Asthma
Conditions
Keywords
Asthma, Pharmacogenetics, Salmeterol, African American, White
Brief summary
This study will help to find out if having a certain genetic makeup influences how a person with asthma responds to salmeterol, one of the two drugs in Advair(R).
Detailed description
Patients are being asked to take part in this research study because they have asthma. This clinical research study is being done to see if an asthmatic's gene make-up (DNA is made up of genes) affects the way they respond to a particular asthma medication called salmeterol. Certain genes make people tall or short. Certain genes give people brown or black hair. Similarly, certain genes may be associated with the way patients respond to asthma medications. Salmeterol xinafoate (a long acting bronchodilator) and fluticasone propionate (an inhaled corticosteroid) are the medicines contained in Advair Diskus. During this study, patients with asthma will receive fluticasone inhaler (called Flovent) and Advair Diskus. The investigators want to find out if patients with asthma with certain genes respond in different ways to the salmeterol in Advair Diskus. The investigators also want to find out if patients with asthma with certain genes who are treated with salmeterol for two weeks have their airways open up less than usual when they use albuterol.
Interventions
None listed
Sponsors
University of Florida
National Heart, Lung, and Blood Institute (NHLBI)
Nemours Children's Clinic
Study design
Observational model
CASE_CROSSOVER
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
10 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Diplotype: Whites with specific diplotype and African Americans with specific diplotypes. * Gender: Male or female. Women are eligible if they are not pregnant or lactating. Females subjects of childbearing potential will undergo a urine pregnancy test prior to each methacholine challenge test. * Age: 10 years and older. * Asthma Diagnosis: Physician diagnosed asthma according to American Thoracic Society criteria for at least 3 months. * Asthma Therapy: There is no requirement for previous asthma therapy to be included in this study. * Asthma Severity: forced expiratory volume in the first second (FEV1) must be \>= 60% of predicted normal values for age, height, and gender. * methacholine challenge test provocative concentration (20% fall in FEV1) of \<=12\]mg/ml.
Exclusion criteria
* History of life-threatening asthma: Any episode of asthma requiring intubation associated with hypercapnia, respiratory arrest, or hypoxic seizures. * Asthma instability: Hospitalization for asthma within 3 months of Visit 1. * Concurrent respiratory disease: Any respiratory disease other than asthma. * Sensitivities: Sensitivities to methacholine, Flovent® MDI, ipratropium bromide, albuterol, or Advair Diskus® that would put the safety of the subject at risk. * Respiratory Tract Infection: Any sinus, middle ear, oropharyngeal, upper or lower respiratory tract infection that has not resolved at least 2 weeks immediately preceding Visit 1, or for which antibiotic therapy has not been completed at least 2 weeks prior to Visit 1. * Expected exposure to pollen allergen to which the patient is sensitive (by medical history of symptoms) during the 29 day study period. These patients can be studied when pollen exposure to which they are sensitive will not occur.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Log10 PC20 to Methacholine After Visit 2 | Visit 2:12 hours after last dose of Flovent | Visit 2 log10 PC20 after receiving 2 weeks of Flovent |
| Log10 PC20 to Methacholine After Visit 3 | Visit 3:12 hours after the last dose of Advair | Visit 3 Log10 PC20 after receiving 2 weeks of Advair |
| Log10 PC20 to Methacholine After Visit 4 | 36 hours after the last dose of Advair | Visit 4 log10 PC20 to Methacholine after stopping Advair |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Bronchodilator Response to Methacholine (PC20) After Visit 2 | 0 (immediately upon completion of nebulization) and at 1, 3, 5, 10, 15, 20, 30, 45, and 60 minutes after nebulization was complete which occurred 12 hours after the last dose of Flovent. | The area under the curve (AUC) bronchodilator response after Visit 2 methacholine challenge. 2.5mg of albuterol was administered at the time of maximal brochoconstriction once the methacholine PC20 was reached and the change in FEV1 was measured over the next 60 minutes post albuterol administration (bronchodilator response). FEV1 was measured at the following times: 0 (immediately upon completion of nebulization) and at 1, 3, 5, 10, 15, 20, 30, 45, and 60 minutes. Participants had received Flovent for 2 weeks at Visit 2. |
