CLINICAL TRIAL OF LOW-DOSE THEOPHYLLINE AND ...

AJRCCM Articles in Press. Published on September 22, 2006 as doi:10.1164/rccm.200603-416OC 

CLINICAL TRIAL OF LOW-DOSE THEOPHYLLINE AND MONTELUKAST IN 

PATIENTS WITH POORLY CONTROLLED ASTHMA 

by 

The American Lung Association Asthma Clinical Research Centers 

(Writing Committee: Charles G. Irvin, PhD 1 , David A. Kaminsky, MD 1 , Nicholas R. 

Anthonisen, MD 2 , Mario Castro, MD, MPH 3 , Nicola A. Hanania, MD 4 , Janet T. Holbrook, PhD, 

MPH 5 , John J. Lima, 6 Pharm.D, Robert A. Wise, MD 5 ) 

1. University of Vermont School of Medicine (CGI, DAK); 2. University of Manitoba School of 

Medicine (NRA); 3. Washington University School of Medicine (MC); 4. Baylor University 

School of Medicine (NAH); 5. Johns Hopkins University School of Public Health (JTH, RAW); 

6. Nemours Children's Clinic (JJL). 

Address for correspondence and reprints: 

Robert A. Wise, M.D. 

Johns Hopkins Asthma & Allergy Center 

5501 Hopkins Bayview Circle 

Baltimore, MD 21224 

Telephone: (410) 550-0546 

FAX: (410) 550-2612 

Email: rwise@jhmi.edu 

Running head: Theophylline and montelukast in asthma 

Descriptor: Category number 67. Asthma Management (Controlled Trials) 

Word count 

Total: 3502 

Abstract: 246 

Methods: 504 

Figures: 1 

Tables: 4 

The writing committee takes responsibility for the integrity and content of the manuscript. 

Supported by the American Lung Association and the Merck Company Foundation 

This article has an online data supplement, which is accessible from this issue's table of contents 

online at http://www.atsjournals.org 

Copyright (C) 2006 by the American Thoracic Society.

Abstract 

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/day) or 

montelukast (10 mg/day). Participants were followed for 24 weeks to measure the rate of 

episodes of poor asthma control (EPACs) defined by: decreased peak flow, increased beta 

agonist use, oral corticosteroid use or unscheduled health care visits. 

Observations 

There was no significant difference in EPAC rates (events/person – year) compared to placebo: 

low-dose theophylline 4.9 (95% CI 3.6 – 6.7; NS); montelukast 4.0 (95% CI 3.0 – 5.4; NS) and 

placebo 4.9 (95% CI 3.8 – 6.4). Both montelukast and theophylline caused small improvements 

in pre-bronchodilator FEV1 of borderline significance. Nausea was more common with 

theophylline only during the first four weeks of treatment. Neither treatment improved asthma 

symptoms or quality of life. However in patients not on inhaled corticosteroids (ICS), addition 

of low-dose theophylline significantly (p

Introduction 

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 anti-inflammatory and immunomodulatory effects at lower serum 

concentrations (

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 healthcare use. 

Moreover, because the interaction of low-dose theophylline with ICS is controversial, we 

enrolled poorly controlled asthmatics who were and were not using ICS. 

Methods (504 Words) 

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, had physician-diagnosed asthma; had been 

prescribed daily asthma medications for ≥1 year; had an FEV1 >50% predicted; 12 and poor 

13 14 

asthma control defined by a score of >1.5 on the Asthma Control Questionnaire (ACQ). 

Volunteers were ineligible if they used oral corticosteroids, leukotriene antagonists or 

theophylline within 4 weeks preceding enrollment, were current smokers or former smokers with 

>20 pack-years, 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 7-14 days and a 

treatment period of 24 weeks (Figure E-1). At Visit 1, participants were assessed for eligibility 

and gave consent. 7-14 days later, participants returned for review of diaries, spirometry, and

completion of the Asthma Symptom Utility Index (ASUI), 15 ACQ 13 and Asthma Quality of Life 

(AQLQ) 16 questionnaires. 

Participants were randomly assigned in equal allocation ratio to theophylline 300mg/day 

(Theochron ® , Inwood Laboratories), montelukast 10mg/day (Singulair ® , Merck) or placebo 

using permuted blocks stratified by clinic. Treatments were masked by opaque capsules and 

taken following the evening meal. 

Participants were telephoned 2 weeks after randomization to assess compliance, side 

effects and asthma control. Participants returned for visits at 4, 12 and 24 weeks. 

Medication adherence was assessed by diary, and plasma montelukast or theophylline 

concentrations at 1 and 6 months. 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 

The primary outcome measure was the annualized rate of episodes of poor asthma control 

(EPACs) defined by any of the following events occurring within a 1-week window recorded by 

diary: a decrease of peak expiratory flow >30% of personal best for 2 or more consecutive days; 

use of bronchodilator rescue medication over baseline by more than 4 metered dose inhalations 

(or 2 nebulizer treatments) in one day; oral corticosteroid treatment for asthma; an unscheduled 

asthma healthcare visit to a physician; emergency department; or hospital. 19 Secondary 

outcomes included the Asthma Symptom Utility Index (ASUI), Asthma Quality of Life (AQLQ), 

Asthma Control (ACQ) scores; pre and post bronchodilator spirometry.

Analysis 

Analyses were performed by intention-to-treat. Poisson regression models with Huber- 

White variance estimates were used to evaluate event rates of EPACs. Linear and logistic 

regression models with GEE variance estimates were used to evaluate differences among 

treatment groups for continuous or dichotomous outcomes, respectively. 20 21 Analyses 

presented are not adjusted for baseline covariates. Results from models adjusted for baseline 

characteristics (age, sex, race, FEV1) were similar to the unadjusted results. Data were analyzed 

using SAS V8 and STATA V9 software. Assuming that 50% of the placebo group 

experienced an EPAC, the sample size of 489 had 80% power to detect a 15% difference (50% 

vs 35%) in the proportion of patients with one or more episodes. (Figure E-2) 22 

Results 

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 data repository. (Figure E-3, Online Repository). Baseline characteristics for the 

participants are shown in Table 1 and Table E-1 (Online Repository). 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 weeks prior to enrollment. Post-bronchodilator lung function was

mildly reduced on average compared to 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 weeks 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 weeks. 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 weeks, respectively. 

