Toll-like receptor 4 agonist, EVT linked to reduced 90-day stroke mortality, disability
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Administration of Toll-receptor 4 antagonist ApTOLL within 6 hours of acute ischemic stroke, along with endovascular treatment, was linked to reduced mortality and disability at 90 days compared with placebo.
“ApTOLL is a [Toll-receptor 4 (TLR4)] antagonist with proven preclinical neuroprotective effect and safe profile in healthy volunteers,” Macarena Hernandez, PhD, professor of neurovascular research at Complutense University in Madrid, and colleagues wrote in research presented at the International Stroke Conference.
Hernandez and colleagues sought to assess safety and efficacy of ApTOLL combined with endovascular treatment in patients with ischemic stroke by conducting a multicenter, phase 1b/2a, double-blind, randomized, placebo-controlled study.
They enrolled individuals aged 18 to 90 years with ischemic stroke and large vessel occlusion within a 6-hour window. All participants had an Alberta Stroke Program Early CT Score (ASPECTS) between 5 and 10, with an estimated infarct core volume on CT-perfusion of 5 to 70 mL.
In the phase 1b portion of the trial, 32 individuals were randomized to receive ascending doses of 0.025, 0.05, 0.1 and 0.2mg/kg of ApTOLL or placebo, with the two best doses — based on safety criteria — selected for the phase 2 trial. All patients received endovascular treatment.
The primary outcome of interest was safety, including incidence of death and other adverse events, while secondary efficacy endpoints included infarct volume at 72 hours via MRI, NIH Stroke Scale Score (NIHSS) at 72 hours and disability at 90 days, measured by modified Rankin Scale (mRS).
Doses of 0.05 mg/kg and 0.2 mg/kg were selected for the second phase of the trial, which occurred between July 2021 and April 2022. A total of 119 patients were assigned to 0.05 mg/kg (dose A, n = 36), 0.2 mg/kg (dose B, n = 36) or placebo (n = 47).
Researchers reported 11 deaths at 90 days for dose A, three for dose B and 10 for placebo. Dose B reduced mean infarct volume (–29.31 cc; 90% CI, –49.28 to –9.34) and NIHSS (–3.94; 90% CI, –6.86 to –1.02) at 72 hours and reduced disability (mRS shift: common OR = 0.41; 90% CI, 0.20-0.85) at 90 days.
“In acute ischemic stroke, 0.2mg/kg of ApTOLL administered within 6 hours of onset in combination with EVT was associated with reduced mortality and disability at 90 days and a favorable safety profile compared to placebo,” Hernandez and colleagues wrote.