Safety and Efficacy of ApTOLL in Patients With Ischemic Stroke Undergoing Endovascular Treatment

Abstract

ImportanceApTOLL is a TLR4 antagonist with proven preclinical neuroprotective effect and a safe profile in healthy volunteers.ObjectiveTo assess the safety and efficacy of ApTOLL in combination with endovascular treatment (EVT) for patients with ischemic stroke.Design, Setting, and ParticipantsThis 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.InterventionsIn 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 MeasuresThe 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).ResultsIn 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 RelevanceIn 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 RegistrationClinicalTrials.gov Identifier: NCT04734548

Brain-derived Tau for Monitoring Brain Injury in Acute Ischemic Stroke

“…BD-tau levels and their dynamics over time might be particularly useful to (i) support clinical decision-making regarding endovascular treatment, e.g. to quantify lost tissue after inter-hospital transfer or to stratify patients presenting with low NIHSS scores according to BD-tau dynamics, (ii) identify ongoing brain injury in patients presenting beyond 24 hours 31 who might still benefit from recanalization strategies, 6 (iii) select patients with successful recanalization but ongoing brain injury for trials evaluating cytoprotection or targeting clinically ineffective reperfusion, 11,12,32,33 and (iv) to diagnose stroke in settings with limited neuroimaging resources. High-frequency monitoring of the development of BD-tau levels over time might further allow to map infarct growth in individual patients and improve our understanding of human stroke pathophysiology by providing insights into the actual timing and extent of neuronal death.…”

Immune-Neurovascular Interactions in Experimental Perinatal and Childhood Arterial Ischemic Stroke

“…One potentially significant direction in the AIS therapeutic field is the demonstration that a novel agent, a TLR4-binding DNA Aptamer, is protective in several adult stroke models 83 and a phase Ib/IIa, double-blind, randomized, placebo-controlled acute stroke trial. 121 In infants, therapeutic hypothermia is the only approved treatment for HIE that offers neuroprotection and reduces long-term disability, 122 but its beneficial role is limited. Pharmacological strategies geared toward promoting neurogenesis after PAIS have been tested.…”

“…One potentially significant direction in the AIS therapeutic field is the demonstration that a novel agent, a TLR4-binding DNA Aptamer, is protective in several adult stroke models 83 and a phase Ib/IIa, double-blind, randomized, placebo-controlled acute stroke trial. 121…”

Immunothrombosis in neurovascular disease

“…In patients who experienced ischemic stroke, 0.2 mg/kg of ApTOLL administered within 6 hours of onset in combination with thrombectomy was safe and associated with significant clinical benefit. ApTOLL significantly reduced infarct volume and stroke severity measured at 72 hours after stroke and reduced mortality and disability at 90 days compared with placebo [ 87 ]. A unique feature of this trial was the innovative selection of eligible patients who experienced stroke.…”