| Bronchodilator Response Following Methacholine Challenge at Visit 3 | 0 (immediately upon completion of nebulization) and at 1, 3, 5, 10, 15, 20, 30, 45, and 60 minutes after nebulization was complete which occurred 12 hours after the last dose of Advair | The area under the curve (AUC) bronchodilator response after Visit 3 methacholine challenge. 2.5mg of albuterol was administered at the time of maximal brochoconstriction once the methacholine PC20 was reached and the change in FEV1 was measured over the next 60 minutes post albuterol administration (bronchodilator response). FEV1 was measured at the following times: 0 (immediately upon completion of nebulization) and at 1, 3, 5, 10, 15, 20, 30, 45, and 60 minutes. Participants had received Advair for 2 weeks at Visit 3. |
| Bronchodilator Response Following Methacholine Challenge at Visit 4 | 0 (immediately upon completion of nebulization) and at 1, 3, 5, 10, 15, 20, 30, 45, and 60 minutes after nebulization was complete which occurred 36 hours after the last dose of Advair | The area under the curve (AUC) bronchodilator response after Visit 4 methacholine challenge. 2.5mg of albuterol was administered at the time of maximal brochoconstriction once the methacholine PC20 was reached and the change in FEV1 was measured over the next 60 minutes post albuterol administration (bronchodilator response). FEV1 was measured at the following times: 0 (immediately upon completion of nebulization) and at 1, 3, 5, 10, 15, 20, 30, 45, and 60 minutes. Participants had discontinued Advair for 36 hours. |
Countries
United States
Participant flow
Recruitment details
Participants were recruited from Nemours Children's Health System, the University of Florida Jacksonville, health fairs and events, Edward Waters College, and from previous study participation. Participants were recruited between January 2008 and October 2011
Pre-assignment details
Enrolled participants were excluded from receiving planned study treatment if they did not meet the ADRB2 genotype criteria and if they did not have a methacholine PC20 of 12.5mg/ml or less.
Participants by arm
| Arm | Count |
|---|---|
| Whites ADRB2:ARG16ARG All participants receive fluticasone for 2-weeks followed by fluticasone / salmeterol or 2-weeks at a dose commensurate with baseline inhaled corticosteroid dose. All participants receive ipratropium bromide for symptom rescue therapy.
fluticasone: Fluticasone propionate MDI(dose to be determined by patient's current treatment) for 2 weeks, followed by Advair(R)Diskus (same dose of fluticasone propionate) for 2 weeks; Ipratropium bromide MDI used for prn symptom relief | 19 |
| Whites ADRB2:GLY16GLY All participants receive fluticasone for 2-weeks followed by fluticasone / salmeterol or 2-weeks at a dose commensurate with baseline inhaled corticosteroid dose. All participants receive ipratropium bromide for symptom rescue therapy.
Salmeterol: Fluticasone propionate MDI(dose to be determined by patient's current treatment) for 2 weeks, followed by Advair(R)Diskus (same dose of fluticasone propionate) for 2 weeks; Ipratropium bromide MDI used for prn symptom relief | 26 |
| African Americans ADRB2:ARG16ARG All participants receive fluticasone for 2-weeks followed by fluticasone / salmeterol or 2-weeks at a dose commensurate with baseline inhaled corticosteroid dose. All participants receive ipratropium bromide for symptom rescue therapy.
fluticasone: Fluticasone propionate MDI(dose to be determined by patient's current treatment) for 2 weeks, followed by Advair(R)Diskus (same dose of fluticasone propionate) for 2 weeks; Ipratropium bromide MDI used for prn symptom relief | 18 |
| African Americans ADRB2:GLY16GLY All participants receive fluticasone for 2-weeks followed by fluticasone / salmeterol or 2-weeks at a dose commensurate with baseline inhaled corticosteroid dose. All participants receive ipratropium bromide for symptom rescue therapy.
