Study Design and Rationale for The Breathe Easier With Tadalafil Therapy for Exercise-Related Dyspnea in COPD-PH (BETTER COPD-PH).

Dyspnea, a debilitating symptom of COPD, worsens health-related quality of life (HRQL), reduces daily physical activity, increases health care utilization, and is more closely associated with survival than airflow limitation. Thus, having treatments that reduce dyspnea in COPD is important. Pulmonary hypertension (PH) is a common complication of COPD that is associated with severe dyspnea, more frequent COPD exacerbations, and increased mortality. Multiple causes of PH, including a reduction in bioavailable vasodilator nitric oxide (NO), are associated with COPD (COPD-PH). Phosphodiesterase type-5 inhibitor (PDE5i) therapy restores NO signaling and improves hemodynamics and dyspnea in patients with Group 1 Pulmonary Arterial Hypertension, but has not been proven effective in COPD-PH. In a prior study (ClinicalTrials. gov identifier: NCT01862536), we investigated effects of 12 months of oral PDE5i therapy with tadalafil on 6-min walk distance (6MWD) in a multi-center, randomized, placebo-controlled trial funded by the Department of Veterans Affairs. While tadalafil did not change 6MWD at 12 months, the treatment group experienced clinically meaningful improvements in patient-reported dyspnea and HRQL at 6 months. Because of the importance of mitigating dyspnea in COPD-PH, we developed a new study protocol examining the effect of PDE-5i therapy in COPD-PH, with a reduction in dyspnea the primary outcome. In the current study (NCT05937854), we will conduct a prospective, randomized, double-blind, multi-center clinical trial to evaluate the effects of 6 months of maximally tolerated therapy with tadalafil (target dose 40 mg/day) versus placebo on dyspnea, as measured by University of California San Diego Shortness of Breath Questionnaire.