(CARE Network Trial - Treating Children to Prevent Exacerbations of Asthma (TREXA)

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. Asthma is
commonly treated with two types of medications: long-term control medication, such as inhaled
corticosteroids (ICS), which is taken on a regular schedule to prevent symptoms and keep
asthma under control, and quick-relief, or "rescue" medication, such as albuterol, which is
used on an as-needed-basis with the onset of symptoms or an asthma attack. The purpose of
this study is to assess the impact and severity of asthma exacerbations that occur in
children with mild persistent asthma who are receiving ICS on a daily basis plus ICS and
albuterol as rescue medications.

This study will begin with a 4-week screening period during which participants will be
monitored while they use an inhaler with a low dose of ICS medication. Study visits will
occur at study entry and Week 4. Participants will undergo a physical examination, lung
function and airway pressure testing, and blood collection. At the Week 4 study visit,
participants will be randomly assigned to one of the following four groups for 44 weeks of
treatment:

- Group 1 will take ICS twice a day and ICS plus albuterol as rescue medication

- Group 2 will take ICS twice a day and placebo ICS plus albuterol as rescue medication

- Group 3 will take placebo ICS twice a day and ICS plus albuterol as rescue medication

- Group 4 will take placebo ICS twice a day and placebo ICS plus albuterol as rescue
medication

Each participant will receive three inhalers with their assigned medication. One inhaler will
be used twice daily throughout the study. The other two inhalers will be used consecutively
on an as-needed-basis as rescue medication. Study visits will occur at Weeks 8, 16, 24, 32,
40, and 48. A physical examination, blood collection, and lung function and airway pressure
testing will occur at selected visits. Questionnaires to assess quality of life and asthma
control will also be completed. A methacholine challenge test will be completed at some study
visits. This test artificially triggers an asthma attack to determine the severity of an
individual's asthma. Throughout the study, participants will record asthma symptoms and
rescue medication usage in a daily diary.

Inclusion Criteria:

- Able to perform reproducible spirometry according to American Thoracic Society (ATS)
criteria

- History of asthma symptoms that are adequately controlled in the 4 weeks prior to
study entry, and meets at least one of the following criteria:

1. History of mild persistent asthma symptoms (on average greater than 2 days per
week with symptoms or albuterol use for symptoms or greater than 2 night-time
awakenings per month during the year prior to study entry) and has been treated
with a single-controller inhaled corticosteroid (ICS) dose less than or equal to
160 mcg per day of a beclomethasone-equivalent or a leukotriene receptor
antagonist (LTRA) (in an age-appropriate dose) for the 4 weeks prior to study
entry; individuals treated with a combination controller therapy (e.g. ICS+LTRA
or ICS+long-acting beta-agonist (LABA)) in the past 8 weeks will not be eligible

2. Not currently being treated with ICS, a history of mild persistent asthma, and 1
to 2 exacerbations in the year prior to study entry (but none in the 3 months
prior to study entry)

- Forced expiratory volume in one second (FEV1) reversibility of greater than or equal
to 12% following bronchodilator administration (4 puffs); individuals who do not meet
this requirement may qualify for enrollment if their methacholine provocative
concentration at 20% (PC20) is less than or equal to 12.5 milligrams per milliliter
(mg/ml)

- 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

Participants will be eligible for the 44 weeks of treatment if, after the 4-week screening
period, their asthma remains controlled, and they demonstrate at least 80% predicted
pre-bronchodilator FEV1. Participants must meet ALL of the criteria stated below during the
8-week screening period to continue in the study:

- Meets the definition of acceptable asthma control, which is NOT having one or more of
the following during ANY 2-week period:

1. On average, on more than 2 days per week, experiences one or more 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 personal best defined as
based on peak expiratory flow (PEF) value obtained at study visit 1

2. More than 1 night-time awakening due to asthma

- Demonstrates adherence with taking study medications (at least 75% of scheduled
doses), rescue medications (using both rescue inhalers for at least 75% of rescue
doses), and completing patient diaries (at least 75% of days)

- Pre-bronchodilator FEV1 greater than or equal to 80% predicted at study visits 2 and 3

- Agrees to not use a spacer with beclomethasone/placebo study and rescue medications

NOTE: In January 2008, the Data and Safety Monitoring Board (DSMB) approved changes in the
TREXA eligibility criteria, by which neither FEV1 reversibility ≥ 12% nor a participant's
methacholine PC20 ≤ 12.5 mg/ml were required for randomization.

Exclusion Criteria:

- Corticosteroid treatment for any condition prior to study entry within the following
defined timepoints:

1. Oral - Use within 2-week period of the screening visit

2. Injectable - Use within 2-week period of the screening visit

3. Nasal corticosteroids 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

- Any hospitalization 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

- History of cataracts, glaucoma, or any other medical disorder associated with an
adverse effect to corticosteroids

- Any asthma exacerbation in the past 3 months or more than 2 in the past year.

- History of a life-threatening asthma exacerbation requiring intubation, mechanical
ventilation, or resulting in a hypoxic seizure

- History of adverse reactions to ICS preparations or any of its ingredients

- Receiving hyposensitization therapy other than an established maintenance regimen
(continuous regimen for at least 3 months)

- Pregnant or breastfeeding

- Cigarette smoking or smokeless tobacco use in the year prior to study entry

- Refusal to consent to a genotype evaluation

- Current participation or participation within 1 month of 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