Effect of β2-adrenergic receptor polymorphism on response to longacting β2 agonist in asthma (LARGE trial)

a genotype-stratified, randomised, placebo-controlled, crossover trial

Michael E. Wechsler, Susan J. Kunselman, Vernon M. Chinchilli, Eugene Bleecker, Homer A. Boushey, William Calhoun, Bill Ameredes, Mario Castro, Timothy J. Craig, Loren Denlinger, John V. Fahy, Nizar Jarjour, Shamsah Kazani, Sophia Kim, Monica Kraft, Stephen C. Lazarus, Robert F. Lemanske, Amy Markezich, Richard J. Martin, Perdita Permaul & 8 others Stephen P. Peters, Joe Ramsdell, Christine A. Sorkness, E. Rand Sutherland, Stanley J. Szefler, Michael J. Walter, Stephen I. Wasserman, Elliot Israel

Research output: Contribution to journalArticle

178 Citations (Scopus)

Abstract

Background: Some studies suggest that patients with asthma who are homozygous for arginine at the 16th aminoacid position of the β2-adrenergic receptor (B16 Arg/Arg) benefit less from treatment with longacting β2 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 β2 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 β2 agonist (salmeterol 50 μg twice a day) or placebo given in a double-blind, crossover design for two 18-week periods. Open-label inhaled corticosteroid (hydrofluoroalkane beclometasone 240 μg 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. Findings: 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. Interpretation: 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 β2 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. Funding: National Institutes of Health.

Original languageEnglish (US)
Pages (from-to)1754-1764
Number of pages11
JournalThe Lancet
Volume374
Issue number9703
DOIs
StatePublished - 2009

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Cross-Over Studies
Adrenergic Receptors
Adrenal Cortex Hormones
Asthma
Genotype
Placebos
Methacholine Chloride
HFA 134a
Forced Expiratory Volume
Therapeutics
Beclomethasone
Salmeterol Xinafoate
Intention to Treat Analysis
National Institutes of Health (U.S.)
Random Allocation
Glycine
Arginine
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Effect of β2-adrenergic receptor polymorphism on response to longacting β2 agonist in asthma (LARGE trial) : a genotype-stratified, randomised, placebo-controlled, crossover trial. / Wechsler, Michael E.; Kunselman, Susan J.; Chinchilli, Vernon M.; Bleecker, Eugene; Boushey, Homer A.; Calhoun, William; Ameredes, Bill; Castro, Mario; Craig, Timothy J.; Denlinger, Loren; Fahy, John V.; Jarjour, Nizar; Kazani, Shamsah; Kim, Sophia; Kraft, Monica; Lazarus, Stephen C.; Lemanske, Robert F.; Markezich, Amy; Martin, Richard J.; Permaul, Perdita; Peters, Stephen P.; Ramsdell, Joe; Sorkness, Christine A.; Sutherland, E. Rand; Szefler, Stanley J.; Walter, Michael J.; Wasserman, Stephen I.; Israel, Elliot.

In: The Lancet, Vol. 374, No. 9703, 2009, p. 1754-1764.

