Intra-arterial Injection of OTR4132, a Novel Neuroprotector in Acute Ischemic Stroke: The MaTRISS Trial.

Abstract

Background and objectives: There is an important need for the development of neuroprotective therapeutic agents that could be combined to reperfusion strategies in acute ischemic stroke to improve patient prognosis. OTR4132 is a polymer of glucose engineered to mimic heparan sulfates (HS), which demonstrated neuroprotective effects in animal models. The aim of this study was to assess the safety of OTR4132 and to identify the highest, and well-tolerated, single dose of OTR4132 in patients with anterior circulation acute ischemic stroke who underwent endovascular thrombectomy (EVT).

Methods: The MaTRISS study is a multi-center, first-in-man, open-label, dose-escalation study. OTR4132 was administered intra-arterially immediately after EVT recanalization. Dose levels were determined on the basis of preclinical studies. Six doses (from 0.2 to 2.5 mg) were planned to be administered in groups of at least three patients. Each dose escalation was authorized by the data safety monitoring board (DSMB) after reviewing all clinical, biological, and radiological data from a dose group up to 7 days post-administration. Key inclusion criteria were an acute ischemic stroke in the anterior circulation territory and endovascular thrombectomy performed with recanalization (thrombolysis in cerebral infarction [TICI] score of 2b-3) confirmed by angiography. The primary endpoint was the rate of investigational treatment-related severe adverse events occurring from baseline to 7 days after injection. All other safety and efficacy endpoints were exploratory and included all serious and non-serious adverse events, stroke lesion volumes, National Institutes of Health Stroke Scale (NIHSS), modified Rankin Scale (mRS), Modified Barthel Index (BI), and Montreal Cognitive Assessment (MoCA) from baseline up to 3 months.

Results: In total, 19 patients were recruited from three centers in France between March 2022 and March 2024 and six different doses of OTR4132 were tested (in n patients): 0.2 mg (3), 0.5 mg (3), 1 mg (3), 1.5 mg (6), 2 mg (3), and 2.5 mg (1). No adverse drug events and no changes in vital signs or laboratory parameters were observed up to 3 months following administration, regardless of administered doses. Four patients presented at least one serious adverse event. None was considered linked to the investigational treatment on the basis of investigator and DSMB assessment. One patient died of intracranial hemorrhagic transformation at 24 h and the causality link between OTR4132 administration and death remained unknown.

Conclusions: The highest tolerated dose of OTR4132 was the highest dose administered (i.e., 2.5 mg). These safety results need to be confirmed in a larger multicenter randomized placebo-controlled clinical trial. The trial was first registered in clinicaltrials.gov on 5 September 2019 (NCT04083001).