Study to Assess the Safety and Efficacy of Sovateltide in Patients With Acute Cerebral Ischemic Stroke

Official title

A Prospective, Multicentric, Randomized, Double-blind, Parallel, Phase IV Study to Assess the Safety and Efficacy of Sovateltide in Patients With Acute Cerebral Ischemic Stroke

Overview

This is a prospective, multicenter, randomized, double-blind, parallel, phase IV study designed to evaluate the safety and efficacy of sovateltide (PMZ-1620, IRL-1620) as a potential treatment for cerebral ischemic stroke.

Detailed description

The presence of stem cells in the brain that become active after brain injury is an interesting aspect of regeneration and repair after stroke. The intravenous administration of sovateltide (TYVALZI™, IRL 1620) enhances the activity of neuronal progenitor cells and angiogenesis in the brain. This promotes the formation of new mature neurons and blood vessels, aiding in the repair process. Additionally, sovateltide exhibits anti-apoptotic activity, preventing cell death, and it can increase cerebral blood flow when administered after ischemia. These properties make sovateltide a promising candidate for promoting brain repair and facilitating recovery following acute ischemic stroke.

The study aims to evaluate the safety and efficacy of sovateltide in 160 patients with acute cerebral ischemic stroke. Sovateltide will be administered intravenously in addition to standard treatment. The patients will be divided into two groups, with 80 patients in each. Group 1 will receive sovateltide along with standard treatment, while Group 2 will receive normal saline along with standard treatment. The study will span approximately 18 months, with a patient enrollment period of around 15 months. Each patient will be followed for a total of 3 months, with three study visits during that period. The study will adhere to ethical guidelines and obtain informed consent from patients or their legally acceptable representatives. Efficacy analysis will be performed using statistical tests to compare outcomes between the groups, including NIHSS (National Institutes of Health Stroke Scale), mRS (Modified Rankin Scale), and BI (Barthel index) scores. Safety analysis will involve monitoring and categorizing adverse events (AEs) and treatment-emergent adverse events (TEAEs) using standardized medical terminology. Adverse events will be evaluated based on their relationship to the study drug, seriousness, severity, actions taken, and outcomes. Clinical laboratory parameters, vital signs, and physical examinations will also be assessed.

Interventions

• Drug Sovateltide
  Sovateltide (Tyvalzi™) is a highly selective ETB receptor agonist (Ki values are 0.016 and 1900 nM at ETB and ETA receptors, respectively). It is being developed as a first-in-class neuronal progenitor cell therapy for acute cerebral ischemic stroke. Sovateltide has demonstrated a significant neuroprotection following cerebral ischemia in animal models, while in a clinical phase I trial it was found safe and well-tolerated in healthy human volunteers (CTRI/2016/11/007509). A phase II study (NCT0
• Other Normal Saline
  Three doses of Normal Saline (0.9% NaCl solution) with a volume equal to the volume of sovateltide will be administered as an IV bolus over one minute, at an interval of 3 hours ± 1 hour on day 1. The dose will be repeated on day 3 and day 6 post-randomization. All the patients in the Normal Saline group will continue receiving standard treatment.

Primary outcome measures

• The proportion of patients with adverse events (AEs) and serious adverse events (SAEs) [Time frame: 90 days]

Secondary outcome measures (11)

• The proportion of cerebral ischemic stroke patients with a change in modified Rankin Scale (mRS) score of ≥2 [Time frame: 90 days]
• The proportion of cerebral ischemic stroke patients with a change in National Institute of Health Stroke Scale (NIHSS) score ≥6 [Time frame: 90 days]
• The proportion of cerebral ischemic stroke patients with a change in Barthel index (BI) score ≥60 [Time frame: 90 days]
• Change in National Institute of Health Stroke Scale (NIHSS) score [Time frame: 90 days]
• Change in modified Rankin Scale (mRS) score [Time frame: 90 days]
• Change in Barthel index (BI) score [Time frame: 90 days]
• Change in Quality-of-life as assessed by EuroQol-EQ-5D [Time frame: 90 days]
• Change in Stroke-Specific Quality of Life (SSQOL) [Time frame: 90 days]
• The proportion of patients with recurrent cerebral ischemic stroke [Time frame: 90 days]
• Number of deaths [Time frame: 90 days]
• Proportion of patients with radiographic or symptomatic intracerebral hemorrhage (ICH) [Time frame: 30 hours]

Eligibility criteria

Inclusion criteria

• Adult males or females aged 18 years through 78 years (have not had their 79th birthday)
• Patient or Legally Acceptable Representative (LAR) willing to give informed consent before study procedure.
• Stroke is ischemic in origin and radiologically confirmed Computed Tomography (CT) scan or diagnostic magnetic resonance imaging (MRI) before enrolment. No hemorrhage as proved by cerebral CT/MRI scan.
• Cerebral ischemic stroke patients presenting within 24 hours after onset of symptoms with mRS score of 3-4 (pre-stroke mRS score of 0 or 1) and NIHSS score >5 (NIHSS Level of Consciousness (1A) score must be < 2). This includes cerebral ischemic stroke patients who completely recovered from earlier episodes before having a new or fresh stroke.
• The patient is <24 hours from the time of stroke onset when the first dose of Sovateltide therapy is administered. Time of onset is when symptoms began; for stroke that occurred during sleep, time of onset is when the patient was last seen or was self-reported to be normal.
• Reasonable expectation of availability to receive the full Sovateltide course of therapy and to be available for subsequent follow-up visits.

