Effect of beta2-adrenergic receptor polymorphism on response to longacting beta2 agonist in asthma (LARGE trial): a genotype-stratified, randomised, placebo-controlled, crossover trial.
BACKGROUND
Some studies suggest that patients with asthma who are homozygous for arginine at the 16th amino acid position of the beta2-adrenergic receptor (B16 Arg/Arg) benefit less from treatment with longacting beta2 agonists and inhaled corticosteroids than do those homozygous for glycine (B16 Gly/Gly). We investigated whether there is a genotype-specific response to treatment with a longacting beta2 agonist in combination with inhaled corticosteroid.


METHODS
In this multicentre, randomised, double-blind, placebo-controlled trial, adult patients with moderate asthma were enrolled in pairs matched for forced expiratory volume in 1 s and ethnic origin, according to whether they had the B16 Arg/Arg (n=42) or B16 Gly/Gly (n=45) genotype. Individuals in a matched pair were randomly assigned by computer-generated randomisation sequence to receive inhaled longacting beta2 agonist (salmeterol 50 microg twice a day) or placebo given in a double-blind, crossover design for two 18-week periods. Open-label inhaled corticosteroid (hydrofluoroalkane beclometasone 240 microg twice a day) was given to all participants during the treatment periods. The primary endpoint was morning peak expiratory flow (PEF). Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00200967.


RESULTS
After 18 weeks of treatment, mean morning PEF in Arg/Arg participants was 21.4 L/min (95% CI 11.8-31.1) higher when participants were assigned to receive salmeterol than when assigned to receive placebo (p<0.0001). In Gly/Gly participants, morning PEF was 21.5 L/min (11.0-32.1) higher when participants were assigned to receive salmeterol than when assigned to receive placebo (p<0.0001). The improvement in PEF did not differ between genotypes (difference [Arg/Arg-Gly/Gly] -0.1, -14.4 to 14.2; p=0.99). In Gly/Gly participants, methacholine PC20 (20% reduction in forced expiratory volume in 1 s; a prespecified secondary outcome) was 2.4 times higher when participants were assigned to salmeterol than when assigned to placebo (p<0.0001). Responsiveness to methacholine did not differ between salmeterol and placebo in Arg/Arg participants (p=0.87). The 2.5 times higher genotype-specific difference in responsiveness to methacholine was significant (1.32 doubling dose difference between genotypes, 0.43-2.21, p=0.0038). Seven Arg/Arg participants (placebo, n=5; salmeterol, n=2) and six Gly/Gly participants (placebo, n=3; salmeterol, n=3) had an asthma exacerbation. Five serious adverse events were reported, one each during the pre-match and run-in phases on open-label inhaled corticosteroid, two during double-blind treatment with salmeterol/inhaled corticosteroid, and one during double-blind treatment with placebo/inhaled corticosteroid. None of the serious events was asthma-related or related to study drugs or procedures.


CONCLUSIONS
In asthma patients with B16 Arg/Arg and B16 Gly/Gly genotypes, combination treatment with salmeterol and inhaled corticosteroid improved airway function when compared with inhaled corticosteroid therapy alone. These findings suggest that patients should continue to be treated with longacting beta2 agonists plus moderate-dose inhaled corticosteroids irrespective of B16 genotype. Further investigation is needed to establish the importance of the genotype-specific difference in responsiveness to methacholine.


BACKGROUND
National Institutes of Health.
Wechsler
Michael E
ME
Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. mwechsler@partners.org
Kunselman
Susan J
SJ
Chinchilli
Vernon M
VM
Bleecker
Eugene
E
Boushey
Homer A
HA
Calhoun
William J
WJ
Ameredes
Bill T
BT
Castro
Mario
M
Craig
Timothy J
TJ
Denlinger
Loren
L
Fahy
John V
JV
Jarjour
Nizar
N
Kazani
Shamsah
S
Kim
Sophia
S
Kraft
Monica
M
Lazarus
Stephen C
SC
Lemanske
Robert F
RF
Markezich
Amy
A
Martin
Richard J
RJ
Permaul
Perdita
P
Peters
Stephen P
SP
Ramsdell
Joe
J
Sorkness
Christine A
CA
Sutherland
E Rand
ER
Szefler
Stanley J
SJ
Walter
Michael J
MJ
Wasserman
Stephen I
SI
Israel
Elliot
E
D000280:Administration, Inhalation; D000318:Adrenergic beta-Agonists / Q000627:therapeutic use*; D000328:Adult; D000420:Albuterol / Q000031:analogs & derivatives* / Q000627:therapeutic use; D001249:Asthma / Q000188:drug therapy* / Q000235:genetics*; D001507:Beclomethasone / Q000008:administration & dosage; D018592:Cross-Over Studies; D004311:Double-Blind Method; D005260:Female; D005838:Genotype; D005938:Glucocorticoids / Q000008:administration & dosage; D006801:Humans; D008297:Male; D008875:Middle Aged; D010366:Peak Expiratory Flow Rate; D011110:Polymorphism, Genetic / Q000235:genetics*; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics*; D000068299:Salmeterol Xinafoate; D016896:Treatment Outcome
D000318:Adrenergic beta-Agonists; D005938:Glucocorticoids; D018343:Receptors, Adrenergic, beta-2; D000068299:Salmeterol Xinafoate; D001507:Beclomethasone; D000420:Albuterol