Safety and Efficacy of Sovateltide (IRL-1620) in a Multicenter Randomized Controlled Clinical Trial in Patients with Acute Cerebral Ischemic Stroke

Anil Gulati, Nilesh Agrawal, Deepti Vibha, U K Misra, Birinder Paul, Dinesh Jain, Jeyaraj Pandian, Rupam Borgohain, Anil Gulati, Nilesh Agrawal, Deepti Vibha, U K Misra, Birinder Paul, Dinesh Jain, Jeyaraj Pandian, Rupam Borgohain

Abstract

Background: Sovateltide (IRL-1620, PMZ-1620), an endothelin-B receptor agonist, has been previously shown to increase cerebral blood flow, have anti-apoptotic activity and produce neurovascular remodeling when administered intravenously following acute cerebral ischemic stroke in rats. Its safety and tolerability were confirmed in healthy human volunteers (CTRI/2016/11/007509).

Objective: Our objective was to determine the safety, tolerability and efficacy of sovateltide as an addition to standard of care (SOC) in patients with acute cerebral ischemic stroke.

Methods: A prospective, multicentric, randomized, double-blind, placebo-controlled study was conducted to compare the safety (primary objective) and efficacy (secondary objective) of sovateltide in patients with acute cerebral ischemic stroke. Adult males or females aged 18-70 years who had experienced a radiologically confirmed ischemic stroke within the last 24 h were included in the study. Patients with intracranial hemorrhage and those receiving endovascular therapy were excluded. Patients randomized to the sovateltide group received three doses of sovateltide (each dose 0.3 µg/kg) administered as an intravenous bolus over 1 min at an interval of 3 ± 1 h on day 1, day 3 and day 6 (total dose of 0.9 µg/kg/day). Patients randomized to the placebo group received an equal volume of saline. Every patient in both groups received SOC for stroke. Efficacy was evaluated using neurological outcomes based on National Institute of Health Stroke Scale (NIHSS), modified Rankin Scale (mRS) and Barthel Index (BI) scores from day 1 through day 90. Quality of life was measured using the EuroQoL-5 Dimensions (EQ-5D) and Stroke-Specific Quality of Life (SSQoL) at 60 and 90 days of follow-up.

Results: A total of 40 patients with acute cerebral ischemic stroke were enrolled in this study, of whom 36 completed the 90-day follow-up. Patients received saline (n = 18; 11 male and 7 female) or sovateltide (n = 18; 15 male and 3 female) within 24 h of onset of stroke. The number of patients receiving investigational drug within 20 h of onset of stroke was 14/18 in the saline group and 10/18 in the sovateltide group. The baseline characteristics and SOC in both cohorts was similar. Sovateltide was well-tolerated, and all patients received complete treatment with no incidence of drug-related adverse events. Hemodynamic, biochemical or hematological parameters were not affected by sovateltide. Sovateltide treatment resulted in improved mRS and BI scores on day 6 compared with day 1 (p < 0.0001), an effect not seen in the saline group. Sovateltide increased the frequency of favorable outcomes at 3 months. An improvement of ≥ 2 points on the mRS was observed in 60 and 40% of patients in the sovateltide and saline groups, respectively (p = 0.0519; odds ratio [OR] 5.25). An improvement on the BI of ≥ 40 points was seen in 64 and 36% of the sovateltide and saline groups, respectively (p = 0.0112; OR 12.44). An improvement of ≥6 points on the NIHSS was seen in 56% of patients in the sovateltide group versus 43% in the saline group (p = 0.2714; OR 2.275). The number of patients with complete recovery (defined as an NIHSS score of 0 and a BI of 100) was significantly greater (p < 0.05) in the sovateltide group than in the saline group. An assessment of complete recovery using an mRS score of 0 did not show a statistically significant difference between the treatment groups. Sovateltide treatment resulted in improved quality of life as measured by the EQ-5D and SSQoL on day 90.

Conclusion: Sovateltide was safe and well-tolerated and resulted in improved neurological outcomes in patients with acute cerebral ischemic stroke 90 days post-treatment.

Trial registration: The study is registered at CTRI/2017/11/010654 and NCT04046484.

Conflict of interest statement

Dr. Anil Gulati (AG) is an employee of Pharmazz, Inc. and has issued and pending patents relating to this study. Nilesh Agrawal, Deepti Vibha, UK Misra, Birinder Paul, Dinesh Jain, Jeyaraj Pandian and Rupam Borgohain have no conflicts of interest that are directly relevant to the content of this article.

Figures

Fig. 1
Fig. 1
Screening and enrollment of patients
Fig. 2
Fig. 2
Time of initiating the treatment after onset of stroke
Fig. 3
Fig. 3
Neurological outcome measures of National Institute of Health Stroke Scale (NIHSS), modified Rankin Scale (mRS) and Barthel Index (BI) in individual patients from day 1 through day 90
Fig. 4
Fig. 4
Neurological outcome measures on day 6 vs day 1 of National Institute of Health Stroke Scale (NIHSS) scores
Fig. 5
Fig. 5
Number of patients with change in National Institute of Health Stroke Scale (NIHSS), modified Rankin Scale (mRS) and Barthel Index (BI) at 90 days of follow up
Fig. 6
Fig. 6
Number of patients with complete recovery as indicated by National Institute of Health Stroke Scale (NIHSS), modified Rankin Scale (mRS) and Barthel Index (BI) at 90 days of follow up
Fig. 7
Fig. 7
Number of patients with improved quality of life at 90 days of follow up. CI confidence interval, EuroQoL EuroQoL 5-Dimensions tool

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