PLASMA will be the first long-term trial conducted by the ACRN. The proposed null hypothesis for the PLASMA trial is as follows:
In patients with mild persistent asthma, continuous daily treatment for three years (1) with inhaled and oral placebos, (2) with an inhaled corticosteroid, or (3) with an oral leukotriene antagonist do not differ in their effects on the development of irreversible airflow obstruction, as reflected by the best achievable FEV1 (i.e., the FEV1 measured after ten days of intense combined therapy with prednisone (0.5 mg/kg/d), an inhaled corticosteroid (in a dose equivalent to Beclomethasone dipropionate 2000 µg/d), and a leukotriene (LT) receptor antagonist (montelukast 10mg/day or zafirlukast 20mg twice a day), and after acute administration of repeated doses of albuterol until maximal FEV1 is achieved).
Secondary null hypotheses to be investigated are as follows. The sum of the direct costs of medications taken regularly, of medications taken "as needed," of unscheduled office, emergency department, or hospital visits, and of the indirect costs for days lost from work or school do not differ with the three treatments. The change in best achievable FEV1 is unrelated to the degree of bronchial reactivity, the percentage of eosinophils in induced sputum samples, or the concentration of exhaled nitric oxide before therapy is started, and is also unrelated to the changes in these indices of airway inflammation over the first six months of treatment or to the change in FEV1 over the third to the ninth month of treatment. The asthma control achieved after six months of treatment with a low dose of an inhaled corticosteroid (ICS; BDP equivalent = 400 µg/day), and a standard dose of a LT-receptor antagonist taken each day does not differ whether the treatment taken over the previous three years was daily inhaled corticosteroid, daily oral LT-receptor antagonist, or only "as needed" use of inhaled and oral corticosteroid therapy. In patients with mild persistent asthma, changes in the values for baseline and best achievable FEV1 for "asthma control" and for "asthma related quality of life" over three years of randomized treatment are unrelated to variations in genetic loci thought to be related to asthma or its severity (e.g. in the promoter regions for IL-4 and 5-LO).
The National Institutes of Health "Guidelines for the Diagnosis and Management of Asthma" recommend daily treatment with an anti-inflammatory controller medication for mild persistent asthma [1, 2]. This recommendation was prompted by studies reporting that improvements in FEV1 and in bronchial reactivity were significantly lower when inhaled corticosteroid (ICS) therapy was delayed than when it was started soon after the appearance of asthma symptoms [3-6]. Although conducted as double-blind, prospective long-term studies of large numbers of subjects, certain limitations of these studies restrict the generalizability of their findings to the asthmatic population for whom the recommendation was made. For example (1) some of the subjects examined in these studies had asthma more severe than "mild persistent asthma" as defined by the NAEPP Guidelines, (2) the differences in FEV1 and PC20 were small on average and do not appear to have occurred in all subjects, (3) only small and often statistically insignificant differences in clinical outcomes were reported in the study groups in whom deteriorations in tests of airway caliber occurred, and (4) it has not been examined whether the deteriorations in FEV1 and PC20 persisted after intense treatment with corticosteroids and bronchodilators. It is thus not known whether these deteriorations were easily reversible or reflected "remodeling" of the airways.
The recommendation that patients with mild persistent asthma be treated daily with an ICS was thus not strictly "evidence based." It was instead derived from the best opinion of asthma experts working with a limited set of data. The essential concern of the experts was that the small differences is reported to occur when inhaled corticosteroid treatment was delayed indicated an increased risk of developing symptomatic irreversible airflow obstruction, now known to be a consequence of chronic asthma in some patients [7-9]. Whether the small decrements in FEV1 noted in subjects in whom ICS therapy had been "delayed" were reversible with a short course of intense therapy was not determined. Whether such changes would occur to a greater or lesser extent with leukotriene modifiers and whether a delay in initiation of treatment with those drugs is of importance is also unknown.
We therefore propose in this study to analyze changes not only in the "baseline" FEV1 (i.e., the FEV1 obtained without prior treatment with bronchodilators) but also in the "best achievable" FEV1, which we have defined as the value measured after ten days of intense combined therapy with prednisone 0.5 mg/kg/day (maximum dose = 50 mg/day), a high dose of an ICS (BDP equivalent = 2000 µg/day), and an LT-receptor antagonist (montelukast 10mg/day or zafirlukast 20 mg bid), and after acute administration of up to eight puffs of albuterol. Because even this treatment may not fully reverse all reversible components of airflow obstruction, we propose to treat all subjects with both a low dose of an ICS (BDP equivalent = 400 µg/day), and a standard dose of an LT-receptor antagonist taken daily for six months after the completion of three years of randomized therapy, and to again assess "baseline" and "best achievable" FEV1. Over this six month period, we will have the opportunity to gain insight into whether the "delay" in any of these therapies affects the "best achievable" FEV1, or whether addition of the alternate agent (or in the case of placebo group, the addition of both agents), permits so called "catch up" in the "best achievable FEV1. Additionally, we will examine the effect of these different treatment modalities on the control of symptoms, need for albuterol, and improvement in peak flow.
