The Effects of Different Long-acting Bronchodilator Medications on Asthma Patients With Different Genetic Variations

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Genotype Stratified Treatment With Anticholinergic vs. Beta-agonist (Long Acting) and Exacerbations (GABLE)

Conditions
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Asthma

Intervention / Treatment
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* Drug: tiotropium bromide
* Drug: Salmeterol
* Drug: Formoterol
* Drug: Fluticasone propionate
* Drug: budesonide


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1 - Tio/ICS in the Arg/Arg genotype<br>Tiotropium bromide 18 mcg qd plus inhaled steroids, either Fluticasone propionate Diskus 100 mcg 1 puff bid, Fluticasone propionate aerosol 44 mcg 2 puffs bid, Fluticasone propionate aerosol 110 mcg 2 puffs bid, Fluticasone propionate aerosol 220 mcg 2 puffs qd, Budesonide 90 mcg 2 puffs bid, or Budesonide 180 mcg 2 puffs bid, in the Arg/Arg genotype | Drug: tiotropium bromide<br>* tiotropium bromide one inhalation a day for one year, along with inhaled steroids at variable dosing based on patient's prior inhaled steroid dosing and treating physician's judgement.<br>* Other names: Spiriva;Drug: Fluticasone propionate<br>* Either fluticasone propionate diskus 100 mcg 1 puff twice a day or fluticasone propionate aersol in 44 mcg, 110 mcg, 2 puffs twice a day OR fluticasone propionate 220 mcg 2 puffs once a day for one year, depending on which dose the patient was on before the start of the trial.<br>* Other names: Flovent;Drug: budesonide<br>* Either budesonide 90 mcg 2 puffs twice a day or 180 mcg 2 puffs twice a day for one year, depending on which dose the patient was on before the start of the trial.<br>* Other names: Pulmicort Flexihaler;|
| Experimental: 2 - Tio/ICS in the Arg/Gly genotype<br>Tiotropium bromide 18 mcg QD plus inhaled steroids, either Fluticasone propionate Diskus 100 mcg 1 puff bid, Fluticasone propionate aerosol 44 mcg 2 puffs bid, Fluticasone propionate aerosol 110 mcg 2 puffs bid, Fluticasone propionate aerosol 220 mcg 2 puffs qd, Budesonide 90 mcg 2 puffs bid, or Budesonide 180 mcg 2 puffs bid, in the Arg/Gly genotype | Drug: tiotropium bromide<br>* tiotropium bromide one inhalation a day for one year, along with inhaled steroids at variable dosing based on patient's prior inhaled steroid dosing and treating physician's judgement.<br>* Other names: Spiriva;Drug: Fluticasone propionate<br>* Either fluticasone propionate diskus 100 mcg 1 puff twice a day or fluticasone propionate aersol in 44 mcg, 110 mcg, 2 puffs twice a day OR fluticasone propionate 220 mcg 2 puffs once a day for one year, depending on which dose the patient was on before the start of the trial.<br>* Other names: Flovent;Drug: budesonide<br>* Either budesonide 90 mcg 2 puffs twice a day or 180 mcg 2 puffs twice a day for one year, depending on which dose the patient was on before the start of the trial.<br>* Other names: Pulmicort Flexihaler;|
| Experimental: 3 - Tio/ICS in the Gly/Gly genotype<br>Tiotropium bromide 18 mcg QD plus inhaled steroids, either Fluticasone propionate Diskus 100 mcg 1 puff bid, Fluticasone propionate aerosol 44 mcg 2 puffs bid, Fluticasone propionate aerosol 110 mcg 2 puffs bid, Fluticasone propionate aerosol 220 mcg 2 puffs qd, Budesonide 90 mcg 2 puffs bid, or Budesonide 180 mcg 2 puffs bid, in the Gly/Gly genotype | Drug: tiotropium bromide<br>* tiotropium bromide one inhalation a day for one year, along with inhaled steroids at variable dosing based on patient's prior inhaled steroid dosing and treating physician's judgement.<br>* Other names: Spiriva;Drug: Fluticasone propionate<br>* Either fluticasone propionate diskus 100 mcg 1 puff twice a day or fluticasone propionate aersol in 44 mcg, 110 mcg, 2 puffs twice a day OR fluticasone propionate 220 mcg 2 puffs once a day for one year, depending on which dose the patient was on before the start of the trial.<br>* Other names: Flovent;Drug: budesonide<br>* Either budesonide 90 mcg 2 puffs twice a day or 180 mcg 2 puffs twice a day for one year, depending on which dose the patient was on before the start of the trial.<br>* Other names: Pulmicort Flexihaler;|
| Active Comparator: 4 - LABA/ICS in the Arg/Arg genotype<br>Salmeterol 50 mcg 1 puff BID or Formoterol 12mcg 1 puff BID plus inhaled steroid, either Fluticasone propionate Diskus 100 mcg 1 puff bid, Fluticasone propionate aerosol 44 mcg 2 puffs bid, Fluticasone propionate aerosol 110 mcg 2 puffs bid, Fluticasone propionate aerosol 220 mcg 2 puffs qd, Budesonide 90 mcg 2 puffs bid, or Budesonide 180 mcg 2 puffs bid, in the Arg/Arg genotype | Drug: Salmeterol<br>* salmeterol diskus 1 puff twice a day for 1 year, depending on which medication the patient was on before the start of the trial. The goal of this intervention is to continue the patient's current therapy of long-acting beta-agonists. In addition, the patients will be on inhaled steroids at variable doses, depending on what dose they were on at the start of the trial and based on the judgement of their treating physicians.