Blacks and Exacerbations on Long Acting Beta Agonists (LABA) vs. Tiotropium (BELT)

Study Overview
=================
Brief Summary
-----------------
We are doing this study to learn how genes affect the way that people, specifically Black people, respond to treatment for asthma. Recent studies suggest that people respond differently to some asthma medications (eg Serevent, Foradil). Some people feel better when they use these inhalers, but others may not, and some people get worse. It seems that this difference shows up more often in Blacks than in Whites, which is why we are looking for Black subjects for this study. In all people, this difference seems to depend on their genes or DNA. This study is comparing the use of long acting asthma medications (Serevent, Foradil) to Tiotropium (Spiriva) for the treatment of asthma. Spiriva is used to treat chronic obstructive pulmonary disease (COPD). This study will help to see if this medication is also useful for treating asthma and whether it works better for some people than the current asthma medications.

Detailed Description
-----------------
Asthma is a chronic respiratory disease that affects over 22 million people in the United States. Asthma produces 500,000 hospital admissions and accounts for 10.1 million days of lost work in adults annually. Asthma has been designated a priority condition of the Effective Health Care Program. Blacks bear a disproportionate burden of asthma morbidity and mortality. In its 2005 report on ethnic disparities in health care, AHRQ identified hospital admissions for asthma as the second largest disparity in quality of health care for Blacks vs. Caucasians. Long-acting beta-agonists (LABAs) produce extended increases in airway caliber among patients with asthma via action at the beta2-adrenergic receptor (ADRB2). Adding a LABA to an inhaled corticosteroid controller medication (ICS), can decrease asthma symptoms for many individuals and appears to decrease asthma exacerbations. LABA/ICS has become the most commonly prescribed ICS containing medication. Drugs acting at ADRB2, including LABAs, have been associated with rare loss of long-term asthma control and increased serious adverse outcomes including death and respiratory failure, even when used with ICS. The risk appears four to five-fold greater in Blacks than non-Black patients with asthma. Consensus guidelines recommend LABAs be added to ICS in those not completely controlled on ICS alone. These recommendations are based on weighing data on the benefit demonstrated in the general population vs. the rare risk of serious adverse outcomes and balancing the apparent benefits vs. the risks of LABAs (Kramer 2009). However, it appears that LABA/ICS may be significantly less effective in Blacks than Caucasians. Comparison of studies with LABA/ICS in Blacks vs. studies where Blacks were a small minority suggests that Blacks may have much less benefit than other racial groups. Additionally, recent data (Wechsler 2009) suggest that a polymorphism at the 16th position of the ADRB2 gene identifies a group of Blacks (those homozygous for arginine (Arg16Arg)) in whom the response of adding a LABA to an ICS is further diminished. This polymorphism is present in  20% of US Blacks.

Official Title
-----------------
Blacks and Exacerbations on LABA vs. Tiotropium (BELT)

Conditions
-----------------
Asthma

Intervention / Treatment
-----------------
* Drug: Tiotropium
* Drug: Salmeterol
* Drug: Formoterol


