Genotype Stratified Treatment With Anticholinergic vs. Beta-agonist (Long Acting) and Exacerbations (GABLE)
试验速览
- 阶段
- 不适用
- 状态
- 终止
- 入组人数
- 255
- 试验地点
- 2
- 主要终点
- Number of Patients With Asthma Exacerbation
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
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
干预措施: tiotropium bromide (Drug)
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
干预措施: Fluticasone propionate (Drug)
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
干预措施: budesonide (Drug)
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
干预措施: tiotropium bromide (Drug)
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
干预措施: Fluticasone propionate (Drug)
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
干预措施: budesonide (Drug)
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
干预措施: tiotropium bromide (Drug)
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
干预措施: Fluticasone propionate (Drug)
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
干预措施: budesonide (Drug)
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
干预措施: Salmeterol (Drug)
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
干预措施: Formoterol (Drug)
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
干预措施: Fluticasone propionate (Drug)
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
干预措施: budesonide (Drug)
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
干预措施: Salmeterol (Drug)
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
干预措施: Formoterol (Drug)
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
干预措施: Fluticasone propionate (Drug)
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
干预措施: budesonide (Drug)
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
干预措施: Salmeterol (Drug)
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
干预措施: Formoterol (Drug)
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
干预措施: Fluticasone propionate (Drug)
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
干预措施: budesonide (Drug)
结局指标
主要结局
Number of Patients With Asthma Exacerbation
时间窗: 1 year
次要结局
- FEV1 (Forced Expiratory Volume)(1 year)
- Asthma-related Quality of Life(1 year)
- Exhaled NO (Nitric Oxide)(1 year)
- Symptom-free Days(1 year)
研究者
Elliot Israel, MD
Director of the Asthma Research Center
Brigham and Women's Hospital