Asthma Clinical Research Network (ACRN) Trial - Long-Acting Beta Agonist Response by Genotype (LARGE)

The purpose of this trial is to determine whether regularly scheduled use of an inhaled long-acting beta agonist (salmeterol) in the setting of concomitant use of inhaled corticosteroids (beclomethasone hydroflouroalkane (HFA) inhaler) will have a detrimental effect on asthma control in people who bear the B16-Arg/Arg genotype of the beta-2 adrenergic receptor gene, as compared to people with asthma of similar severity who bear the B16-Gly/Gly genotype.

Study Overview

• Status: Completed
• Conditions: Asthma
• Intervention / Treatment: Drug: salmeterol; Drug: beclomethasone HFA

Detailed Description

BACKGROUND:

The purpose of this study is to compare the effects of a long-acting beta agonist in patients with asthma receiving inhaled corticosteroids who express two distinct polymorphisms of the beta-2 adrenergic receptor.

DESIGN NARRATIVE:

Participants were homozygous for arginine or glycine at the 16th amino-acid position of the β-2 adrenergic receptor (B16 Arg/Arg or B16 Gly/Gly). Individuals were matched against their opposite genotype by forced expiratory volume in one second (FEV1) and race. Matched participants entered an 8-week run-in period. This is a 62-week crossover design where subjects receive the following therapies:

• Beclomethasone HFA (240 µg twice a day (BID)) + as-needed (PRN) albuterol: 8-week run-in
• Beclomethasone HFA (240 µg BID) + salmeterol (50 µg BID) + PRN ipratropium bromide + PRN albuterol: 18-week treatment period
• Beclomethasone HFA (240 µg BID) + PRN albuterol: 8-week run-out
• Beclomethasone HFA (240 µg BID) + placebo salmeterol + PRN ipratropium bromide + PRN albuterol: 18-week treatment period
• Beclomethasone HFA (240 µg BID) + PRN albuterol: 10-week run-out

The order of treatments received during the two treatment periods is randomized.

• Study Type: Interventional
• Enrollment (Actual): 87
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • California
    • San Diego, California, United States, 92103
      • University of California, San Diego
    • San Francisco, California, United States, 94143-0130
      • University of California, San Francisco
  • Colorado
    • Denver, Colorado, United States, 80206
      • National Jewish Medical & Research Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Brigham & Women's Hospital
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University
  • North Carolina
    • Winston-Salem, North Carolina, United States, 27103
      • Wake Forest University Health Sciences
  • Wisconsin
    • Madison, Wisconsin, United States, 53792-3244
      • University of Wisconsin Madison

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 90 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Male or female, ages 18 and older
• Clinical history consistent with asthma
• For subjects regularly using inhaled corticosteroids, FEV1 50% of predicted, methacholine PC20 FEV1 16 mg/ml or 12% and 200 ml, improvement in FEV1 after 2 puffs of inhaled albuterol
• For subjects not regularly using inhaled corticosteroids, FEV1 40% of predicted, methacholine PC20 FEV1 8 mg/ml or 12% and 200 ml, improvement in FEV1 after 2 puffs of inhaled albuterol
• Genotype eligibility (determined during screening)

Exclusion Criteria:

• Smoker (total smoking history must be less than 10 pack years)
• Significant unstable medical condition other than asthma
• History of life-threatening asthma requiring treatment with intubation and mechanical ventilation in the past 10 years
• Pregnant or lactating

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: B16 Arg/Arg; B16 Arg/Arg genotype Sequence 1: inhaled salmeterol + inhaled beclomethasone hydroflouroalkane (HFA), followed by inhaled placebo salmeterol + inhaled beclomethasone HFA Sequence 2: inhaled placebo salmeterol + inhaled beclomethasone HFA, followed by inhaled salmeterol + inhaled beclomethasone HFA	Drug: salmeterol; 50 micrograms (mcg) twice per day (BID) (Serevent 50 mcg diskus, GlaxoSmithKline (GSK), North Carolina); Other Names: Serevent; Drug: beclomethasone HFA; 240 mcg beclomethasone HFA (QVAR, Teva Pharmaceutical Industries); Other Names: QVAR
EXPERIMENTAL: B16 Gly/Gly; B16 Gly/Gly genotype Sequence 1: inhaled salmeterol + inhaled beclomethasone HFA, followed by inhaled placebo salmeterol + inhaled beclomethasone HFA Sequence 2: inhaled placebo salmeterol + inhaled beclomethasone HFA, followed by inhaled salmeterol + inhaled beclomethasone HFA	Drug: salmeterol; 50 micrograms (mcg) twice per day (BID) (Serevent 50 mcg diskus, GlaxoSmithKline (GSK), North Carolina); Other Names: Serevent; Drug: beclomethasone HFA; 240 mcg beclomethasone HFA (QVAR, Teva Pharmaceutical Industries); Other Names: QVAR

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Morning (AM) Peak Expiratory Flow (PEF) Rate	Change between placebo salmeterol and active salmeterol for AM PEF rate	Measured daily using a hand-held peak flow meter, and then averaged between weeks 0, 2, 6, 10, 14, and 18 of each treatment period