For montelukast the plasma concentrations were 123±163 and 125±157 ng/ml, at 4 and 24 weeks 

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 (Table E2, Online Data Supplement) 

Symptoms that were considered potential adverse effects of theophylline were acquired 

by direct questioning which lead to relatively high rates of reporting in all treatment groups. 

Reports of nausea at 4 weeks were more frequent in the theophylline group (33%) compared to 

placebo (22%) and montelukast (13%). Similarly, at 4 weeks nervousness was reported in 33%

of the theophylline group compared to 21% and 22% of the montelukast and placebo groups 

respectively. The proportion of patients reporting nervousness declined from baseline in the 

placebo and montelukast groups, but remained essentially unchanged in the theophylline group. 

At 12 and 24 weeks the prevalence of nausea and nervousness were similar among the three 

groups. Poor appetite was less common in the montelukast group than the other two treatment 

groups at 4 weeks, but was similar at 12 and 24 weeks. There were no differences between 

treatment groups at any time point for symptoms of tremor, heart palpitation, vomiting or 

insomnia. 

Episodes of Poor Asthma Control (EPACs) (Figure E-4, Table 2) 

Asthma control rates were analyzed using EPAC composite events as well as each 

component individually. Overall unadjusted event rates were similar among the groups. The 

overall EPAC rates and 95% confidence intervals (CI) were: 4.9 (episodes/person – year) (CI: 

3.8-6.4) for placebo, 4.0 (CI: 3.0-5.4) for montelukast and 4.9 (CI: 3.6- 6. 1) for theophylline. 

The proportion of participants who experienced one or more episodes of poor asthma control was 

close to our projected figure of 50%: Theophylline – 53%, Montelukast – 49%, and Placebo 

52%. Thus, it seems implausible that increasing the size of the study would have increased the 

power of the study enough to demonstrate a clinically meaningful significant treatment effect. 

The incidence of peak flow drops greater than 30% was significantly less with montelukast 

compared to placebo (P=0.008). There were no other components that were different between 

theophylline and montelukast. Adjustment for baseline covariates (age, gender, race, obesity, 

and baseline FEV1 % predicted) did not alter this outcome. Subgroup analysis of adherent 

patients only, defined by detectable 24-week drug concentrations, also did not show a significant

improvement in EPACS for theophylline or montelukast compared to the aggregate placebo 

group. 

Asthma symptoms (Table 3) 

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 to placebo. At 4 weeks, the montelukast group was 

significantly better than placebo, but not at the later time points. 

Lung function (Table 4) 

Overall, pre-bronchodilator FEV1 was improved in both the theophylline (P=0.006) and the 

montelukast (P=0.003) groups (Figure 1); however, the overall change in pre-bronchodilator 

FVC was not improved in either group. The post-bronchodilator FEV1 was improved only by 

theophylline at 4 (P=0.006) and 12 weeks (P= 0.04), but not at 24 weeks (P= 0.15). Overall, the 

improvement in post-BD 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-BD FVC was not significantly improved by either of the active treatments. 

Influence of inhaled corticosteroid use (Online Data Supplement Figure E-4, Tables E3, E4, E5) 

It has been hypothesized that there is a beneficial anti-inflammatory interaction between 

corticosteroids and theophylline based on additive molecular effects on histone deacetylase. 

However, a previous clinical study in 24 asthmatics on ICS showed no anti-inflammatory 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 

4 23

separate analyses for those taking and not taking ICS. The p-values for an interaction of ICS use 

and outcomes were: 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 to 3.0) compared to the event rate on placebo of 5.7 (CI 3.3 to 

9.9) (Figure E-4). Theophylline reduced both the fall in peak expiratory flow (P=0.02) and beta 

agonist inhaler/nebulizer use (P=0.01) components of the event rate, but did not alter the use of 

healthcare, 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 treatments between users and non-users of ICS suggesting 

treatment adherence did not account for the observed differences.

Discussion 

The purpose of this study was to compare the effectiveness of adding either low-dose 

theophylline or montelukast to the treatment of asthmatics with poorly controlled disease. The 

primary outcome was selected to be the rate of episodes of poor asthma control (EPACs), as this 

is a measure of asthma control that is relevant to quality of life, 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 is 

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 episodes of poor asthma control, reducing asthma symptoms, 

or improving quality of life compared to placebo. Both theophylline and montelukast improved 

pre-bronchodilator 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 four weeks that abated with continuing treatment. Secondary

subgroup analysis showed that theophylline substantially reduced both event rates and symptoms 

in those asthmatics 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 beta-agonists and ICS has largely 

supplanted theophylline. Like montelukast, low-dose oral theophylline remains an attractive 

alternative for asthma control in patients who will not or cannot take ICS insofar as it can be 

given as a once-daily oral formulation, does not require blood level monitoring, is inexpensive 

and is reasonably well tolerated. Adherence was reasonably good in all treatment groups when 

measured by diary self-report at four weeks and 24 weeks. However, by 24 weeks, detectable 

blood concentrations were absent in 40% of patients in both the montelukast and theophylline 

groups, a fall-off in adherence that is comparable to biological or electronic monitoring in other 

clinical trials and clinical practice. 24 Although this limited adherence certainly would have 

reduced any drug treatment effect on asthma symptom control, the intention-to-treat results still 

reflect the utility of the treatments in clinical practice and did not prevent us from observing 

significant bronchodilating effects of the active treatments. Moreover, secondary analysis of 

efficacy excluding those without 24-week detectable blood concentrations did not show a 

beneficial impact of either theophylline or montelukast. 

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 non-adherence 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 anti-inflammatory properties. These include: inhibition of 

neutrophil migration, inhibition of neutrophil, lymphocyte, and monocyte activation, production 

of the anti-inflammatory cytokine IL-10, and inhibition of inflammatory mediators and the pro- 

inflammatory gene regulator NF-Kappa B. 4 25 26 27 28 29 30 Low-dose theophylline has been 

shown to reduce airway eosinophilia in asthmatics even in the absence of bronchodilation 

response or reduction in expired NO concentrations. 31 Ito et al have postulated that the likely 

mechanism for these anti-inflammatory effects is the activation of histone deacetylase (HDAC). 

