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 (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