Official Title: “Childhood Asthma Research and Education (CARE) Network Trial - Best Add-On Therapy Giving Effective Response (BADGER)”

Asthma is a common, serious illness among children in the United States. While a low dose of inhaled corticosteroids (ICS) may effectively control symptoms, some children may require additional medications to maintain adequate asthma control. This study will compare the effectiveness of a higher dose of ICS, ICS combined with a long-acting beta-agonist (LABA) medication, and ICS combined with a leukotriene receptor antagonist (LTRA) medication at reducing the impact and severity of asthma exacerbations that occur in children with mild to moderate persistent asthma.

Study Type: Interventional

Study Design: Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Active Control, Crossover Assignment, Safety/Efficacy Study

Study Primary Completion Date: March 2009

Almost 9 million children in the United States have asthma, and it is a leading cause of hospitalizations and school absenteeism. Common asthma symptoms include wheezing, shortness of breath, chest tightness, and coughing. While there is no cure for asthma, most children who receive proper treatment are able to control symptoms and lead a normal life. Low doses of ICS are commonly prescribed to prevent symptoms and keep asthma under control. While this is usually sufficient to prevent asthma attacks, some children do not respond well to low dose ICS alone. For these children, their asthma symptoms may be more effectively controlled by either receiving a higher dose of ICS or receiving LABA or LTRA medications in combination with a low dose of ICS. Both LABA and LTRA medications are used to help control moderate to severe asthma. The purpose of this study is to compare the effectiveness of a high dose of ICS versus a low dose of ICS plus either LABA or LTRA medication at improving asthma control and reducing the severity of symptoms that occur in children with mild to moderate persistent asthma.

This study will begin with an 8-week screening period during which participants will be monitored while they use an inhaler with a low dose of ICS medication. During this time, participants will also attend one or two study visits. At each visit, participants will undergo a physical examination, exhaled nitric oxide analysis, and lung function and airway pressure testing. Once enrollment criteria are met, participants will undergo these same evaluations again, and they will complete questionnaires to assess asthma control, quality of life, and home environmental factors. Blood will be collected and a methacholine challenge test will be completed, which will artificially trigger an asthma attack to determine the severity of an individual's asthma. Participants will then be randomly assigned to one of six treatment sequences, each of which will include the following three regimens in a different order: - Low dose of ICS and salmeterol, a LABA medication - Low dose of ICS and montelukast, a LTRA medication - Double dose of ICS

Each treatment period will last 16 weeks, with study visits occurring weekly. A physical examination, blood collection, lung function and airway pressure testing, a methacholine challenge test, and questionnaires will occur at selected visits. Throughout the study, participants will record asthma symptoms, peak expiratory flow rates, and rescue medication usage in a daily diary. The entire length of the study will not exceed 56 weeks.

Intervention(s) in this Clinical Trial

• Drug: Fluticasone propionate
  • Dry-powder inhaler fluticasone 100 mcg bid (Flovent Diskus®, GlaxoSmithKline)
• Drug: Montelukast
  • Montelukast 5 or 10 mg qd (Singulair®, Merck)
• Drug: Fluticasone propionate
  • Dry-powder inhaler fluticasone 250 mcg bid (Flovent Diskus®, GlaxoSmithKline)
• Drug: Fluticasone propionate/salmeterol
  • Dry-powder inhaler fluticasone/salmeterol combination 100 mcg/50 mcg bid (Advair Diskus®, GlaxoSmithKline)

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: 1
  • Dry-powder inhaler fluticasone 100 mcg bid (Flovent Diskus®, GlaxoSmithKline) + montelukast 5 or 10 mg qd (Singulair®, Merck)
• Active Comparator: 2
  • Dry-powder inhaler fluticasone 250 mcg bid (Flovent Diskus®, GlaxoSmithKline)
• Active Comparator: 3
  • Dry-powder inhaler fluticasone/salmeterol combination 100 mcg/50 mcg bid (Advair Diskus®, GlaxoSmithKline)

Primary Measures

• Number of annualized asthma control days
  • Time Frame: Measured during the last 12 weeks of each 16-week treatment period
    Safety Issue?: No

Secondary Measures

• Pre-bronchodilator forced expiratory volume in one second (FEV1)
  • Time Frame: Measured during the last 12 weeks of each 16-week treatment period
    Safety Issue?: No
• Post-bronchodilator forced FEV1
  • Time Frame: Measured during the last 12 weeks of each 16-week treatment period
    Safety Issue?: No
• Forced vital capacity (FVC)
  • Time Frame: Measured during the last 12 weeks of each 16-week treatment period
    Safety Issue?: No
• FEV1/FVC
  • Time Frame: Measured during the last 12 weeks of each 16-week treatment period
    Safety Issue?: No
• Morning peak expiratory flow rate (PEFR)
  • Time Frame: Measured during the last 12 weeks of each 16-week treatment period
    Safety Issue?: No
• Evening PEFR
  • Time Frame: Measured during the last 12 weeks of each 16-week treatment period
    Safety Issue?: No
• PEFR variability
  • Time Frame: Measured during the last 12 weeks of each 16-week treatment period
    Safety Issue?: No
• Impulse oscillometry
  • Time Frame: Measured during the last 12 weeks of each 16-week treatment period
    Safety Issue?: No
• Methacholine PC20
  • Time Frame: Measured during the last 12 weeks of each 16-week treatment period
    Safety Issue?: No
• Exhaled nitric oxide
  • Time Frame: Measured during the last 12 weeks of each 16-week treatment period
    Safety Issue?: No
• Asthma control test
  • Time Frame: Measured during the last 12 weeks of each 16-week treatment period
    Safety Issue?: No
• Asthma quality of life
  • Time Frame: Measured during the last 12 weeks of each 16-week treatment period
    Safety Issue?: No
• Time until first asthma exacerbation
  • Time Frame: Measured during the last 12 weeks of each 16-week treatment period
    Safety Issue?: No
• Adverse events
  • Time Frame: Measured during each 16-week treatment period
    Safety Issue?: Yes