fluticasone: Fluticasone propionate MDI(dose to be determined by patient's current treatment) for 2 weeks, followed by Advair(R)Diskus (same dose of fluticasone propionate) for 2 weeks; Ipratropium bromide MDI used for prn symptom relief | 25 |
| Total | 88 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Physician Decision | 0 | 3 | 1 | 2 |
| Overall Study | Withdrawal by Subject | 1 | 2 | 0 | 1 |
Baseline characteristics
| Characteristic | Whites ADRB2:ARG16ARG | Whites ADRB2:GLY16GLY | African Americans ADRB2:ARG16ARG | African Americans ADRB2:GLY16GLY | Total |
|---|---|---|---|---|---|
| ADRB2 Genotype at Codon 16 | 19 Participants | 26 Participants | 18 Participants | 25 Participants | 88 Participants |
| Age, Categorical <=18 years | 5 Participants | 6 Participants | 9 Participants | 10 Participants | 30 Participants |
| Age, Categorical >=65 years | 1 Participants | 3 Participants | 2 Participants | 0 Participants | 6 Participants |
| Age, Categorical Between 18 and 65 years | 13 Participants | 17 Participants | 7 Participants | 15 Participants | 52 Participants |
| Age, Continuous | 34 years STANDARD_DEVIATION 19 | 37 years STANDARD_DEVIATION 20 | 27 years STANDARD_DEVIATION 21 | 28 years STANDARD_DEVIATION 17 | 32 years STANDARD_DEVIATION 19 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 18 Participants | 25 Participants | 43 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 19 Participants | 26 Participants | 0 Participants | 0 Participants | 45 Participants |
| Region of Enrollment United States | 19 Participants | 26 Participants | 18 Participants | 25 Participants | 88 Participants |
| Sex: Female, Male Female | 14 Participants | 16 Participants | 13 Participants | 18 Participants | 61 Participants |
| Sex: Female, Male Male | 5 Participants | 10 Participants | 5 Participants | 7 Participants | 27 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 19 | 0 / 26 | 0 / 18 | 0 / 25 |
| other Total, other adverse events | 0 / 19 | 1 / 26 | 0 / 18 | 0 / 25 |
| serious Total, serious adverse events | 0 / 19 | 0 / 26 | 0 / 18 | 0 / 25 |
Outcome results
Primary
Log10 PC20 to Methacholine After Visit 2
Visit 2 log10 PC20 after receiving 2 weeks of Flovent
Time frame: Visit 2:12 hours after last dose of Flovent
Population: All participants who had a methacholine challenge at Visit 2. All participants had received Flovent for 2 weeks.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Whites ADRB2:ARG16ARG | Log10 PC20 to Methacholine After Visit 2 | 0.54 log10 mg/mL | Standard Deviation 0.65 |
| Whites ADRB2:Gly16Gly | Log10 PC20 to Methacholine After Visit 2 | 0.48 log10 mg/mL | Standard Deviation 0.71 |
| African Americans ADRB2:ARG16ARG | Log10 PC20 to Methacholine After Visit 2 | 0.16 log10 mg/mL | Standard Deviation 0.57 |
| African Americans ADRB2:GLY16GLY | Log10 PC20 to Methacholine After Visit 2 | 0.53 log10 mg/mL | Standard Deviation 0.67 |
p-value: 0.27ANOVA
Primary
Log10 PC20 to Methacholine After Visit 3
Visit 3 Log10 PC20 after receiving 2 weeks of Advair
Time frame: Visit 3:12 hours after the last dose of Advair
Population: All participants who had a methacholine challenge at Visit 3. All participants had received Advair for 2 weeks.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Whites ADRB2:ARG16ARG | Log10 PC20 to Methacholine After Visit 3 | 0.75 log10 mg/mL | Standard Deviation 0.65 |
| Whites ADRB2:Gly16Gly | Log10 PC20 to Methacholine After Visit 3 | 0.78 log10 mg/mL | Standard Deviation 0.6 |
| African Americans ADRB2:ARG16ARG | Log10 PC20 to Methacholine After Visit 3 | 0.35 log10 mg/mL | Standard Deviation 0.63 |
| African Americans ADRB2:GLY16GLY | Log10 PC20 to Methacholine After Visit 3 | 0.75 log10 mg/mL | Standard Deviation 0.65 |
p-value: 0.15ANOVA
Primary
Log10 PC20 to Methacholine After Visit 4
Visit 4 log10 PC20 to Methacholine after stopping Advair
Time frame: 36 hours after the last dose of Advair
Population: All participants who had a methacholine challenge at Visit 4. All participants had discontinued Advair for 36 hours.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Whites ADRB2:ARG16ARG | Log10 PC20 to Methacholine After Visit 4 | 0.73 log10 mg/mL | Standard Deviation 0.61 |
| Whites ADRB2:Gly16Gly | Log10 PC20 to Methacholine After Visit 4 | 0.89 log10 mg/mL | Standard Deviation 0.57 |
| African Americans ADRB2:ARG16ARG | Log10 PC20 to Methacholine After Visit 4 | 0.36 log10 mg/mL | Standard Deviation 0.52 |
| African Americans ADRB2:GLY16GLY | Log10 PC20 to Methacholine After Visit 4 | 0.70 log10 mg/mL | Standard Deviation 0.66 |
p-value: 0.06ANOVA
Secondary
Bronchodilator Response Following Methacholine Challenge at Visit 3
The area under the curve (AUC) bronchodilator response after Visit 3 methacholine challenge. 2.5mg of albuterol was administered at the time of maximal brochoconstriction once the methacholine PC20 was reached and the change in FEV1 was measured over the next 60 minutes post albuterol administration (bronchodilator response). FEV1 was measured at the following times: 0 (immediately upon completion of nebulization) and at 1, 3, 5, 10, 15, 20, 30, 45, and 60 minutes. Participants had received Advair for 2 weeks at Visit 3.