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Black (self-identified, with at least one biological parent identified as Black) Male and female subjects, ages 18-75 Ability to provide informed consent Clinical history consistent with asthma for > 1 year. Ability to perform pulmonary function tests FEV1 > 40% of predicted Receiving inhaled corticosteroids (ICS)/LABA combination therapy, or ICS moderate dose monotherapy and baseline ACQ>1.25 Non-smoker for past year (total lifetime smoking history < 10 pack-years) Exclusion Criteria: Use of greater than the equivalent of 1000 mcg inhaled fluticasone daily Chronic use of oral corticosteroids or Anti IgE for asthma Lung disease other than asthma or diagnosis of vocal cord dysfunction. Significant medical illness (other than asthma) that is not stable. Pregnancy or lactation or an unwillingness to maintain effective birth control. History of a significant exacerbation of asthma or respiratory tract infection in the prior 4 weeks History of life-threatening asthma requiring treatment with intubation and mechanical ventilation within 5 years. Hypo sensitization therapy other than an established maintenance regimen. Use of inhaled anticholinergic therapy (ipratropium, tiotropium) in prior month Known contraindication to inhaled tiotropium e.g. narrow angle glaucoma, history of bladder neck obstruction or significant symptoms related to prostatic hypertrophy. Inability to speak and read English.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tiotropium<br>Tiotropium bromide will be evaluated as a treatment for asthma. | Drug: Tiotropium<br>* Tiotropium bromide 18 mcg once daily for one year of treatment.<br>* Other names: Spiriva;|
| Active Comparator: Salmeterol or Formoterol<br>Long acting beta agonists (Serevent, Foradil) are the standard treatments for moderate asthma. The efficacy of Tiotropium will be compared to this standard. | Drug: Salmeterol<br>* Salmeterol 50 mcg twice daily for one year of treatment.<br>* Other names: Serevent;Drug: Formoterol<br>* Formoterol 12 mcg twice daily for one year<br>* Other names: Foradil;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Asthma Exacerbation (Mean Number of Exacerbations/Person-year) | We summarize the survival experience using mean number of exacerbations/person-year and compare it using the log-rank test comparing kaplan-meier survival curve. | evaluated monthly (on average) via questionnaire for 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in FEV1 | Average change in lung function (FEV1) evaluated by spirometry per participant over 12 months | from baseline to 12 months | 
| Change in Asthma Control Questionnaire (ACQ) | Average Change in Asthma Control Score Per Participant Over 12 Months Using the Asthma Control Questionnaire (ACQ). The ACQ has six questions regarding symptoms, rescue short-acting β-agonist use and one about FEV1 % predicted. A 7-point scale (0 = no impairment, 6 = maximum impairment) is used for each question and the ACQ score is the mean value of these questions - hence between 0 (totally controlled) and 6 (severely uncontrolled). | from baseline to 12 months | 
| Change in Asthma Quality of Life (AQLQ) | Average Change in Asthma Quality of Life Score Per Participant Over 12 Months Using the Asthma Quality of Life Questionnaire (AQLQ). The AQLQ has 32 questions in four domains (symptoms, activity limitation, emotional function, and environmental stimuli) and measures the functional problems that are troublesome to individuals with asthma. Symptoms (11 items), Activity Limitation (12 items, 5 of which are individualized), Emotional Function (5 items), and Environmental Exposure (4 items); 7-point Likert scale (7 = not impaired at all - 1 = severely impaired); scores range 1-7, with higher scores indicating better quality of life. | from baseline to 12 months | 
| Change in Asthma Symptom Utility Index (ASUI) | Average Change in Asthma Symptom Utility Score Per Participant Over 12 Months Using the Asthma Symptom Utility Index (ASUI). The ASUI is an 11-item preference-based outcome measure used in clinical trials and cost-effectiveness studies for asthma and is designed to assess the frequency and severity of cough, wheeze, dyspnea, nighttime awakenings, and side effects, weighted according to patient preferences. 4-point Likert scale to assess frequency (not at all, 1 to 3 days, 4 to 7 days, and 8 to 14 days) and severity (not applicable, mild, moderate and severe); scores range from 0 (worst possible symptoms) to 1 (no symptoms). | from baseline to 12 months | 
| Change in Symptom-Free Day Questionnaire (SFDQ) | Average Change in Symptom-Free Days Per Participant Over 12 Months Using the Symptom-Free Day Questionnaire (SFDQ). The asthma symptom free day questionnaire (SFDQ) quantifies the number of days with neither daytime nor nighttime asthma symptoms, nor awakenings due to asthma symptoms. | from baseline to 12 months | 
| Change in Rescue Medication Use | Average Change in Rescue Medication Use Per Participant Over 12 Months. Monthly questionnaires will evaluate the amount of rescue medication subjects have used on average, measured in puffs per day. | from baseline to 12 months | 
| Change in Moderate Asthma Deterioration | Average Change in Moderate Asthma Deterioration Per Participant Over 12 Months. The definition of a moderate asthma deterioration should include one or more of the following: deterioration in symptoms, deterioration in lung function, or increased rescue bronchodilator use. These features should last for 2 days or more, but not be severe enough to warrant systemic corticosteroid use and/or hospitalization. | from baseline to 12 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Asthma, Blacks, LABA, Tiotropium, Spiriva, African American, Serevent, salmeterol, Foradil, formoterol, Advair, Symbicort, Dulera