Rationale and Design of the Roflumilast or Azithromycin to Prevent COPD Exacerbations Clinical Trial

Rationale: Chronic obstructive pulmonary disease (COPD) is a leading cause of hospitalization and death, particularly among patients with chronic bronchitis and frequent exacerbations. Results of placebo-controlled clinical trials indicate that treatment escalation with either long-term oral roflumilast or azithromycin can reduce COPD exacerbations. However, head-to-head comparative data from clinical trials are lacking, so the relative harms and benefits of these treatments are unclear.

The RofLumilast or Azithromycin to preveNt COPD Exacerbations (RELIANCE) study is an investigator-initiated, multicenter, randomized, pragmatic clinical trial embedded in clinical practice to evaluate the effectiveness of treatment escalation with long-term azithromycin versus roflumilast in patients with COPD and chronic bronchitis.

We solicited preferences from patients, clinicians, and other stakeholders during the design and implementation phases of the study, including feedback that informed modifications related to the COVID-19 pandemic. Eligibility criteria did not require assessments outside of clinical practice, with exclusions principally for safety. The composite endpoint of first all-cause hospitalization or death served as the primary outcome. Enrollment was initially through university-affiliated clinical centers but was subsequently expanded to recruit patients in community-based practices who might not otherwise participate in research. We employed human-centered design principles to improve the usability of study activities from the perspective of participants, study staff, and treating clinicians.

The final study design offered the option for patients with COPD and chronic bronchitis at high-risk of hospitalization or death to be remotely consented, prescribed a medication according to the randomized treatment allocation, and complete virtual follow-up study visits in a decentralized clinical trial.