Time frame: 0 (immediately upon completion of nebulization) and at 1, 3, 5, 10, 15, 20, 30, 45, and 60 minutes after nebulization was complete which occurred 12 hours after the last dose of Advair
Population: The area under the curve (AUC) bronchodilator response after Visit 3 methacholine challenge. 2.5mg of albuterol was administered at the time of maximal brochoconstriction once the methacholine PC20 was reached. Participants had received Advair for 2 weeks at Visit 3.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Whites ADRB2:ARG16ARG | Bronchodilator Response Following Methacholine Challenge at Visit 3 | 183.6 Liters*min | Standard Deviation 67.02 |
| Whites ADRB2:Gly16Gly | Bronchodilator Response Following Methacholine Challenge at Visit 3 | 189.2 Liters*min | Standard Deviation 61.08 |
| African Americans ADRB2:ARG16ARG | Bronchodilator Response Following Methacholine Challenge at Visit 3 | 160.0 Liters*min | Standard Deviation 48.01 |
| African Americans ADRB2:GLY16GLY | Bronchodilator Response Following Methacholine Challenge at Visit 3 | 157.7 Liters*min | Standard Deviation 45.28 |
Secondary
Bronchodilator Response Following Methacholine Challenge at Visit 4
The area under the curve (AUC) bronchodilator response after Visit 4 methacholine challenge. 2.5mg of albuterol was administered at the time of maximal brochoconstriction once the methacholine PC20 was reached and the change in FEV1 was measured over the next 60 minutes post albuterol administration (bronchodilator response). FEV1 was measured at the following times: 0 (immediately upon completion of nebulization) and at 1, 3, 5, 10, 15, 20, 30, 45, and 60 minutes. Participants had discontinued Advair for 36 hours.
Time frame: 0 (immediately upon completion of nebulization) and at 1, 3, 5, 10, 15, 20, 30, 45, and 60 minutes after nebulization was complete which occurred 36 hours after the last dose of Advair
Population: The area under the curve (AUC) bronchodilator response after Visit 3 methacholine challenge. 2.5mg of albuterol was administered at the time of maximal brochoconstriction once the methacholine PC20 was reached. Participants had received Advair for 2 weeks at Visit 3.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Whites ADRB2:ARG16ARG | Bronchodilator Response Following Methacholine Challenge at Visit 4 | 187.3 Liters*min | Standard Deviation 66.17 |
| Whites ADRB2:Gly16Gly | Bronchodilator Response Following Methacholine Challenge at Visit 4 | 187.1 Liters*min | Standard Deviation 58.31 |
| African Americans ADRB2:ARG16ARG | Bronchodilator Response Following Methacholine Challenge at Visit 4 | 163.2 Liters*min | Standard Deviation 46.7 |
| African Americans ADRB2:GLY16GLY | Bronchodilator Response Following Methacholine Challenge at Visit 4 | 157.7 Liters*min | Standard Deviation 36.44 |
Secondary
Bronchodilator Response to Methacholine (PC20) After Visit 2
The area under the curve (AUC) bronchodilator response after Visit 2 methacholine challenge. 2.5mg of albuterol was administered at the time of maximal brochoconstriction once the methacholine PC20 was reached and the change in FEV1 was measured over the next 60 minutes post albuterol administration (bronchodilator response). FEV1 was measured at the following times: 0 (immediately upon completion of nebulization) and at 1, 3, 5, 10, 15, 20, 30, 45, and 60 minutes. Participants had received Flovent for 2 weeks at Visit 2.
Time frame: 0 (immediately upon completion of nebulization) and at 1, 3, 5, 10, 15, 20, 30, 45, and 60 minutes after nebulization was complete which occurred 12 hours after the last dose of Flovent.
Population: All participants who had received Flovent for 2 weeks at Visit 2.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Whites ADRB2:ARG16ARG | Bronchodilator Response to Methacholine (PC20) After Visit 2 | 188.5 Liters*min | Standard Deviation 67.55 |
| Whites ADRB2:Gly16Gly | Bronchodilator Response to Methacholine (PC20) After Visit 2 | 196.6 Liters*min | Standard Deviation 63.3 |
| African Americans ADRB2:ARG16ARG | Bronchodilator Response to Methacholine (PC20) After Visit 2 | 169.9 Liters*min | Standard Deviation 58.97 |
| African Americans ADRB2:GLY16GLY | Bronchodilator Response to Methacholine (PC20) After Visit 2 | 161.4 Liters*min | Standard Deviation 42.7 |