Safety and Efficacy of ApTOLL in Patients With Ischemic Stroke Undergoing Endovascular Treatment: A Phase 1/2 Randomized Clinical Trial.

Autor:	Hernández-Jiménez M; aptaTargets, Madrid, Spain., Abad-Santos F; Clinical Pharmacology Department, Hospital Universitario de La Princesa, Universidad Autónoma de Madrid, Instituto de Investigación Sanitaria La Princesa, Madrid, Spain.; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Instituto de Salud Carlos III, Madrid, Spain., Cotgreave I; Department of Chemical and Pharmaceutical Safety, Division of Bioeconomy and Health, Research Institutes of Sweden, Södertälje, Sweden., Gallego J; Neurological Center of Navarra, Navarra, Spain., Jilma B; Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria., Flores A; Stroke Unit, Hospital Joan XXIII, Tarragona, Spain., Jovin TG; Cooper Neurological Institute, Cherry Hill, New Jersey., Vivancos J; Stroke Unit, Department of Neurology, Hospital La Princesa, Madrid, Spain., Hernández-Pérez M; Stroke Unit, Department of Neuroscience Hospital Germans Trias I Pujol, Barcelona, Spain., Molina CA; Stroke Unit, Department of Neurology, Hospital Vall d'Hebron, Barcelona, Spain., Montaner J; Department of Neurology, Hospital Macarena, Sevilla, Spain., Casariego J; Aldebaran Health Intelligence, Madrid, Spain., Dalsgaard M; Cureteq, Zug, Switzerland., Liebeskind DS; Neurovascular Imaging Research Core, Department of Neurology, UCLA Stroke Center, Los Angeles, California., Cobo E; Statistics and Operations Research, Barcelona-Tech, Barcelona, Spain., Castellanos M; Department of Neurology, Complejo Hospitalario Universitario/Biomedical Research Institute, A Coruña, Spain., Portela PC; Department of Neurology, Hospital Universitari Bellvitge, Barcelona, Spain., Masjuán J; Stroke Unit, Department of Neurology, Ramón y Cajal University Hospital, Departamento de Medicina, Facultad de Medicina, Universidad de Alcalá, Instituto Ramón y Cajal de Investigación Sanitaria, Madrid, Spain., Moniche F; Stroke Unit, Department of Neurology, Virgen del Rocio University Hospital, Seville, Spain., Tembl JI; Stroke Unit, Department of Neurology, La Fe Hospital, Valencia, Spain., Terceño Izaga M; Stroke Unit, Department of Neurology, Institut d'Investigació Biomèdica de Girona, Hospital Doctor Josep Trueta de Girona, Spain., Arenillas JF; Stroke Unit, Department of Neurology, Hospital de Valladolid, Spain., Callejas P; Department of Neurology and Stroke Center, University Hospital 12 de Octubre, Instituto de Investigación Hospital 12 de Octubre, Madrid, Spain., Olivot JM; Department of Vascular Neurology and Clinical Investigating Center 1435, Toulouse University Hospital, France., Calviere L; Department of Vascular Neurology and Clinical Investigating Center 1435, Toulouse University Hospital, France., Henon H; University Lille, Inserm, CHU Lille, U1172, Lille Neuroscience and Cognition, Lille, France., Mazighi M; Université Paris Cité, INSERM 1148, Department of Neurology, Hopital Lariboisière-APHP Nord, and Interventional Neuroradiology, Hopital Fondation Adolphe Rothschild, FHU Neurovasc, Paris, France., Piñeiro D; aptaTargets, Madrid, Spain., Pugliese M; aptaTargets, Madrid, Spain., González VM; Aptus Biotech, Madrid, Spain.; Grupo de Aptámeros, Departamento de Bioquímica-Investigación, Instituto Ramón y Cajal de Investigación Sanitaria, Ramón y Cajal University Hospital, Madrid, Spain., Moro MA; Unidad de Investigación Neurovascular, Department of Pharmacology and Toxicology, Faculty of Medicine, Universidad Complutense, Instituto de Investigación Hospital 12 de Octubre, Madrid, Spain.; Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain., Garcia-Tornel A; Stroke Unit, Department of Neurology, Hospital Vall d'Hebron, Barcelona, Spain., Lizasoain I; Unidad de Investigación Neurovascular, Department of Pharmacology and Toxicology, Faculty of Medicine, Universidad Complutense, Instituto de Investigación Hospital 12 de Octubre, Madrid, Spain., Ribo M; aptaTargets, Madrid, Spain.; Stroke Unit, Department of Neurology, Hospital Vall d'Hebron, Barcelona, Spain.
