Childhood Asthma Management Program (CAMP) Phases I (Trial), II (CAMPCS), III (CAMPCS/2), and IV (CAMPCS/3)

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the long term effects of anti-inflammatory therapy compared to bronchodilator therapy on the course of asthma, particularly on lung function and bronchial hyperresponsiveness, and on physical and psychosocial growth and development.

Detailed Description
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BACKGROUND: Asthma is a serious chronic condition, affecting approximately 14 million Americans. People with asthma experience well over 100 million days of restricted activity annually, and costs for asthma care exceed $10 billion a year. Asthma is much more prevalent among children than adults. Hospitalizations for asthma have been increasing among children. For example, from 1979 to 1987, the hospital discharge rate with asthma as the first-listed diagnosis rose 43 percent among children less than 15 years of age, from 19.8 to 28.4 discharges per 10,000 population. Death rates for asthma are greater in Blacks than in whites, and the difference is increasing. In 1979, Blacks of both sexes were about twice as likely to die from asthma as whites. Over the past decade this ratio has increased, and by 1987 the asthma death rate was almost three times greater among Blacks than whites. In children, these mortality differences between Blacks and whites are even more striking. Current knowledge about the epidemiology and natural history of childhood asthma is incomplete, but the relationship between asthma early in life and development of chronic obstructive pulmonary disease (COPD) in adulthood is becoming more apparent. Asthmatic children with persistent and severe asthma symptoms have lower levels of lung function by young adulthood than those with milder disease. Recent longitudinal studies have confirmed a decrease in rate of growth of lung function as measured by FEV1 among symptomatic (primarily wheeze) children compared to asymptomatic children. Among persons who develop COPD, initial level of lung function is the strongest predictor of subsequent rapid decline of ventilatory function. Thus, less than maximally attained levels of lung function among children with asthma may predispose them to greater than normal decline of lung function later in life. Although the long-term effect of treatment on the course of asthma is not known, the treatment goal of decreasing bronchial hyperresponsiveness and maximizing lung function and growth during childhood may have a beneficial effect on lung health throughout life and prevent progression to irreversible airflow obstruction. Two classes of medications are currently available for treatment of inflammation--corticosteroids and cromolyn sodium. Inhaled corticosteroids have significantly fewer side effects than systemic administration. Corticosteroids do not inhibit the early asthmatic response, but are effective in suppressing the inflammation and bronchial hyperresponsiveness of the late phase response. Long-term studies of inhaled corticosteroids have shown beneficial effects on lung function as measured by FEV1. However, there has been concern about possible effects of long-term use of inhaled corticosteroids. Although epidemiological studies of the use of inhaled corticosteroids have shown no significant adverse effects, large-scale randomized controlled studies of their effects on children's growth and development are needed. When CAMP was initiated in the United States, bronchodilator treatment was the most common approach to therapy. Two classes of bronchodilators, inhaled beta-2-adrenergic agonists and oral theophylline, are most frequently prescribed for asthma. To date, no randomized, controlled studies have compared the two classes of anti-inflammatory medications to each other and to bronchodilator therapy on the course of asthma. The initiative was proposed by the Pulmonary Disease Advisory Committee working group in October 1987 and approved by the full committee at the February 1988 meeting and by the National Heart, Lung, and Blood Advisory Council in May 1990. The Request for Proposals was released in October 1990. Awards were made in September 1991. DESIGN NARRATIVE: Children were randomized to one of three treatment groups to receive either: inhaled albuterol alone, albuterol with inhaled budesonide, albuterol with nedocromil. Upon randomization, data were collected on demographic factors, physical and psychosocial development, clinical factors including medical history and extent of allergies, and quality of life factors including limitation of activity, absenteeism from school, emergency room visits, and hospitalizations. All subjects received a common educational program, differing only in the information presented regarding the medication used by the subjects. Each subject was given a standard protocol for dealing with asthma attacks. All subjects were treated and followed for five years with quarterly visits yearly. Recruitment began in July 1993 and ended in June 1995 with the accrual of 1,041 subjects. The study has been extended through June 2011 through three funding phases to observe the subjects but not provide asthma treatment. This will allow CAMP to (1.) determine the full impact of 4 to 6 years of anti-inflammatory therapy on attaining maximal lung function and final height; (2.) examine the natural history of asthma through age 26; and (3.) define patterns of reduced lung function growth and early decline of lung function in young adults.