<br>* Other names: Serevent;Drug: Formoterol<br>* formoterol aerolizer 12 mcg 1 puff twice a day for 1 year, depending on which medication the patient was on before the start of the trial. The goal of this intervention is to continue the patient's current therapy of long-acting beta-agonists. In addition, the patients will be on inhaled steroids at variable doses, depending on what dose they were on at the start of the trial and based on the judgement of their treating physicians.<br>* Other names: Foradil;Drug: Fluticasone propionate<br>* Either fluticasone propionate diskus 100 mcg 1 puff twice a day or fluticasone propionate aersol in 44 mcg, 110 mcg, 2 puffs twice a day OR fluticasone propionate 220 mcg 2 puffs once a day for one year, depending on which dose the patient was on before the start of the trial.<br>* Other names: Flovent;Drug: budesonide<br>* Either budesonide 90 mcg 2 puffs twice a day or 180 mcg 2 puffs twice a day for one year, depending on which dose the patient was on before the start of the trial.<br>* Other names: Pulmicort Flexihaler;|
| Active Comparator: 5 - LABA/ICS in the Arg/Gly genotype<br>Salmeterol 50 mcg 1 puff BID or Formoterol 12mcg 1 puff BID plus inhaled steroid, either Fluticasone propionate Diskus 100 mcg 1 puff bid, Fluticasone propionate aerosol 44 mcg 2 puffs bid, Fluticasone propionate aerosol 110 mcg 2 puffs bid, Fluticasone propionate aerosol 220 mcg 2 puffs qd, Budesonide 90 mcg 2 puffs bid, or Budesonide 180 mcg 2 puffs bid, in the Arg/Gly genotype | Drug: Salmeterol<br>* salmeterol diskus 1 puff twice a day for 1 year, depending on which medication the patient was on before the start of the trial. The goal of this intervention is to continue the patient's current therapy of long-acting beta-agonists. In addition, the patients will be on inhaled steroids at variable doses, depending on what dose they were on at the start of the trial and based on the judgement of their treating physicians.<br>* Other names: Serevent;Drug: Formoterol<br>* formoterol aerolizer 12 mcg 1 puff twice a day for 1 year, depending on which medication the patient was on before the start of the trial. The goal of this intervention is to continue the patient's current therapy of long-acting beta-agonists. In addition, the patients will be on inhaled steroids at variable doses, depending on what dose they were on at the start of the trial and based on the judgement of their treating physicians.<br>* Other names: Foradil;Drug: Fluticasone propionate<br>* Either fluticasone propionate diskus 100 mcg 1 puff twice a day or fluticasone propionate aersol in 44 mcg, 110 mcg, 2 puffs twice a day OR fluticasone propionate 220 mcg 2 puffs once a day for one year, depending on which dose the patient was on before the start of the trial.<br>* Other names: Flovent;Drug: budesonide<br>* Either budesonide 90 mcg 2 puffs twice a day or 180 mcg 2 puffs twice a day for one year, depending on which dose the patient was on before the start of the trial.<br>* Other names: Pulmicort Flexihaler;|
| Active Comparator: 6 - LABA/ICS in the Gly/Gly genotype<br>Salmeterol 50 mcg 1 puff BID or Formoterol 12mcg 1 puff BID plus inhaled steroid, either Fluticasone propionate Diskus 100 mcg 1 puff bid, Fluticasone propionate aerosol 44 mcg 2 puffs bid, Fluticasone propionate aerosol 110 mcg 2 puffs bid, Fluticasone propionate aerosol 220 mcg 2 puffs qd, Budesonide 90 mcg 2 puffs bid, or Budesonide 180 mcg 2 puffs bid, in the Gly-Gly genotype | Drug: Salmeterol<br>* salmeterol diskus 1 puff twice a day for 1 year, depending on which medication the patient was on before the start of the trial. The goal of this intervention is to continue the patient's current therapy of long-acting beta-agonists. In addition, the patients will be on inhaled steroids at variable doses, depending on what dose they were on at the start of the trial and based on the judgement of their treating physicians.<br>* Other names: Serevent;Drug: Formoterol<br>* formoterol aerolizer 12 mcg 1 puff twice a day for 1 year, depending on which medication the patient was on before the start of the trial. The goal of this intervention is to continue the patient's current therapy of long-acting beta-agonists. In addition, the patients will be on inhaled steroids at variable doses, depending on what dose they were on at the start of the trial and based on the judgement of their treating physicians.<br>* Other names: Foradil;Drug: Fluticasone propionate<br>* Either fluticasone propionate diskus 100 mcg 1 puff twice a day or fluticasone propionate aersol in 44 mcg, 110 mcg, 2 puffs twice a day OR fluticasone propionate 220 mcg 2 puffs once a day for one year, depending on which dose the patient was on before the start of the trial.<br>* Other names: Flovent;Drug: budesonide<br>* Either budesonide 90 mcg 2 puffs twice a day or 180 mcg 2 puffs twice a day for one year, depending on which dose the patient was on before the start of the trial.<br>* Other names: Pulmicort Flexihaler;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With Asthma Exacerbation |  | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| FEV1 (Forced Expiratory Volume) |  | 1 year | 
| Exhaled NO (Nitric Oxide) |  | 1 year | 
| Symptom-free Days |  | 1 year | 
| Asthma-related Quality of Life |  | 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Asthma, Pharmacogenetics, Beta agonists, salmeterol, formoterol, tiotropium, beta adrenergic receptor, single nucleotide polymorphism