23 32 HDAC is a component of the pathway by which corticosteroids are thought to inhibit pro- 

inflammatory gene expression, and its activity is reduced in some asthmatics, especially cigarette 

smokers. 33 The restoration of this enzyme by theophylline permits both endogenous and 

corticosteroid-mediated down-regulation of inflammatory genes and occurs at concentrations 

(4.3 ± 0.8 mg/L) below those typically used in the past for bronchodilator activity (10-20 

mg/L). 32, 33 Accordingly, we hypothesized that patients using inhaled steroids may benefit by the 

addition of low-dose theophylline more than those patients not using inhaled steroids. 

Surprisingly, we did not find this to be the case. When we stratified our patient population by 

use of ICS, participants assigned to theophylline who were not using ICS had both statistically 

and clinically significant improvement in their asthma control and symptoms. The reason for 

this is not clear, but presumably ICS are such effective anti-inflammatory agents that the addition 

of other drugs is of minimal additional benefit. 

ICS are generally considered to be the mainstay of anti-inflammatory 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 asthmatics 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 asthmatics already treated with 

ICS. 

We compared add-on therapy with low dose theophylline to montelukast, a widely 

prescribed oral once-daily asthma control therapy. Like theophylline, montelukast has been 

8 34 35 

shown in some studies to improve lung function or symptoms when used together with ICS. 

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, beta-agonist use, and healthcare use. In the subgroup of 

participants not taking ICS at baseline, the use of montelukast did not improve asthma control 

although the rate reduction approached statistical significance, an outcome that is consistent with 

previous reports. 37 

Most asthma guidelines recommend a bronchodilator such as a long-acting beta agonists 

(LABAs) 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 LABA with low-dose theophylline. 

However, recent studies have raised questions about the safety of long-acting beta-agonists. 

Because of this, some have suggested that low-dose theophylline may be a useful to alternative 

40 41

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 conducted a 2-week 

cross-over trial in 24 subjects comparing low-dose theophylline (400-600 mg/day) to zafirlukast, 

a leukotriene receptor antagonist, in patients who were taking either low dose (100 ug/day 

beclomethasone) or medium dose (400 ug/day beclomethasone) ICS. They found that the added 

anti-inflammatory effects of zafirlukast and theophylline, measured with either exhaled NO 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. They 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 episodes of poor asthma control, although both 

agents improved lung function. However, in the subgroup of poorly controlled asthmatics 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.

CONFLICT OF INTEREST STATEMENT 

CI has received an investigator initiated grant ($150,000) from GlaxoSmithKline, has received 

honorarium from several organizations (Sepracor, Birgen, ISIS) and has been a Merck-sponsored 

visiting professor in 2004 ($2000) and 2005 ($2005). DK has no financial relationship with a 

commercial entity that has an interest in the subject of this manuscript. NA has served on 

Advisory Boards for GlaxoSmithKline and Altona, receiving approximately $2000 per year for 

five years, and has given 2-3 talks over the past five years for GlaxoSmithKline, with an 

honorarium of $2500 for each. MC has no financial relationship with a commercial entity that 

has an interest in the subject of this manuscript. NH has served on the Advisory Board of 

GlaxoSmithKline and Dey Pharmaceuticals and has received honoraria for speaking at scientific 

meetings for GlaxoSmithKline ($8000 over the last two years); he also has received grant 

support from GlaxoSmithKline, Boehringer-Ingleheim, Sepracor, AstraZeneca and Novartis. JL 

has no financial relationship with a commercial entity that has an interest in the subject of this 

manuscript. RW received consulting fees from GlaxoSmithKline, Pfizer, Sanofi-Aventis, 

Emphasys, Spiration and Forest in the past three years for research oversight and review 

committees; he has served on advisory boards for Boehringer-Ingleheim, Pfizer, 

GlaxoSmithKline, Hill-Rom, Otsuka, Ortho, and Amgen; he has also received research grants 

from Boehringer-Ingleheim, Otsuka, and Pfizer; conflict of interest regarding human research are 

managed by The Johns Hopkins University. JH has no financial relationship with a commercial 

entity that has an interest in the subject of this manuscript.

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modulation of cytokine production. Ann Allergy Asthma Immunol. 1996; 77:34–38. 

26 Tenor H, Hatzelmann A, Church MK, Schudt C, Shute JK. Effects of theophylline and 

rolipram on leukotriene C4 (LTC4) synthesis and chemotaxis of human eosinophils from 

normal and atopic subjects. Br J Pharmacol. 1996; 118:1727–1735. 

27 Condino-Neto A, Vilela MM, Cambiucci EC, Ribeiro JD, Guglielmi AA, Magna LA, De 

Nucci G. Theophylline therapy inhibits neutrophil and mononuclear cell chemotaxis from 

chronic asthmatic children. Br J Clin Pharmacol. 1991; 32: 557-61.

28 Umeda M, Ichiyama T, Hasegawa S, Kaneko M, Matsubara T, Furukawa S. Theophylline 

inhibits NF-kappaB activation in human peripheral blood mononuclear cells. Int Arch 

Allergy Immunol. 2002; 128:130-5. 

29 Kidney J, Dominguez M, Taylor PM, Rose M, Chung KF, Barnes PJ. Immunomodulation by 

theophylline in asthma. Am J Respir Crit Care Med. 1995; 151:1907–1914. 

30 Sullivan P, Bekir S, Jaffar Z, Page C, Jeffery P, Costello J. Anti-inflammatory effects of low- 

dose oral theophylline in atopic asthma. The Lancet. 1994; 343:1006-1008. 

31 Lim S, Tomita K, Carramori G, Jatakanon A, Oliver B, Keller A, Adcock I, Ching KF, Barnes 

P. Low-dose theophylline reduces eosinophilic inflammation but not exhaled nitric oxide 

in mild asthma. Am J Respir Crit Care Med. 2001; 164: 273-276. 

32 Ito K, Caramori G, Lim S, Oates T, Chung KF, Barnes PJ, Adcock IM. Expression and activity 

of histone deacetylases in human asthmatic airways. Am J Respir Crit Care Med. 2002; 

166:392-6. 

33 Ito K, Lim S, Caramori G, Chung KF, Barnes PJ, Adcock IM. Cigarette smoking reduces 

histone deacetylase 2 expression, enhances cytokine expression, and inhibits 

glucocorticoid actions in alveolar macrophages. FASEB J. 2001; 15:1110–1112. 

34 Laviolette M, Malmstrom K, Lu S, Chervinsky P, Pujet J-C, Peszek I, Zhang JI, Reiss TF. 

Montelukast added to inhaled beclomethasone in treatment of asthma. Am J Respir Crit 

Care Med. 1999; 160:1862-1868.