Population studies of elderly, non-smoking asthmatics show that some have developed chronic, apparently irreversible, airflow obstruction. The proportion of asthmatics who develop such changes is unknown, and also unknown is whether those at risk can be identified by an easily measurable marker of disease activity. An aim of this study is to examine the relationship between the change in FEV1 over time (whether on or off continuous therapy) and bronchial reactivity and pathobiologic markers of bronchial inflammation. Tests of airway caliber at entry (e.g., FEV1), bronchial reactivity (PC20), markers of airway inflammation (sputum eosinophil percent; exhaled nitric oxide), and markers of sensitization to environmental allergens (skin test reactions, serum IgE levels, blood eosinophils), as well as the changes in these markers observed over the first six months of treatment and the change in FEV1 from the third to ninth month of treatment will be examined.
Further complicating an easy determination of the best treatment for mild persistent asthma is the NAEPP guidelines' recommendation that regular treatment with a leukotriene antagonist can be used as an alternative to regular treatment with an ICS. Leukotrienes antagonists have been shown to reduce the incidence of steroid-requiring exacerbations, and some studies have suggested that they can be used to reduce or substitute for ICS [10-13]. They are available in oral formulation. Oral leukotriene antagonists are now commonly prescribed for patients with asthma, possibly because patients have been shown to be more likely to comply with regular oral therapy than with regular inhaled therapy [14]. Studies of renewal patterns for ICS prescriptions indeed suggest that most patients do not take them regularly [15].
A 44-month study with 22 scheduled visits is proposed. After an eight-week run-in period, subjects who meet NAEPP criteria for mild persistent asthma will be assigned to one of three treatment arms for three years: (1) daily oral placebo and twice daily inhalation of placebo from a turbuhaler (placebo treatment); (2) daily oral placebo and twice daily inhalation of an inhaled corticosteroid (BDP equivalent = 400 µg/day) (regular inhaled corticosteroid treatment); (3) daily oral LT-receptor antagonist and twice daily inhalation of placebo (regular oral leukotriene antagonist treatment). Subjects in all treatment arms will be instructed to take short courses of an inhaled cortocosteroid or prednisone on an "as needed" basis as guided by a symptom based action plan. Treatment assignment will be made by double blind randomized parallel group design, stratified by center and blocks of subjects. Within each block, an adaptive randomization scheme will be invoked in order to ensure balance across treatment arms with respect to PC20, age and race. This will provide equal representation of subjects with mild (PC20 > 1 mg/ml) and more severe (PC20 < 1 mg/ml) bronchial reactivity, with ages less than and greater than 25 years, and with racial categorization as African-American (reported to have a higher prevalence of polymorphism at the 5-LO promoter locus) in each treatment group. At the completion of three years of randomized treatment, all subjects will be followed for an additional 6 months while taking regular ICS therapy, and the study end-points assessed again.
The protocol can be viewed as consisting of three phases: a run-in period of 8 weeks, a blinded treatment phase of 36 months, and an open ICS + oral LT-receptor antagonist treatment phase of six months. In the run-in phase, subjects will make 5 visits to the clinic. The purposes of these visits are first to determine that the subjects indeed have mild persistent asthma and qualify for inclusion in the study, and second to obtain baseline data on the outcomes to be followed. At the end of the run-in, all subjects will be treated with intense combined therapy to determine the principal outcome measure, the "best achievable" FEV1. This treatment will consist of prednisone, 0.5 mg/kg/day, a high dose of an ICS (BDP equivalent = 1000 µg b.i.d), and a standard daily dose of an oral LT-receptor antagonist, for ten days, followed by acute administration of up to 8 puffs of albuterol until the maximal value for FEV1 is measured. In the active treatment phase, subjects will be randomized to one of the three treatment arms and will be seen every three months. At the end of the third year, intense combination therapy will again be given to determine "best achievable" FEV1. In the third phase of the study, all subjects will be treated with an inhaled corticosteroid (BDP equivalent = 400 µg/day), and a standard daily dose of an oral LT-receptor antagonist, and asthma control, "baseline" FEV1, and "best achievable" FEV1 will again be assessed.
The target sample size for the PLASMA trial is 270 randomized subjects. It is anticipated that the trial will begin in Fall, 1999 and be completed in 2005.
References
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