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Evening (PM) Peak Expiratory Flow (PEF) Rate	Change between placebo salmeterol and active salmeterol for PM PEF rate	Measured daily using a hand-held peak flow meter, and then averaged between weeks 0, 2, 6, 10, 14, and 18 of each treatment period
Peak Expiratory Flow (PEF) Variability	Change between placebo salmeterol and active salmeterol for PEF variability, where PEF variability is defined as 100% x (PM PEF - AM PEF)/(PM PEF)	Measured daily using a hand-held peak flow meter, and then averaged between weeks 0, 2, 6, 10, 14, and 18 of each treatment period
Asthma Symptoms	Change between placebo salmeterol and active salmeterol for asthma symptoms (0=absent, 1=mild, 2=moderate, 3=severe).	Recorded daily on a diary card, and then averaged between weeks 0, 2, 6, 10, 14, and 18 of each treatment period
Rescue Medication (Ipratropium and Albuterol) Use	Change between placebo salmeterol and active salmeterol for rescue medication use	Recorded daily on a diary card, and then averaged between weeks 0, 2, 6, 10, 14, and 18 of each treatment period
Spirometry Forced Expiratory Volume in One Second (FEV1), Pre-bronchodilator	Change between placebo salmeterol and active salmeterol for Spirometry FEV1, pre-bronchodilator	Clinic visits at weeks 0, 2, 6, 10, 14, and 18 of each treatment period
Spirometry Forced Vital Capacity (FVC), Pre-bronchodilator	Change between placebo salmeterol and active salmeterol for Spirometry FVC, pre-bronchodilator	Clinic visits at weeks 0, 2, 6, 10, 14, and 18 of each treatment period
Spirometry Peak Expiratory Flow (PEF) Rate, Pre-bronchodilator	Change between placebo salmeterol and active salmeterol for Spirometry PEF rate, pre-bronchodilator	Clinic visits at weeks 0, 2, 6, 10, 14, and 18 of each treatment period
Exhaled Nitric Oxide (eNO)	Change between placebo salmeterol and active salmeterol for eNO	Clinic visits at weeks 0, 2, 6, 10, 14, and 18 of each treatment period
Exhaled Breath Condensate (EBC)	Change between placebo salmeterol and active salmeterol for EBC	Clinic visits at weeks 0, 10, and 18 of each treatment period
Methacholine Provocative Concentration 20 (PC20)	Change between placebo salmeterol and active salmeterol for methacholine PC20	Clinic visits at weeks 0 and 18 of each treatment period
Asthma Control Questionnaire (ACQ)	Change between placebo salmeterol and active salmeterol for ACQ, where ACQ ranges from 0 (best asthma control) to 6 (worst asthma control).	Clinic visits at weeks 0 and 18 of each treatment period

Collaborators and Investigators

• Sponsor: Milton S. Hershey Medical Center
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI); Asthma Clinical Research Network
• Investigators: Principal Investigator: Homer Boushey, University of California, San Francisco; Principal Investigator: Mario Castro, Washington University School of Medicine; Principal Investigator: Vernon M. Chinchilli, PhD, Milton S. Hershey Medical Center; Principal Investigator: Elliot Israel, Brigham and Women's Hospital; Principal Investigator: Robert Lemanske, University of Wisconsin, Madison; Principal Investigator: Richard Martin, National Jewish Medical & Research Center; Principal Investigator: Stephen Peters, Wake Forest University Health Sciences; Principal Investigator: Stephen Wasserman, University of California, San Diego

Publications and helpful links

General Publications

• Wechsler ME, Kunselman SJ, Chinchilli VM, Bleecker E, Boushey HA, Calhoun WJ, Ameredes BT, Castro M, Craig TJ, Denlinger L, Fahy JV, Jarjour N, Kazani S, Kim S, Kraft M, Lazarus SC, Lemanske RF Jr, Markezich A, Martin RJ, Permaul P, Peters SP, Ramsdell J, Sorkness CA, Sutherland ER, Szefler SJ, Walter MJ, Wasserman SI, Israel E; National Heart, Lung and Blood Institute's Asthma Clinical Research Network. Effect of beta2-adrenergic receptor polymorphism on response to longacting beta2 agonist in asthma (LARGE trial): a genotype-stratified, randomised, placebo-controlled, crossover trial. Lancet. 2009 Nov 21;374(9703):1754-64. doi: 10.1016/S0140-6736(09)61492-6.

Helpful Links

• Asthma Clinical Research Network (ACRN) Website

Study record dates

Study Major Dates

• Study Start: December 1, 2004
• Primary Completion (ACTUAL): February 1, 2008
• Study Completion (ACTUAL): February 1, 2008

Study Registration Dates

• First Submitted: September 12, 2005
• First Submitted That Met QC Criteria: September 12, 2005
• First Posted (ESTIMATE): September 20, 2005

Study Record Updates

• Last Update Posted (ACTUAL): January 23, 2018
• Last Update Submitted That Met QC Criteria: December 26, 2017
• Last Verified: December 1, 2017

More Information

Terms related to this study

• 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; Autonomic Agents; Peripheral Nervous System Agents; Anti-Inflammatory Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Adrenergic Agonists; Bronchodilator Agents; Anti-Asthmatic Agents; Respiratory System Agents; Adrenergic beta-2 Receptor Agonists; Adrenergic beta-Agonists; Salmeterol Xinafoate; Beclomethasone
• Other Study ID Numbers: 262 (RoPCCT); U10HL074231 (U.S. NIH Grant/Contract); 5U10HL074231 (U.S. NIH Grant/Contract); U10HL074204 (U.S. NIH Grant/Contract); U10HL074073 (U.S. NIH Grant/Contract); U10HL074208 (U.S. NIH Grant/Contract); U10HL074212 (U.S. NIH Grant/Contract); U10HL074218 (U.S. NIH Grant/Contract); U10HL074225 (U.S. NIH Grant/Contract); U10HL074227 (U.S. NIH Grant/Contract)