Official Title
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Childhood Asthma Management Program

Conditions
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Asthma, Lung Diseases

Intervention / Treatment
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* Drug: Placebo
* Drug: Nedocromil
* Drug: Budesonide


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Age 5 to 12 years at time of screening Chronic asthma as evidenced by one or more of the following historical findings for at least 6 months during the past year: Asthma symptoms at least 2 times per week 2 or more usages per week of an inhaled bronchodilator Daily asthma medication Current asthma symptoms either by diary symptom code of 1 or greater or am or pm PEFR less than 80% of personal best post-bronchodilator value by diary, on 8 or more days during the prn screening period Methacholine sensitivity: estimated PC20 FEV1 less than or equal to 12.5 mg/ml Consent of guardian and assent of child Ability to comply with trial for 5 - 6.5 years Exclusion criteria: Presence of one or more of the following confounding or complicating problems: Any other active pulmonary disease Any chronic condition presumed to interfere with the successful completion of the project or confound its interpretation Pulmonary function testing findings suggesting a ventilatory defect other than asthma, or evidence of existing irreversible lung damage Severe chronic sinusitis or nasal polyposis Introduction of or a change in allergen immunotherapy within the past month Use of more than 4 sprays of nasal steroids daily (only beclomethasone allowed) Pregnancy Current use of metoclopramide, ranitidine, or cimetidine Treatment for gastroesophageal reflux Participation in another drug study Evidence of severe asthma as indicated by one or more of the following: Two or more hospitalizations for asthma in the past year Six or more steroid bursts in the past year Demonstrated need for continuous use of glucocorticoids, either oral or inhaled When off inhaled O2-agonist for more than 4 hrs and theophylline for more than 24 hrs, FEV1 less than 65% predicted Intubation for asthma at any time in the past Need for 9 or more puffs/day of albuterol for each of 3 consecutive days (excluding preventive use prior to exercise), or nocturnal asthma awakenings more than 1.5 times per week on average, or average diary card symptom code greater than 2, or requirement for other medications to control asthma, during prn screening period Inability to perform 3 acceptable FVC maneuvers of which at least 2 reproducible FEV1s are within 10% of the largest FEV1 Inability to complete the methacholine challenge or methacholine PC20 FEV1 greater than 12.5 mg/ml Evidence that patient or family may be unreliable or non-compliant or may move from the metropolitan area before trial completion

Ages Eligible for Study
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Minimum Age: 5 Years
Maximum Age: 12 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 1 Budesonide<br>Budesonide (Pulmicort), two 100 microgram puffs bid + two microgram puffs albuterol (Ventolin) prn | Drug: Budesonide<br>* Two 100 Og puffs bid + two 90 Og puffs albuterol prn.<br>* Other names: Pulmicort;|
| Active Comparator: 2 Nedocromil<br>Nedocromil (Tilade), four 2 mg puffs bid + two 90 microgram puffs albuterol prn | Drug: Nedocromil<br>* Four 2 mg puffs bid + two 90 Og puffs albuterol prn<br>* Other names: Tilade;|
| Placebo Comparator: 3 Placebo<br>Two 100 microgram puffs budesonide placebo bid + two 90 microgram puffs albuterol prn or four 2 mg puffs nedocromil placebo bid + two 90 microgram puffs albuterol prn. | Drug: Placebo<br>* Two 100 Og puffs budesonide placebo bid + two 90 Og puffs albuterol prn OR four 2 mg puffs nedocromil placebo bid + two 90 Og puffs albuterol prn.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pulmonary Function as Measured by Normalized FEV1 Over a 4-6 Year Period | Change in FEV1 % of predicted, post-bronchodilator use, from baseline to the end of treatment (4-6 years after randomization). Percent predicted determined from three separate published sets of reference equations for white, black, and Hispanic children - see NEJM 343: 1054-1062, 2000 for more details and references. | At the end of treatment, 4-6 years from baseline assessment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Bronchial Responsiveness to Serial Methacholine Concentrations Inhaled Into the Lungs | Bronchial responsiveness to serial concentrations of inhaled methacholine solution (mg/ml) as measured by serial ratios of follow-up to baseline FEV1 (forced volume of air expired from the lungs in one second). A dose-response curve is calculated from the serial ratios in relation to the serial concentrations to determine PC20, the concentration associated with a 20% drop from baseline in FEV1; this PC20 is the outcome measure with units mg/ml of methacholine. | 4-6 years from baseline | 
| Change From Baseline in the Rate of Asthma Free Days | Change from baseline proportion of days without asthma symptoms or other asthma related events to proportion of days during the 4-6 years of follow-up. Asthma free days were determined from daily asthma diaries kept from baseline to the end of treatment, 4-6 years later. | 4-6 years from baseline | 
| Need for Urgent Care for Asthma | Counts during the period of treatment (4-6 years) of visits to emergency rooms or equivalent urgent care settings for asthma treatment. | 4-6 years from baseline | 
| Mortality | Counts of deaths from asthma. | 4-6 years from baseline | 
| Change in Height From Baseline to End of Treatment, 4-6 Years Later | Change in standing height from baseline to end of treatment. Standing height is measured three times without shoes using a calibrated Harpenden stadiometer; the average of the three repeated heights to the nearest 0.1 cm is the height measure at either baseline or end of treatment. | 4-6 years from baseline | 
| Standardized Depression Scale -- Children's Depression Inventory | Change in total score on the Children's Depression Inventory from baseline to the end of treatment, 4-6 years later. The total score ranges from 0-54 with higher scores indicating greater levels of depression. | 4-6 years from baseline |