35 Bjermer L, Bisgaard H, Bouquet J, Fabbri LM, Greening AP, Haahtela t, Holgate ST, Picado 

C, Menten J, Dass SB, Leff JA, Polos PG. Montelukast and fluticasone compared with 

salmeterol and fluticasone in protecting against asthma exacerbation in adults: One year, 

double blind, randomized, comparative trial. BMJ. 2003; 327:891. 

36 Ducharme FM. Inhaled glucocorticoid versus leukotriene receptor antagonists as single agent 

asthma treatment: Systematic review of current evidence. BMJ. 2003; 136:621 

37 Malmstrom K, Rodriguez-Gomez G, Guerra J, Villaran C, Pineiro A, Wei LX, Seidenberg BC, 

Reiss TF. Oral montelukast, inhaled beclomethasone, and placebo for chronic asthma: A 

randomized, controlled trial. Annals Internal Med. 1999; 130:487-495. 

38 Nelson HS, Busse WW, Kerwin E, Church N, Emmett A, Rickard K, Knobil K. Fluticasone 

propionate/salmeterol combination provides more effective asthma control than low-dose 

inhaled corticosteroid plus montelukast. J Allergy Clin Immunol. 2000; 106:1088-95. 

Erratum in: J Allergy Clin Immunol 2001;107:614. 

39 Ringdal N, Eliraz A, Pruzinec R, Weber HH, Mulder PG, Akveld M, Bateman ED. The 

salmeterol/fluticasone combination is more effective than fluticasone plus oral 

montelukast in asthma. Respir Med. 2003; 97:234-41. 

40 Harold S. Nelson, Scott T. Weiss, Eugene R. Bleecker, Steven W. Yancey, Paul M. Dorinsky 

the SMART Study Group. The Salmeterol Multicenter Asthma Research Trial: A 

Comparison of Usual Pharmacotherapy for Asthma or Usual Pharmacotherapy Plus 

Salmeterol. Chest 2006; 129: 15 – 26. 

41 Salpeter SR, Buckley NS, Ormiston TM, Salpeter EE. Meta-analysis: effect of long-acting 

beta-agonists on severe asthma exacerbations and asthma-related deaths. Ann Intern 

Med. 2006;144:904-12.

42 Martinez FD. Safety of long-acting beta-agonists--an urgent need to clear the air. N Engl J 

Med. 2005; 22; 353:2637-9.

Figure Legend 

Figure 1: Lung function. The change in forced expiratory volume in one second (FEV1) in 

liters (L) before (Pre-upper panel) and after (Post-lower panel) bronchodilator (BD). Treatments 

are placebo (black square, dotted line), montelukast (white triangle, solid line) and low-dose 

theophylline (black circle, dashed lines). Data points are mean ±95% confidence intervals for 

change in lung function at scheduled follow-up Visits. All of the data lines originate at zero at 

baseline.

Table 1 – Participant Baseline Characteristics by Treatment Assignment 

Treatment Assignment 

Theophylline Montelukast Placebo 

N 161 164 164 

Years of age, mean ± SD 41± 15 40 ± 15 40± 15 

Male (%) 25 28 26 

% White 60 62 60 

Age at asthma onset, mean ± SD 22 ± 21 21 ± 21 21 ± 19 

Pulmonary Function (post-BD), mean ± SD 

Pre-BD FEV1 (% predicted) † 78.3 ± 16.5 77.5 ± 17.5 80.2 ± 16.2 

Pre-BD FVC (% predicted) † 87.2 ± 14.8 87.1 ± 16.9 88.5 ± 14.8 

Post-BD FEV1 (% predicted) † 84.4 ± 15.6 83.7 ± 17.1 86.8 ± 15.2 

Post-BD FVC (% predicted) † 91.8 ± 15.7 91.6 ± 16.0 91.7 ± 14.1 

FEV1 bronchodilator % change 9.2 ± 12.6 9.3 ± 11.7 8.9 ± 10.3 

Daily asthma treatment (%) 

Inhaled long-acting β-agonist (percent on 

monotherapy without ICS) 

22(14) 

23(19) 

18(20) 

Leukotriene antagonist‡ 4 7 7 

Inhaled corticosteroid 79 74 75 

Inhaled anticholinergic 3 5 4 

Inhaled short-acting β-agonist 

Combination drugs (e.g., fluticasone / salmeterol 

58 60 57 

or ipratropium / albuterol) 

37 

40 37 

Using asthma medication daily (%) 90 93 93 

†Predicted values of Hankinson et al. Am J Resp Crit Care Med 1999; 159:179 

‡ These patients discontinued this treatment at least 4 weeks prior to enrollment 

Includes patients taking combination medications that include inhaled corticosteroid

Table 2: Annualized Rates of Episodes of Poor Asthma Control (EPACs) by Treatment 

Assignment 

Relative risk 


95% Confidence Interval 

P-values for treatment contrast* 

T vs M T vs P M vs P 

N 

Asthma EPACs 

151 160 154 

#Events 271 236 293 

Rate (events/person-year) 4.9 4.0 4.9 1.22 0.99 0.82 

95% confidence interval 3.6-6.7 3.0-5.4 3.8-6.4 0.80-1.86 0.67-1.50 0.55-1.21 

#Patients with >1 event (%) 80(53) 79(49) 81(52) 

Episode Components 

Peak flow, 30% drop 

#Events 75 43 100 

Rate (events/person-year) 1.3 0.7 1.6 1.85 0.81 0.44§ 



Increased medication use, 

MDI or nebulizer 

#Events 198 179 200 




New use of oral 

corticosteroids 

#Events 32 32 34 




Unscheduled health care 

#Events 41 34 41 

` Rate (events/person-year) 0.7 0.5 0.6 1.27 1.08 0.85 



Key: EPACs – Episodes of poor asthma control. T – Theophylline; M – montelukast; P – Placebo; MDI – metered 

dose inhaler; *P-values for treatment effects on rates of episodes of poor asthma control are based on Poisson 

regression with robust variance; P-values for treatment effects on percent of patients with an event are based on Chisquare 

test. P = 0.07, § P = 0.008.

