Childhood Asthma Research and Education (CARE) Network Trial - Montelukast or Azithromycin for Reduction of Inhaled Corticosteroids in Childhood Asthma (MARS)
Childhood Asthma Research and Education (CARE) Network Trial - Montelukast or Azithromycin for Reduction of Inhaled Corticosteroids in Childhood Asthma (MARS)
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.
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 (Mac - azithromycin) or a leukotriene receptor
 antagonist (LTRA - montelukast) will provide a steroid-sparing effect when compared to
 placebo as the dose of inhaled corticosteroids (ICS - budesonide) is reduced. This will be
 tested following achievement of control of symptoms with moderate to high-dose ICS in
 combination with a long-acting bronchodilator agonist (LABA - salmeterol). Use of these doses
 for the inhaled corticosteroid will be based on NHLBI step-up guidelines to achieve asthma
 control. Inadequate asthma control is defined as either:

 1. chronic poor control: a) symptoms, or albuterol use for symptoms or low peak flow, or
 peak flow less than 80% baseline on greater than 3 days per week on average, or b)
 nocturnal awakenings for asthma symptoms requiring albuterol 2 or more nights over 2
 weeks of observation, or c) FEV1 less than 80% of the best pre-randomization value on 2
 consecutive visits 1-4 days apart, or

 2. an asthma exacerbation as determined by need for systemic corticosteroids

 Treatment in the run-in period will be determined by the child's status at the first visit.
 At enrollment (V0) all patients will be given budesonide as the ICS and salmeterol as the
 LABA. Children will be treated with salmeterol BID and a dose of ICS based on chronic
 medication use with stepping-down based on time and symptoms until criteria for inadequate
 control as indication for stepping-up the dose of ICS. When inadequate control is documented
 (V1), a four-day course of prednisone will be administered and the dose of ICS (still
 administered with salmeterol BID) will be doubled to establish control. The children will be
 followed with monthly clinic visits and interim phone calls, emphasizing use of daily diary
 to document symptoms and doses of albuterol required. Reestablishment of control during a
 2-week interval will prompt randomization. If control is not yet established by the first
 increase in ICS dose during the stabilization period, the dose can be doubled along with a
 second prednisone course until a maximum of budesonide of 1600 mcg/day is attained. The daily
 dose of budesonide at randomization will be a minimum of 800 mcg to allow for a maximum of
 4-fold reduction of dose, and a maximum of 1600 mcg to allow for patient safety considering
 side effects of high dose ICS.

 When clinical control is achieved by the increased dose of ICS, a child will then be
 randomized (V2) to one of the three treatment arms, (1) placebo (one placebo tablet and one
 or two placebo capsules), (2) azithromycin (one placebo tablet and one or two capsules
 containing azithromycin with the dose based on weight), or (3) montelukast (one tablet
 containing montelukast with the dose based on age as indicated in the package insert and one
 or two placebo capsule). Children will be followed for an additional six weeks on the dose of
 ICS that achieved control ("1X") + salmeterol BID with the study medication (V3). They will
 then undergo three 6-week periods of ICS reduction (V4, V5, V6), first to ¾ of the control
 dose ("0.75X"), then ½ of the control dose ("0.5X") and then ¼ of the control dose ("0.25X"),
 each using salmeterol BID as concomitant medication. The ICS dosing and salmeterol will be
 open-label. Criteria for treatment failure and discharge from the study will be an
 established set of criteria that indicate reappearance of inadequate control of asthma or an
 exacerbation of asthma.

 At the end of the double-blind administration of oral study medication (V6), patients not
 discharged from the study because of having met one of the criteria for inadequate control of
 asthma will have their study medication discontinued, with subjects continuing to take
 placebo capsules in addition to ¼ ICS plus salmeterol. They will then be followed for an
 additional 6-week single-blind wash-out period with an interim contact by phone at 3 weeks to
 determine the course of asthma control to determine the persistence of effect off of the
 study medication (V7).

 The procedures to be performed at V0 are informed consent, pregnancy test, complete physical
 exam, spirometry, and bronchodilator response. The procedures to be performed at V1 are
 spirometry, complete blood count, blood IgE and eosinophils, brief physical exam, EKG, and
 genotyping. The following procedures will be performed at each of V2 through V7: brief
 physical exam, spirometry, forced oscillometry, exhaled nitric oxide, asthma control
 questionnaire, asthma-specific quality-of-life questionnaire, and sinusitis questionnaire. In
 addition, allergy skin testing will be performed at V2, pregnancy tests at V2 through V6,
 methacholine challenge at V2 and V3, and polymerase chain reaction for atypical organisms and
 macrolide antibiotic resistance (nasal wash) at V2, V5, and V7.

 Finally, children will maintain daily diary records of morning and evening symptoms, peak
 expiratory flow rates, and rescue medication use.
Inclusion Criteria:

 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:

 1. 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.

 2. 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

 3. 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.

 1. Bronchodilator responsiveness testing will be done at Visit 0 (Enrollment) in all
 patients using 4 puffs albuterol.

 2. 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

 Exclusion Criteria:

 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

 -  Immunodeficiency disorders

 -  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