The European respiratory journal · 2026
A self-controlled case series to evaluate the effects of clinical trial eligibility criteria on biologic-associated reductions in severe asthma exacerbations: an analysis of the CHRONICLE Study.
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Boakye-Dankwa Ernest, Kiddle Steven J, Koo Hyewon Nina, Harper Andrew R, Ambrose Christopher S, Douglas Ian J, Quint Jennifer K
Аннотация
BACKGROUND: The trade-offs between regulatory preferences, trial success probability, and patient exclusion by eligibility criteria in randomised controlled trials (RCTs) of biologics for severe asthma remain poorly understood. We assessed biologic effectiveness and effect modification by nine RCT-derived criteria in a large real-world cohort of subspecialist-treated patients with severe asthma.
METHODS: CHRONICLE was a multicentre, prospective, noninterventional cohort of US adults (aged ≥18 years) with severe asthma (NCT03373045). We performed a meta-analysis of six RCTs to estimate pooled rate ratios (RRs) for FDA-approved biologics and compared with incidence rate ratios (IRRs) from a self-controlled case-series (SCCS) using CHRONICLE data, analysing severe asthma exacerbation rates during biologic-exposed and unexposed periods. Subgroup analyses examined between-group comparisons (inclusion versus exclusion) across nine RCT-based criteria.
FINDINGS: Biologics reduced exacerbation rates in both RCT meta-analysis (RR 0.53, 95% CI 0.47-0.60) and real-world SCCS of 480 patients from 85 sites (enrolled February 28, 2018-October 28, 2024) (IRR 0.43, 0.39-0.48). Significant effect modification (ratio of ratios, ratio of IRR, 95% CI), with exclusion as the reference) was observed for smoking history (0.50, 0.38-0.66), exacerbation history (0.49, 0.36-0.65), FeNO (0.63, 0.42-0.92), and BEC (0.65, 0.51-0.82). No significant differences were observed for COPD, bronchiectasis, or FEV1-based criteria, which excluded the most patients in the cohort.
INTERPRETATION: Criteria based on elevated type 2 biomarkers, minimal smoking, and exacerbation history enrich trial populations likely to benefit from biologics. Spirometry-based exclusions appear to have limited influence on treatment response, and there is a risk that they unduly restrict generalisability.
FUNDING: AstraZeneca.
METHODS: CHRONICLE was a multicentre, prospective, noninterventional cohort of US adults (aged ≥18 years) with severe asthma (NCT03373045). We performed a meta-analysis of six RCTs to estimate pooled rate ratios (RRs) for FDA-approved biologics and compared with incidence rate ratios (IRRs) from a self-controlled case-series (SCCS) using CHRONICLE data, analysing severe asthma exacerbation rates during biologic-exposed and unexposed periods. Subgroup analyses examined between-group comparisons (inclusion versus exclusion) across nine RCT-based criteria.
FINDINGS: Biologics reduced exacerbation rates in both RCT meta-analysis (RR 0.53, 95% CI 0.47-0.60) and real-world SCCS of 480 patients from 85 sites (enrolled February 28, 2018-October 28, 2024) (IRR 0.43, 0.39-0.48). Significant effect modification (ratio of ratios, ratio of IRR, 95% CI), with exclusion as the reference) was observed for smoking history (0.50, 0.38-0.66), exacerbation history (0.49, 0.36-0.65), FeNO (0.63, 0.42-0.92), and BEC (0.65, 0.51-0.82). No significant differences were observed for COPD, bronchiectasis, or FEV1-based criteria, which excluded the most patients in the cohort.
INTERPRETATION: Criteria based on elevated type 2 biomarkers, minimal smoking, and exacerbation history enrich trial populations likely to benefit from biologics. Spirometry-based exclusions appear to have limited influence on treatment response, and there is a risk that they unduly restrict generalisability.
FUNDING: AstraZeneca.