Table 3. Change in Asthma Symptom Scores by Treatment Assignment 


Change from baseline score N Theophylline Montelukast Placebo 

AQLQ score 

ASUI score 

408 

462 

Mean, 95% Confidence Intervals 

0.7 

0.6, 0.9 

0.10 

0.07, 0.12 

0.8 

0.6, 1.0 

0.10 

0.08, 0.12 

0.8 

0.6, 1.0 

0.08 

0.05, 0.10 

ACQ 

-0.7 -0.7 -0.7 

462 

-0.8, -0.6 -0.8, -0.6 -0.8, -0.5 

KEY: Key: N – Number of participants; T – Theophylline; M – montelukast; P – Placebo; MDI – metered dose 

inhaler. ASUI– Asthma Symptom Utility Index Questionnaire, 

ACQ – Asthma Control Questionnaire AQLQ – Asthma Quality of Life Questionnaire 

For the AQLQ and ASUI scores, a positive value indicates improvement. For the ACQ and negative value indicates 

improvement. P-values for treatment effects, mean questionnaire scores, and 95% confidence intervals were 

estimated from linear regression models with robust variance estimation and adjusted for visit, where appropriate 

(i.e., for repeated measures of ASUI and ACQ). None of the treatments were significantly different from placebo 

or from each other.

Table 4. Change in Pulmonary Function Measures by Treatment Assignment 


Change from baseline N Theophylline Montelukast Placebo 

FEV1, pre-BD (L) 

4 weeks 460 0.07* 

0.02, 0.13 

12 weeks 427 0.07* 

0.01, 0.12 

24 weeks 408 0.08* 

0.02, 0.15 

FVC, pre-BD (L) 

4 weeks 460 0.06 

0.01, 0.12 

12 weeks 427 0.06 

-0.00, 0.12 

24 weeks 408 0.08 

0.01, 0.16 

FEV1, post-BD (L) 

4 weeks 456 0.06 

0.02, 0.10 

12 weeks 422 0.05* 

0.00, 0.10 

24 weeks 404 0.03 

-0.02, 0.08 

FVC, post-BD (L) 

4 weeks 456 0.04 

-0.01, 0.10 

12 weeks 422 0.01 

-0.05, 0.06 

Mean, 95% Confidence Interval 

0.06 

0.01, 0.11 

0.06 

0.01, 0.11 

0.09* 

0.03, 0.15 

0.07* 

0.02, 0.13 

0.02 

-0.03, 0.08 

0.10 

0.02, 0.17 

0.02 

-0.01, 0.06 

0.01 

-0.03, 0.06 

0.04 

-0.01, 0.09 

0.03 

-0.02, 0.08 

-0.02 

-0.07, 0.03 

-0.01 

-0.06, 0.05 

-0.01 

-0.07, 0.04 

-0.01 

-0.07, 0.05 

-0.01 

-0.06, 0.05 

0.01 

-0.05, 0.07 

0.01 

-0.06, 0.09 

-0.02 

-0.06, 0.02 

-0.02 

-0.07, 0.03 

-0.02 

-0.07, 0.03 

0.01 

-0.04, 0.06 

0.02 

-0.03, 0.07 

24 weeks 404 -0.01 0.01 0.00 

-0.06, 0.05 -0.04, 0.07 -0.05, 0.06 

KEY: Key: N – Number of participants; T – Theophylline; M – montelukast; P – Placebo; MDI – metered dose 

inhaler; FEV1 – Forced expiratory volume in 1 second; FVC – Forced vital capacity; BD – Bronchodilator, 2 

inhalations (90 mcg) of albuterol by metered dose inhaler 

P-values, means and 95% confidence intervals are derived from linear regression model. * P < 0.05 vs. Placebo, P 

< 0.01 vs. placebo. There were no significant differences between theophylline and montelukast.

Figure 1 

Change from baseline 

Pre-BD FEV1(L) 

Change from baseline 

Post-BD FEV1 (L) 

0.2 

0.15 

0.1 

0.05 

0 

-0.05 

-0.1 

0.2 

0.15 

0.1 

0.05 

0 

-0.05 

-0.1 

4 weeks 12 weeks 24 weeks 

Time 


4 weeks 12 weeks 24 weeks 

Time 


1

ONLINE DATA SUPPLEMENT 

CLINICAL TRIAL OF LOW-DOSE THEOPHYLLINE AND MONTELUKAST IN 

POORLY CONTROLLED ASTHMA 

by 

The American Lung Association Asthma Clinical Research Centers 

(Writing Committee: Charles G. Irvin, PhD, David A. Kaminsky, MD, Nicholas R. 

Anthonisen, MD, Mario Castro, MD, Nicola A. Hanania, MD, Janet T. Holbrook, PhD, 

MPH, John J. Lima, Pharm.D, Robert A. Wise, MD) 

E-1

En Rz 

V1 

(- 2 wks) 

PFT 

DC 

V2 

(0 wks) 

PFT 

ASUI 

AQLQ 

AC 

Blood 

STUDY DESIGN 

Theophylline 300 mg/day 

Montelukast 10mg/day 

Placebo 

V3 

(4 wks) 

PFT 

ASUI 

AC 

Blood 

E-2 

V4 

(12 wks) 

PFT 

ASUI 

AC 

V5 

(24 wks) 

PFT 

ASUI 

AQLQ 

AC 

Blood 

Figure E-1: Schematic study design. EN- enrollment; Rz – randomization; V1-V5 – visit 

#; PFT – pulmonary function testing, DC – diary cards, ASUI-Asthma Symptom Utility 

Index Questionnaire, AQLQ – Asthma Quality of Life Questionnaire, AC – Asthma 

Control Questionnaire, Blood - blood sample for drug concentration.

Figure E-2. Power calculations for 489 participants assuming the proportion of patients 

in the placebo group with exacerbations of 50% (red dotted line). The abscissa indicates 

the proportion of patients with exacerbations in the hypothetical treatment group. The 

ordinate shows the calculated power for alpha error of 0.05. With an observed proportion 

of exacerbations of 50%, the study had 80% power to detect a 15% reduction in 

exacerbations (50% in control group and 35% in the treatment group). The figure also 

indicates, for the purpose of comparison, the effect that a lower proportion of events 

would have on power of the study. The solid blue line indicates the situation if only 30% 

of control patients had exacerbations. 

E-3

Figure E-3. CONSORT flow chart illustrating the patient flow through the study from 

screening to analysis. 

