Key PointsQuestion
What is the safety and efficacy as a neuroprotectant drug of
ApTOLL in patients with ischemic stroke in combination with endovascular
treatment?
Findings
In this randomized clinical trial including patients with
acute stroke, the mortality at 90 days was significantly lower with
ApTOLL compared with placebo.
Meaning
In patients with acute stroke and anterior circulation large
vessel occlusion, the administration of ApTOLL immediately before
endovascular treatment may have a neuroprotective effect.
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
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