleep) (moderate = symptom was sufficiently troublesome to interfere with normal daily activity or sleep) (severe = symptom was so severe as to prevent normal activity and/or sleep )
Time Frame	Asthma symptoms were measured daily during each of the three 14-week treatment periods. The primary analysis constructed the change between week 14 and week 0.

Outcome Measure Data

Analysis Population Description

All randomized participants were included in the linear mixed-effects model analysis

Arm/Group Title	Tio + 1xICS	LABA + 1xICS	2xICS
Arm/Group Description	tiotropium bromide inhalation powder 18 mcg once daily (Tio) plus beclomethasone dipropionate 80 mcg twice daily (1xICS)	salmeterol xinafoate inhalation powder 50 mcg twice daily (LABA) plus beclomethasone dipropionate 80 mcg twice daily (1xICS)	beclomethasone dipropionate 160 mcg twice daily (2xICS)
Measure Participants	210	210	210
Least Squares Mean (Standard Error) [units on a scale]	-0.09 (0.018)	-0.04 (0.018)	0.03 (0.018)

4. Secondary Outcome

Title	Change Between Week 14 and Week 0 in the Asthma Quality-of-life Questionnaire Score
Description	Scores on the Asthma Quality-of-Life Questionnaire range from 1 to 7, with a higher score indicating a better quality of life.
Time Frame	The asthma quality-of-life questionnaire score was measured on four occasions during each of the three 14-week treatment periods. The primary analysis constructed the change between week 14 and week 0.

Outcome Measure Data

Analysis Population Description

All randomized participants were included in the linear mixed-effects model analysis

Arm/Group Title	Tio + 1xICS	LABA + 1xICS	2xICS
Arm/Group Description	tiotropium bromide inhalation powder 18 mcg once daily (Tio) plus beclomethasone dipropionate 80 mcg twice daily (1xICS)	salmeterol xinafoate inhalation powder 50 mcg twice daily (LABA) plus beclomethasone dipropionate 80 mcg twice daily (1xICS)	beclomethasone dipropionate 160 mcg twice daily (2xICS)
Measure Participants	210	210	210
Least Squares Mean (Standard Error) [units on a scale]	0.15 (0.058)	0.28 (0.050)	0.05 (0.052)

5. Secondary Outcome

Title	Change Between Week 14 and Week 0 in the Asthma Control Questionnaire Score
Description	Scores on the Asthma Control Questionnaire range from 0 to 6, with a higher score indicating worse asthma control.
Time Frame	The asthma control questionnaire score was measured on four occasions during each of the three 14-week treatment periods. The primary analysis constructed the change between week 14 and week 0.

Outcome Measure Data

Analysis Population Description

All randomized participants were included in the linear mixed-effects model analysis

Arm/Group Title	Tio + 1xICS	LABA + 1xICS	2xICS
Arm/Group Description	tiotropium bromide inhalation powder 18 mcg once daily (Tio) plus beclomethasone dipropionate 80 mcg twice daily (1xICS)	salmeterol xinafoate inhalation powder 50 mcg twice daily (LABA) plus beclomethasone dipropionate 80 mcg twice daily (1xICS)	beclomethasone dipropionate 160 mcg twice daily (2xICS)
Measure Participants	210	210	210
Least Squares Mean (Standard Error) [units on a scale]	-0.22 (0.055)	-0.31 (0.045)	-0.03 (0.048)

6. Secondary Outcome

Title	Change Between Week 14 and Week 0 in the Albuterol Rescue Puffs Per Day
Description	Total number of puffs from the albuterol (rescue) inhaler during the previous 24 hours (excluding those puffs for preventive use).
Time Frame	Albuterol rescue puffs were measured daily during each of the three 14-week treatment periods. The primary analysis constructed the change between week 14 and week 0.

Outcome Measure Data

Analysis Population Description

All randomized participants were included in the linear mixed-effects model analysis

Arm/Group Title	Tio + 1xICS	LABA + 1xICS	2xICS
Arm/Group Description	tiotropium bromide inhalation powder 18 mcg once daily (Tio) plus beclomethasone dipropionate 80 mcg twice daily (1xICS)	salmeterol xinafoate inhalation powder 50 mcg twice daily (LABA) plus beclomethasone dipropionate 80 mcg twice daily (1xICS)	beclomethasone dipropionate 160 mcg twice daily (2xICS)
Measure Participants	210	210	210
Least Squares Mean (Standard Error) [puffs per day]	-0.11 (0.058)	-0.16 (0.063)	-0.07 (0.063)

7. Secondary Outcome

Title	Change Between Week 14 and Week 0 in the Proportion of Asthma Control Days
Description	An asthma control day was defined as a day in which there were no symptoms and no albuterol (rescue) puffs.
Time Frame	An asthma control day was determined daily during each of the three 14-week treatment periods. The primary analysis constructed the change between week 14 and week 0.

Outcome Measure Data

Analysis Population Description

All randomized participants were included in the linear mixed-effects model analysis

Arm/Group Title	Tio + 1xICS	LABA + 1xICS	2xICS
Arm/Group Description	tiotropium bromide inhalation powder 18 mcg once daily (Tio) plus beclomethasone dipropionate 80 mcg twice daily (1xICS)	salmeterol xinafoate inhalation powder 50 mcg twice daily (LABA) plus beclomethasone dipropionate 80 mcg twice daily (1xICS)	beclomethasone dipropionate 160 mcg twice daily (2xICS)
Measure Participants	210	210	210
Least Squares Mean (Standard Error) [proportion of asthma control days]	0.13 (0.020)	0.14 (0.023)	0.05 (0.021)

Adverse Events

Time Frame	1 year
Adverse Event Reporting Description	does not differ from clinicaltrials.gov definitions
Arm/Group Title	Tio + 1xICS		LABA + 1xICS		2xICS
Arm/Group Description	tiotropium bromide inhalation powder 18 mcg once daily (Tio) plus beclomethasone dipropionate 80 mcg twice daily (1xICS)		salmeterol xinafoate inhalation powder 50 mcg twice daily (LABA) plus beclomethasone dipropionate 80 mcg twice daily (1xICS)		beclomethasone dipropionate 160 mcg twice daily (2xICS)
All Cause Mortality
	Tio + 1xICS		LABA + 1xICS		2xICS
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Tio + 1xICS		LABA + 1xICS		2xICS
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/203 (1.5%)		4/196 (2%)		4/195 (2.1%)
General disorders
unrelated events	1/203 (0.5%)	1	4/196 (2%)	4	3/195 (1.5%)	3
Respiratory, thoracic and mediastinal disorders
hospitalization due to pneumonia	2/203 (1%)	2	0/196 (0%)	0	1/195 (0.5%)	1
Other (Not Including Serious) Adverse Events
	Tio + 1xICS		LABA + 1xICS		2xICS
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/203 (1%)		2/196 (1%)		6/195 (3.1%)
Respiratory, thoracic and mediastinal disorders
urgent care visit due to asthma	2/203 (1%)	2	2/196 (1%)	2	6/195 (3.1%)	6

Limitations/Caveats

We evaluated only a small number of patients, with no treatment lasting longer than 14 weeks. We could not examine either the rate of asthma exacerbations or long-term safety issues, so our findings cannot be considered clinically directive.

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.