E-4

EPACS 

(events/pt-yr) 

EPACS 

(events/pt-yr) 

10 

8 

6 

4 

2 

0 

10 

8 

6 

4 

2 

0 

P=0.35 

All Subjects 

P= 0.99 

P= 0.31 



Not on daily ICS 

P=0.12 

P= 0.002 

P= 0.08 



Figure E-4: Annualized rates of episodes of poor asthma control (EPACS) and 95% 

confidence intervals. The upper Panel shows all participants for each of three treatment 

arms; placebo. The lower panel shows only those patients not taking inhaled 

corticosteroids. Placebo (P) N = 35, Montelukast (M) N = 41 and low-dose theophylline 

(T) N = 31. Data are mean ± 95 percent confidence intervals of asthma event rates in 

events per person-year. 

E-5

Table E1 – Participant Baseline Demographic and Asthma Control Characteristics 

by Treatment Assignment 

E-6 



N 161 164 164 

Years of age, mean ± SD 41 + 15 40+ 15 40+ 15 

Male (%) 25 28 26 

Race or ethnic group (%) 

White 60 62 60 

Black 31 26 30 

Hispanic 5 11 8 

Other 4 1 2 

Asthma characteristics 

Years of age at asthma onset, mean ± SD 22+ 21 21+ 21 21+ 19 

>1 Unscheduled health care visits for asthma in 

previous 12 months (%) 

> 1 Course of oral corticosteroids in previous 12 

months (%) 

Use of inhaled short-acting β-agonist >2 

times/week (%) 

Use of nebulized β-agonist > 1 time/week (%) 5 4 7 

Asthma Scores, mean ± SD 

AQLQ score* 

(score range: 1-6, ↑ ~ better control) 

ASUI score* 

(score range: 0-1, ↑ ~ better control ) 

44 

44 

46 

51 

44 

49 

45 

42 

47 

4.2+ 1.1 4.2+ 1.0 4.2+ 1.2 

0.66+ 0.15 0.68+ 0.15 0.70+ 0.15 

ACQ* 

2.4+ 0.7 2.3+ 0.7 2.3+ 0.6 

(score range: 1-6, ↓~ better control ) 

*↓ Lower value indicates less severe asthma (AQLQ, ASUI): ↑ higher value indicates 

less severe asthma (ACQ) 

ASUI– Asthma Symptom Utility Index Questionnaire, 

ACQ – Asthma Control Questionnaire 

AQLQ – Asthma Quality of Life Questionnaire

Table E2 – Self-reported side effects 1 by Treatment Assignment 


E-7 

P-values* 

N Theophylline Montelukast Placebo T vs M T vs P M vs P 

Nausea % of Participants 

Baseline 468 17 21 19 

4 weeks 461 33 13 22 0.0001 0.03 0.04 

12 weeks 428 20 17 16 0.51 0.33 0.75 

24 weeks 411 12 17 14 0.25 0.69 0.45 

Any during follow-up 

Nervousness 

462 40 27 32 0.06 0.16 0.61 

Baseline 468 33 27 35 

4 weeks 461 33 21 22 0.02 0.03 0.88 

12 weeks 428 22 23 19 0.84 0.61 0.47 

24 weeks 411 30 28 23 0.73 0.24 0.39 

Any during follow up 

Poor appetite 

462 47 38 35 0.28 0.10 0.56 

Baseline 468 14 12 12 

4 weeks 461 17 8 16 0.02 0.76 0.05 

12 weeks 428 13 12 10 0.74 0.48 0.71 

24 weeks 411 9 11 12 0.54 0.39 0.80 

Any during follow up 462 24 19 26 0.32 0.91 0.36 

Key: T – Theophylline; M – montelukast; P – Placebo 

1 

In addition no significant differences were observed between treatment groups in 

terms of self reported side effects of skin rash, tremor, heart palpitation, vomiting 

or insomnia 

* P values are based on logistic regression models.

Table E3 – Baseline Characteristics of Participants by use of Daily Inhaled 

Corticosteroid at Randomization 

Daily ICS use 

No ICS ICS P-values* 

Number of participants 117 371 

Years of age at randomization, mean ± SD 36 ± 15 42 ± 14 0.0001 

Male (%) 

Race or ethnic group (%) 

29 25 0.42 

White 54 63 0.08 

Black 34 27 

Hispanic 7 8 

Other 5 1 

Former smoker (%) 18 19 0.87 

Secondhand smoke exposure (%) 44 39 0.26 

In home 18 13 0.18 

Outside home 

Asthma characteristics 

37 32 0.32 

Years of age at asthma onset, mean ± SD 

>1 Unscheduled health care visits for asthma 

18 ± 19 23 ± 21 0.01 

in previous 12 months (%) 

> 1 Course of oral corticosteroids in previous 

56 53 0.57 

12 months (%) 

Use of inhaled short-acting β-agonist >2 

27 49 1 time/week (%) 

Asthma Scores, mean ± SD 

2 6 0.06 

AQLQ score* 

(score range: 1-6, ↑ ~ better control) 

ASUI score* 

(score range: 0-1, ↑ ~ better control ) 

ACQ* 

(score range: 1-6, ↓~ better control ) 

Post-BD Pulmonary Function Measures, mean ± SD 

E-8 

4.08±1.09 

0.65± 0.17 

2.52±0.68 

4.22±1.10 

0.69± 0.15 

2.29±0.61 

0.24 

0.03 

0.0006 

FEV1 (%predicted) 85.9 ± 15.3 84.7± 16.3 0.29 

FVC (%predicted) 91.9± 16.6 91.6± 14.8 0.80 

Peak flow (%predicted) 82.3± 20.6 82.3 ± 19.8 0.85 

FEV1 BD % change 9.3± 12.5 9.0± 11.2 0.86 

FVC BD % change 4.6± 9.5 5.7± 11.2 0.92

Daily asthma treatment (%) 

E-9 

Daily ICS use 

No ICS ICS P-values* 

Inhaled long-acting β-agonist 15 23 0.08 

Inhaled corticosteroid** 0 100 

Inhaled anticholinergic 6 3 0.13 

Inhaled short-acting β-agonist 66 56 0.06 

Cromolyn 0 1 0.34 

Combination drugs (e.g. Fluticasone / 

Salmeterol or Ipratropium / albuterol) 

