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

Abstract

Objective: Otaplimastat is a neuroprotectant that inhibits matrix metalloprotease pathway, and reduces edema and intracerebral hemorrhage induced by recombinant tissue plasminogen activator (rtPA) in animal stroke models. We aimed to assess the safety and efficacy of otaplimastat in patients receiving rtPA.

Methods: This was a phase 2, 2-part, multicenter trial in stroke patients (19-80 years old) receiving rtPA. Intravenous otaplimastat was administered <30 minutes after rtPA. Stage 1 was a single-arm, open-label safety study in 11 patients. Otaplimastat 80 mg was administered twice daily for 3 days. Stage 2 was a randomized, double-blind, placebo-controlled study involving 69 patients, assigned (1:1:1) to otaplimastat 40 mg, otaplimastat 80 mg, or a placebo. The primary endpoint was the occurrence of parenchymal hematoma (PH) on day 1. Secondary endpoints included serious adverse events (SAEs), mortality, and modified Rankin scale (mRS) distribution at 90 days (clinicaltrials.gov identifier: NCT02787278).

Results: No safety issues were encountered in stage 1. The incidence of PH during stage 2 was comparable: 0 of 22 with the placebo, 0 of 22 with otaplimastat 40 mg, and 1 of 21 with the 80 mg dose. No differences in SAEs (13%, 17%, 14%) or death (8.3%, 4.2%, 4.8%) were observed among the 3 groups. Three adverse events (chills, muscle rigidity, hepatotoxicity) were judged to be related to otaplimastat.

Interpretation: Intravenous otaplimastat adjunctive therapy in patients receiving rtPA is feasible and generally safe. The functional efficacy of otaplimastat needs to be investigated with further large trials. ANN NEUROL 2020;87:233-245.

Conflict of interest statement

Nothing to report.

© 2019 American Neurological Association.

Figures

Figure 1

Trial profile. In stage 1, 1 patient was excluded because of low (10 g/dl) hemoglobin (exclusion criterion). In stage 2, 1 patient in the otaplimastat 40 mg group received warfarin (international normalized ratio

Figure 2

Secondary efficacy outcomes. (A) Distribution of the modified Rankin score (mRS) at 90 days and (B) National Institutes of Health Stroke Scale (NIHSS) score changes from baseline (modified intention‐to‐treat population). mRS distribution at 90 days uses imputed data only for death cases (mRS = 6). Error bars indicate standard deviation values. mRS on day 90: placebo, n = 21; otaplimastat 40 mg, n = 20; 80 mg, n = 20. NIHSS: placebo, n = 22; otaplimastat 40 mg, n = 22; 80 mg, n = 21 on day 0 to day 2. Placebo, n = 20; otaplimastat 40 mg, n = 22; 80 mg, n = 19 on day 3. Placebo, n = 20; otaplimastat 40 mg, n = 20; 80 mg, n = 19 on days 4, 5, and 28. Placebo, n = 19; otaplimastat 40 mg, n = 17; 80 mg, n = 17 on day 90. (C) Fold change of infarct growth was calculated as (individual infarct volume on day 5 − individual infarct volume on day 0)/mean of infarct volumes on day 0. Each point represents an individual patient, with the median (red bar) and interquartile ranges (black bars). Placebo, n = 20; otaplimastat 40 mg, n = 20; 80 mg, n = 19.