Abstract Rationale Chronic obstructive pulmonary disease (COPD) is characterized by airflow limitation and acute exacerbations, which drive morbidity, mortality, and healthcare burden. Preventing and managing acute exacerbations of COPD (AECOPD) is critical, and clinical trials often use enrichment strategies to identify subjects at higher risk. Currently, only one blood biomarker, plasma fibrinogen, is FDA-approved for this purpose despite the need for better enrichment strategies. The biomarker C4Ma3 (quantifying type IV collagen alpha-3 chain degradation mediated by MMPs) reflects alveolar wall destruction and has shown prognostic promise. In this study, we evaluated serum C4Ma3 for enriching COPD trial populations and compared its performance to plasma fibrinogen. Methods We analyzed data from COPD subjects from the multicenter ECLIPSE study (NCT00292552). NordicC4Ma3TM was assessed in serum samples collected at the three-month visit at ISO-certified laboratories, then categorized into quartiles (Q1: low; Q2-Q4: high). Matched three-months plasma fibrinogen data previously measured, were corrected and dichotomized at 350 mg/dL, according to published standards. Subjects were stratified by exacerbation history in the 15 months prior to sampling, excluding those with events within four weeks of collection. The primary outcome was time-to-first AECOPD hospitalization over 365 days. Kaplan-Meier estimates compared AECOPD rates across biomarker and prior-exacerbation strata. Results Of the 2,164 ECLIPSE COPD subjects, 1,536 were included in the analysis: 48.8% had no prior exacerbations, 24.6% had one, and 26.6% had two or more. Demographics were similar across groups (mean age 63 years, 67% men), but disease severity increased with prior exacerbation history. Subjects with two or more prior exacerbations had the worst lung function, highest medication use, worst questionnaire scores, and elevated biomarker levels. Over one year, 226 subjects were hospitalized for AECOPD. High serum C4Ma3 was consistently associated with increased AECOPD risk across all prior-exacerbation strata: difference of 3.5% (no prior), 11.7% (one prior), and 15.4% (≥2 prior exacerbations) (Figure 1A). In comparison, plasma fibrinogen showed smaller differences between high and low levels (3.3%, 9.0%, and 12.5%, respectively), indicating lower prognostic discrimination (Figure 1B). Conclusion High serum C4Ma3 levels robustly identified COPD subjects at increased risk of hospitalization due to AECOPD, outperforming plasma fibrinogen with greater prognostic discrimination. These results support serum C4Ma3 as a biomarker for enriching COPD clinical trial populations and guiding targeted interventions. Future work should prospectively validate C4Ma3 in independent, prospective COPD cohorts to confirm its prognostic value. This abstract is funded by: GSK, Nordic Bioscience
Sand et al. (Fri,) studied this question.
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