Blacks and Exacerbations on Long Acting Beta Agonists (LABA) vs. Tiotropium (BELT)

Asthma is a chronic respiratory disease that affects over 22 million people in the United
States. Asthma produces 500,000 hospital admissions and accounts for 10.1 million days of
lost work in adults annually. Asthma has been designated a priority condition of the
Effective Health Care Program.

Blacks bear a disproportionate burden of asthma morbidity and mortality. In its 2005 report
on ethnic disparities in health care, AHRQ identified hospital admissions for asthma as the
second largest disparity in quality of health care for Blacks vs. Caucasians.

Long-acting beta-agonists (LABAs) produce extended increases in airway caliber among patients
with asthma via action at the beta2-adrenergic receptor (ADRB2). Adding a LABA to an inhaled
corticosteroid controller medication (ICS), can decrease asthma symptoms for many individuals
and appears to decrease asthma exacerbations. LABA/ICS has become the most commonly
prescribed ICS containing medication.

Drugs acting at ADRB2, including LABAs, have been associated with rare loss of long-term
asthma control and increased serious adverse outcomes including death and respiratory
failure, even when used with ICS. The risk appears four to five-fold greater in Blacks than
non-Black patients with asthma.

Consensus guidelines recommend LABAs be added to ICS in those not completely controlled on
ICS alone. These recommendations are based on weighing data on the benefit demonstrated in
the general population vs. the rare risk of serious adverse outcomes and balancing the
apparent benefits vs. the risks of LABAs (Kramer 2009). However, it appears that LABA/ICS may
be significantly less effective in Blacks than Caucasians. Comparison of studies with
LABA/ICS in Blacks vs. studies where Blacks were a small minority suggests that Blacks may
have much less benefit than other racial groups. Additionally, recent data (Wechsler 2009)
suggest that a polymorphism at the 16th position of the ADRB2 gene identifies a group of
Blacks (those homozygous for arginine (Arg16Arg)) in whom the response of adding a LABA to an
ICS is further diminished. This polymorphism is present in ~20% of US Blacks.

Inclusion Criteria:

1. Black (self-identified, with at least one biological parent identified as Black)

2. Male and female subjects, ages 18-75

3. Ability to provide informed consent

4. Clinical history consistent with asthma for > 1 year.

5. Ability to perform pulmonary function tests

6. FEV1 > 40% of predicted

7. Receiving inhaled corticosteroids (ICS)/LABA combination therapy, or ICS moderate dose
monotherapy and baseline ACQ>1.25

8. Non-smoker for past year (total lifetime smoking history < 10 pack-years)

Exclusion Criteria:

1. Use of greater than the equivalent of 1000 mcg inhaled fluticasone daily

2. Chronic use of oral corticosteroids or Anti IgE for asthma

3. Lung disease other than asthma or diagnosis of vocal cord dysfunction.

4. Significant medical illness (other than asthma) that is not stable.

5. Pregnancy or lactation or an unwillingness to maintain effective birth control.

6. History of a significant exacerbation of asthma or respiratory tract infection in the
prior 4 weeks

7. History of life-threatening asthma requiring treatment with intubation and mechanical
ventilation within 5 years.

8. Hypo sensitization therapy other than an established maintenance regimen.

9. Use of inhaled anticholinergic therapy (ipratropium, tiotropium) in prior month

10. Known contraindication to inhaled tiotropium e.g. narrow angle glaucoma, history of
bladder neck obstruction or significant symptoms related to prostatic hypertrophy.

11. Inability to speak and read English.