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)

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.

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.)