The Effects of Different Long-acting Bronchodilator Medications on Asthma Patients With Different Genetic Variations
The Effects of Different Long-acting Bronchodilator Medications on Asthma Patients With Different Genetic Variations
This study is looking at the effects of certain long-acting bronchodilators on patients with
 asthma who have specific genetic variations. The investigators are interested in a certain
 common genetic variation in the receptor for beta-agonists, which is found in as many of
 one-sixth of the population. There is evidence that patients with asthma who have this
 variation may not do as well when treated with albuterol on a regular basis. The
 investigators will be looking at whether patients with this variation have more asthma
 exacerbations over the course of a year when treated with salmeterol or formoterol, which are
 long-acting forms of albuterol; and whether these patients have fewer exacerbations when
 treated with tiotropium, which is a different long-acting bronchodilator that does not act at
 this receptor. In both groups patients will also be receiving inhaled steroids.
Asthma affects 7% of the population in the United States. Asthma morbidity and mortality has
 increased over the past decade. Long-acting β-agonists (LABAs) combined with inhaled
 corticosteroids are the most rapidly growing form of asthma therapy in the USA. The only
 currently USA licensed pharmaceutical that combines a long-acting beta-agonist, salmeterol,
 and an inhaled corticosteroid is a product know as Advair®. It has become the most widely
 prescribed asthma controller medication in the United States. While studies have suggested
 that the combination of a LABA and an inhaled corticosteroid (LABA/ICS), on average, improves
 asthma control, other studies have suggested that a subpopulation of asthmatics may be at
 risk for severe exacerbations or death with the use of these agents. These latter studies
 have caused the FDA to place a "black box" warning on Advair®.

 The primary site of therapeutic action of the β-agonists is the beta-adrenergic receptor
 (ADRB2). One of the common SNPs (allele frequency 0.4 in caucasians) in the coding region of
 ADRB2 codes for arginine instead of glycine at the 16th amino-acid position of the receptor.
 In a retrospective association study, we reported that homozygosity for the arginine
 polymorphism at the 16th amino-acid position (B16 Arg/Arg) as compared to homozygosity for
 glycine at that position (B16 Gly/Gly) was associated with adverse pulmonary function
 outcomes when patients used short-acting β-agonists regularly. This report was followed by a
 study from another group associating increased rates of exacerbations with regular use of
 short-acting β-agonist in B16 Arg/Arg patients. We subsequently organized and led the first
 non-oncologic prospective, controlled, double-blinded, genotype stratified trial. In this
 trial we randomized B16 Arg/Arg and B16 Gly/Gly patients with asthma to regular short-acting
 β-agonist therapy vs. as needed anti-cholinergic bronchodilator therapy. We showed that
 patients harboring B16 Arg/Arg, as compared with B16 Gly/Gly, benefited when their use of
 short-acting β-agonists was minimized by substituting an anti-cholinergic bronchodilator for
 the β-adrenergic bronchodilator.

 Recently, we performed a genotype stratified analysis of patients who had participated in
 randomized trials using the LABA, salmeterol. We demonstrated that B16 Arg/Arg was associated
 with adverse outcomes even when the LABA was used with a concomitant inhaled corticosteroid.
 A recent cross-sectional analysis of pediatric patients using LABAs with ICS suggested that
 the OR was 3.4 for exacerbations over 6 months in Arg/Arg patients as compared with Gly/Gly
 patients. In this study, the OR for exacerbation in the presence of the B16 Arg allele in a
 codominant model was 1.8. Of interest, an industry-sponsored 12 week trial in press did not
 uncover such an association emphasizing the importance of prospectively confirming these
 finding[9].

 In summary, substantial evidence suggests that asthmatic patients harboring B16 Arg/Arg are
 at increased risk for adverse outcomes when using a LABA and that they may benefit from the
 use of an anticholinergic.

 A search of the RPDR across all Partners' sites in October 2006, revealed that 13,682 adults
 age 18-70 with a diagnosis of asthma are receiving a salmeterol containing preparation. At
 minimum 2.200 of these patients are Arg/Arg (likely more, since the frequency of B16 Arg/Arg
 is higher in Blacks and Asians). Multiple studies have suggested that patients requiring
 LABA/ICS therapy experience on average 0.3-0.6 exacerbations per year. The Palmer and Taylor
 studies suggest that the risk of exacerbations in Arg/Arg patients may be increased from
 50-100% by exposure to regular β-agonist therapy. Based on these risks, alternative therapies
 could potentially reduce the rates of exacerbations by 1/3 to 1/2 in this subpopulation.

 We therefore propose a prospective trial in which patients prescribed Advair®, or another
 combination of a LABA/ICS, are randomized, in a genotype stratified manner, to either
 continue on therapy with LABA/ICS preparations or to therapy with a long-acting
 anti-cholinergic/ICS. The primary outcome will be exacerbations as defined by events
 requiring oral corticosteroids, emergency room visits, or hospitalizations over the one year
 after randomization[1]. Secondary outcomes will include symptom-free days and quality of life
 (which we have assessed in prior studies utilizing validated instruments), days lost from
 work or school, lung function, and non-invasive measures of lung inflammation through
 collection of exhaled nitric oxide and exhaled breath condensate for assessment of oxidative
 stress through measures of pH. All techniques and procedures have been utilized by our team
 at BWH in the course of our prior asthma clinical studies and pharmacogenetic studies.

 The primary objective of this study will be address the questions of whether the presence of
 the arginine polymorphism at the 16th amino-acid of ADRB2 increases the rate of exacerbations
 in patients with asthma treated with LABA/ICS and whether treatment with an
 anti-cholinergic/ICS in patients with asthma homozygous for the arginine polymorphism at the
 16th amino-acid of ADRB2 reduce exacerbations as compared with treatment with LABA/ICS.
Inclusion Criteria:

 -  Clinical history consistent with asthma

 -  Has a current prescription for a long-acting beta agonist, either along or in
 combination with an inhaled corticosteroid (salmeterol, formoterol,
 fluticasone/salmeterol, or budesonide/formoterol)

 -  Ability to provide informed consent

 -  Non-smoker (total lifetime smoking history < 10 pack-years; no more than five
 occasions of smoking any substance or using smokeless tobacco products in the past
 year)

 -  No smoking or use of smokeless tobacco in the past 30 days

 -  No known contraindication to inhaled tiotropium e.g. narrow angle glaucoma, history of
 bladder neck obstruction or significant symptoms related to prostatic hypertrophy

 Exclusion Criteria:

 -  Lung disease other than asthma

 -  Established or suspected diagnosis of vocal cord dysfunction

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

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

 -  History of respiratory tract infection within the previous 4 weeks (only applies at
 screening visits)

 -  Hyposensitization therapy other than an established maintenance regimen

 -  Allergy to tiotropium

 -  Pregnancy or lactation. If potentially able to bear children, not using an acceptable
 form of birth control

 -  Inability to use inhaler devices

 -  Inability to participate over the one year period

 -  Current use of tiotropium