Published ahead of print on September 22, 2006, doi:10.1164/rccm.200603-416OC
© 2007 American Thoracic Society doi: 10.1164/rccm.200603-416OC
Clinical Trial of Low-Dose Theophylline and Montelukast in Patients with Poorly Controlled AsthmaThe American Lung Association Asthma Clinical Research Centers*Correspondence and requests for reprints should be addressed to Robert A. Wise, M.D., Johns Hopkins Asthma & Allergy Center, 5501 Hopkins Bayview Circle, Baltimore, MD 21224. E-mail: rwise{at}jhmi.edu
Background: Asthma treatment guidelines recommend addition of controller medications for patients with poorly controlled asthma. We compared the effectiveness of once-daily oral controller therapy with either an antileukotriene receptor antagonist (montelukast) or low-dose theophylline added to existing medications in patients with poorly controlled asthma.
Methods: We conducted a randomized, double-masked, placebo-controlled trial in 489 participants with poorly controlled asthma randomly assigned to placebo, theophylline (300 mg/d), or montelukast (10 mg/d). Participants were monitored for 24 wk to measure the rate of episodes of poor asthma control (EPACs) defined by decreased peak flow, increased Observations: There was no significant difference in EPAC rates (events/person/yr) compared with placebo: low-dose theophylline, 4.9 (95% confidence interval [CI], 3.6–6.7; not significant); montelukast, 4.0 (95% CI, 3.0–5.4; not significant); and placebo, 4.9 (95% CI, 3.8–6.4). Both montelukast and theophylline caused small improvements in prebronchodilator FEV1 of borderline significance. Nausea was more common with theophylline only during the first 4 wk of treatment. Neither treatment improved asthma symptoms or quality of life. However, in patients not receiving inhaled corticosteroids, addition of low-dose theophylline significantly (p < 0.002) improved asthma control and symptoms as well as lung function. Conclusions: Neither montelukast nor low-dose theophylline lowered the EPAC rate of poor asthma control in patients with poorly controlled asthma despite improved lung function. For patients not using inhaled corticosteroids, low-dose theophylline improved asthma symptom control more than montelukast or placebo, and provides a safe and low-cost alternative asthma treatment.
Key Words: antiasthmatic agents • bronchodilator agents • clinical trial • multicenter studies
Asthma treatment guidelines recommend the addition of controller medication in patients with poorly controlled asthma (1, 2). Usually, inhaled corticosteroids (ICS) are the mainstay of asthma controller therapy, but some patients require additional treatment or prefer not to use ICS. In such patients, oral once-daily medication is an attractive alternative, with a choice of either theophylline or a leukotriene antagonist. Theophylline, once widely used for asthma symptom control, has fallen into disfavor in recent years because of concerns about side effects and the expense and inconvenience of monitoring blood levels (3). Recent studies, however, suggest that theophylline has significant antiinflammatory and immunomodulatory effects at lower serum concentrations (< 10 mg/L), and can be given as once-daily oral medication, which does not require monitoring of blood levels (4). Antileukotriene agents, such as the leukotriene receptor antagonist montelukast, are also recommended as add-on therapy for inadequately controlled asthma (1, 2). Montelukast is effective in improving lung function and asthma symptoms and also is given as a once-daily oral preparation not requiring titration and monitoring of blood concentrations, but it is more expensive than generic theophylline. The use of low-dose theophylline as add-on therapy to ICS has shown benefit in some studies (5, 6) but not others (7, 8). Recent meta-analyses have questioned the efficacy of antileukotrienes as asthma therapy when added to ICS (9, 10). Moreover, the comparative effectiveness of low-dose theophylline and montelukast for patients with poorly controlled asthma is unknown, and no previous studies have directly compared the effectiveness of these two once-daily oral agents for control of asthma symptoms. Accordingly, we conducted a double-masked, randomized, placebo-controlled clinical trial to compare the effectiveness of these two drugs in controlling asthma. Because the goal of asthma therapy is to minimize episodic deterioration in terms of peak flow reduction, increased use of bronchodilators, and heath care use, the present study focused on asthma control as a primary outcome rather than intermediate endpoints such as lung function or inflammatory markers (11). The composite outcome measure of episodes of poor asthma control (EPACs) was used to reflect the several dimensions of good asthma control, including physiology, symptoms, and health care use. Moreover, because the interaction of low-dose theophylline with ICS is controversial, we enrolled patients with poorly controlled asthma who were and were not using ICS.
