ObjectiveNeutrophilic inflammation, a key feature of chronic obstructive pulmonary disease (COPD), is associated with exacerbations and poor outcomes. Myeloperoxidase (MPO) is released from activated neutrophil granules. High or increasing MPO levels are associated with tissue damage, lung function decline and increased exacerbation risk in patients with COPD. We hypothesize that treatment with mitiperstat, a novel oral MPO inhibitor, may reduce lung oxidative stress, inflammation and exacerbations, thereby improving symptoms, lung function, and comorbidities in patients with COPD.Patients and methodsCRESCENDO is a partially decentralized, Phase 2a, randomized, 24-week, double-blind study evaluating the efficacy and safety of mitiperstat versus placebo in patients (40-80 years, inclusive) with COPD at high risk of exacerbation (based on a documented history of ≥1 moderate or severe acute COPD exacerbation, frequent productive cough, or severe airflow limitation [forced expiratory volume in 1 second <50% predicted]). Patients recruited from approximately 100 sites across 14 countries, from primary or secondary care and community-based facilities, will be randomized 1:1 to receive mitiperstat 5 mg or placebo orally, once daily. The primary endpoint is the time to first CompEx event, a novel composite endpoint reflecting disease worsening, including changes in symptoms, reliever use, lung function, treatment for exacerbation, or study dropout. The study period is planned to take between 18 and 30 weeks for each patient.ConclusionCRESCENDO will assess efficacy and safety of mitiperstat using a novel, patient-centric trial design to enhance participant recruitment, partially via community-based facilities, helping to overcome restrictive trial designs and better reflect the real-world population with COPD, as well as reducing its environmental impact.