Low-dose theophylline in mild to moderate Chronic Obstructive Pulmonary Disease: A randomized clinical trial in China

Clinical Snapshot

Key Findings

• P Value: FEV1 at 12 months: p=0.031; FEV1 annual change: p=0.063; Exacerbations: p=0.607

• Effect Size: FEV1 improvement: 30ml [95% CI: 3-57ml]; Exacerbation RR: 1.07 [95% CI: 0.84-1.36]

• Primary Outcome: Pre-bronchodilator FEV1 improved by 30ml at 12 months; no difference in annual exacerbation rates

• Nnt Or Sensitivity: Not calculable - minimal clinical benefit observed

• Confidence Interval: FEV1: 95% CI 3-57ml; Annual change: 95% CI -2 to 58ml/year

Clinical Application

Low-dose theophylline is readily available and well-tolerated, but requires therapeutic monitoring Theophylline is PBS-listed in Australia but not routinely recommended for COPD. Results unlikely to change current RACGP/COPD-X guidelines favouring bronchodilators and ICS Adults with mild to moderate COPD, particularly in Asian populations

Abstract

BACKGROUND: Low-dose theophylline has anti-inflammatory effects, but its efficacy in mild to moderate COPD remains controversial. RESEARCH QUESTION: Is low dose theophylline effective and safe in patients with mild to moderate COPD? METHODS: In this prospective, parallel-group, randomised, double-blind, placebo-controlled trial across ten centres in China, subjects with mild to moderate COPD were randomized 2:1 to oral low-dose theophylline sustained-release tablets (100 mg twice daily) or matching placebo for 12 months. Primary endpoints were between-group differences in pre-bronchodilator FEV1 change from baseline to 12 months and annual exacerbation rate. FINDINGS: 734 subjects were randomized; 615 completed the study. Compared with placebo, low-dose theophylline significantly ameliorated FEV1 before bronchodilator use by 30 ml [95% CI, 3 to 57 ml] (p = 0.031) at month 12, with a between-group difference in mean change from baseline of 28 ml/year [95% CI, -2 to 58 ml/year] (p = 0.063). The annual exacerbation rate did not differ between groups (0.46 ± 0.03 vs 0.43 ± 0.04 per patient-year; RR, 1.07 [95% CI, 0.84 to 1.36]; p = 0.607). In addition, the incidence of adverse events was comparable between both groups. INTERPRETATION: In mild to moderate COPD, low-dose theophylline was well-tolerated but did not reduce exacerbation rates. A modest improvement in pre-bronchodilator FEV1 was observed, though its magnitude was limited. Larger trials are needed to further evaluate its potential to improve lung function in this population. What is already known on this topic:The efficacy of low-dose theophylline specifically in the mild to moderate COPD population remains unclear.What this study adds:Our study indicated that low-dose theophylline treatment alone was associated with a significant improvement in pre-bronchodilator FEV1 and demonstrated good tolerability in patients with mild to moderate COPD.How this study might affect research, practice or policy:What we found in this study presented promising opportunities for intervention with theophylline alone in patients with mild to moderate COPD.