Clinical trial NCT04047563: Efficacy of Sovateltide (PMZ-1620) in Patients of Acute Ischemic Stroke
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Cerebral Ischemia
Cerebral Infarction
Stroke, Acute
Keywords: Endothelin
Neurogenesis
Neural progenitor cells
Lead sponsor: Pharmazz, Inc.
Sponsor class: INDUSTRY
First posted: 2019-08-06
Enrollment: 158
Sex: ALL
Minimum age (years): 18
Maximum age (years): 78
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention 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.
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: Inclusion Criteria:

1. Adult males or females Aged 18 years through 78 years (have not had their 79th birthday).
2. Patient or Legally Authorized Representative willing to give informed Consent before study procedure.
3. 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.
4. 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.
5. 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.
6. Reasonable expectation of availability to receive the full PMZ-1620 course of therapy, and to be available for subsequent follow-up visits.

Exclusion Criteria:

1. 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.
2. 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).
3. Evidence of intracranial hemorrhage (intracerebral hematoma, intraventricular hemorrhage, subarachnoid hemorrhage, epidural hemorrhage, acute or chronic subdural hematoma on the baseline CT or MRI scan.
4. Known pregnancy.
5. Confounding pre-existing neurological or psychiatric disease.
6. Concurrent participation in any other therapeutic clinical trial.
7. 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.

Primary outcomes:
measure: Change in National Institute of Health Stroke Scale (NIHSS)
timeFrame: 90 days
measure: Change in modified Rankin Scale (mRS)
timeFrame: 90 days
measure: Change in Barthel index [BI]
timeFrame: 90 days
measure: Change in the proportion of ischemic stroke patients with NIHSS score <6
timeFrame: 90 days
measure: Change in the proportion of ischemic stroke patients with mRS score <2
timeFrame: 90 days
measure: Change in the proportion of ischemic stroke patients with Barthel index (BI) score >60
timeFrame: 90 days
Secondary outcomes:
measure: Change in Quality-of-life as assessed by EuroQol-EQ-5D
timeFrame: 90 days
measure: Change in Stroke-Specific Quality of Life (SSQOL)
timeFrame: 90 days
measure: Incidence in recurrence of ischemic stroke
timeFrame: 90 days
measure: Incidence of mortality
timeFrame: 90 days
measure: Incidence of Intra-Cerebral Hemorrhage (ICH)
timeFrame: 30 hours
measure: Incidence of PMZ-1620 related adverse events
timeFrame: 90 days
Other outcomes:
Locations:
city: Agra
country: India
facility: Pushpanjali Hospital & Research Centre Pvt. Ltd
state: Uttar Pradesh
city: Amravati
country: India
facility: Radiant Superspeciality Hospital
city: Chandigarh
country: India
facility: Post Graduate Institute of Medical Education and Research
city: Guntur
country: India
facility: Lalitha Superspecialities Hospital
city: Ludhiana
country: India
facility: Dayanand Medical College & Hospital
city: Ludhiana
country: India
facility: Department of Neurology, Christian Medical College and Hospital
city: Ludhiana
country: India
facility: Sidhu Hospital Pvt. Ltd.
city: Nagpur
country: India
facility: New Era Hospital & Research Institute
city: Nashik
country: India
facility: Chopda Medicare & Research Centre
city: New Delhi
country: India
facility: All India Institute of Medical Sciences
city: New Delhi
country: India
facility: Indian Spinal Injury Centre
Study officials:
affiliation: Chairman and CEO
name: Anil Gulati, MD, PhD
role: STUDY_CHAIR
References:
citation: 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.
citation: Cifuentes EG, Hornick MG, Havalad S, Donovan RL, Gulati A. Neuroprotective Effect of IRL-1620, an Endothelin B Receptor Agonist, on a Pediatric Rat Model of Middle Cerebral Artery Occlusion. Front Pediatr. 2018 Oct 23;6:310. doi: 10.3389/fped.2018.00310. eCollection 2018.
citation: 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.
citation: Bhalla S, Leonard MG, Briyal S, Gulati A. Distinct Alteration in Brain Endothelin A and B Receptor Characteristics Following Focal Cerebral Ischemia in Rats. Drug Res (Stuttg). 2016 Apr;66(4):189-95. doi: 10.1055/s-0035-1559779. Epub 2015 Sep 23.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: Gulati A, Agrawal N, Vibha D, Misra UK, Paul B, Jain D, Pandian J, Borgohain R. Safety and Efficacy of Sovateltide (IRL-1620) in a Multicenter Randomized Controlled Clinical Trial in Patients with Acute Cerebral Ischemic Stroke. CNS Drugs. 2021 Jan;35(1):85-104. doi: 10.1007/s40263-020-00783-9. Epub 2021 Jan 11.