Findings of a phase 2 assessment has suggested that otaplimastat can be safely administered in patients with stroke who are being treated with recombinant tissue plasminogen activator and is realistic to be further studied.
Jong S. Kim, MD, department of neurology, Asan Medical Center, University of Ulsan College of Medicine
Jong S. Kim, MD
Intravenous otaplimastat, when used as adjunctive therapy in patients receiving recombinant tissue plasminogen activator (rtPA) to treat stroke, has been found to be generally safe and feasible, according to the results of a study.
All told, the incidence of parenchymal hematoma (PH), the study’s primary endpoint, was comparable between otaplimastat and placebo. Treatment with the Shin Poong Pharmaceutical product also resulted in a comparable incidence of serious adverse events (AEs) and mortality.
“Although rtPA treatment grants better clinical outcomes, the risk of intracranial hemorrhage and mortality are increased when the treatment is delayed,” lead author Jong S. Kim, MD, department of neurology, Asan Medical Center, University of Ulsan College of Medicine, and colleagues wrote. “Previous studies have consistently shown that otaplimastat reduces the incidence of intracranial hemorrhage in experimental animals with stroke receiving rtPA, while it did not interfere with the fibrinolytic activity of rtPA.”
The phase 2, two-part multicenter SAFE-TPA trial included 80 patients—11 in stage 1, which was a single-arm open-label safety assessment, and 69 in stage 2, which was a randomized, double-blind, placebo-controlled evaluation. Patients were randomized 1:1:1 to otaplimastat 40 mg (n = 24), 80 mg (n = 21), or placebo (n = 24) during stage 2, with 88% of the placebo (n = 21) and 40-mg (n = 21), and 91% (n = 19) receiving all 6 doses.
All patients in stage 1 received otaplimastat 80 mg, in 6 doses. In the initial stage, there was no incidence of PH identified on brain computed tomography (CT) scan at the 24-hour mark. As well, there was no incidence of symptomatic intracranial hemorrhage or major systemic bleeding.
Treatment-emergent AEs were reported in all patients, though none were serious nor related to otaplimastat. The most common were nausea, dysuria, and pyrexia, each occurring in 27% of patients (n = 11). There were 39 total AEs recorded with the majority, 74% (n = 29) deemed mild and 26% (n = 10) of moderate severity. No deaths occurred.
In stage 2, PH was absent in both the placebo group and the 40-mg group, though a single case was identified in the 80-mg group, in a patient who underwent endovascular thrombectomy (4.8%; 90% CI, 0.2—20.7), which was found to be insignificant compared to placebo (treatment difference, 4.8%; 90% CI, 20.2–29.1).
Secondary efficacy outcomes included the National Institutes of Health Stroke Scale (NIHSS), modified Rankin scale (mRS), and Barthel Index (BI) measurements to demonstrate feasibility.
There was a significant difference in the distribution of mRS scores between the otaplimastat 40-mg group and placebo at 90 days (P = .026), but not with the 80-mg group (P = .502). Notably, Kim and co. noted that this trend was limited by small sample size (adjusted odds ratio [OR], 3.2; 95% CI, 0.9—10.9; P = .068).
NIHSS scores were more pronounced in the 40-mg group, though at the 28-day mark, they failed to separate significantly from placebo (P = .234). Similar results were observed at 90 days (P = .414). BI was also not significantly different between the 3 groups at Day 90.
“There was also an intriguing signal that otaplimastat 40 mg may improve neurological outcomes in these patients,” Kim and colleagues detailed. “Further clinical studies on otaplimastat or other potentially useful adjunctive therapies for rtPA may help identify novel ways to improve the clinical outcomes of patients with acute ischemic stroke receiving rtPA.”
Notably, diffusion-weighted imaging identified a median lesion volume growth (minimal, maximal) of 3.2 (—0.3, 57.2) with placebo, compared to 1.7 (–3.3, 26.4) with otaplimastat 40 mg, and 3.0 (0.0, 89.1) with otaplimastat 80 mg.
The incidence of any intracranial hemorrhage was comparable between groups, with 35% (7 of 20) of the placebo group, compared to 35% (7 of 20) of the 40-mg group (treatment difference, 0%; 90% CI, —27.8 to 27.8), and 37% (7 of 19) of the 80-mg group (treatment difference, 1.8%; 90% CI, –25.7 to 27.6). However, there was a trend of increased hemorrhage volumes and infarction recurrence in the otaplimastat 80 mg group. Of the 69 total patients, 78% (n = 54) were treated with antiplatelet agents and 33% (18) of those patients developed any ICH.
Kim and coinvestigators noted that there were some limitations to the work, including the small number of enrolled patients, and a lack of evaluation of otaplimastat’s potential benefit in those not treated with rtPA. “Despite the limitations, we provided evidence that administering otaplimastat to patients with acute ischemic stroke receiving rtPA is feasible and generally safe,” Kim and colleagues concluded.
Kim JS, Bok Lee K, Park JH, et al. Safety and Efficacy of Otaplimastat in Patients with Acute Ischemic Stroke Requiring tPA (SAFE‐TPA): A Multicenter, Randomized, Double‐blind, Placebo‐Controlled Phase 2 Study. Annals Neurol. Published online November 13, 2019. doi: 10.1002/ana.25644.