Win Ratio Analysis of BOREAS and NOTUS: Faster Trials, Clearer Wins for Patients With Chronic Obstructive Pulmonary Disease With Type 2 Inflammation
Bibliographic record
Abstract
Abstract RATIONALE: Evaluation of multiple endpoints in clinical trials is often limited by the occurrence of an endpoint of lower clinical importance. Win ratio analysis categorizes outcomes by importance, allowing comparisons of multiple endpoints between treatments. In this analysis, we used win ratio to compare the efficacy of add-on dupilumab 300 mg every 2 weeks (q2w) vs placebo using pooled data from the BOREAS and NOTUS phase 3 trials in patients with chronic obstructive pulmonary disease (COPD) and type 2 inflammation. METHODS: BOREAS (NCT03930732) and NOTUS (NCT04456673) were phase 3 randomized, double-blind, placebo-controlled trials that enrolled patients with COPD, moderate-to-severe airflow limitation and type 2 inflammation (blood eosinophil count ≥300 cells/µL at screening) on triple therapy. Patients were randomized 1:1 to receive add-on dupilumab 300 mg or placebo subcutaneously q2w for 52 weeks. Win ratio analysis compares each patient on dupilumab to each patient on placebo for occurrence of events in the pooled ITT populations. For each pair of comparison, multiple endpoints were ordered regarding clinical importance, with 3 outcomes possible for each endpoint for dupilumab vs placebo: dupilumab win, tie, placebo win. Endpoints were ranked by clinical importance; avoiding hospital was most important, followed by moderate exacerbations, lung function loss, and symptom deterioration. RESULTS: Evaluation of the pooled populations (dupilumab n = 938; placebo n = 934) across the composite endpoints for occurrence-of-event resulted in participants receiving dupilumab being 32% more likely to avoid hierarchically important clinical deterioration with dupilumab compared with placebo (1.32; 95% CI 1.17, 1.49). We also observed a higher win ratio for dupilumab for all 5 occurrence-of-event endpoints evaluated: death/hospital admission/emergency department (ED) visit ≥24 h (7.6% vs 5.6%), moderate exacerbation or ED visit <24 h (22.1% vs 17.9%), total number of moderate or severe (hospitalized) exacerbations during the study period (3.8% vs 2.8%), percent predicted post-bronchodilator forced expiratory volume in 1 second (FEV1) worsening from baseline by ≥ 10%, or post-bronchodilator FEV1 worsening for ≥ 100 mL at Week 52 (12.1% vs 8.2%) and improvement in St. George's Respiratory Questionnaire or Respiratory Symptom Tool for COPD scores (2.0% vs 1.5%). CONCLUSIONS: In patients with COPD and type 2 inflammation, receiving dupilumab increased the likelihood of avoiding the composite of death, hospitalization, exacerbations, worsening symptoms, and worsening lung function by 32% over 12 months of treatment. The win ratio provides a powerful clinically meaningful endpoint that could change how phase 3 trials are conducted in COPD.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.003 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.002 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".