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CHEST: Low-Dose Theophylline Effective as Monotherapy in Corticosteroid Naïve Asthmatics
By Peggy Peck
ORLANDO, FL -- October 30, 2003 -- A post-hoc analysis of data from an American Lung Association-Asthma Clinical Research Center (ALA-ACRC) trial suggests that low-dose theophylline, as add-on therapy, is most effective in asthmatic patients who are corticosteroid naïve.
Charles Irvin, PhD, professor of pulmonary disease and critical care medicine, University of Vermont, and principal investigator for the ALA-ACRC Low-Dose Theophylline as Add-On Therapy (LoDo) trial, presented the findings here October 27th at a late-breaking clinical science session at CHEST 2003, the Annual Scientific Assembly of the American College of Chest Physicians.
Dr. Irvin said that "a single pill -- 300 mg -- taken at night time improved lung function when it was used as monotherapy."
In an interview Dr. Irvin said the results were "not what we expected and not what we were looking for in this study." The study was designed to test the theory that theophylline would be useful as an add-on therapy.
He noted that theophylline is "a very old drug with a bad profile." The agent is associated with a number of side-effects including "tremor, nervousness and nausea. It has pretty much been overlooked since the 1970s because of these side-effects," Dr. Irvin said. He added, however, that a small number of patients have continued to take theophylline and "it is very difficult to get those patients off the drug, which is why we decided to look at the drug in this study."
The study enrolled 489 patients who were randomized to a 6-month course of theophylline 300 mg/day, montelukast (Singulair) 10 mg/day or placebo. All patients "had to demonstrate that their asthma was poorly controlled -- an average Juniper Asthma Control Score of 2.3"
Patients were assessed during the course of the study at three clinic visits and by completing daily asthma diaries. The primary outcome variable was asthma exacerbation in the use of rescue beta-agonists, a new course of oral corticosteroid therapy, or seeking unscheduled medical help for asthma.
"What surprised us was that we saw no significant effect of either the low dose theophylline or the montelukast," he said. The asthma exacerbation rate was lower with both low dose theophylline (6.3, 95% CI: 4.8, 8.4) and montelukast (6.2, 95% CI: 4.7, 8.1.) compared to placebo (7.7 95% CI: 5.9, 10.0). These differences were not statistically significant (P = .47).
Low-dose theophylline was associated with improved lung function compared to placebo, with a mean change in post-bronchodilator forced expiratory volume in 1 second (FEV1) of 0.046 L versus -0.02 L, respectively (P < .005).
When data from those patients who had not been on inhaled corticosteroids at randomization (31, 41, and 35 patients for theophylline, montelukast, and placebo groups respectively) were analyzed separately, theophylline had a lower exacerbation rate than placebo (2.2 95% CI: 1.4, 3.5 versus 11.2 95% CI: 6.9, 18.0; P < .001). "But there was still no difference for montelukast," he said.
Adverse effects were also insignificant, he said. "Only two side-effects -- nausea and nervousness -- were significant, but by the third month these were no longer a problem," he said. The lower dose could explain the improved tolerance, he added, noting, "We're dosing [the drug] at half the level that was standard dose in the 1970s."
Although, Dr. Irvin declined to make a clinical recommendation based on a single study, he noted that more studies are needed. "This [finding] could be huge [in impact]; especially in developing countries where bronchodilators are too expensive. Using a single pill -- which would probably cost just pennies -- would be a welcome alternative," he said.
He added that the study results contradict other studies that suggested theophylline added to a corticosteroid could improve asthma management. "Our study is going in the other direction. We are reporting that theophylline is a corticosteroid antagonist," he said.
Theochron-Inwood Laboratories supplied theophylline and Merck supplied Singulair.
[Study title: Effectiveness of Low-Dose Theophylline as Add-on Therapy in the Treatment of Asthma: The LoDo Trial.]
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