Efficacy of Sovateltide (PMZ-1620) in Patients of Acute Ischemic Stroke

Study Overview
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Brief Summary
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In the present prospective, multicentric, randomized, double-blind, parallel, saline-controlled phase II clinical study; the investigators plan to evaluate the efficacy of sovateltide (IRL-1620 or PMZ-1620) therapy along with standard supportive care in patients of acute ischemic stroke.

Detailed Description
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The peptide Sovateltide (IRL-1620) is a highly selective ETB receptor agonist. There are hidden stem cells in the brain, which becomes active following injury to the brain. Intravenous administration of PMZ-1620 (sovateltide) augments the activity of neuronal progenitor cells in the brain to repair the damage by formation of new mature neurons and blood vessels. In addition, PMZ-1620 has anti-apoptotic activity and also increases cerebral blood flow when administered following ischemia. It was discovered that in rat model of ischemic stroke, sovateltide, significantly improved survival, reduces neurological and motor function deficit while effectively decreasing infarct volume, edema and oxidative stress. The convincing results of preclinical efficacy studies of Sovateltide in ischemic stroke and its safety affirmation from phase I and phase II clinical studies encouraged us to investigate its efficacy in human patients of ischemic stroke. In the present prospective, multicentric, randomized, double-blind, parallel, saline-controlled phase II clinical study; the investigators plan to evaluate the efficacy of Sovateltide therapy along with standard supportive care in patients of acute ischemic stroke.

Official Title
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A Prospective, Multicentric, Randomized, Double-blind, Parallel, Phase III Clinical Study to Assess Efficacy of PMZ-1620 Along With Standard Treatment in Patients of Acute Ischemic Stroke

Conditions
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Cerebral Ischemia, Cerebral Infarction, Stroke, Acute

Intervention / Treatment
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* Drug: Normal Saline along with standard treatment
* Drug: PMZ-1620 (sovateltide) along with standard treatment