Protocol This study was a randomized, double-masked, placebo-controlled trial of the effectiveness of low-dose theophylline or montelukast for patients with poor asthma control. Participants were recruited from 19 centers in the American Lung Association Asthma Clinical Research Centers. Participants were age 15 yr or older, had physician-diagnosed asthma, had been prescribed daily asthma medications for 1 yr or more, had an FEV1 of 50% or more of predicted values (12), and had poor asthma control defined by a score of 1.5 or greater on the Asthma Control Questionnaire (ACQ) (13, 14). Volunteers were ineligible if they used oral corticosteroids, leukotriene antagonists, or theophylline within 4 wk preceding enrollment, were current or former smokers with 20 pack-years or more smoking history, or had other significant illness. The protocol was approved by the institutional review boards at each institution. Participants completed five study visits, including a run-in period of 7 to 14 d and a treatment period of 24 wk (Figure E1 of the online supplement). At Visit 1, participants were assessed for eligibility and gave consent. After 7 to 14 d, participants returned for review of diaries, spirometry, and completion of the Asthma Symptom Utility Index (ASUI) (15), ACQ (13), and Asthma Quality-of-Life Questionnaire (AQLQ) (16). Participants were randomly assigned in equal allocation ratio to theophylline 300 mg/d (Theochron; Inwood Laboratories, New York, NY), montelukast 10 mg/d (Singulair; Merck, Whitehouse Station, NJ), or placebo using permuted blocks stratified by clinic. Treatments were masked by opaque capsules and taken after the evening meal. Participants were telephoned 2 wk after randomization to assess compliance, side effects, and asthma control. Participants returned for visits at 4, 12, and 24 wk. Medication adherence was assessed by diary, and plasma montelukast or theophylline concentrations at 1 and 6 mo. Theophylline concentration was measured by particle-enhanced turbidimetric inhibition immunoassay (analytic range, 2.0–40 mg/L) (17), and montelukast concentration by reversed-phase liquid chromatography (detection limit, 5 ng/ml) (18).
Outcomes
Analysis
Baseline Characteristics A total of 489 participants were randomized, with 95% completing diary cards and 94% completing follow-up spirometry. The enrollment and follow-up flow diagram is available in the online supplement (Figure E3). Baseline characteristics for the participants are shown in Table 1 and Table E1. The participants were on average middle-aged, predominantly female, and with adult-onset asthma. The treatment groups were well matched for baseline asthma characteristics, with approximately three-fourths of all subjects using ICS. About 9% of participants were prescribed daily asthma medication, but did not use it. Six percent of participants had been prescribed a leukotriene antagonist and less than 1% of participants had been prescribed theophylline at some time in the past year, which they had discontinued at least 4 wk before enrollment. Post-bronchodilator lung function was mildly reduced on average compared with a normal population. By design, the participants had poorly controlled asthma, with an ACQ score of 2.3 to 2.4 (with a score greater than 1.5 indicating poor asthma control) (14). The group assigned to theophylline tended to have a slightly lower ASUI score, indicating slightly greater asthma symptoms than the other groups (0.66 for theophylline vs. 0.68 for montelukast and 0.70 for placebo, p = 0.16 for overall comparison).