Research output: Contribution to journalArticle

Wechsler, ME, Kunselman, SJ, Chinchilli, VM, Bleecker, E, Boushey, HA, Calhoun, W, Ameredes, B, Castro, M, Craig, TJ, Denlinger, L, Fahy, JV, Jarjour, N, Kazani, S, Kim, S, Kraft, M, Lazarus, SC, Lemanske, RF, Markezich, A, Martin, RJ, Permaul, P, Peters, SP, Ramsdell, J, Sorkness, CA, Sutherland, ER, Szefler, SJ, Walter, MJ, Wasserman, SI & Israel, E 2009, 'Effect of β2-adrenergic receptor polymorphism on response to longacting β2 agonist in asthma (LARGE trial): a genotype-stratified, randomised, placebo-controlled, crossover trial', The Lancet, vol. 374, no. 9703, pp. 1754-1764. https://doi.org/10.1016/S0140-6736(09)61492-6
Wechsler, Michael E. ; Kunselman, Susan J. ; Chinchilli, Vernon M. ; Bleecker, Eugene ; Boushey, Homer A. ; Calhoun, William ; Ameredes, Bill ; Castro, Mario ; Craig, Timothy J. ; Denlinger, Loren ; Fahy, John V. ; Jarjour, Nizar ; Kazani, Shamsah ; Kim, Sophia ; Kraft, Monica ; Lazarus, Stephen C. ; Lemanske, Robert F. ; Markezich, Amy ; Martin, Richard J. ; Permaul, Perdita ; Peters, Stephen P. ; Ramsdell, Joe ; Sorkness, Christine A. ; Sutherland, E. Rand ; Szefler, Stanley J. ; Walter, Michael J. ; Wasserman, Stephen I. ; Israel, Elliot. / Effect of β2-adrenergic receptor polymorphism on response to longacting β2 agonist in asthma (LARGE trial) : a genotype-stratified, randomised, placebo-controlled, crossover trial. In: The Lancet. 2009 ; Vol. 374, No. 9703. pp. 1754-1764.
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title = "Effect of β2-adrenergic receptor polymorphism on response to longacting β2 agonist in asthma (LARGE trial): a genotype-stratified, randomised, placebo-controlled, crossover trial",
abstract = "Background: Some studies suggest that patients with asthma who are homozygous for arginine at the 16th aminoacid position of the β2-adrenergic receptor (B16 Arg/Arg) benefit less from treatment with longacting β2 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 β2 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 β2 agonist (salmeterol 50 μg twice a day) or placebo given in a double-blind, crossover design for two 18-week periods. Open-label inhaled corticosteroid (hydrofluoroalkane beclometasone 240 μg 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. Findings: 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. Interpretation: 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 β2 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. Funding: National Institutes of Health.",
author = "Wechsler, {Michael E.} and Kunselman, {Susan J.} and Chinchilli, {Vernon M.} and Eugene Bleecker and Boushey, {Homer A.} and William Calhoun and Bill Ameredes and Mario Castro and Craig, {Timothy J.} and Loren Denlinger and Fahy, {John V.} and Nizar Jarjour and Shamsah Kazani and Sophia Kim and Monica Kraft and Lazarus, {Stephen C.} and Lemanske, {Robert F.} and Amy Markezich and Martin, {Richard J.} and Perdita Permaul and Peters, {Stephen P.} and Joe Ramsdell and Sorkness, {Christine A.} and Sutherland, {E. Rand} and Szefler, {Stanley J.} and Walter, {Michael J.} and Wasserman, {Stephen I.} and Elliot Israel",
year = "2009",
doi = "10.1016/S0140-6736(09)61492-6",
language = "English (US)",
volume = "374",
pages = "1754--1764",
journal = "The Lancet",
issn = "0140-6736",
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}

TY - JOUR

T1 - Effect of β2-adrenergic receptor polymorphism on response to longacting β2 agonist in asthma (LARGE trial)

T2 - a genotype-stratified, randomised, placebo-controlled, crossover trial

AU - Wechsler, Michael E.

AU - Kunselman, Susan J.

AU - Chinchilli, Vernon M.

AU - Bleecker, Eugene

AU - Boushey, Homer A.

AU - Calhoun, William

AU - Ameredes, Bill

AU - Castro, Mario

AU - Craig, Timothy J.

AU - Denlinger, Loren

AU - Fahy, John V.

AU - Jarjour, Nizar

AU - Kazani, Shamsah

AU - Kim, Sophia

AU - Kraft, Monica

AU - Lazarus, Stephen C.

AU - Lemanske, Robert F.

AU - Markezich, Amy

AU - Martin, Richard J.

AU - Permaul, Perdita

AU - Peters, Stephen P.

AU - Ramsdell, Joe

AU - Sorkness, Christine A.

AU - Sutherland, E. Rand

AU - Szefler, Stanley J.

AU - Walter, Michael J.

AU - Wasserman, Stephen I.

AU - Israel, Elliot

PY - 2009

Y1 - 2009

N2 - Background: Some studies suggest that patients with asthma who are homozygous for arginine at the 16th aminoacid position of the β2-adrenergic receptor (B16 Arg/Arg) benefit less from treatment with longacting β2 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 β2 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 β2 agonist (salmeterol 50 μg twice a day) or placebo given in a double-blind, crossover design for two 18-week periods. Open-label inhaled corticosteroid (hydrofluoroalkane beclometasone 240 μg 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. Findings: 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. Interpretation: 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 β2 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. Funding: National Institutes of Health.

AB - Background: Some studies suggest that patients with asthma who are homozygous for arginine at the 16th aminoacid position of the β2-adrenergic receptor (B16 Arg/Arg) benefit less from treatment with longacting β2 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 β2 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 β2 agonist (salmeterol 50 μg twice a day) or placebo given in a double-blind, crossover design for two 18-week periods. Open-label inhaled corticosteroid (hydrofluoroalkane beclometasone 240 μg 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. Findings: 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. Interpretation: 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 β2 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. Funding: National Institutes of Health.

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