Randomizirano, placebom kontrolirano ispitivanje koje procjenjuje efekte lebrikizumaba na eozinofilnu upalu i remodeliranje disajnih puteva kod nekontrolirane astme (CLAVIER).
Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology
Sažetak istraživanja
Pozadina Anti-interleukin 13 (IL-13) monoklonsko antitijelo lebrikizumab poboljšava funkciju pluća kod pacijenata sa umjerenom do teškom nekontroliranom astmom, ali njegovi efekti na upalu i remodeliranje disajnih puteva nisu poznati. CLAVIER je dizajniran da procijeni učinak lebrikizumaba na eozinofilnu upalu i remodeliranje.
Cilj Izvještavanje o rezultatima sigurnosti i efikasnosti upisanih učesnika sa dostupnim podacima iz CLAVIER-a.
Metode Radili smo bronhoskopiju kod pacijenata sa nekontrolisanom astmom pre i posle 12 nedelja randomizovanog dvostruko-slepog tretmana lebrikizumabom (n = 31) ili placebom (n = 33). Unaprijed specificirana primarna krajnja tačka bila je relativna promjena subepitelnih eozinofila disajnih puteva po mm2 bazalne membrane (ćelije/mm2). Unaprijed specificirani sekundarni i istraživački ishodi uključivali su promjenu biomarkera povezanih s IL-13 i mjere remodeliranja disajnih puteva.
Rezultati Postojala je osnovna neravnoteža u tkivnim eozinofilima i velika varijabilnost između tretiranih grupa. Nije bilo uočljive promene u prilagođenim srednjim vrednostima subepitelnih eozinofila/mm 2 kao odgovor na lebrikizumab (95% CI, -82,5%, 97,5%). Kao što je ranije uočeno, FEV 1 se povećao nakon liječenja lebrikizumabom. Štaviše, debljina subepitelnog kolagena smanjena je za 21,5% nakon tretmana lebrikizumabom (95% CI, -32,9%, -10,2%), a smanjena je i frakciona ekspresija azotnog oksida, CCL26 i SERPINB2 mRNA u bronhijalnim tkivima. Lebrikizumab se dobro podnosio, sa sigurnosnim profilom koji je u skladu sa drugim studijama o astmi lebrikizumaba.
Zaključci i klinička relevantnost Nismo uočili smanjen broj tkivnih eozinofila u vezi sa liječenjem lebrikizumabom. Međutim, u unaprijed specificiranim eksplorativnim analizama, liječenje lebrikizumabom je bilo povezano sa smanjenim stupnjem subepitelne fibroze, karakteristikama remodeliranja disajnih puteva, kao i poboljšanom funkcijom pluća i smanjenim ključnim farmakodinamičkim biomarkerima u bronhijalnim tkivima. Ovi rezultati potvrđuju važnost IL-13 u patobiologiji disajnih puteva i sugeriraju da neutralizacija IL-13 može smanjiti astmatično remodeliranje disajnih puteva. Registracija kliničkog ispitivanja NCT02099656.
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A randomized, placebo-controlled trial evaluating effects of lebrikizumab on airway eosinophilic inflammation and remodelling in uncontrolled asthma (CLAVIER).
Background The anti-interleukin 13 (IL-13) monoclonal antibody lebrikizumab improves lung function in patients with moderate-to-severe uncontrolled asthma, but its effects on airway inflammation and remodelling are unknown. CLAVIER was designed to assess lebrikizumab's effect on eosinophilic inflammation and remodelling.
Objective To report safety and efficacy results from enrolled participants with available data from CLAVIER.
Methods We performed bronchoscopy on patients with uncontrolled asthma before and after 12 weeks of randomized double-blinded treatment with lebrikizumab (n = 31) or placebo (n = 33). The pre-specified primary end-point was relative change in airway subepithelial eosinophils per mm 2 of basement membrane (cells/mm 2 ). Pre-specified secondary and exploratory outcomes included change in IL-13-associated biomarkers and measures of airway remodelling.
Results There was a baseline imbalance in tissue eosinophils and high variability between treatment groups. There was no discernible change in adjusted mean subepithelial eosinophils/mm 2 in response to lebrikizumab (95% CI, -82.5%, 97.5%). As previously observed, FEV 1 increased after lebrikizumab treatment. Moreover, subepithelial collagen thickness decreased 21.5% after lebrikizumab treatment (95% CI, -32.9%, -10.2%), and fractional exhaled nitric oxide, CCL26 and SERPINB2 mRNA expression in bronchial tissues also reduced. Lebrikizumab was well tolerated, with a safety profile consistent with other lebrikizumab asthma studies.
Conclusions & clinical relevance We did not observe reduced tissue eosinophil numbers in association with lebrikizumab treatment. However, in pre-specified exploratory analyses, lebrikizumab treatment was associated with reduced degree of subepithelial fibrosis, a feature of airway remodelling, as well as improved lung function and reduced key pharmacodynamic biomarkers in bronchial tissues. These results reinforce the importance of IL-13 in airway pathobiology and suggest that neutralization of IL-13 may reduce asthmatic airway remodelling. Clinical trial registration NCT02099656.
Izvorni podaci
- DOI
- 10.1111/cea.13731
- PMID
- 32909660
- PMCID
- PMC7756263
- Provjereno
- 2026-07-26
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