Jazyk:	angličtina
Zdroj:	JAMA neurology [JAMA Neurol] 2023 Aug 01; Vol. 80 (8), pp. 779-788.
DOI:	10.1001/jamaneurol.2023.1660
Abstrakt:	Importance: ApTOLL is a TLR4 antagonist with proven preclinical neuroprotective effect and a safe profile in healthy volunteers. Objective: To assess the safety and efficacy of ApTOLL in combination with endovascular treatment (EVT) for patients with ischemic stroke. Design, Setting, and Participants: This phase 1b/2a, double-blind, randomized, placebo-controlled study was conducted at 15 sites in Spain and France from 2020 to 2022. Participants included patients aged 18 to 90 years who had ischemic stroke due to large vessel occlusion and were seen within 6 hours after stroke onset; other criteria were an Alberta Stroke Program Early CT Score of 6 to 10, estimated infarct core volume on baseline computed tomography perfusion of 5 to 70 mL, and the intention to undergo EVT. During the study period, 4174 patients underwent EVT. Interventions: In phase 1b, 0.025, 0.05, 0.1, or 0.2 mg/kg of ApTOLL or placebo; in phase 2a, 0.05 or 0.2 mg/kg of ApTOLL or placebo; and in both phases, treatment with EVT and intravenous thrombolysis if indicated. Main Outcomes and Measures: The primary end point was the safety of ApTOLL based on death, symptomatic intracranial hemorrhage (sICH), malignant stroke, and recurrent stroke. Secondary efficacy end points included final infarct volume (via MRI at 72 hours), NIHSS score at 72 hours, and disability at 90 days (modified Rankin Scale [mRS] score). Results: In phase Ib, 32 patients were allocated evenly to the 4 dose groups. After phase 1b was completed with no safety concerns, 2 doses were selected for phase 2a; these 119 patients were randomized to receive ApTOLL, 0.05 mg/kg (n = 36); ApTOLL, 0.2 mg/kg (n = 36), or placebo (n = 47) in a 1:1:√2 ratio. The pooled population of 139 patients had a mean (SD) age of 70 (12) years, 81 patients (58%) were male, and 58 (42%) were female. The primary end point occurred in 16 of 55 patients (29%) receiving placebo (10 deaths [18.2%], 4 sICH [7.3%], 4 malignant strokes [7.3%], and 2 recurrent strokes [3.6%]); in 15 of 42 patients (36%) receiving ApTOLL, 0.05 mg/kg (11 deaths [26.2%], 3 sICH [7.2%], 2 malignant strokes [4.8%], and 2 recurrent strokes [4.8%]); and in 6 of 42 patients (14%) receiving ApTOLL, 0.2 mg/kg (2 deaths [4.8%], 2 sICH [4.8%], and 3 recurrent strokes [7.1%]). ApTOLL, 0.2 mg/kg, was associated with lower NIHSS score at 72 hours (mean difference log-transformed vs placebo, -45%; 95% CI, -67% to -10%), smaller final infarct volume (mean difference log-transformed vs placebo, -42%; 95% CI, -66% to 1%), and lower degrees of disability at 90 days (common odds ratio for a better outcome vs placebo, 2.44; 95% CI, 1.76 to 5.00). Conclusions and Relevance: In acute ischemic stroke, 0.2 mg/kg of ApTOLL administered within 6 hours of onset in combination with EVT was safe and associated with a potential meaningful clinical effect, reducing mortality and disability at 90 days compared with placebo. These preliminary findings await confirmation from larger pivotal trials. Trial Registration: ClinicalTrials.gov Identifier: NCT04734548.
Databáze:	MEDLINE
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