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

Blacks and Exacerbations on LABA vs. Tiotropium (BELT)

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01290874

Acronym

BELT

Enrollment

1070

Registered

2011-02-07

Start date

2011-03-30

Completion date

2013-07-31

Last updated

2018-03-30

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Asthma

Keywords

Asthma, Blacks, LABA, Tiotropium, Spiriva, African American, Serevent, salmeterol, Foradil, formoterol, Advair, Symbicort, Dulera

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.

Interventions

DRUGTiotropium

Tiotropium bromide 18 mcg once daily for one year of treatment.

DRUGSalmeterol

Salmeterol 50 mcg twice daily for one year of treatment.

DRUGFormoterol

Formoterol 12 mcg twice daily for one year

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to 75 Years

Healthy volunteers

Inclusion criteria

1. Black (self-identified, with at least one biological parent identified as Black) 2. Male and female subjects, ages 18-75 3. Ability to provide informed consent 4. Clinical history consistent with asthma for \> 1 year. 5. Ability to perform pulmonary function tests 6. FEV1 \> 40% of predicted 7. Receiving inhaled corticosteroids (ICS)/LABA combination therapy, or ICS moderate dose monotherapy and baseline ACQ\>1.25 8. Non-smoker for past year (total lifetime smoking history \< 10 pack-years)

Exclusion criteria

1. Use of greater than the equivalent of 1000 mcg inhaled fluticasone daily 2. Chronic use of oral corticosteroids or Anti IgE for asthma 3. Lung disease other than asthma or diagnosis of vocal cord dysfunction. 4. Significant medical illness (other than asthma) that is not stable. 5. Pregnancy or lactation or an unwillingness to maintain effective birth control. 6. History of a significant exacerbation of asthma or respiratory tract infection in the prior 4 weeks 7. History of life-threatening asthma requiring treatment with intubation and mechanical ventilation within 5 years. 8. Hypo sensitization therapy other than an established maintenance regimen. 9. Use of inhaled anticholinergic therapy (ipratropium, tiotropium) in prior month 10. Known contraindication to inhaled tiotropium e.g. narrow angle glaucoma, history of bladder neck obstruction or significant symptoms related to prostatic hypertrophy. 11. Inability to speak and read English.

Design outcomes

Primary

Measure	Time frame	Description
Time to Asthma Exacerbation (Mean Number of Exacerbations/Person-year)	evaluated monthly (on average) via questionnaire for 12 months	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.

Secondary

Measure	Time frame	Description
Change in FEV1	from baseline to 12 months	Average change in lung function (FEV1) evaluated by spirometry per participant over 12 months
Change in Asthma Quality of Life (AQLQ)	from baseline to 12 months	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.
Change in Asthma Symptom Utility Index (ASUI)	from baseline to 12 months	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).
Change in Asthma Control Questionnaire (ACQ)	from baseline to 12 months	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).
Change in Rescue Medication Use	from baseline to 12 months	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.
Change in Moderate Asthma Deterioration	from baseline to 12 months	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.
Change in Symptom-Free Day Questionnaire (SFDQ)	from baseline to 12 months	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.

Countries

United States

Participant flow

Recruitment details

Initial enrollment began March 30, 2011 at the Asthma Research Center at Brigham and Women's Hospital. Subjects were recruited with print advertisements, internet postings, physician referrals, and by contacting patients in databases who asked to be contacted for studies.

Pre-assignment details

Subjects on combination ICS/LABA were switched to equivalent-dose ICS monotherapy at the same time they were assigned to the Tiotropium vs. LABA arm of the study.

Participants by arm

Arm	Count
Tiotropium Tiotropium bromide will be evaluated as a treatment for asthma. Tiotropium: Tiotropium bromide 18 mcg once daily for one year of treatment.	532
Salmeterol or Formoterol Long acting beta agonists (Serevent, Foradil) are the standard treatments for moderate asthma. The efficacy of Tiotropium will be compared to this standard. Salmeterol: Salmeterol 50 mcg twice daily for one year of treatment. Formoterol: Formoterol 12 mcg twice daily for one year	538
Total	1,070

Baseline characteristics

Characteristic	Salmeterol or Formoterol	Total	Tiotropium
Age, Continuous	45.1 years STANDARD_DEVIATION 12.6	45.15 years STANDARD_DEVIATION 12.6	45.2 years STANDARD_DEVIATION 12.6
Ethnicity (NIH/OMB) Hispanic or Latino	36 Participants	67 Participants	31 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	502 Participants	1003 Participants	501 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Black or African American	538 Participants	1070 Participants	532 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) White	0 Participants	0 Participants	0 Participants
Sex: Female, Male Female	408 Participants	813 Participants	405 Participants
Sex: Female, Male Male	130 Participants	257 Participants	127 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	— / —	— / —
other Total, other adverse events	338 / 532	342 / 538
serious Total, serious adverse events	84 / 532	69 / 538

Outcome results

Primary

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.

Time frame: evaluated monthly (on average) via questionnaire for 12 months

Population: intention-to-treat

Arm	Measure	Value (MEAN)
Tiotropium	Time to Asthma Exacerbation (Mean Number of Exacerbations/Person-year)	0.37 event per person-year
Salmeterol or Formoterol	Time to Asthma Exacerbation (Mean Number of Exacerbations/Person-year)	0.42 event per person-year

p-value: 0.31Log Rank

Secondary

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).