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 Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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)

Conditions
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Asthma

Intervention / Treatment
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* Drug: tiotropium bromide
* Drug: salmeterol xinafoate
* Drug: beclomethasone dipropionate


Participation Criteria
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Eligibility Criteria
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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: Beta-agonist reversibility to 4 puffs albuterol of at least 12% OR 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: Received prescription for or used asthma controller within the 12 months prior to study entry OR 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.)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tio + 1xICS || LABA + 1xICS || 2xICS<br>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<br>* tiotropium bromide inhalation powder 18 mcg once daily<br>* Other names: SPIRIVA® HandiHaler®;Drug: salmeterol xinafoate<br>* salmeterol xinafoate inhalation powder 50 mcg twice daily<br>* Other names: Serevent® Diskus®;Drug: beclomethasone dipropionate<br>* beclomethasone dipropionate 80 mcg twice daily (1xICS) or 160 mcg twice daily (2xICS)<br>* Other names: QVAR® Inhalation Aerosol;|
| Experimental: TIO + 1xICS || 2xICS || LABA + 1xICS<br>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<br>* tiotropium bromide inhalation powder 18 mcg once daily<br>* Other names: SPIRIVA® HandiHaler®;Drug: salmeterol xinafoate<br>* salmeterol xinafoate inhalation powder 50 mcg twice daily<br>* Other names: Serevent® Diskus®;Drug: beclomethasone dipropionate<br>* beclomethasone dipropionate 80 mcg twice daily (1xICS) or 160 mcg twice daily (2xICS)<br>* Other names: QVAR® Inhalation Aerosol;|
| Experimental: LABA + 1xICS || Tio + 1xICS || 2xICS<br>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<br>* tiotropium bromide inhalation powder 18 mcg once daily<br>* Other names: SPIRIVA® HandiHaler®;Drug: salmeterol xinafoate<br>* salmeterol xinafoate inhalation powder 50 mcg twice daily<br>* Other names: Serevent® Diskus®;Drug: beclomethasone dipropionate<br>* beclomethasone dipropionate 80 mcg twice daily (1xICS) or 160 mcg twice daily (2xICS)<br>* Other names: QVAR® Inhalation Aerosol;|
| Experimental: LABA + 1xICS || 2xICS || Tio + 1xICS<br>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<br>* tiotropium bromide inhalation powder 18 mcg once daily<br>* Other names: SPIRIVA® HandiHaler®;Drug: salmeterol xinafoate<br>* salmeterol xinafoate inhalation powder 50 mcg twice daily<br>* Other names: Serevent® Diskus®;Drug: beclomethasone dipropionate<br>* beclomethasone dipropionate 80 mcg twice daily (1xICS) or 160 mcg twice daily (2xICS)<br>* Other names: QVAR® Inhalation Aerosol;|
| Experimental: 2xICS || Tio + 1xICS| || LABA + 1xICS<br>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<br>* tiotropium bromide inhalation powder 18 mcg once daily<br>* Other names: SPIRIVA® HandiHaler®;Drug: salmeterol xinafoate<br>* salmeterol xinafoate inhalation powder 50 mcg twice daily<br>* Other names: Serevent® Diskus®;Drug: beclomethasone dipropionate<br>* beclomethasone dipropionate 80 mcg twice daily (1xICS) or 160 mcg twice daily (2xICS)<br>* Other names: QVAR® Inhalation Aerosol;|
| Experimental: 2xICS || LABA + 1xICS || Tio + 1xICS<br>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<br>* tiotropium bromide inhalation powder 18 mcg once daily<br>* Other names: SPIRIVA® HandiHaler®;Drug: salmeterol xinafoate<br>* salmeterol xinafoate inhalation powder 50 mcg twice daily<br>* Other names: Serevent® Diskus®;Drug: beclomethasone dipropionate<br>* beclomethasone dipropionate 80 mcg twice daily (1xICS) or 160 mcg twice daily (2xICS)<br>* Other names: QVAR® Inhalation Aerosol;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 
| Change Between Week 14 and Week 0 in Asthma Symptoms | 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 ) | 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. | 
| Change Between Week 14 and Week 0 in the Asthma Quality-of-life Questionnaire Score | Scores on the Asthma Quality-of-Life Questionnaire range from 1 to 7, with a higher score indicating a better quality of life. | 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. | 
| Change Between Week 14 and Week 0 in the Asthma Control Questionnaire Score | Scores on the Asthma Control Questionnaire range from 0 to 6, with a higher score indicating worse asthma control. | 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. | 
| Change Between Week 14 and Week 0 in the Albuterol Rescue Puffs Per Day | Total number of puffs from the albuterol (rescue) inhaler during the previous 24 hours (excluding those puffs for preventive use). | 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. | 
| Change Between Week 14 and Week 0 in the Proportion of Asthma Control Days | An asthma control day was defined as a day in which there were no symptoms and no albuterol (rescue) puffs. | 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. |