Clinical trial NCT04046484: PMZ-1620 (Sovateltide) in Acute Ischemic Stroke Patients
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Acute Stroke
Cerebral Ischemia
Lead sponsor: Pharmazz, Inc.
Sponsor class: INDUSTRY
First posted: 2019-08-06
Enrollment: 40
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
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: 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: 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.

Eligibility criteria: Inclusion Criteria:

1. Adult males or females Aged 18 years through 70 years (have not had their 71st birthday)
2. 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
3. Stroke is ischemic in origin, supratentorial, and radiologically confirmed Computed Tomography (CT) scan or diagnostic magnetic resonance imaging (MRI) prior to enrolment
4. 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)
5. No hemorrhage as proved by cerebral CT/MRI scan
6. 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
7. Reasonable expectation of availability to receive the full PMZ-1620 course of therapy, and to be available for subsequent follow-up visits
8. Subjects receiving thrombolytic therapy
9. Reasonable expectation that subject will receive standard post- stroke physical, occupational, speech, and cognitive therapy as indicated
10. 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:

1. Subjects receiving endovascular therapy
2. Subjects presenting with lacunar, hemorrhagic and/or brain stem stroke
3. 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)
4. 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)
5. 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
6. Known valvular heart disease with CHF in the last 6 months
7. Known (or in the Investigator's clinical judgment) existence of severe aortic stenosis or mitral stenosis
8. Cardiac surgery involving thoracotomy (e.g., coronary artery bypass graft, (CABG), valve replacement surgery) in the last 6 months
9. Subject is a candidate for any surgical intervention for treatment of stroke which may include but not limited to endovascular techniques
10. Subjects who are obese, body mass index (BMI) \> 30 and/or on hormonal contraceptives
11. 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
12. Patient has systolic BP \< 90 mmHg or \> 220 mmHg or diastolic BP \< 40 mmHg or \> 130 mmHg
13. Acute myocardial infarction in the last 6 months
14. Signs or symptoms of acute myocardial infarction, including electrocardiogram findings, on admission
15. Concomitant treatment with neuroprotective or nootropic drugs (e.g. piracetam, citicoline, investigational, neuroprotecti-ve substances)
16. Qualitative estimation of troponin on admission
17. Suspicion of aortic dissection on admission
18. Acute arrhythmia (including any tachy- or bradycardia) with hemodynamic instability on admission (systolic BP \< 100 mmHg)
19. 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
20. Current acute or chronic lung disease requiring supplemental chronic or intermittent oxygen therapy
21. Serum creatinine \> 2.0 mg/dL or 180 μmol/L
22. Severe chronic anemia (hemoglobin \< 7.5 g/dL)
23. Pregnancy, breastfeeding or positive pregnancy test. (Women of childbearing age must have a negative pregnancy test prior to study drug administration)
24. Concurrent participation in any other therapeutic clinical trial
25. 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

Primary outcomes:
measure: Incidence of PMZ-1620 related adverse events
timeFrame: 90 days
measure: Number of patients not receiving full treatment
timeFrame: 90 days
Secondary 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 EuroQol
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
Other outcomes:
Locations:
city: Gurgaon
country: India
facility: Paras Hospital
city: Hyderabad
country: India
facility: Nizam's Institute of Medical Sciences
city: Lucknow
country: India
facility: Sanjay Gandhi Post Graduate Institute of Medical Sciences
city: Ludhiana
country: India
facility: Dayanand Medical College & Hospital
city: Ludhiana
country: India
facility: Department of Neurology, Christian Medical College and Hospital
city: Nagpur
country: India
facility: New Era Hospital & Research Institute
city: New Delhi
country: India
facility: All India Institute of Medical Sciences
Study officials:
affiliation: Pharmazz, Inc.
name: Anil Gulati
role: STUDY_CHAIR
References:
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, 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: 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: 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: 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.