Effectiveness of Low-dose Theophylline for the Management of Biomass-Associated COPD (LODOT-BCOPD): Study Protocol for a Randomized Controlled Trial

<title>Abstract</title> <bold>Background: </bold>COPD is a leading cause of death globally, with the majority of morbidity and mortality occurring in low- and middle-income country (LMIC) settings. While tobacco-smoke exposure is the most important risk factor for COPD in high-income settings, household air pollution from biomass-smoke combustion is a leading risk factor for COPD in LMICs. Despite the high burden of biomass smoke-related COPD, few studies have evaluated the efficacy of pharmacotherapy in this context. Currently recommended inhaler-based therapy for COPD is neither available nor affordable in most resource-limited settings. Low-dose theophylline is an oral, once-a-day therapy, long used in high-income countries (HIC), which has been proposed for the management of COPD in LMICs in the absence of inhaled steroids and/or bronchodilators. The Low-dose Theophylline for the Management of Biomass-Associated COPD (LODOT-BCOPD) trial investigates the clinical efficacy and cost-effectiveness of low-dose theophylline for the management of biomass-related COPD in a low-income setting. <bold>Methods: </bold>LODOT-BCOPD is a randomized, double-blind, placebo-controlled trial to test the efficacy of low-dose theophylline in improving respiratory symptoms in 110 participants with moderate to severe COPD in central Uganda. The inclusion criteria are as follows: (1) age 40 to 80 years; (2) full-time resident of the study area; (3) daily biomass exposure, (4) post-bronchodilator FEV₁/FVC below the 5^th percentile of the Global Lung Initiative mixed ethnic reference population; (5) GOLD Grade B-D COPD. Participants will be randomly assigned to receive once daily, low-dose theophylline (200 mg ER, Unicontin-E) or placebo for 52 weeks. All participants will receive education about self-management of COPD and rescue salbutamol inhalers. We will measure health status using the St. George’s Respiratory Questionnaire (SGRQ) and quality of life using the EuroQol-5D (EQ-5D) at baseline and every six months. In addition, we will assess household air pollution levels, serum inflammatory biomarkers (fibrinogen, hs-CRP) and theophylline levels at baseline, one month and 6 months. The primary outcome is change in SGRQ score at 12 months. Lastly, we will assess the cost-effectiveness of the intervention by calculating quality-adjusted life years (QALYs) from the EQ-5D.<bold>Trial Registration: </bold>NCT03984188 Registered June 12, 2019<bold>Trial acronym:</bold> Low-dose Theophylline for the Management of Biomass-Associated COPD (LODOT-BCOPD)