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult males or females Aged 18 years through 78 years (have not had their 79th birthday). Patient or Legally Authorized Representative 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) prior to enrolment. No hemorrhage as proved by cerebral CT/MRI scan. Cerebral ischemic stroke patients presenting upto 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 also includes patients who had ischemic stroke in the past and are completely recovered from earlier episode before having new or fresh stroke. Patient is < 24 hours from time of stroke onset when the first dose of PMZ-1620 therapy is administered. Time of onset is when symptoms began; for stroke that occurred during sleep, time of onset is when patient was last seen or was self- reported to be normal. Reasonable expectation of availability to receive the full PMZ-1620 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 treatment of stroke which may include but not limited to endovascular techniques. Patients classified as comatose, defined as a patient who required 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, acute or chronic subdural hematoma on the baseline CT or MRI scan. 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 PMZ-1620 therapy would be contraindicated or might cause harm to the patient.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 78 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: In PMZ group, 3 doses of PMZ-1620, at 0.3 μg/kg body weight will be administered as an intravenous bolus over 1 minute every 3 hours ± 1 hour on day 1, 3, and day 6 (total dose/day: 0.9 µg/kg body weight). In control group, 3 doses of equal volume of normal saline will be administered as an IV bolus over 1 minutes every 3 hours ± 1 hour on day 1, 3 and day 6 post randomization. In both treatment groups, subjects will be provided the best available standard of care.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Normal Saline + Standard of care<br>Patients will receive the best available standard of care. In control group, 3 doses of equal volume of normal saline will be administered as an IV bolus over 1 minutes every 3 hours ± 1 hour on day 1, 3 and day 6 post randomization. | Drug: Normal Saline along with standard treatment<br>* PMZ-1620 (sovateltide) is an endothelin-B receptor agonist. PMZ-1620 has the potential to be a first-in-class neuronal progenitor cell therapeutics that is likely to promote quicker recovery and improve neurological outcome in cerebral ischemic stroke patients. In this arm normal saline along with standard treatment will be given for active comparison.<br>* Other names: Vehicle;|
| Experimental: PMZ-1620 (sovateltide) + Standard of care<br>Patients will receive the best available standard of care. In PMZ group, 3 doses of PMZ-1620, at 0.3 μg/kg body weight will be administered as an intravenous bolus over 1 minute every 3 hours ± 1 hour on day 1, 3, and day 6 (total dose/day: 0.9 µg/kg body weight). | Drug: PMZ-1620 (sovateltide) along with standard treatment<br>* PMZ-1620 (sovateltide) is an endothelin-B receptor agonist. PMZ-1620 has the potential to be a first-in-class neuronal progenitor cell therapeutics that is likely to promote quicker recovery and improve neurological outcome in cerebral ischemic stroke patients.<br>* Other names: PMZ-1620;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in National Institute of Health Stroke Scale (NIHSS) | Neurological outcome as assessed by National Institute of Health Stroke Scale (NIHSS) score post randomization. NIHSS is 42 point scale where 0 is the best and 42 is the worst outcome. | 90 days | 
| Change in modified Rankin Scale (mRS) | Neurological outcome as assessed by modified Rankin Scale (mRS) score post randomization. mRS is a 7 grade scale from 0 to 6, where 0 is the best and 6 is the worst outcome. | 90 days | 
| Change in Barthel index [BI] | Overall clinical outcome as assessed by Barthel index [BI] scores) at 3 months post randomization. BI is a 10 item scale with scores ranging from 0 to 100, where a score of 100 is the best and 0 is the worst outcome. | 90 days | 
| Change in the proportion of ischemic stroke patients with NIHSS score <6 | Change in the proportion of ischemic stroke patients with National Institute of Health Stroke Scale (NIHSS) score <6 at day 6, 1 month and 3 months. NIHSS is 42 point scale where 0 is the best and 42 is the worst outcome. | 90 days | 
| Change in the proportion of ischemic stroke patients with mRS score <2 | Change in the proportion of ischemic stroke patients with modified Rankin Scale (mRS) score <2 at day 6, 1 month and 3 months. mRS is a 7 grade scale from 0 to 6, where 0 is the best and 6 is the worst outcome. | 90 days | 
| Change in the proportion of ischemic stroke patients with Barthel index (BI) score >60 | Change in the proportion of ischemic stroke patients with Barthel index (BI) score >60 at day 6, 1 month and 3 months. BI is a 10 item scale with scores ranging from 0 to 100, where a score of 100 is the best and 0 is the worst outcome. | 90 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Quality-of-life as assessed by EuroQol-EQ-5D | Quality-of-life as assessed by EuroQol-EQ-5D will be determined at 1 month and 3 months post randomization. EuroQol-EQ-5D is a concise, generic instrument that could be used to measure, compare and value health status across disease areas. It is a five dimension instrument with scores ranging from 0 to 100, where a score of 100 is the best and 0 is the worst outcome. | 90 days | 
| Change in Stroke-Specific Quality of Life (SSQOL) | Stroke-Specific Quality of Life (SSQOL) will be assessed at 1 month and 3 months post randomization. SSQOL is composed of 49 items with scores ranging from 49 to 245, where a score of 245 is the best and 49 is the worst outcome. | 90 days | 
| Incidence in recurrence of ischemic stroke | Incidence of recurrent ischemic stroke within 1 month and 3 months post-randomization, as assessed by Questionnaire to Validate Stroke-Free Status | 90 days | 
| Incidence of mortality | Incidence of mortality within 3 months post-randomization | 90 days | 
| Incidence of Intra-Cerebral Hemorrhage (ICH) | Incidence of symptomatic Intra Cerebral Hemorrhage (ICH) within 24 (± 6) hours of randomization | 30 hours | 
| Incidence of PMZ-1620 related adverse events | Another objective of the study is to determine incidence of drug (PMZ-1620) related adverse events. | 90 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Endothelin, Neurogenesis, Neural progenitor cells