Design paperThe Prevention of Early Asthma in Kids study: design, rationale and methods for the Childhood Asthma Research and Education network☆
Introduction
Asthma is one of the most important challenges to public health in the United States in the pediatric age group [1]. Not only is the prevalence of the disease increasing, especially during the early school years, but also the financial burden of childhood asthma on the health care system is also on the rise [2]. With these issues in mind, the National Heart, Lung and Blood Institute (NHLBI) released a Request for Proposal (RFP) for the Childhood Asthma Research and Education (CARE) Network in January 1999. The RFP called for proposals for innovative studies on therapies for childhood asthma. The NHLBI awarded contracts for the clinics and coordinating center in July 1999 (see Appendix A).
The CARE Network steering committee (SC) recognized that although effective therapy is available for the treatment of asthma, the evidence that such treatment can change the natural course of the disease was limited. Well-controlled prospective studies note that prolonged treatment with inhaled corticosteroid (ICS) are associated with significant improvement in lung function and bronchial hyperresponsiveness (BHR) in children with moderate asthma [3]. These improvements, however, are transient and subjects revert to their previous status after treatment is discontinued [3], [4]. Agertoft and Pedersen [5] demonstrated an inverse relationship between duration of childhood asthma at the time of initiation of therapy with ICS and degree of response to therapy, as assessed by level of lung function at the end of follow-up. This study, however, was not randomized and age of asthma onset was obtained retrospectively; therefore, bias due to disease severity at the time of the initiation of therapy could not be excluded [6]. The Childhood Asthma Management Program (CAMP) study examined the effect on post-bronchodilator lung function in 1041 five- to twelve-year-old children with mild or moderate persistent asthma randomized to receive placebo, nedocromil or budesonide for an average length of treatment of 4.3 years [4]. No significant difference in lung function after bronchodilator was seen between these three groups [4], [7]. This may have been due to an inadequate dose of asthma medication, the need for a combination of different asthma medications or the failure to initiate the intervention early enough in life to see an effect. These studies suggest that strategies for the primary and secondary prevention of asthma will require a thorough knowledge of the natural history of the disease in order to identify potential critical periods during which therapeutic intervention may abrogate the development of the asthma phenotype. Longitudinal, randomized, clinical trials that will avoid the potential biases of retrospective studies are also mandatory.
Studies of the natural history of the disease have shown that, in most cases of persistent asthma, the initial asthma-like symptoms occur during the first years of life [8] with three quarters of children exhibiting symptoms by the age of 3 years [9]. Moreover, children who had persistent asthma at age 10 years had forced expiratory volumes in 1 s (FEV1) that were significantly lower than those of children with mild asthma or no asthma at that age [10]. Lung function also tracked by age since subjects with persistent asthma have similar levels of airway obstruction at age 35 as they showed at age 10 [11]. Persistent asthmatics whose symptoms start in early life are thus at risk for the development of chronic airflow limitation [12].
It is possible that effective airway caliber may already be reduced in the first few months of life in at risk children that may hamper secondary asthma prevention. However, recent reports from the Tucson Children's Respiratory Study (TCRS) and Australia suggest this situation may not be true [13], [14]. Martinez et al. have shown that children who wheezed during lower respiratory tract illnesses (LRIs) in the first 3 years of life and were still wheezing at age 6 (“persistent wheezers”) had slightly but not significantly lower levels of premorbid lung function (measured before any wheezing had occurred) than children who never wheezed before age 6. By age 6, however, persistent wheezers had significant deficits in lung function, which could not entirely be reversed with a bronchodilator [13]. These results strongly suggest that persistent wheezers start out life with normal lung function that declines over time and that this process may be due to airways inflammation secondary to the disease process itself. However, since it is transient wheezers that start life with the lowest levels of lung function that improves over time, the data strongly suggest that it is not the levels of lung function at birth that determine prognosis in children at risk for asthma.
These data suggest that an important preventable risk factor for asthma is the early development of chronic airway inflammation that is characteristic of the disease and which may be associated with airway structural changes termed remodeling. This remodeling predisposes to BHR and losses in lung function that in turn predispose to asthma chronicity. We therefore hypothesize that, if a strategy for the secondary prevention of asthma were to be successful, it would need to start during the first years of life in order to control airway inflammation in this critical period of lung growth.
A randomized, controlled clinical trial was designed to determine if the natural course of childhood asthma could be altered through long-term use of ICS early in life. Fluticasone, an inhaled glucocorticosteroid, is being compared with placebo. All participants use albuterol, an inhaled short-acting β-agonist bronchodilator, as needed for asthma symptoms and signs and prednisolone for continued symptoms despite albuterol. Study outcome variables are assessed during the last year of the study when the intervention with ICS is discontinued to determine if the number of symptom-free days differ between the two treatment groups. This report details the Prevention of Asthma in Kids (PEAK) trial design, its rationale and the procedures utilized to measure treatment response.
Section snippets
Study design and rationale
The PEAK study was a multicenter, double blind, randomized, placebo-controlled, parallel-group comparison of inhaled fluticasone to placebo in children 2 and 3 years of age at high risk of developing asthma (Fig. 1). Children were randomized to one of two treatment groups, one receiving active treatment and the other placebo. The study was based on a continuous treatment schedule for a period of 24 months, followed by an observation period of 12 months during which the main outcomes were
Data collection and study visits
Eligibility assessment included medical history, allergy skin testing, an eosinophil count, successful completion of a 28-day screening period with daily recording of asthma symptoms and measurement of compliance with an electronic meter (Doser®) Table 1, Table 2. Data collected for baseline measurements, not directly related to eligibility assessment, included a physical examination, quality of life questionnaires [a general quality of life measure (PedsQL) [30], an asthma-specific quality of
Overview of organization
The operational units of the trial consisted of five clinical centers, two resource centers and seven standing committees (see Appendix A). The SC was the primary decision-making body of the CARE Network. The SC, with input from other members of the CARE Network, designed and executed the study. The Executive Committee, a subcommittee of the SC, was empowered to make interim decisions between the SC meetings. The Publications Committee (PC), a subcommittee of the SC, organized, nurtured and
Sample size calculation
The target sample size for the PEAK study was based on both the primary (proportion of asthma-free days) and secondary (rate of wheezing exacerbations) outcomes. The target sample size was N=250 for the primary outcome and N=280 for the secondary outcome. Since the sample size required for the secondary outcome was only marginally higher than for the primary outcome, it was decided to set the recruitment goal at 280 in order to ensure adequate statistical power for both the primary and
Discussion
The main purpose of the PEAK study was to determine if early intervention with anti-inflammatory agents in young children at high risk for the development of asthma prevented the subsequent development of persistent asthma. Although there was some indirect evidence in the literature that prolonged treatment with ICS may prevent lung function losses in young asthmatics, the issue was still controversial and remained substantially unresolved.
There is strong evidence suggesting that children with
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The manuscript was supported by the following grants: U10HL64307, 5K08H071742-01, 5K30HL004519-04.