Asthma
Conditions
Keywords
Asthma, Levalbuterol, Albuterol, Children
Brief summary
This study will use a randomized, double-blind, controlled trial design in order to assess the safety and efficacy of levalbuterol (LEV) compared to racemic albuterol (RAC) when delivered continuously in a high-dose regimen for children with severe exacerbations of asthma. Primary hypothesis * Children with severe asthma receiving continuous levalbuterol will have a shorter duration of continuous therapy as compared to racemic albuterol. Secondary hypotheses * Children receiving continuous levalbuterol will have improved lung function measured by forced expiratory volume at 1 second (FEV1) as compared to racemic albuterol. * Children receiving continuous levalbuterol will have improved clinical asthma score as compared to racemic albuterol.
Detailed description
High-dose nebulized albuterol is standard therapy for severe asthma exacerbations at The Children's Hospital of Philadelphia (CHOP) and other tertiary care pediatric hospitals throughout the United States. For the most severe exacerbations, albuterol is provided continuously at high doses until improvement is observed. This regimen has been standardized in a treatment protocol that has been used at CHOP for more than 5 years. Recently, levalbuterol (LEV), the purified active (R)-enantiomer of albuterol, has been approved for use in acute asthma. Preliminary evidence suggests that LEV may improve pulmonary function and clinical outcomes in children with asthma based on studies using standard dosing regimens. Laboratory and clinical evidence suggest that the (S)-enantiomer of albuterol may have detrimental effects that contribute to poor response to racemic albuterol (RAC). Limited data exist about the efficacy of LEV in high-dose regimens. This study will use a randomized, double-blind, controlled trial design in order to assess the safety and efficacy of LEV compared to RAC when delivered continuously in a high-dose regimen for severe exacerbations of asthma. Children treated for asthma exacerbations in the CHOP emergency department (ED) will be eligible for study enrollment. Those that meet enrollment criteria will be randomized to receive either high dose RAC according to the standard asthma care protocol or equivalent dosing of LEV. Approximately 128 patients with 64 in each arm of the study will be enrolled. An interim safety analysis will be conducted after the first 40 patients are enrolled. This study should be completed in six to nine months. The primary outcome will be duration of continuous therapy. Secondary outcomes will include improvement of clinical asthma score and change in forced expiratory volume in one second (FEV1). In addition, (R)-albuterol and (S)-albuterol levels will be measured at study entry and at 6-hour intervals in the first 40 patients enrolled. These values will be used to determine prior RAC exposure and to determine serum levels of (R) and (S) albuterol during continuous therapy.
Interventions
DRUGRacemic albuterol (R+S albuterol)
20mg/hr continuous racemic albuterol
DRUGLevalbuterol (R albuterol)
10mg/hr continuous nebulized levalbuterol
Sponsors
Sumitomo Pharma America, Inc.
Children's Hospital of Philadelphia
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
6 Years to 18 Years
Healthy volunteers
No
Inclusion criteria
* Age 6-18 years of age * Diagnosis of asthma with two previous visits to emergency department (ED) or primary care provider for asthma care * Clinical decision by ED attending physician to begin continuous albuterol after standardized initial ED treatment.
Exclusion criteria
* Clinical decision to begin continuous intravenous beta-agonist infusion (e.g. terbutaline) * Clinical decision to admit to the Pediatric Intensive Care Unit * Drug allergy or other contraindication to RAC or LEV * Other concurrent disease such as sickle cell disease, cystic fibrosis, or cardiac disease * Pregnancy * Prior enrollment in the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Continuous Therapy | During hospitalization | standard intention to treat (ITT) analysis |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Pediatric Asthma Severity Score | After 12 hours of continuous nebulization | Change in Pediatric Asthma Severity Score. Range 0 (best) - 6 (worst) Score at each time point is calculated by adding 3 elements: Wheeze (0= None/Mild, 1=Moderate, 2=Severe) Prolonged expiration (0= None/Mild, 1=Moderate, 2=Severe) Work of breathing (0= None/Mild, 1=Moderate, 2=Severe) |
| Heart Rate | After 12 hours of continuous nebulization | — |
| Serum Potassium Levels | After 12 hours of continuous nebulization | — |
| Serum Albuterol S Isomer Levels | After 6 hours of continuous albuterol | — |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Continuous Levalbuterol (R) Nebulized Solution Continuous levalbuterol nebulized solution 10mg/hr given as continuous nebulization | 40 |
| Continuous Racemic (R+S) Albuterol Continuous racemic albuterol 20mg/hr given as continuous nebulization | 41 |
| Total | 81 |
Baseline characteristics
| Characteristic | Continuous Racemic (R+S) Albuterol | Continuous Levalbuterol (R) Nebulized Solution | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 41 Participants | 40 Participants | 81 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants |
| Age Continuous | 10.7 years STANDARD_DEVIATION 3.3 | 10.4 years STANDARD_DEVIATION 3.5 | 10.6 years STANDARD_DEVIATION 3.4 |
| Region of Enrollment United States | 41 participants | 40 participants | 81 participants |
| Sex: Female, Male Female | 16 Participants | 14 Participants | 30 Participants |
| Sex: Female, Male Male | 25 Participants | 26 Participants | 51 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 40 | 0 / 41 |
| serious Total, serious adverse events | 0 / 40 | 0 / 41 |
Outcome results
Primary
Duration of Continuous Therapy
standard intention to treat (ITT) analysis
Time frame: During hospitalization
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Continuous Levalbuterol (R) Nebulized Solution | Duration of Continuous Therapy | 18.3 Hours |
| Continuous Racemic (R+S) Albuterol | Duration of Continuous Therapy | 16 Hours |
Secondary
Change in Pediatric Asthma Severity Score
Change in Pediatric Asthma Severity Score. Range 0 (best) - 6 (worst) Score at each time point is calculated by adding 3 elements: Wheeze (0= None/Mild, 1=Moderate, 2=Severe) Prolonged expiration (0= None/Mild, 1=Moderate, 2=Severe) Work of breathing (0= None/Mild, 1=Moderate, 2=Severe)
Time frame: After 12 hours of continuous nebulization
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Continuous Levalbuterol (R) Nebulized Solution | Change in Pediatric Asthma Severity Score | -1.0 units on a scale | Standard Deviation 1.2 |
| Continuous Racemic (R+S) Albuterol | Change in Pediatric Asthma Severity Score | -0.64 units on a scale | Standard Deviation 1.7 |
Secondary
Heart Rate
Time frame: After 12 hours of continuous nebulization
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Continuous Levalbuterol (R) Nebulized Solution | Heart Rate | 132 beats per minute | Standard Deviation 16.4 |
| Continuous Racemic (R+S) Albuterol | Heart Rate | 132 beats per minute | Standard Deviation 18.4 |
Secondary
Serum Albuterol S Isomer Levels
Time frame: After 6 hours of continuous albuterol
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Continuous Levalbuterol (R) Nebulized Solution | Serum Albuterol S Isomer Levels | 5.5 ng/mL | Standard Deviation 3.3 |
| Continuous Racemic (R+S) Albuterol | Serum Albuterol S Isomer Levels | 28.6 ng/mL | Standard Deviation 11.7 |
Secondary
Serum Potassium Levels
Time frame: After 12 hours of continuous nebulization
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Continuous Levalbuterol (R) Nebulized Solution | Serum Potassium Levels | 3.6 mg/dL | Standard Deviation 0.6 |
| Continuous Racemic (R+S) Albuterol | Serum Potassium Levels | 3.6 mg/dL | Standard Deviation 0.4 |