The Effects of Different Long-acting Bronchodilator Medications on Asthma Patients With Different Genetic Variations
| Status: | Terminated |
|---|---|
| Conditions: | Asthma |
| Therapuetic Areas: | Pulmonary / Respiratory Diseases |
| Healthy: | No |
| Age Range: | 18 - 75 |
| Updated: | 10/14/2017 |
| Start Date: | June 2008 |
| End Date: | September 2011 |
Genotype Stratified Treatment With Anticholinergic vs. Beta-agonist (Long Acting) and Exacerbations (GABLE)
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 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.
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
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