Low-dose theophylline does not significantly reduce the number of exacerbations in patients with COPD when added to inhaled corticosteroids, new results show.
The findings from the TWICS (Theophylline With Inhaled CorticoSteroids) trial do not support the use of low-dose theophylline as adjunctive therapy to inhaled corticosteroids for prevention of COPD exacerbations, UK investigators concluded.
The team, which included Professor David Price, Chair of Primary Care Respiratory Medicine at the University of Aberdeen, conducted a pragmatic multicentre randomised trial in 1,567 patients with COPD who were receiving inhaled corticosteroids and had a history of two or more exacerbations in the previous year. Patients were randomised to receive low-dose theophylline (200mg once or twice daily to provide plasma concentration of 1 to 5 mg/L determined by ideal body weight) or placebo.
Results published in JAMA showed that low-dose theophylline had no effect in reducing the mean number of exacerbations compared to placebo over a one-year period (2.24/year vs 2.23/year, respectively).
Professor Price told the limbic he expects the findings to have a substantial impact on clinical practice because theophylline is something that clinicians consider for patients who still exacerbate in spite of triple therapy (LAMA/LABA/ICS).
Low-dose theophylline did significantly reduce the number of severe COPD exacerbations requiring hospital admission (0.17 vs 0.24 with placebo), with most benefit being seen in a small (1–2%) subgroup of patients frequently hospitalised with COPD.
The investigators say this could be due to a lack of correction for multiple statistical comparisons, but suggest it warrants further investigation, particularly in light of a recent report that another phosphodiesterase inhibitor (roflumilast) is most beneficial in people with previous COPD hospitalisation for exacerbation and greater exacerbation frequency.
However, Professor Price thinks it’s extremely unlikely that a clinical trial of theophylline in this subgroup will be conducted.
“Maybe some people might still use it in the very high risk patients who have frequent exacerbations leading to hospitalisation,” he said.
“Otherwise it will be unused,” he added.
In an accompanying editorial, Gerard Criner, Professor of Thoracic Medicine and Surgery at the Lewis Katz School of Medicine at Temple University, Pennsylvania, says that even though the evidence for the use of low-dose theophylline in COPD has been contradictory, there has been a recent resurgence of interest in adding it to corticosteroid therapy to prevent exacerbations because of its potential synergistic anti-inflammatory effect.
“It is somewhat disappointing that low-dose theophylline did not result in a reduction in exacerbation risk because the drug is relatively inexpensive, and its rationale was based on sound preclinical and human mechanistic studies,” Professor Criner writes.
“Perhaps future formulations that can deliver theophylline to the airway via the inhaled route or pharmacological analogues that can mimic its effect on increasing HDAC levels with a better safety profile are possible approaches that can help in the development of targeted therapies for patients with COPD who are at increased risk for exacerbation despite use of current best inhaled agents.”
Results are still awaited from TASCS (theophylline and steroids in COPD study), a trial of low-dose theophylline in 2,400 people in China due to complete this year.
For now, though, it appears that theophylline has no current role as add-on therapy to prevent future exacerbations for patients already treated with combination long-acting bronchodilator and inhaled corticosteroid therapy, Professor Criner said.