Exclusion criteria

• Patients receiving endovascular therapy or is a candidate for any surgical intervention for the treatment of stroke, which may include but not limited to endovascular techniques.
• Patients classified as comatose are defined as a patient who requires repeated stimulation to attend or is obtunded and requires strong or painful stimulation to make movements (NIHSS Level of Consciousness (1A) score ≥ 2).
• Evidence of intracranial hemorrhage (intracerebral hematoma, intraventricular hemorrhage, subarachnoid hemorrhage, epidural hemorrhage, an acute or chronic subdural hematoma on the baseline CT or MRI scan 4. Known pregnancy.
• Confounding pre-existing neurological or psychiatric disease.
• Concurrent participation in any other therapeutic clinical trial.
• Evidence of any other major life-threatening or serious medical condition that would prevent completion of the study protocol, impair the assessment of outcome, or in which Sovateltide therapy would be contraindicated or might cause harm to the patient.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

India · 6 centers

• Guntur Medical College and Government General Hospital — Guntur
• Lalitha Super Specialities Hospital Pvt. Ltd. — Guntur
• Radiant Superspeciality Hospital — Amravati
• Government Medical College and attached Hospitals — Kota
• KG Hospital and Post Graduate Medical Institute — Coimbatore
• Maharani Laxmibai Medical College — Jhānsi

Publications

• Gulati A, Hornick MG, Briyal S, Lavhale MS. A novel neuroregenerative approach using ET(B) receptor agonist, IRL-1620, to treat CNS disorders. Physiol Res. 2018 Jun 27;67(Suppl 1):S95-S113. doi: 10.33549/physiolres.933859. PMID 29947531
• Leonard MG, Briyal S, Gulati A. Endothelin B receptor agonist, IRL-1620, reduces neurological damage following permanent middle cerebral artery occlusion in rats. Brain Res. 2011 Oct 28;1420:48-58. doi: 10.1016/j.brainres.2011.08.075. Epub 2011 Sep 7. PMID 21959172
• Leonard MG, Briyal S, Gulati A. Endothelin B receptor agonist, IRL-1620, provides long-term neuroprotection in cerebral ischemia in rats. Brain Res. 2012 Jun 29;1464:14-23. doi: 10.1016/j.brainres.2012.05.005. Epub 2012 May 9. PMID 22580085
• Leonard MG, Gulati A. Endothelin B receptor agonist, IRL-1620, enhances angiogenesis and neurogenesis following cerebral ischemia in rats. Brain Res. 2013 Aug 28;1528:28-41. doi: 10.1016/j.brainres.2013.07.002. Epub 2013 Jul 11. PMID 23850649
• Leonard MG, Prazad P, Puppala B, Gulati A. Selective Endothelin-B Receptor Stimulation Increases Vascular Endothelial Growth Factor in the Rat Brain during Postnatal Development. Drug Res (Stuttg). 2015 Nov;65(11):607-13. doi: 10.1055/s-0034-1398688. Epub 2015 Mar 25. PMID 25806822
• Briyal S, Ranjan AK, Hornick MG, Puppala AK, Luu T, Gulati A. Anti-apoptotic activity of ETB receptor agonist, IRL-1620, protects neural cells in rats with cerebral ischemia. Sci Rep. 2019 Jul 18;9(1):10439. doi: 10.1038/s41598-019-46203-x. PMID 31320660
• Ranjan AK, Briyal S, Gulati A. Sovateltide (IRL-1620) activates neuronal differentiation and prevents mitochondrial dysfunction in adult mammalian brains following stroke. Sci Rep. 2020 Jul 29;10(1):12737. doi: 10.1038/s41598-020-69673-w. PMID 32728189
• Ranjan AK, Briyal S, Khandekar D, Gulati A. Sovateltide (IRL-1620) affects neuronal progenitors and prevents cerebral tissue damage after ischemic stroke. Can J Physiol Pharmacol. 2020 Sep;98(9):659-666. doi: 10.1139/cjpp-2020-0164. Epub 2020 Jun 23. PMID 32574518

Identifiers

NCT: NCT05955326 · Sovateltide/CT-4.1/2022

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