Childhood Asthma Research and Education (CARE) Network Trial - Montelukast or Azithromycin for Reduction of Inhaled Corticosteroids in Childhood Asthma (MARS) (MARS)
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ClinicalTrials.gov Identifier: NCT00471809
(The CARE Network DSMB recommended to the NHLBI that the MARS trial be terminated, based on a futility analysis with 55 randomized children.)
The MARS trial is a randomized, double-blind, parallel group study that compares the capacity of azithromycin or montelukast to placebo as effective adjunctive therapy that allows reduction of inhaled corticosteroids in children ages 6 to 17 years with moderate to severe persistent asthma. The primary null hypothesis is that in children with moderate-to-severe persistent asthma, a macrolide antibiotic (azithromycin) or a leukotriene receptor antagonist (montelukast) will provide a steroid-sparing effect when compared to placebo as the dose of inhaled corticosteroid is reduced. This will be tested following achievement of control of symptoms with moderate to high-dose inhaled corticosteroid in combination with a long-acting bronchodilator agonist. Use of these doses for the inhaled corticosteroid will be based on NHLBI step-up guidelines to achieve asthma control.
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Ages Eligible for Study:
6 Years to 17 Years (Child)
Sexes Eligible for Study:
Accepts Healthy Volunteers:
At Enrollment (V0):
Age 6-17 years at time of enrollment. A goal of 33% minority and 40% female subjects will be incorporated in recruitment
Weighs at least 25 kg
Asthma diagnosed by a physician and present for at least one year prior to study entry
Moderate to severe persistent asthma:
Patients will be identified in the following general categories. The general principle is that patients will be uncontrolled on a relatively low dose of ICS that can be stepped-up, or controlled on a moderate or high dose of ICS that can be stepped-down.
i) On low dose ICS with or without salmeterol and uncontrolled. This patient will be treated with budesonide and salmeterol to determine eligibility criteria. If the addition of salmeterol results in control of symptoms, the patient would be excluded from MARS. If control was not established on low dose budesonide and salmeterol, the dose of budesonide would be increased and entry criteria evaluated based on the algorithm in Figure 1.
ii) On a dose of ICS equivalent to budesonide at 400 mcg per day with or without any other medication and uncontrolled. This patient will be treated with budesonide and salmeterol to determine eligibility criteria.
iii) On a dose of ICS equivalent to budesonide at 800 mcg per day with or without any other medication and controlled.
iv) On a dose of ICS equivalent to budesonide at 1600 mcg per day with or without any other medication and uncontrolled but not requiring prednisone acutely. These patients will be followed to see if they become well controlled with increased adherence or more careful monitoring of symptoms.
Examples are given for Advair as this drug is a commonly used form of ICS and LABA:
i) Patients on Advair 100/50 bid and inadequately controlled ii) Patients on Advair 250/50 bid and inadequately controlled iii) Patients on Advair 250/50 bid and well controlled for greater than 3 months and being considered for stepping-down to Advair 100/50 iv) Patients well controlled on Advair 100/50 bid + either montelukast or theophylline for greater than 3 months and being considered for stepping-down to Advair 100/50 bid alone v) Patients on Advair 500/50 bid and well controlled for greater than 3 months and being considered for stepping-down to Advair 250/50 vi) Patients well controlled on Advair 250/50 bid + either montelukast or theophylline for greater than 3 months and being considered for stepping-down to Advair 250/50 bid alone
Patients on an equivalent of budesonide 400 mcg, 800 mcg, or 1600 mcg per day with no symptoms, but with an FEV1 less than 80% predicted, will be enrolled as uncontrolled and observed closely for symptoms or low peak flows for 2 weeks. The rationale for enrolling these patients and observing them as "uncontrolled" is that patients with an FEV1 below the range of normal may be having symptoms and/or low peak flows that will become apparent under close observation after appropriate education. Note that a percent predicted value for FEV1 will be used only at the enrollment visit, with criteria for control and inadequate control during both run-in and during the double-blind portions of the study using the highest FEV1 value obtained during run-in for decisions prior to randomization and the FEV1 at randomization for decisions subsequent to that visit.
FEV1 at least 80% predicted if there is going to be step-down at enrollment or at least 50% predicted if already suboptimally controlled historically and to be observed for 2 weeks to define baseline symptoms. FEV1 measurements will be obtained pre-bronchodilator.
Demonstrate a bronchodilator response with an improvement in FEV1 of at least 12% or airway responsiveness to methacholine with a PC20 less than 12.5 mg/ml.
Bronchodilator responsiveness testing will be done at Visit 0 (Enrollment) in all patients using 4 puffs albuterol.
Methacholine challenge will be done at Visit 1 (Step-up) in patients who did not respond to bronchodilator at Visit 0. Patients with a FEV1 less than 70% predicted or an upper respiratory infection at the time of Visit 1 will have a second bronchodilator challenge rather than a methacholine.
Varicella immunization complete (unless the subject has already had clinical varicella). If the subject needs varicella vaccine, this will be arranged with the primary care physician and must be received prior randomization
Willingness to provide informed consent by the child's parent or guardian
Nonsmoker in the past year; in addition, no use of smokeless tobacco products in the year prior to study entry
At Enrollment (V0):
More than four courses of systemic corticosteroids for asthma during the 12 months prior to study entry
More than one hospitalization for wheezing illnesses within the 12 months prior to study entry
Current treatment with antibiotics for diagnosed sinus disease
History of severe sinusitis requiring sinus surgery within the past 12 months
Use of maintenance oral or systemic antibiotics for treatment of an ongoing condition
Use of macrolide antibiotics within the 6 weeks prior to study entry
Requirement for prednisone therapy for concurrent illness, e.g., RA, SLE, IBD
Asthma exacerbation requiring systemic corticosteroids within 4 weeks of study entry
Contraindication for use of macrolide or LTRA
Presence of lung disease other than asthma, such as cystic fibrosis and bronchopulmonary dysplasia. Evaluation during the screening process will assure that an adequate evaluation of other lung diseases has been performed
Presence of other significant medical illnesses (cardiac, liver, gastrointestinal, endocrine, any seizure disorder except febrile seizure in infancy) that would place the study subject at increased risk of participating in the study
Use of digoxin, ergotamine or dihydroergotamine, triazolam, carbamazepine, cyclosporine, hexobarbital, and phenytoin, and similar classes of medication will be specifically excluded
Use of omalizumab within one year of study entry
Gastroesophageal reflux symptoms not controlled by standard medical therapy
History of respiratory failure requiring mechanical ventilation for asthma within 5 years
History of hypoxic seizure due to asthma
Inability of the child to ingest the study drug
Participation presently or in the past month in another investigational drug trial
Evidence that the family may be unreliable or nonadherent, or may move from the clinical center area before trial completion
Pregnant or breastfeeding
Receiving hyposensitization therapy other than an established maintenance (continuous for 3 months duration or longer) regimen
At Randomization (V2):
Still uncontrolled on step-up dosing of 1600 mcg budesonide + salmeterol BID
Abnormal liver enzyme laboratory test results
Abnormal QTc interval or evidence of a rhythm abnormality
Failure to complete diary cards at expected levels (at least 75% of days) during the observation period
Failure to adhere with oral medication use at least 80% during run-in
Need for oral corticosteroids for a reason other than Step Up during run-in period