- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT00706446
The Effects of Different Long-acting Bronchodilator Medications on Asthma Patients With Different Genetic Variations (GABLE)
Genotype Stratified Treatment With Anticholinergic vs. Beta-agonist (Long Acting) and Exacerbations (GABLE)
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
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.
Study Type
Enrollment (Actual)
Phase
- Not Applicable
Contacts and Locations
Study Locations
-
-
Massachusetts
-
Boston, Massachusetts, United States, 02115
- Brigham and Women's Hospital
-
Boston, Massachusetts, United States, 02114
- Massachusetts General Hospital
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
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
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: 1 - Tio/ICS in the Arg/Arg genotype
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
|
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.
Other Names:
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.
Other Names:
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.
Other Names:
|
Experimental: 2 - Tio/ICS in the Arg/Gly genotype
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
|
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.
Other Names:
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.
Other Names:
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.
Other Names:
|
Experimental: 3 - Tio/ICS in the Gly/Gly genotype
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
|
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.
Other Names:
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.
Other Names:
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.
Other Names:
|
Active Comparator: 4 - LABA/ICS in the Arg/Arg genotype
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
|
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.
Other Names:
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.
Other Names:
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.
Other Names:
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.
Other Names:
|
Active Comparator: 5 - LABA/ICS in the Arg/Gly genotype
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
|
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.
Other Names:
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.
Other Names:
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.
Other Names:
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.
Other Names:
|
Active Comparator: 6 - LABA/ICS in the Gly/Gly genotype
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
|
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.
Other Names:
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.
Other Names:
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.
Other Names:
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.
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Time Frame |
---|---|
Number of Patients With Asthma Exacerbation
Time Frame: 1 year
|
1 year
|
Secondary Outcome Measures
Outcome Measure |
Time Frame |
---|---|
FEV1 (Forced Expiratory Volume)
Time Frame: 1 year
|
1 year
|
Exhaled NO (Nitric Oxide)
Time Frame: 1 year
|
1 year
|
Symptom-free Days
Time Frame: 1 year
|
1 year
|
Asthma-related Quality of Life
Time Frame: 1 year
|
1 year
|
Collaborators and Investigators
Sponsor
Publications and helpful links
Helpful Links
Study record dates
Study Major Dates
Study Start
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Respiratory Tract Diseases
- Immune System Diseases
- Lung Diseases
- Hypersensitivity, Immediate
- Bronchial Diseases
- Lung Diseases, Obstructive
- Respiratory Hypersensitivity
- Hypersensitivity
- Asthma
- Physiological Effects of Drugs
- Adrenergic Agents
- Neurotransmitter Agents
- Molecular Mechanisms of Pharmacological Action
- Parasympatholytics
- Autonomic Agents
- Peripheral Nervous System Agents
- Cholinergic Antagonists
- Cholinergic Agents
- Anti-Inflammatory Agents
- Glucocorticoids
- Hormones
- Hormones, Hormone Substitutes, and Hormone Antagonists
- Adrenergic Agonists
- Dermatologic Agents
- Anticonvulsants
- Bronchodilator Agents
- Anti-Asthmatic Agents
- Respiratory System Agents
- Anti-Allergic Agents
- Adrenergic beta-2 Receptor Agonists
- Adrenergic beta-Agonists
- Budesonide
- Fluticasone
- Xhance
- Salmeterol Xinafoate
- Tiotropium Bromide
- Bromides
- Formoterol Fumarate
Other Study ID Numbers
- 2008-P-000285
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
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