3 49

Table E4 – Annual Rates of Episodes of Poor Asthma Control and Change in 

Asthma Symptom Scores by Treatment Assignment for Participants not taking 

Inhaled Corticosteroids Daily at Randomization 

Treatment Assignment Relative rates 

95%Confidence Interval 


/P-value* 

T vs M T vs P M vs P 

N 

Episodes of poor asthma control 

31 41 35 

#Events 22 47 76 


95% confidence interval 1.1- 3.0 2.0-4.7 3.3-9.9 0.31-1.14 0.15-0.67 0.27-1.08 

0.12 0.002 0.08 

Episode Components 

Peak flow, 30% drop 

#Events 6 9 27 



0.80 0.02 0.02 

Increased medication use, MDI 

or nebulizer 

#Events 14 36 49 


95% Confidence interval 0.7-2.1 1.5-4.0 1.9-8.4 0.24-1.04 0.12-0.77 0.25-1.50 

0.06 0.01 0.28 

Asthma symptom scores 

Mean 

95% Confidence Interval 

E-10 

P-value for treatment 

contrast† 

Change from baseline score 

AQLQ score 

1.3 

0.9 0.9 

0.11 0.11 0.95 

(↑ indicates improvement) 0.9, 1.8 0.6, 1.2 0.5, 1.2 

ASUI score 

0.18 0.10 0.08 

0.04 0.03 0.64 

(↑ indicates improvement) 0.12, 0.24 0.06, 0.15 0.02, 0.15 

ACQ 

-1.1 -0.8 -0.7 

0.15 0.02 0.34 

(↓ indicates improvement) -1.4, -0.8 -1.1, -0.6 -0.9, -0.4 

*P-values and relative rates are based on Poisson regression with robust variance for 

episodes of poor asthma control 

†P-values, means and confidence intervals are based on linear regression model with 

robust variance estimates. 

KEY: N – Number of participants; ICS – Inhaled corticosteroids. AQLQ – Asthma 

Quality of Life Questionnaire; ASUI – Asthma Symptom Utility Index; ACQ – Asthma 

Control Score. A higher score on the AQLQ and ASUI indicate improved asthma 

symptoms 

The rates for health care visits or courses of corticosteroid were not significantly different

Table E5 – Change in Pulmonary Function Measures by Treatment Assignment for 

Participants not taking Inhaled Corticosteroids Daily at Randomization 

P-values for treatment 


contrast* 


FEV1 (L) pre-bronchodilator Mean, 95% Confidence Interval 

Baseline (L) 2.48 

2.21, 2.74 

4 weeks 107 0.07 

-0.05, 0.19 

12 weeks 101 0.13 

-0.01, 0.26 

24 weeks 96 0.22 

0.04, 0.39 

FVC (L) pre-bronchodilator 

Baseline 3.34 

3.00, 3.69 

4 weeks 107 0.10 

-0.04, 0.24 

12 weeks 101 0.13 

-0.03, 0.29 

24 weeks 96 0.29 

0.08, 0.50 

FEV1 (L) post-bronchodilator 

Baseline 2.67 

2.39, 2.95 

4 weeks 107 0.06 

-0.03, 0.15 

12 weeks 101 0.05 

-0.05, 0.16 

24 weeks 96 0.08 

-0.04, 0.20 

FVC (L) post-bronchodilator 

Baseline 3.54 

3.18, 3.89 

E-11 

2.55 

2.32, 2.79 

0.12 

0.02, 0.22 

0.08 

-0.04, 0.20 

0.17 

0.02, 0.31 

3.52 

3.22, 3.82 

0.10 

-0.03, 0.22 

0.04 

-0.10, 0.18 

0.17 

-0.01, 0.34 

2.80 

2.56, 3.05 

0.10 

0.03, 0.18 

0.08 

-0.01, 0.17 

0.15 

0.05, 0.25 

3.71 

3.40, 4.02 

2.68 

2.44, 2.93 

-0.10 

-0.20, 0.01 

-0.08 

-0.20, 0.04 

-0.04 

-0.20, 0.12 

3.50 

3.19, 3.80 

0.00 

-0.13, 0.13 

-0.02 

-0.17, 0.13 

0.04 

-0.15, 0.24 

2.87 

2.62, 3.12 

-0.07 

-0.16, 0.01 

-0.08 

-0.18, 0.02 

-0.06 

-0.17, 0.05 

3.55 

3.24, 3.87 

0.68 0.26 0.45 

0.51 0.03 0.003 

0.63 0.03 0.06 

0.68 0.03 0.06 

0.45 0.52 0.92 

0.97 0.31 0.30 

0.42 0.18 0.56 

0.39 0.09 0.35 

0.48 0.29 0.71 

0.46 0.03 0.002 

0.75 0.07 0.02 

0.37 0.10 0.007 

0.46 0.94 0.48

4 weeks 107 0.05 

-0.05, 0.16 

12 weeks 101 0.06 

-0.08, 0.21 

24 weeks 96 0.07 

-0.07, 0.20 

L-liters (BTPS) 


E-12 

P-values for treatment 

contrast* 


0.06 

-0.03, 0.16 

0.05 

-0.07, 0.18 

0.10 

-0.02, 0.21 

0.05 

-0.05, 0.15 

0.08 

-0.05, 0.21 

0.05 

-0.08, 0.17 

*P-values for treatment effect, mean and 95% confidence interval at each time point were 

estimated from linear regression model. 

0.88 0.98 0.86 

0.92 0.86 0.77 

0.73 0.84 0.57

Credit Roster: American Lung Association Asthma Clinical Research Centers 

This study was supported by the American Lung Association and the Merck Company 

Foundation. 

The following persons participated in the study: 

Baylor College of Medicine, Houston: N. A. Hanania (principal investigator), P. 

Enright (co-principal investigator), M. Sockrider (co-principal investigator), A. Delgado 

(principal clinic coordinator), M. Brock, G. Melville; 

Maria Fareri Children’s Hospital at Westchester Medical Center and New York 

Medical College, Valhalla, N.Y.: A. Dozor (principal investigator), N. Amin (coprincipal 

investigator), M. Heydendael (principal clinic coordinator), J. Boyer, S. Gjonaj, 

D. Lowenthal, J. Thorpe (principal clinic nurse); 

Columbia University–New York University Consortium, New York: P. Rothman 

(principal investigator), J. Reibman (co-principal investigator), E. DiMango (co-principal 

investigator), A. Kahn (clinic coordinator at Columbia University), J. Sormillon (clinic 

coordinator at Columbia University), W. Hoerning (clinic coordinator at New York 

University), R. Mellins (Columbia University), G. Turino (Columbia University), L. 