Adherence to Therapy Self-reported adherence to the study drugs was 84% for theophylline and 88% for both montelukast and placebo. We also measured adherence using biological measures, defined as a plasma drug concentration that exceeded the lower limit of detection (> 2 mg/L for theophylline and > 5 ng/ml for montelukast). Using biological measures, adherence was lower and fell over time. Adherence at 4 wk was 79% (n = 136) for theophylline and 71% (n = 136) for montelukast. Adherence fell to 60% (theophylline, n = 120; montelukast, n = 127) in both groups at 24 wk. In participants with detectable drug concentrations, the mean ± SD plasma concentrations of theophylline were 6.8 ± 2.6 and 6.2 ± 2.7 mg/L at 4 and 24 wk, respectively. For montelukast, the plasma concentrations were 123 ± 163 and 125 ± 157 ng/ml at 4 and 24 wk, respectively. Reasons for treatment termination were similar among the treatment groups and included loss to follow-up (range between groups, 7–12%), adverse events (3–8%), withdrawal of consent (2–6%), and other (2–4%).
Adverse Events
EPACs
Asthma Symptoms The overall mean changes in asthma symptoms assessed by the ASUI, quality of life assessed by the AQLQ and control of asthma by the ACQ scores were not statistically different in either treatment group compared with placebo (Table 3). At 4 wk, the montelukast group was significantly better than placebo, but not at the later time points.
Lung Function Overall, prebronchodilator FEV1 was improved in both the theophylline (p = 0.006) and the montelukast (p = 0.003) groups (Table 4; Figure 1); however, the overall change in prebronchodilator FVC was not improved in either group. The post-bronchodilator FEV1 was improved only by theophylline at 4 (p = 0.006) and 12 wk (p = 0.04), but not at 24 wk (p = 0.15). Overall, the improvement in post-bronchodilator FEV1 by theophylline, including all measurements, was significant (p = 0.005 vs. placebo), and the trend for montelukast was similar but smaller (p = 0.13 vs. placebo). The post-bronchodilator FVC was not significantly improved by either of the active treatments.
Influence of ICS Use It has been hypothesized that there is a beneficial antiinflammatory interaction between corticosteroids and theophylline based on additive molecular effects on histone deacetylase (4, 23). However, a previous clinical study in 24 patients with asthma receiving ICS showed no antiinflammatory effect of low-dose theophylline (8). Therefore, we analyzed the data stratified by use of ICS. There were significant statistical interactions between ICS use and outcome measures, so we conducted separate analyses for those taking and not taking ICS. The p values for an interaction of ICS use and outcomes were as follows: 0.008 for EPAC rate, 0.08 for the ACQ, 0.12 for the AQLQ, and 0.04 for the ASUI. Contrary to expectation, we found that there was a significant (p = 0.002) beneficial effect of theophylline on EPAC rate in participants not using ICS, with a substantial reduction of events to 1.8 events/person-year (CI, 1.1–3.0) compared with the event rate on placebo of 5.7 (CI, 3.3–9.9; Figure E4). Theophylline reduced both the fall in peak expiratory flow (p = 0.02) and  -agonist inhaler/nebulizer use (p = 0.01) components of the event rate, but did not alter the use of health care, an infrequent event. Participants not taking ICS who were assigned to montelukast had a borderline reduction in asthma event rate (p = 0.08), with the rate of peak flow declines significantly lower than placebo (p = 0.02). Treatment with low-dose theophylline in participants not using ICS also showed significant improvement in symptoms as assessed by the ASUI (p = 0.03) and the ACQ (p = 0.02). There were no significant differences in plasma drug levels or adherence rates for either add-on treatment between users and nonusers of ICS, suggesting treatment adherence did not account for the observed differences (Tables E3–E5).
