Win Ratio Analysis to Clarify Clinical Benefits: A Post Hoc Analysis of Phase 3 BOREAS and NOTUS.

Abstract

Clinical trials often assess multiple end points; however, many do not consider the value of composite end points. Although some evaluations of composite end points consider each outcome to be of equal importance, win ratio analysis ranks outcomes by clinical severity, prioritizing more serious events that have the biggest impact on patients. Does win ratio analysis, incorporating multiple clinician- and patient-relevant outcomes, show benefits for dupilumab over placebo in patients with COPD and type 2 inflammation? BOREAS and NOTUS, phase 3, randomized, double-masked, placebo-controlled trials-enrolled patients with COPD, moderate to severe airflow limitation, and type 2 inflammation (screening blood eosinophil count ≥ 300 cells/μL) receiving inhaled triple or dual therapy (where inhaled corticosteroids were contraindicated). Patients were randomized to add-on dupilumab 300 mg (n = 938) every 2 weeks or matched placebo (n = 934) for 52 weeks. Win ratio analysis evaluated the relative efficacy of dupilumab vs placebo using data from the pooled intention-to-treat safety population. Hierarchical composite end points were occurrence of death, hospitalization, emergency department visit, exacerbations, lung function decline, and symptoms. Win ratios were calculated to quantify treatment effects and to assess differences in event occurrence and timing between treatment arms. Dupilumab showed a higher win ratio than placebo after consideration of key end points, reinforcing its clinical benefits. Dupilumab increased the likelihood of improved clinically significant outcomes by 31% (win ratio, 1.31; 95% CI, 1.15-1.48). For any given untied pair of dupilumab vs placebo recipients, the estimated probability of a better outcome for dupilumab recipients was 57%. Our results show that dupilumab improved patient- and clinician-important outcomes by reducing the risks of clinically significant severe outcomes, together with improving symptoms and lung function. This analysis provides meaningful insights into the value of composite end points and win ratio analysis that could guide future phase 3 trial designs. ClinicalTrials.gov; No.: NCT03930732 and NCT04456673; URL: www. gov.