Inclusion Criteria:

• Able to perform reproducible spirometry according to American Thoracic Society (ATS) criteria
• History of asthma symptoms (e.g., cough, wheezing, shortness of breath) and meets at least one of the following criteria:
• 1. Naïve to controller therapy and meeting National Asthma Education and Prevention
• Program (NAEPP) criteria for mild-moderate persistent asthma (symptoms at least 2 days per week and/or night-time awakenings due to asthma at least 2 nights per month)
• 2. Current uncontrolled asthma (meets NAEPP criteria for mild-moderate persistent asthma) while receiving an ICS dose greater than or equal to 200 ug per day of fluticasone equivalent or some form of non-ICS controller therapy (e.g., montelukast, theophylline, cromolyn)
• 3. Asthma is currently under control while receiving an ICS dose between 300 to 400 ug per day of fluticasone equivalent and willing to consider changing current treatment to monotherapy with one dose of ICS (current standard of care)
• 4. Asthma is currently under control while receiving some form of combination therapy, such as ICS less than or equal to 200 ug per day of fluticasone equivalent in addition to a non-ICS controller therapy (e.g., LABA, montelukast, theophylline, cromolyn), and willing to consider changing current treatment to monotherapy with one dose of ICS (current standard of care)
• FEV1 reversibility of at least 12% following bronchodilator administration (4 puffs) at study visit 1. Individuals will need to hold albuterol, montelukast, theophylline, ipratropium bromide (or other anticholinergics) and LABAs per study instructions prior to reversibility testing. If an individual is receiving these types of medications prior to study visit 1, he/she may be brought back to the clinical center within 1 week following appropriate medication withholding to attempt qualification by reversibility criteria. If the individual does not meet this requirement, they may qualify for enrollment if their PC20 methacholine FEV1 is less than or equal to 12.5 mg/ml at the time of randomization. If FEV1 is less than 70%, thus precluding the methacholine challenge at this visit, then completion of the visit will be postponed several days and an additional attempt to obtain a methacholine challenge test will be made. If the methacholine challenge still cannot be performed, an individual may still qualify by reversibility criteria at this visit.
• History of clinical varicella or varicella vaccine; individuals needing the vaccine may receive it from their primary care physician prior to study entry
• Ability of parent to provide informed consent; verbal assent must be obtained from children less than 7 years of age and written assent must be obtained from children between 7 and 18 years of age
• If female, willing to use an effective form of contraception
• Prior to being randomly assigned to a treatment group, participants must meet the following criteria to remain in the study:
• Lack of acceptable asthma control during the 8-week screening period as defined by the following criteria:
• 1) On average, on more than 2 days per week, one or all of the following:
• 1. Diary-reported symptoms
• 2. The use of inhaled bronchodilator (not including pre-exercise)
• 3. Peak flows in the yellow zone (less than 80% of post bronchodilator PEF value obtained at study visit 1) OR
• On average, more than 1 night-time awakening due to asthma, during each 2-week period

Exclusion Criteria:

• Corticosteroid treatment for any condition prior to study entry within the following defined timepoints:
• 1. Oral - Use within 2 weeks of the screening visit
• 2. Injectable - Use within 2 weeks of the screening visit
• 3. Nasal - May be used at any time during the study at the discretion of the study investigator or primary care physician
• Current or prior use of medications known to significantly interact with corticosteroid disposition (within a 2-week period of study visit 1), including but not limited to carbamazepine, erythromycin or other macrolide antibiotics, phenobarbital, phenytoin, rifampin, or ketoconazole
• Pre-bronchodilator FEV1 less than 60% predicted at study visit 1
• More than three hospitalizations for asthma in the year prior to study entry
• Presence of chronic or active lung disease other than asthma
• Significant medical illness other than asthma, including thyroid disease, diabetes mellitus, Cushing's disease, Addison's disease, hepatic disease, or concurrent medical problems that could require oral corticosteroids during the study or would place the participant at increased risk while participating in the study
• History of cataracts, glaucoma, or any other medical disorder associated with an adverse effect to corticosteroids
• Gastroesophageal reflux symptoms not controlled by standard medical therapy
• History of significant asthma exacerbation within 2 weeks of study visit 1 or more than 5 courses of systemic corticosteroids in the year prior to study entry
• History of a life-threatening asthma exacerbation requiring intubation, mechanical ventilation, or resulting in a hypoxic seizure within the 5 years prior to study entry
• History of adverse reactions to ICS, LTRA, or LABA preparations or any of their ingredients
• Receiving hyposensitization therapy other than an established maintenance regimen (i.e., continuous regimen for at least 3 months prior to study entry)
• Pregnant or breastfeeding
• Inability to perform study procedures
• Refusal to consent to a genotype evaluation
• Inability of the child to ingest the study drug
• Cigarette smoking or smokeless tobacco use in the year prior to study entry
• Current participation or participation in the month prior to study entry in another investigational drug trial
• Evidence that the family may be unreliable or nonadherent, or may move from the clinical center area before study completion

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 6 Years

Maximum Age for this Clinical Trial: 18 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: National Heart, Lung, and Blood Institute (NHLBI)

Overall Clinical Trial Officials and Contacts

David T. Mauger, PhD Principal Investigator Penn State College of Medicine  

Information obtained from ClinicalTrials.gov on November 20, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00395304

Study ID Number: 444

ClinicalTrials.gov Identifier: NCT00395304

Health Authority: United States: Federal Government

Click here for the Childhood Asthma Research and Education (CARE) Network web site