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 J.
AU - Ameredes, Bill T.
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
N1 - Funding Information:
The study was funded by the National Heart, Lung, and Blood Institute (NHLBI) of the US National Institutes of Health (NIH). An NHLBI-appointed protocol review committee approved the study design and reviewed the final manuscript. Funding references: US NIH/NHLBI : K23-HL04285, U10-HL74227, U10-HL74231, U10-HL074204, U10-HL74212, U10-HL74073, U10-HL074206, U10-HL074208, U10-HL74225, U10-HL74218 . Open-label ipratropium bromide was provided by Boehringer Ingelheim Pharmaceuticals (Ridgefield, CT, USA), and open-label beclometasone hydrofluoroalkane was provided by Teva Pharmaceuticals Industry (Petach Tikva, Israel). The ACRN data safety monitoring board reviewed the final version of the report. We thank the Asthma Clinical Research Network research coordinators and study staff.
Funding Information:
HAB, RFL, RJM, their institutions, and the Brigham and Women's Hospital are inventors on a patent concerning the use of genotype at the β 2 -adrenergic receptor and effects of regular salbutamol use. MEW reports that he has consulted for or participated in advisory boards or speaker bureaus for AstraZeneca, GlaxoSmithKline, Schering-Plough, Novartis, Genentech, Merck, Medicinova, and Sepracor. EB reports serving as a consultant, giving presentations and performing clinical trials that were administered by Wake Forest University Health Sciences for AstraZeneca, GlaxoSmithKline, and Novartis. HAB reports research project support from GlaxoSmithKline, participating on a scientific advisory committee for GlaxoSmithKline; ad-hoc consulting for Altana, Boehringer Ingelheim, Genentech, Nanomix, Novartis, Sumitomo, Theravance, and Watermark Research; and honoraria for lectures and presentations from Merck, Novartis, Sanofi-Aventis, and Genentech. BTA has received consulting fees from Sepracor. TJC reports performing research with Schering, Merck, GlaxoSmithKline, Boehringer Ingelheim, Altana, Genentech/Novartis, and Forrest; grants for investigator initiated research from Viropharma, CSL Mehring, GlaxoSmithKline, and Merck; honorarium for consultative services from Teva, Alcon, Novartis, Genentech, Dyax, CSL Behring, Viropharma, Shire, and Pharming; and honorarium for speaking from Teva Schering, Merck, AstraZeneca, Sanofi-Aventis, Genentech, and Novartis. LD reports receiving consultation honoraria from Merck. JVF reports providing consulting services for Abgenix, Aerovance, Amira, Biogen, Cytokinetics, Gilead, Merck, Oxagen, and Roche; grants for research from Aerovance, Roche, Genentech, and Boehringer Ingelheim. NJ reports receiving advisory board honorarium and clinical trial support from GlaxoSmithKline; consulting fees from Asthmatx; advisory board compensation, lecture honorarium and clinical trial support from Genentech-Novartis; trial support from MedImmune; and clinical trial support and lecture honorarium from Merck. MK reports speaker's bureau for GlaxoSmithKline; advisory board/consultation for GlaxoSmithKline, Merck, Novartis, and Amira; and research funding from GlaxoSmithKline, Bronchus, GE Healthcare, Asthmatx, Novartis, and Genentech. RFL reports receiving speaker honorarium from Merck, AstraZeneca, Medicus Group, Park Nicolet Institute; consultant honorarium from AstraZeneca, MAP Pharmaceuticals, Gray Consulting, Smith Research, Merck Childhood Asthma Network, Novartis, Quintiles/ANOVAs, and RCHorowitz & Company; and serving as an author of UpToDate. RJM reports serving as a consultant/lecturer for Adelphi, Abbott, Schering, Novartis, Genentech, Nitec, Covidien, AstraZeneca, KaloBios, and Sepracor. SPP reports pharmaceutical trial support as a member of the Wake Forest University Clinical Trials Group sponsored by Abaris, Amgen, Altana, Boehringer Ingelheim, Contocor, Genentech, GlaxoSmithKline, Medimmune, Novartis, Pfizer, Schering, and Wyeth; consulting under the auspices of Adelphi, Exocrine, AstraZeneca, Bristol-Meyers Squibb, Ception Therapeutics, Dey, Dyson, Genentech, Johnson & Johnson, Merck, Novartis, RAD Foundation, Respiratory Medicine, Respiratory Research, Sepracor, and Teva; and participating in Physician Education Programs sponsored by AdvanceMed, AstraZeneca, Creative Educational Concepts, DIME, Merck Pharmaceuticals, Genentech, Novartis, Practicome, Pri-Med/SCIOS, Respiratory and Allergic Disease (RAD) Foundation, and UpToDate. CAS reports receiving honorarium for speaker's bureau and consultation from GlaxoSmithKline; and receiving research support from Pharmaxis and Schering. ERS reports serving as an adviser or consultant to Dey, GlaxoSmithKline, and Schering-Plough; and receiving grant funding from National Institutes of Health and Novartis. SJS reports serving as a consultant for GlaxoSmithKline, Genentech, and Merck; and research funding from Ross and GlaxoSmithKline. SW reports grant support from Merck and Schering-Plough; and serving as a consultant for Amylin. EI conducted sponsored research with Aerovance, Asthmatx, AstraZeneca, Boehringer Ingelheim, Centocor, Ception Therapeutics, Genentech, GlaxoSmithKline, Icagen, Johnson & Johnson, MedImmune, Merck, Novartis, Schering-Plough, and Wyeth; consulted and/or served on advisory boards for Abbott, Amgen, Astellas Pharma US, Asthmatx, AstraZeneca, Aventis, Cowen & Co, Critical Therapeutics, Genentech, Icagen, IDEC, MedImmune, Merck, newMentor, Novartis, Pfizer, PDL Biopharma, Schering-Plough, Sepracor, Teva Specialty Pharmaceuticals, USB, Wyeth; and received speaker's fees from Genentech, Merck, Novartis, and Schering-Plough. SJK, VMC, WJC, MC, SKa, SKi, SCL, AM, PP, JR, and MJW declare that they have no conflicts of interest.
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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U2 - 10.1016/S0140-6736(09)61492-6
DO - 10.1016/S0140-6736(09)61492-6
M3 - Article
C2 - 19932356
AN - SCOPUS:70449652591
VL - 374
SP - 1754
EP - 1764
JO - The Lancet
JF - The Lancet
SN - 0140-6736
IS - 9703
ER -