Heterogeneity of treatment effect of vilobelimab in COVID-19: a secondary analysis of a randomised controlled trial
Authors: van Amstel Rombout B. E. , Slim Marleen A. , Lim Endry H. T. , Rückinger Simon , Seymour Christopher W. , Burnett Bruce P. , Bos Lieuwe D. J. , van Vught Lonneke A. , Riedemann Niels C. , van de Beek Diederik , Vlaar Alexander P. J. , Witzenrath Martin , van Paassen Pieter , Heunks Leo M. A. , Mourvillier Bruno , de Bruin Sanne , Brouwer Matthijs C. , Tuinman Pieter R. , Saraiva José Francisco K. , Marx Gernot , Lobo Suzana M. , Boldo Rodrigo , Simon-Campos Jesus A. , Cornet Alexander D. , Grebenyuk Anastasia , Engelbrecht Johannes M. , Mukansi Murimisi , Jorens Philippe G. , Zerbib Robert , Pilz Korinna , Guo Renfeng , Bulpa Pierre , Taccone Fabio S. , Hermans Greet , Diltoer Marc , Piagnerelli Michael , De Neve Nikolaas , Freire Antonio T. , Pizzol Felipe D. , Marinho Anna Karolina , Sato Victor H. , da Cunha Clovis Arns , Neuville Mathilde , Dellamonica Jean , Annane Djillali , Roquilly Antoine , Diehl Jean Luc , Schneider Francis , Mira Jean Paul , Lascarrou Jean Baptiste , Desmedt Luc , Dupuis Claire , Schwebel Carole , Thiéry Guillaume , Gründling Matthias , Berger Marc , Welte Tobias , Bauer Michael , Jaschinski Ulrich , Matschke Klaus , Mercado-Longoria Roberto , Quintana Belinda Gomez , Zamudio-Lerma Jorge Alberto , Abril Juan Moreno Hoyos , Marquez Angel Aleman , Pickkers Peter , Otterspoor Luuk , Vásquez Luis Hercilla , Ramos Carlos Rafael Seas , Villalobos Alejandro Peña , Malca Gonzalo Gianella , Chávez Victoria , Filimonov Victor , Kulabukhov Vladimir , Acharya Pinak , Timmermans Sjoerd A. M. E. G. , Busch Matthias H. , van Baarle Floor L. F. , Koning Rutger , ter Horst Liora , Chekrouni Nora , van Soest Thijs M. , van Amstel Rombout B. E. , Olie Sabine E. , van Zeggeren Ingeborg E. , van de Poll Marcel C. G. , Thielert Claus , Neukirchen Dorothee ,   the PANAMO Study Group
Published: July 2024

In a phase 3 trial (PANAMO, NCT04333420), vilobelimab, a complement 5a (C5a) inhibitor, reduced 28-day mortality in mechanically ventilated COVID-19 patients. This post hoc analysis of 368 patients aimed to explore treatment heterogeneity through unsupervised learning. All available clinical variables at baseline were used as input. Treatment heterogeneity was assessed using latent class analysis (LCA), Ward’s hierarchical clustering (HC) and the adjudication to previously described clinical sepsis phenotypes. The primary outcome was 28-day mortality. For LCA, a 2-class latent model was deemed most suitable. In the LCA model, 82 (22%) patients were assigned to class 1 and 286 (78%) to class 2. Class 1 was defined by more severely ill patients with significantly higher mortality. In an adjusted logistic regression, no heterogeneity of treatment effect (HTE) between classes was observed (p = 0.998). For HC, no significant classes were found (p = 0.669). Using the previously described clinical sepsis subtypes, 41 patients (11%) were adjudicated subtype alpha (α), 17 (5%) beta (β), 112 (30%) delta (δ) and 198 (54%) gamma (γ). HTE was observed between clinical subtypes (p = 0.001) with improved 28-day mortality after treatment with vilobelimab for the δ subtype (OR = 0.17, 95% CI 0.07–0.40, p < 0.001). No signal for harm of treatment with vilobelimab was observed in any class or clinical subtype. Overall, treatment effect with vilobelimab was consistent across different classes and subtypes, except for the δ subtype, suggesting potential additional benefit for the most severely ill patients.