Effect of Gly16Arg Polymorphism in ADRB2 Gene on Asthma Control in Children Receiving Long Acting Beta Agonists

May 25, 2023 updated by: Nemours Children's Clinic
Asthma is the most common chronic disease of childhood affecting 6.2 million children between 2 and 18 years of age, and is the most common cause of school absenteeism due to chronic disease. African American children are 3 to 4 times more likely to be hospitalized for asthma and 4 to 6 times more likely to die from the disease compared to European Americans. The economic burden in this country from asthma is enormous, exceeding $16 billion in 2004. Though there is no cure for asthma, several drugs are available that have been shown to be generally safe and effective in controlling symptoms. Beta 2 agonists are the most commonly used asthma drugs. When inhaled these drugs relax cells in the lungs, which helps patients with asthma breath easier. Two types of beta agonists in use are short-acting beta agonists (SABA) and long-acting beta agonists (LABA). SABA, like albuterol, are used to provide quick relief of chest tightening which help patients to breathe easier. Long-acting beta agonists (LABA) also help patients breathe easier and for a longer period of time. Continued SABA use (for example, inhale albuterol 3 or 4 times a day) is not recommended, and continued LABA use is recommended only if used together with inhaled corticosteroids (ICS). ICS are the most commonly used drug used in asthma that protects against inflammation in the lung. Studies over the past 50 years suggest that continued use of SABA, LABA, and the combination of ICS+LABA may worsen asthma in some patients by reducing the effect of the beta agonists, increasing the rate of asthma attacks, decreasing the ability of the lung to work efficiently, and death. Recent studies suggest asthma worsening by continued beta agonist use occurs in individuals with a certain genotype. Genotype refers to form of the protein, called the beta2 adrenergic receptor (b2AR), in the lung that beta agonists work on. Because of differences in genetic make up, there are different forms of the b2AR. One form is called the Arg16 genotype the other form is called the Gly16 genotype. Compared to Gly16 genotypes, patients with asthma genotyped as Arg16 appear to be more susceptible to asthma worsening that has been associated with continued use SABA, LABA or ICS+LABA. Most of the studies of the influence of genotype on asthma worsening associated with beta agonist use have been performed in adults. The results of a small number of studies suggest children are more susceptible to asthma worsening from chronic beta agonist use compared to adults, and that children with the Arg16 genotype are more susceptible to having asthma attacks than children with the Gly16 genotype. Some evidence suggest that children with asthma should not be treated with ICS+LABA, yet since 2000, the rate at which children with asthma are switched from ICS therapy alone to ICS+LABA has increased significantly. The major question posed by the proposed study is: Does treatment with ICS+LABA compared to ICS alone cause worsening of asthma in children with asthma genotyped as Arg16 homozygotes but not in Gly16 homozygotes? The specific aim of the project is to evaluate the safety of ICS+LABA in children with asthma when separated according genotype. Children with asthma will be screened, be assented and their care taker (parent, for example) consented. A sample of saliva will be collected from which genetic material (DNA) will be collected for the purpose of genotyping. A total of 90 European and African American children, 45 Arg16 and 45 Gly16 genotypes, will be treated for 16 weeks. Half of each genotype will be randomly assigned to receive ICS alone for 16 weeks the other half will receive ICS+LABA. At the end of 16 weeks, those starting with ICS will be then receive ICS+LABA while those who received ICS+LABA first will then take ICS alone. Before and once a month during treatment, each participant will visit the clinic to undergo tests that will assess lung function, how well asthma is being controlled, level of inflammation and quality of life. The results of our study are expected to have a major impact on the way children with asthma are being treated with drugs. If the results of our study show that Arg16 genotypes have worse asthma when they are taking ICS+LABA compared to ICS alone we will conclude that the safety of combination in children is questionable and should be tested in a larger population of children to determine if this popular combination should be used in children with asthma. If the results show that the combination in both genotypes does not worsen asthma compared to ICS treatment, we will conclude that the combination is safe to use in children, at least for 16 weeks.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Withdrawn

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 4

Participation Criteria

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Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

