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)”

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.

Study Type: Interventional

Study Design: Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Active Control, Crossover Assignment, Safety/Efficacy Study

Study Primary Completion Date: June 2010

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 plus a single dose of ICS - Long-acting beta-agonist plus a single dose of ICS - Double dose of ICS

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.

Intervention(s) in this Clinical Trial

• Drug: Tiotropium bromide
  • Tiotropium bromide inhalation powder (SPIRIVA® HandiHaler®)
• Drug: Salmeterol xinofoate
  • Salmeterol xinofoate inhalation powder bid (Serevent® Diskus® 50 mcg)
• Drug: Beclomethasone dipropionate
  • Beclomethasone dipropionate 80 mcg bid or 160 mcg bid (QVAR® Inhalation Aerosol)

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: 1
  • Participants will take part in three 16-week treatment periods, which will occur in the following order: Tiotropium bromide plus a single dose of ICS Long-acting beta-agonist plus a single dose of ICS Double dose of ICS 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.
• Experimental: 2
  • Participants will take part in three 16-week treatment periods, which will occur in the following order: Tiotropium bromide plus a single dose of ICS Double dose of ICS Long-acting beta-agonist plus a single dose of ICS 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.
• Experimental: 3
  • Participants will take part in three 16-week treatment periods, which will occur in the following order: Long-acting beta-agonist plus a single dose of ICS Tiotropium bromide plus a single dose of ICS Double dose of ICS 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.
• Experimental: 4
  • Participants will take part in three 16-week treatment periods, which will occur in the following order: Long-acting beta-agonist plus a single dose of ICS Double dose of ICS Tiotropium bromide plus a single dose of ICS 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.
• Experimental: 5
  • Participants will take part in three 16-week treatment periods, which will occur in the following order: Double dose of ICS Tiotropium bromide plus a single dose of ICS Long-acting beta-agonist plus a single dose of ICS 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.
• Experimental: 6
  • Participants will take part in three 16-week treatment periods, which will occur in the following order: Double dose of ICS Long-acting beta-agonist plus a single dose of ICS Tiotropium bromide plus a single dose of ICS 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.

Primary Measures

• AM peak expiratory flow (PEF)
  • Time Frame: Measured during each of the three 14-week treatment periods
    Safety Issue?: No

Secondary Measures

• Forced expiratory volume in one second (FEV1)
  • Time Frame: Measured during each of the three 14-week treatment periods
    Safety Issue?: No
• Asthma symptoms, number of asthma-control days, rescue inhaler use
  • Time Frame: Measured during each of the three 14-week treatment periods
    Safety Issue?: No
• Asthma control, asthma quality-of-life
  • Time Frame: Measured during each of the three 14-week treatment periods
    Safety Issue?: No
• Asthma exacerbations
  • Time Frame: Measured during each of the three 14-week treatment periods
    Safety Issue?: No
• Biomarkers of inflammation and oxidative stress
  • Time Frame: Measured during each of the three 14-week treatment periods
    Safety Issue?: No
• Adverse events
  • Time Frame: Measured during each of the three 14-week treatment periods
    Safety Issue?: Yes

Inclusion Criteria for TALC and BASALT Studies:

• Clinical history consistent with asthma
• 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. PC20 FEV1 methacholine of 8 mg/mL or less when not on an 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 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 A.M. 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.)

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: National Heart, Lung, and Blood Institute (NHLBI)

Overall Clinical Trial Officials and Contacts

Homer A. Boushey, MD Principal Investigator University of California, San Francisco  

Overall Contact: Vernon M. Chinchilli, PhD 717-531-4262 vchinchi@psu.edu

Information obtained from ClinicalTrials.gov on August 28, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00565266

Study ID Number: 547

ClinicalTrials.gov Identifier: NCT00565266

Health Authority: United States: Federal Government

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