PMZ-1620 (Sovateltide) in Acute Ischemic Stroke Patients

Study Overview
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Brief Summary
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This was a prospective, multicentric, randomized, double blind, parallel, saline controlled Phase II clinical study to compare the safety and efficacy of PMZ-1620 (INN: Sovateltide) therapy along with standard supportive care in patients of acute ischemic stroke.

Detailed Description
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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.

Official Title
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A Prospective, Multicentric, Randomized, Double Blind, Parallel, Saline Controlled Phase II Clinical Study to Compare the Safety and Efficacy of PMZ-1620 Therapy Along With Standard Supportive Care in Subjects of Acute Ischemic Stroke

Conditions
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Acute Stroke, Cerebral Ischemia

Intervention / Treatment
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* Drug: Normal Saline along with standard treatment
* Drug: PMZ-1620 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 70 years (have not had their 71st birthday) Signed and dated informed Consent from Legally Acceptable Representative, if subject is not in the condition to give consent. However, when the subject is stable and is able to give consent, consent would be obtained on a separate informed consent form to confirm his/her willingness to continue in the study Stroke is ischemic in origin, supratentorial, and radiologically confirmed Computed Tomography (CT) scan or diagnostic magnetic resonance imaging (MRI) prior to enrolment New (first time) cerebral ischemic strokes subjects presenting upto 24 hours after onset of symptoms (mRS score of 3-4) with a prestroke mRS score of 0 or 1 and NIHSS score of 5-14) No hemorrhage as proved by cerebral CT/MRI scan Subject 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 subject 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 Subjects receiving thrombolytic therapy Reasonable expectation that subject will receive standard post- stroke physical, occupational, speech, and cognitive therapy as indicated Female subject is either: Not of childbearing potential, defined as postmenopausal for at least 1 year or surgically sterile (bilateral tubal ligation, bilateral oophorectomy or hysterectomy) or, If of childbearing potential, agrees to use any of the following effective separate forms of contraception throughout the study, up to and including the follow-up visits: Condoms, sponge, foams, jellies, diaphragm or intrauterine device, OR A vasectomised partner OR abstinence Exclusion Criteria: Subjects receiving endovascular therapy Subjects presenting with lacunar, hemorrhagic and/or brain stem stroke Subjects classified as comatose, defined as a subject who required repeated stimulation to attend, or is obtunded and requires strong or painful stimulation to make movements (NIHSS Level of Consciousness (1A) score must be < 2) Episode/exacerbation of congestive heart failure (CHF) from any cause in the last 6 months. (An episode of CHF is any heart failure that required a change in medication, change in diet or hospitalization) Evidence of intracranial hemorrhage (intracerebral hematoma, intraventricular hemorrhage, subarachnoid hemorrhage (SAH), epidural hemorrhage, acute or chronic subdural hematoma (SDH) on the baseline CT or MRI scan Known valvular heart disease with CHF in the last 6 months Known (or in the Investigator's clinical judgment) existence of severe aortic stenosis or mitral stenosis Cardiac surgery involving thoracotomy (e.g., coronary artery bypass graft, (CABG), valve replacement surgery) in the last 6 months Subject is a candidate for any surgical intervention for treatment of stroke which may include but not limited to endovascular techniques Subjects who are obese, body mass index (BMI) > 30 and/or on hormonal contraceptives Hypo- or hyperglycemia sufficient to account for the neurological symptoms; patient should be excluded if their blood glucose is < 3.0 or > 20.0 mmol/L Patient has systolic BP < 90 mmHg or > 220 mmHg or diastolic BP < 40 mmHg or > 130 mmHg Acute myocardial infarction in the last 6 months Signs or symptoms of acute myocardial infarction, including electrocardiogram findings, on admission Concomitant treatment with neuroprotective or nootropic drugs (e.g. piracetam, citicoline, investigational, neuroprotecti-ve substances) Qualitative estimation of troponin on admission Suspicion of aortic dissection on admission Acute arrhythmia (including any tachy- or bradycardia) with hemodynamic instability on admission (systolic BP < 100 mmHg) Findings on physical examination of any of the following: (1) jugular venous distention (JVP > 4 cm above the sternal angle); (2) 3rd heart sound; (3) resting tachycardia (heart rate > 100/min) attributable to CHF; (4) lower extremity pitting edema attributable to CHF; (5) bilateral rales; and/or (6) if a chest x-ray is performed, definite evidence of pulmonary edema, bilateral pleural effusion, or pulmonary vascular redistribution Current acute or chronic lung disease requiring supplemental chronic or intermittent oxygen therapy Serum creatinine > 2.0 mg/dL or 180 μmol/L Severe chronic anemia (hemoglobin < 7.5 g/dL) Pregnancy, breastfeeding or positive pregnancy test. (Women of childbearing age must have a negative pregnancy test prior to study drug administration) 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 subject

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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 (Dose: Equal volume) + 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>* The arm is for active comparison for PMZ-1620 (sovateltide), 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. Normal saline (vehicle) with standard treatment will be provided.<br>* Other names: Vehicle;|
| Experimental: PMZ-1620 + 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 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: Sovateltide (IRL-1620) along with standard treatment;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of PMZ-1620 related adverse events | The primary objective of the study is to determine incidence of drug (PMZ-1620) related adverse events. | 90 days | 
| Number of patients not receiving full treatment | Tolerability will be determined by the number of patients that do not receive all the 9 doses of PMZ-1620. | 90 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in National Institute of Health Stroke Scale (NIHSS) | To determine whether PMZ-1620 therapy over and above standard of care increases the proportion of ischemic stroke subjects with National Institute of Health Stroke Scale (NIHSS) score ≥ 6 score at 3 months. NIHSS is 42 point scale where 0 is the best o and 42 is the worst outcome. | 90 days | 
| Change in modified Rankin Scale (mRS) | Neurological outcome as assessed by modified Rankin Scale (mRS) score ≤ 2 at 3 months 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 EuroQol | Quality-of-life (QoL) as assessed by EuroQol at 3 months post randomization. European quality of life 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) at 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 (QVSFS) | 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 |