Efficacy of sovateltide (IRL-1620) in a multicenter randomized controlled clinical trial in patients with acute cerebral ischemic stroke

Abstract

AbstractBackgroundSovateltide (IRL-1620, PMZ-1620), an endothelin-B receptor agonist, administered intravenously following acute cerebral ischemic stroke increased cerebral blood flow, had anti-apoptotic activity and produced neurovascular remodeling. Its safety and tolerability were confirmed in healthy human volunteers (CTRI/2016/11/007509).ObjectiveTo determine safety, tolerability and efficacy of sovateltide as an adjuvant to standard of care (SOC) in acute cerebral ischemic stroke patients.MethodsA prospective, multi-centric, randomized, double-blind, controlled study to compare efficacy of sovateltide in patients with acute cerebral ischemic stroke was conducted in 40 patients, of which 36 completed 90-day follow-up. Patients who had stroke within the last 24 hours with a radiologic confirmation of ischemic stroke were included in the study. Patients with intracranial hemorrhage and those receiving endovascular therapy were excluded. All patients in both groups received SOC for stroke. Patients randomized in the sovateltide group received three doses of sovateltide (each dose 0.3 µg/kg) administered as an IV bolus over 1 minute at an interval of 3 hours ± 1 hour on day 1, day 3 and day 6 (total dose of 0.9 µg/kg/day). Patients randomized in the placebo group received equal volume of saline. Efficacy was evaluated by neurological outcomes based on National Institute of Health Stroke Scale (NIHSS), modified Rankin Scale (mRS) and Barthel Index (BI) scales. Quality of Life was measured by EuroQoL (EQ-5D) and stroke specific quality-of-life (SS-QoL).ResultsPatients received saline (n = 18; 11 male and 7 female) or sovateltide (n = 18; 15 male and 3 female) within 24 hours of onset of stroke. Number of patients receiving investigational drug within 20 hours of onset of stroke were 14/18 in saline and 10/18 in sovateltide cohorts. The baseline characteristics and SOC in both cohorts was similar. Sovateltide treatment resulted in a significantly quicker recovery as measured by improvements in neurological outcomes in mRS and BI scales on day 6 compared to day 1 (p< 0.0001). Moreover, sovateltide increased the frequency of favorable outcomes in all scales at 3 months. An improvement of ≥2 points in mRS was observed in 60% and 40% patients in sovateltide and saline groups, respectively (p = 0.0519; odds ratio 5.25). BI improvement of ≥40 points was 64% and 36% in sovateltide and saline groups, respectively (p = 0.0112; odds ratio 12.44). An improvement of ≥6 points was seen in NIHSS in 56% of patients in sovateltide vs 43% in saline groups (p = 0.2714; odds ratio 2.275). Number of patients with complete recovery achieving NIHSS score of 0 and BI of 100 were significantly more (p< 0.05) in sovateltide group compared to saline group. Sovateltide treatment resulted in improved Quality of Life as measured by EuroQoL and SS-QoL (stroke specific quality-of-life) on day 90. Sovateltide was well tolerated and all patients received complete treatment with no incidence of drug related adverse event reported. Hemodynamic, biochemical or hematological parameters were not affected with sovateltide.ConclusionSovateltide was safe, well tolerated, and resulted in quicker recovery and improved neurological outcome in acute cerebral ischemic stroke patients 90 days post-treatment.Trial RegistrationThe study is registered at CTRI/2017/11/010654 and NCT04046484Key PointsA phase II trial was conducted to evaluate safety, tolerability and efficacy of sovateltide, an ETB receptor agonist, in patients with acute cerebral ischemic stroke.Sovateltide was administered in three doses, each dose of 0.3 µg/kg, as an intravenous bolus over one minute at an interval of 3 hours ± 1 hour on day 1, day 3, and day 6 (total dose/day: 0.9 µg/kg) post randomization.It was found to be safe and well tolerated. No adverse event was reported in patients.Sovateltide significantly improved outcome parameters of NIHSS, mRS and BI at day 6 compared to day 1, however no significant improvement was observed in control arm.Number of patients showing an improvement in mRS and BI were greater in sovateltide compared to control cohort at 90 days of treatment.