6 years to 18 years (Child, Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Age of participants will be 5 to 18 yo. FORADIL® is FDA-approved for children in this age group.
  • Ethnicity; European and African American will be selected for study. Other minorities will not be studied owing to the problem of population stratification, which refers to differences in allele frequency between cases and controls that are due to differences in ancestry rather than associations of genes with disease or drug response (47). For European Americans, the frequency of Arg16 homozygosity is about 15% compared to about 30% in African Americans (48). In previous studies, the PI restricted his analyses to European Americans because of the potential confounding of population stratification (48;49). .
  • Participants must have a diagnosis of asthma. In addition, participants must have persistent asthma as defined by NAEPP guidelines: asthma symptoms > 2 days; > 3 to 4 nighttime awakenings; SABA use >2 days/week; pre-bronchodilator % predicted >60%; FEV1/FVC normal or reduced by 5%.
  • Bronchodilator reversibility 12% from baseline; or a history of 12% reversibility during past 12 months; methacholine PC20 < 16 mg/ml.

Exclusion Criteria:

  • FEV1< 50% of predicted. Methacholine bronchoprovocation limited to participants with FEV1> 70% of predicted.

    • Other major chronic illnesses: non-skin cancer, cystic fibrosis, bronchiectasis, myelomeningocele, sickle cell anemia, endocrine disease, congenital heart disease, congestive heart failure, stroke, severe hypertension, insulin-dependent diabetes mellitus, renal failure, liver disorders, immunodeficiency state, significant neuro-developmental delay or behavioral disorders (excluding mild attention deficit hyperactivity disorder), or other conditions that would interfere with participation in the study.
    • Participants will discontinue all asthma medications for the duration of the study including theophylline, LTRAs (montelukast), LABA monotherapy, ipratropium bromide. The design of the study ensures that participants will be on ICS (or ICS+LABA) throughout the study and access to SABA for relief.
    • Allergy to methacholine
    • Non-adherence during run-in, or inability or unwillingness of the legal guardian to provide consent or inability or unwillingness of child to provide assent
    • Inability of perform baseline measurements
    • < 80% completion of screening period diaries
    • Inability to contract by telephone
    • Intention to move out of area with 12 months
    • Participants of appropriate age who might be pregnant at time of enrollment will be screened and cannot participant if pregnant.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Crossover Assignment
  • Masking: Triple

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Active Comparator: corticosteroid + long acting beta agonist; steroids
Drug: open-labeled inhaled corticosteroids (ICS); FORADIL® AEROLIZER®
• Drugs. The study drugs are open-labeled inhaled corticosteroids (ICS); FORADIL® AEROLIZER® and FORADIL placebo. FORADIL® AEROLIZER® consists of a capsule dosage form containing a dry powder formulation of FORADIL (formoterol fumarate) intended for oral inhalation only with the AEROLIZER Inhaler. Each clear, hard gelatin capsule contains a dry powder blend of 12 mcg of formoterol fumarate and 25 mg of lactose (which contains trace levels of milk proteins) as a carrier. Ten capsules are contained in each package, which is clearly labeled. To use the delivery system, a FORADIL capsule is placed in the well of the AEROLIZER Inhaler, and the capsule is pierced by pressing and releasing the buttons on the side of the device. The formoterol fumarate formulation is dispersed into the air stream when the patient inhales rapidly and deeply through the mouthpiece.
Drug: foradil
open-labeled inhaled corticosteroids (ICS); foradil
Placebo Comparator: placebo + corticosteroid + long acting beta agonist; steroids
Drug: foradil placebo
open-labeled inhaled corticosteroids (ICS); foradil placebo

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Time Frame
Asthma Control Scores will be compared between treatments and genotypes
Time Frame: 16 weeks
16 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Nemours Children's Clinic

Study record dates

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Study Major Dates

Study Start

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
October 1, 2010

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
December 1, 2011

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
December 1, 2011

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
April 19, 2010

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
April 20, 2010

First Posted (Estimated)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
April 22, 2010

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
May 26, 2023

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
May 25, 2023

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
May 1, 2023

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • 3203534014

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