Exploring Global Geographic Variation in Exacerbation Rates in Randomized Controlled Trials of Biologics in Patients With Severe Asthma: A Systematic Literature Review
Bibliographic record
Abstract
Abstract Rationale: Depemokimab is the first ultra-long-acting biologic with enhanced interleukin-5 binding affinity, high potency and extended half-life, enabling twice-yearly dosing for patients with asthma. In the Phase III SWIFT-1/2 studies, depemokimab significantly reduced exacerbations rates versus placebo; however, a high placebo response was seen in patients from Central East Europe. Previous reports have highlighted treatment effect differences across countries. This systematic literature review (SLR) summarized geographic variations in exacerbation rates and biologic treatment responses in randomized controlled trials (RCTs) enrolling patients with severe asthma. Methods: Following a predefined protocol, MEDLINE, Embase, and Evidence-based Medicine Reviews Databases were searched from inception to May 7, 2024, for RCTs of respiratory biologics for adult patients with severe asthma reporting exacerbation rates by geographic region. Key respiratory conferences (2019-2024) were also searched. Records were screened by one reviewer in two phases (abstract then full text), with 10% of screened publications validated by a second reviewer. Results were synthesized qualitatively. Results: Six publications reporting five unique trials reported on exacerbations by geographic region. Data from the SWIFT-1/2 studies were also included for reference. Subgroup and post hoc analyses by geographic region of RCTs for tezepelumab (NAVIGATOR), benralizumab (CALIMA/SIROCCO), reslizumab (NCT02452190), dupilumab (TRAVERSE open-label extension), and depemokimab (SWIFT-1/2) consistently reported the smallest treatment effects on exacerbation rates in Central East European countries (Table). Across four trials reporting arm-level exacerbation rates for tezepelumab, benralizumab, depemokimab, and dupilumab, patients from Central East Europe had the lowest exacerbation rates while on placebo. Only CALIMA and SIROCCO (benralizumab) reported patient baseline characteristics by geographic region, with patients from Central East Europe reporting the lowest exacerbation rate (suggesting less severe disease) of all regions in the year preceding study entry. While subgroup analyses of exacerbation rates by region were prespecified in most trials, some population sizes were small, limiting the ability to draw strong conclusions. Conclusions: Geographical variation in exacerbation rate was consistently observed across biologic RCTs in patients with severe asthma. Lower biologic treatment effects were observed in Central East Europe versus other regions due to lower exacerbation rates in the placebo arm. This could lead to misinterpretation of efficacy results if not considered in future studies. Further studies are needed to better understand how patient characteristics, background treatment adherence, clinical practice, and biologic access may affect the observed geographic differences in exacerbation rates, and how these may impact trial participation, and interpretation of trial results.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.052 | 0.175 |
| Meta-epidemiology (narrow) | 0.002 | 0.002 |
| Meta-epidemiology (broad) | 0.017 | 0.015 |
| Bibliometrics | 0.020 | 0.018 |
| Science and technology studies | 0.001 | 0.002 |
| Scholarly communication | 0.004 | 0.004 |
| Open science | 0.003 | 0.003 |
| Research integrity | 0.003 | 0.002 |
| Insufficient payload (model declined to judge) | 0.005 | 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 source (direct Gemma or distilled Codex), 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".