The purpose of this study was to compare the effectiveness of adding either low-dose theophylline or montelukast to the treatment of patients with poorly controlled asthma. The primary outcome was selected to be the rate of EPACs, as this is a measure of asthma control that is relevant to quality of life and costs of medical care, and is the goal of asthma care under current practice guidelines. Secondary outcomes were lung function, asthma symptom scores, and asthma-related quality of life. We studied both low-dose theophylline and montelukast because both are taken as once-daily oral formulations, which are convenient for patients and therefore should optimize adherence. We purposely designed the study to reproduce the clinically realistic situation where therapies are added to existing treatment regimens as prescribed by their usual asthma care provider. Our aim was to evaluate the effectiveness of these treatments in a clinically realistic situation with clinically relevant outcomes rather than to evaluate treatment efficacy in an ideal setting using intermediate physiologic and biological outcomes. The main finding of this trial was that neither theophylline nor montelukast had additional benefit in reducing the EPACs, reducing asthma symptoms, or improving quality of life compared with placebo. Both theophylline and montelukast improved prebronchodilator spirometry, but only theophylline improved FEV1 after bronchodilator. Thus, theophylline appeared to augment the bronchodilator effect of the albuterol inhalation, thus overcoming residual bronchoconstriction in that group of patients. However, the magnitudes of the spirometric changes were small (0.08–0.09 L) and of uncertain clinical importance. We found that low-dose theophylline was relatively well tolerated, but did cause gastrointestinal symptoms during the first 4 wk that abated with continuing treatment. Secondary subgroup analysis showed that theophylline substantially reduced both event rates and symptoms in those patients with asthma who were not using ICS.
In the past, theophylline was widely used as maintenance bronchodilator therapy for asthma. However, the introduction of inhaled long-acting Development of tolerance to the adverse effects of theophylline has long been observed with high-dose theophylline, as we observed in this study. Usually, this has been attributed to induction of metabolic pathways or central nervous system adaptation. Because of the discrepancy between self-reported adherence and serum concentrations, it is also possible that the adaptation may be due, in part, to nonadherence in patients who experienced more side effects.
A growing body of evidence, mostly in the setting of asthma and allergic inflammation, suggests that theophylline has antiinflammatory properties. These include the following: inhibition of neutrophil migration; inhibition of neutrophil, lymphocyte, and monocyte activation; production of the antiinflammatory cytokine interleukin-10; and inhibition of inflammatory mediators and the proinflammatory gene regulator nuclear factor- ICS are generally considered to be the mainstay of antiinflammatory controller treatment in asthma. Some patients or asthma care providers may find ICS to be too expensive, difficult, or inconvenient to use, or have concerns about long-term adverse effects. Thus, the current study suggests that monotherapy low-dose theophylline holds promise as an alternative to ICS in the treatment of selected patients with asthma with inadequate symptom control. Because the subgroup on ICS was small and was not the primary focus of the study, more research investigating this group is necessary to confirm this result. Theophylline, although a mild bronchodilator, is only of marginal benefit, if any, in terms of asthma symptom control for patients with asthma already treated with ICS.
We compared add-on therapy with low-dose theophylline with montelukast, a widely prescribed, oral, once-daily asthma control therapy. Like theophylline, montelukast has been shown in some studies to improve lung function or symptoms when used together with ICS (8, 34, 35). As monotherapy, however, leukotriene antagonists are generally not as effective as ICS (36, 37). The current study demonstrated that, aside from improvements in lung function, montelukast, like theophylline, had no additional beneficial effect on asthma control as measured by a composite measure of lung function variability, Most asthma guidelines recommend a bronchodilator such as an LABA as the first choice for add-on therapy when ICS do not provide adequate asthma control. Studies comparing montelukast to LABA therapy as add-on treatment to ICS have shown that LABAs produce greater bronchodilation, and more reduction in symptoms and exacerbations (38, 39). No such studies have compared LABAs with low-dose theophylline. However, recent studies have raised questions about the safety of LABAs (40, 41). Because of this, some