Rogers (New York University); 

Duke University Medical Center, Durham, N.C.: L. Williams (principal investigator), 

J. Sundy (co-principal investigator), M. Wilson (principal clinic coordinator); 

Emory University School of Medicine, Atlanta: W.G. Teague (principal investigator), 

S. Khatri (co-principal investigator), J. Costolnick (principal clinic coordinator); 

Illinois Consortium, Chicago: L. Smith (principal investigator), J. Hixon (principal 

clinic coordinator), J. Moy, C.S. Olopade, E. Naureckas, L. Wilken, A. Brees, G. Zagaja; 

Indiana University, Asthma Clinical Research Center, Indianapolis: W. Martin II 

(principal investigator), J. Mastronarde (co-principal investigator), M. Busk (co-principal 

investigator), C. Williams (co-investigator), F. Leickly (co-investigator), A. Corne 

(principal clinic coordinator); 

Jefferson Medical College, Philadelphia: S. Peters (principal investigator), F. Leone 

(co-principal investigator), M. Hayes (principal clinic coordinator), A. Skariya (technical 

assistance); 

Louisiana State University Health Sciences Center, Ernest N. Morial Asthma, 

Allergy, and Respiratory Disease Center, New Orleans: W.R. Summer (principal 

investigator), D. Thomas (co-principal investigator), C. Glynn (principal clinic 

coordinator); 

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National Jewish Medical and Research Center, Denver: S. Wenzel (principal 

investigator), P Silkoff (co-principal investigator), C. Hancock (principal clinic 

coordinator), L. Reed, K. Mitchell, A. Busacker; 

Nemours Children’s Clinic–University of Florida Consortium, Jacksonville: J. Lima 

(principal investigator), K. Blake (co-principal investigator), L. Duckworth (principal 

clinic coordinator), D. Schaeffer, D. Schrum, D. Coultas; 

North Shore–Long Island Jewish Health System, New Hyde Park, N.Y.: A. Fein 

(principal investigator), J. Karpel (co-principal investigator), R. Cohen (co-principal 

investigator), S. Scharf (co-principal investigator), P. Logalbo, N. Dengler (principal 

clinic coordinator), D. Mayer, S. Markovics, A. Mensch; 

Northern New England Consortium formerly Vermont Lung Center at the 

University of Vermont), Colchester, Vt.: C.G. Irvin (principal investigator), D.A. 

Kaminsky (co-principal investigator), A.E. Dixon (co-principal investigator), M. Lynn 

(principal clinic coordinator), L.A. Baggott, G.S. Davis, M.K. Doucette, A.E. Filderman, 

L.J. Filderman, R.K. Fischer, V. Gardiner, K.J. Girard, E.F. Kent, S.E. Lang, T.R. 

Leclair, M. Lowe, J.L. Lynn, C. Mackillop, S.A. Mette, D. Schlichting, P.A. Shapero, 

K.D. Siegel, H. Singh, T.A. Viola, K.D. White; 

The Ohio State University Medical Center/Columbus Children’s Hospital, 

Columbus: K. McCoy (principal investigator), L. Raterman (principal clinic 

coordinator); 

University of Alabama at Birmingham, Birmingham: W.C. Bailey (principal 

investigator), L.B. Gerald (co-principal investigator), G.A. DuBois (investigator), S. 

Erwin (principal clinic coordinator), A. Kelley (clinic coordinator), D. Laken (clinic 

coordinator), J. Newsome (clinic coordinator); 

University of Miami, Miami–University of South Florida, Tampa: A. Wanner 

(principal investigator), R. Lockey (principal investigator), G. Baldarrago (principal 

clinic coordinator for University of Miami), M. Hernandez (principal clinic coordinator 

for University of South Florida), S. Mohapatra; 

University of Minnesota, Minneapolis: M.N. Blumenthal (principal investigator), G. 

Berman (co-principal investigator) at the Clinical Research Institute, G. Brottman (coprincipal 

investigator) at Hennepin County Medical Center, J. Parker (co-principal 

investigator) at St. Mary’s Duluth, R. Sveum (co-principal investigator) at Park Nicollet 

Medical Center, S. Leikam and E. Corazalla (principal clinic coordinators) at the 

University of Minnesota, C. Quintard (clinic coordinator) at the Clinical Research 

Institute, J. Bertrand (clinic coordinator) at Hennepin County Medical Center, J. 

Blankush (clinic coordinator) at St. Mary’s Duluth, L. Rillo (clinic coordinator) at Park 

Nicollet Medical Center; 

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University of Missouri, Kansas City School of Medicine, Kansas City: G. Salzman 

(principal investigator), D. Pyszczynski (co-principal investigator), R. Shriver (coprincipal 

investigator), Y. Oba (co-principal investigator), P. Haney and S. Schmitz 

(clinical trial managers); 

St. Louis Asthma Clinical Research Center: Washington University, St. Louis 

University, and Clinical Research Center, St. Louis: M. Castro (principal 

investigator), M.E. Scheipeter (principal clinic coordinator), B. Becker, P. Korenblat, R. 

Slavin, R. Strunk, J. Tillinghast (co-investigators), B. Press, E. Albers, D. Keaney, G. 

Sanders (clinic coordinators); 

Chairman’s Office, Respiratory Hospital, Winnipeg, Man., Canada: N. Anthonisen 

(research group chair); 

Data Coordinating Center, Johns Hopkins University Center for Clinical Trials, 

Baltimore: R. Wise (center director), J. Holbrook (deputy director), E. Brown (principal 

coordinator), C. Levine, R. Masih, D. Nowakowski, D. Shade, X. Wang; 

Data and Safety Monitoring Board: L. Hudson (chair), V. Chinchilli, P. Lanken, B. 

McWilliams, C. Rinaldo, D. Tashkin; 

Project Office, American Lung Association, New York: R. Vento (project officer), S. 

Rappaport, G. Pezza, N. Edelman (scientific consultant); 

ALA Scientific Advisory Committee: N. Anthonisen, M. Castro, J. Fish, D. Ingbar, S. 

Jenkinson, D. Mannino, H. Perlstadt, L. Rosenwasser, J. Samet, T. Standiford, J. Smith, 

L. Smith, G. Snider (chair), D. Schraufnagel, A. Wanner, T. Weaver. 

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CLINICAL TRIAL OF LOW-DOSE THEOPHYLLINE AND ...

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