1. Efficacy and Safety of Sovateltide in Patients with Acute Cerebral Ischaemic Stroke: A Randomised, Double-Blind, Placebo-Controlled, Multicentre, Phase III Clinical Trial.
- Author
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Gulati A, Adwani SG, Vijaya P, Agrawal NR, Ramakrishnan TCR, Rai HP, Jain D, Sundarachary NV, Pandian JD, Sardana V, Sharma M, Sidhu GK, Anand SS, Vibha D, Aralikatte S, Khurana D, Joshi D, Karadan U, and Siddiqui MSI
- Subjects
- Humans, Middle Aged, Double-Blind Method, Male, Aged, Female, Adult, Treatment Outcome, Young Adult, Adolescent, Brain Ischemia drug therapy, Stroke drug therapy, India, Peptide Fragments, Endothelins, Ischemic Stroke drug therapy
- Abstract
Background and Objectives: Sovateltide (Tycamzzi™), an endothelin-B (ET-B) receptor agonist, increases cerebral blood flow, has anti-apoptotic activity, and promotes neural repair following cerebral ischaemic stroke. The objectives of this study were to evaluate the efficacy and safety of sovateltide in adult participants with acute cerebral ischaemic stroke., Methods: This was a randomised, double-blind, placebo-controlled, multicentre, Phase III clinical trial of sovateltide in participants with cerebral ischaemic stroke receiving standard of care (SOC) in India. Patients aged 18-78 years presenting up to 24 h after the onset of symptoms with radiologic confirmation of ischaemic stroke and a National Institutes of Health Stroke Scale score (NIHSS) of ≥ 6 were enrolled. Patients with recurrent stroke, receiving endovascular therapy, or with intracranial haemorrhage were excluded. The study drug (saline or sovateltide [0.3 µg/kg] was administered intravenously in three doses at 3 ± 1 h intervals on Days 1, 3, and 6, and follow-up was 90 days). The Multivariate Imputation by Chained Equations (MICE) was used to impute the missing assessments on the endpoints. An unpaired t-test, two-way analysis of variance with Tukey's multiple comparison test, and the Chi-square test were used for the statistical analysis. The objective was to determine at Day 90 (1) the number of patients with a modified Rankin Scale score (mRS) 0-2, and (2) the number of patients with an NIHSS 0-5 at 90 days., Results: Patients were randomised with 80 patients in the sovateltide and 78 in the control group. Patients received the investigational drug at about 18 h of stroke onset in both control and sovateltide groups. The median NIHSS at randomisation was 10.00 (95% CI 9.99-11.65) in the control group and 9.00 (95% CI 9.11-10.46) in the sovateltide group. Seventy patients completed the 90-day follow-up in the control group and 67 in the sovateltide group. The proportion of intention-to-treat (ITT) patients with mRS 0-2 score at Day 90 post-randomisation was 22.67% higher (odds ratio [OR] 2.75, 95% CI 1.37-5.57); similarly, the proportion of patients with NIHSS score of 0-5 at Day 90 was 17.05% more (OR 2.67, 95% CI 1.27-5.90) in the sovateltide group than in the control group. An improvement of ≥ 2 points on the mRS was observed in 51.28% and 72.50% of patients in the control and sovateltide groups, respectively (OR 2.50, 95% CI 1.29-4.81). Seven of 78 patients (8.97%) in the control group and 7 of 80 (8.75%) in the sovateltide group developed intracranial haemorrhage (ICH). The adverse events were not related to sovateltide., Conclusions: The sovateltide group had a greater number of cerebral ischaemic stroke patients with lower mRS and NIHSS scores at 90 days post-treatment than the control group. This trial supported the regulatory approval of sovateltide in India, but a multinational RESPECT-ET
B trial will be conducted for US approval., Trial Registration: Clinical Trials Registry, India (CTRI/2019/09/021373) and the United States National Library of Medicine, ClinicalTrials.gov (NCT04047563)., Competing Interests: Declarations. Funding: Pharmazz Inc., Willowbrook, IL, USA, funded the study. The funder contributed and reviewed the study design and protocol but had no role in conducting the study, data collection, management, analysis, and interpretation. All the authors had access to the data and have reviewed and approved the preparation and submission of this manuscript for publication. Conflicts of interest: Anil Gulati has issued and pending patents and is an employee and stockholder of Pharmazz Inc. No conflicts related to the content of this article are reported by Sikandar Gokuldas Adwani, Pamidimukkala Vijaya, Nilesh Radheshyam Agrawal, TCR Ramakrishnan, Hari Prakash Rai, Dinesh Jain, Nagarjunakonda Venkata Sundarachary, Jeyaraj Durai Pandian, Vijay Sardana, Mridul Sharma, Gursaran Kaur Sidhu, Sidharth Shankar Anand, Deepti Vibha, Saroja Aralikatte, Dheeraj Khurana, Deepika Joshi, Ummer Karadan, Mohd. Shafat Imam Siddiqui. Ethics Approval: The study protocol PMZ-1620/CT-3.1/2019) dated April 29, 2019, was approved by the Drugs Controller General of India (DCGI) (DCGI CT NOC. No.: CT/ND/66/2019). Furthermore, each institutional ethics committee reviewed and approved the study protocol before initiating patient enrolment. The trial registration was done at the Clinical Trials Registry, India (CTRI/2019/09/021373) and the United States National Library of Medicine, ClinicalTrials.gov (NCT04047563). Consent to Participate: Informed written consent was obtained from patients or their legally authorised representatives. Consent for Publication: Not applicable. Code Availability: Not applicable. Data and Material: The anonymised patient datasets created and/or analysed for the current study can be accessed from the corresponding author at a reasonable request from a bona fide researcher/research group. Authors' Contributions: Study concept and design: AG and JDP; Investigation: SGA, PV, NRA, TCRR, HPR, DJ, NVS, JDP, VS, MS, GKS, SSA, DV, SA, DK, DJ, UK, and MSIS; Acquisition of data: SGA, PV, NRA, TCRR, HPR, DJ, NVS, JDP, VS, MS, GKS, SSA, DV, SA, DK, DJ, UK, and MSIS; Analysis and interpretation of data: AG; Drafting of the manuscript: AG; Review of the manuscript: SGA, PV, NRA, TCRR, HPR, DJ, NVS, JDP, VS, MS, GKS, SSA, DV, SA, DK, DJ, UK, and MSIS. All authors contributed to the data collection, had full access to the data room having all the data in the study, and accept responsibility to submit for publication., (© 2024. The Author(s).)- Published
- 2024
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