have suggested that low-dose theophylline may be a useful alternative to LABAs when ICS alone do not adequately control asthma (42). Although we did not compare them directly, this study does not support the use of add-on therapy with montelukast or low-dose theophylline as an efficacious alternative to LABA add-on therapy for asthma control. To our knowledge, only one previous trial has directly compared the efficacy of theophylline with leukotriene receptor antagonists. Dempsey and colleagues (8) conducted a 2-wk crossover trial in 24 subjects comparing low-dose theophylline (400–600 mg/d) with zafirlukast, a leukotriene receptor antagonist, in patients who were taking either low-dose (100 µg/d beclomethasone) or medium-dose (400 µg/d beclomethasone) ICS. They found that the added antiinflammatory effects of zafirlukast and theophylline, measured with either exhaled nitric oxide or methacholine reactivity were only present with low-dose but not with medium-dose ICS. This study, therefore, supports our finding that the clinical benefit of these agents is diminished in the background of ICS use. The authors did not, however, include participants who were not using ICS, and did not specifically focus on measures of asthma control. In summary, add-on therapy with either low-dose theophylline or montelukast in patients with poorly controlled asthma did not reduce EPACs, although both agents improved lung function. However, in the subgroup of patients with poorly controlled asthma who were not taking ICS, both low-dose theophylline and montelukast had similarly beneficial effects on asthma control, but only the theophylline-treated group reached statistical significance. Although low-dose theophylline and montelukast had similar adherence, efficacy, and tolerability, theophylline is considerably less expensive. Therefore, for patients with poorly controlled asthma who cannot or will not use ICS because of side effects, preference, lack of efficacy, or cost, low-dose theophylline is an inexpensive alternative asthma controller therapy and should be more widely applied.
Supported by the American Lung Association and the Merck Company Foundation.
* The American Lung Association Asthma Clinical Research Centers Writing Committee takes responsibility for the integrity and content of the manuscript. For a list of the members of the Writing Committee, see the end of this article. This article has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org Originally Published in Press as DOI: 10.1164/rccm.200603-416OC on September 22, 2006 Conflict of Interest Statement: C.G.I. has received an investigator-initiated grant ($150,000) from GlaxoSmithKline (GSK), has received honoraria from several organizations (Sepracor, Biogen, Isis), and has been a Merck-sponsored visiting professor in 2004 ($2,000) and 2005 ($2,000). D.A.K. has no financial relationship with a commercial entity that has an interest in the subject of this manuscript. N.R.A. has served on advisory boards for GSK and ALTANA, receiving approximately $2,000/yr for 5 yr, and has given two to three talks over the past 5 yr for GSK, with an honorarium of $2,500 for each. M.C. has no financial relationship with a commercial entity that has an interest in the subject of this manuscript. N.A.H. has served on the advisory board of GSK and DEY Pharmaceuticals and has received honoraria for speaking at scientific meetings for GSK ($8,000 over the last 2 yr); he also has received grant support from GSK, Boehringer-Ingelheim, Sepracor, AstraZeneca, and Novartis. J.T.H. has no financial relationship with a commercial entity that has an interest in the subject of this manuscript. J.J.L. has no financial relationship with a commercial entity that has an interest in the subject of this manuscript. R.A.W. received consulting fees from GSK, Pfizer, sanofi-aventis, Emphasys, Spiration, and Forest in the past 3 yr for research oversight and review committees; he has served on advisory boards for Boehringer-Ingelheim, Pfizer, GSK, Hill-Rom, Otsuka, Ortho, and Amgen; he has also received research grants from Boehringer-Ingelheim, Otsuka, and Pfizer; conflict of interest regarding human research is managed by the Johns Hopkins University. American Lung Association Asthma Clinical Research Centers Writing Committee: Members are as follows: Charles G. Irvin, Ph.D., and David A. Kaminsky, M.D., University of Vermont School of Medicine; Nicholas R. Anthonisen, M.D., University of Manitoba School of Medicine; Mario Castro, M.D., M.P.H., Washington University School of Medicine; Nicola A. Hanania, M.D., Baylor College of Medicine; Janet T. Holbrook, Ph.D., M.P.H., The Johns Hopkins University School of Public Health; John J. Lima, Pharm.D., Nemours Children's Clinic; and Robert A. Wise, M.D., The Johns Hopkins University School of Medicine. Received in original form March 23, 2006; accepted in final form August 30, 2006
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