Clinical trial NCT05691244: Assess the Safety and Efficacy of Sovateltide in Patients With Acute Cerebral Ischemic Stroke
Official title: A Multicentric, Randomized, Double-blind, Parallel, Placebo-controlled Phase III Study to Assess the Safety and Efficacy of Sovateltide in Patients With Acute Cerebral Ischemic Stroke.
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE3
Conditions: Acute Ischemic Stroke
Cerebral Stroke
Keywords: Endothelin B Receptors
Lead sponsor: Pharmazz, Inc.
Sponsor class: INDUSTRY
First posted: 2023-01-19
Enrollment: 514
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: This is a multi-centric, randomized, double-blind, placebo-controlled phase-III clinical study to assess the safety and efficacy of sovateltide in patients with acute cerebral ischemic stroke.
Primary purpose: TREATMENT

Brief summary: Extensive research is being conducted in search of neuroprotective agents for possible use in the acute phase of stroke and agents that can be used for neurorepair in later stages of stroke. Several trials have been conducted and are in progress using different pharmacological agents, but none of the studies involve the stimulation of ETB receptors to treat cerebral ischemic stroke. Sovateltide (IRL-1620, PMZ-1620) has been effective in animal models of cerebral ischemic stroke. Its safety and tolerability have been demonstrated in a human phase I study with 7 subjects. Clinical phase II and III results indicate that sovateltide is a novel, first-in-class, highly effective drug candidate for treating cerebral ischemic stroke. Safety and significant efficacy in improving the National Institutes of Health Stroke Scale (NIHSS), Modified Rankin scale (mRS), and Barthel index (BI) obtained in phase II and III studies in patients with cerebral ischemic stroke in India are convincing and encouraged us to investigate its safety and efficacy in cerebral ischemic stroke patients in the United States. Therefore, the plan is to conduct a phase III clinical study to evaluate the safety and efficacy of sovateltide therapy along with standard of care in patients of acute ischemic stroke.

Detailed description: A stroke is a syndrome defined as an abrupt neurological outburst due to impaired blood flow to part of the brain. There are two types of stroke: hemorrhagic stroke and ischemic stroke. A hemorrhagic stroke follows the rupture of a weakened blood vessel in the brain causing accumulation of blood and compression of the surrounding brain tissue. An ischemic stroke follows a blocked blood vessel by a thrombus (blood clot) or embolism. In both types of strokes, the specific region of the brain supplied by the affected blood vessel is deprived of oxygenated blood, causing local hypoxia that damages the brain tissue and cells. Both types of stroke are very serious, however ischemic stroke is more common.

The global burden of ischemic stroke is nearly 4-fold greater than hemorrhagic stroke with close to 87% of the total incidence of stroke attributed to acute cerebral ischemic stroke (ACIS). ACIS is a critical care emergency caused by a significant reduction in blood flow to the brain by a blood clot or embolism. This nearly halts cerebral blood flow to the affected region leading to neuronal death. Neuronal cell death is followed by plasma membrane disruption, swelling of organelles, leaking of cell contents into extracellular space, and loss of neuronal function. Other events that take place include inflammation, excitotoxicity, free radical mediated toxicity, cytokine mediated cytotoxicity, impaired blood-brain-barrier, and oxidative stress.

Therapeutic management of ACIS is a multidisciplinary approach with a primary goal of revascularization and limiting neuronal injury. A stroke team consists of emergency medicine physicians, neurologists/neurosurgeons, radiologists, nurses and advanced care providers, clinical pharmacists, therapists, technicians, and laboratory personnel. Currently, the only FDA-approved pharmacological agent for ischemic stroke is tissue plasminogen activator (t-PA). It is a thrombolytic agent which restores blood flow by breaking down a clot. However, timing is crucial in administration of t-PA as the therapeutic time window is very narrow and the patient must receive it within 4.5 hours of onset of stroke symptoms. Therapeutic administration after this timeframe can result in hemorrhagic transformation, leading to additional brain damage. Nevertheless, even upon timely administration of t-PA in ACIS, only about 30% of patients obtain stroke resolution having minimal or no disability at the 90-day mark.

Sovateltide (PMZ-1620, IRL-1620) is a highly selective ETB receptor agonist and a synthetic analog of ET-1. Studies conducted to determine the effects brought about by sovateltide upon its interaction with neural ETB receptors and have found that it enhances angiogenesis and neurogenesis as well as promotes neural repair and regeneration. In a rat model of ischemic stroke, sovateltide was found to be neuroprotective as well as enhance angiogenic and neurogenic remodeling. Sovateltide significantly improved survival, reduced neurological and motor function deficit, while effectively decreasing infarct volume, edema, and oxidative stress.

Sovateltide was also found to be safe and well tolerated in healthy human volunteers in a phase I clinical trial (CTRI/2016/11/007509). A phase II study was also conducted in patients with acute ischemic stroke where sovateltide demonstrated significant improvement when compared to standard of care (CTRI/2017/11/010654, NCT04046484). A recent phase III study conducted in patients of acute ischemic stroke demonstrated improved favorable functional and neurological outcome at 3 months compared to standard of care (CTRI/2019/09/021373, NCT04047563).

Clinical phase II and III results indicate that sovateltide is a first-in-class neuronal progenitor cell therapeutic that promotes quick recovery and significantly improves neurological outcomes in cerebral ischemic stroke patients. With this convincing evidence, the plan is to conduct a multicentric, randomized, double-blind, parallel, placebo-controlled phase III clinical study in the United States, Canada, United Kingdom and Europe (the demographics and standard of treatment being similar in these countries) to further assess the safety and efficacy of sovateltide in patients with acute cerebral ischemic stroke.

Eligibility criteria: Inclusion Criteria:

A patient will be eligible for inclusion in the study if he/she fulfills the following criteria:

1. Adult males or females aged 18 - 80 years of age.
2. Consent obtained per national laws and regulations, and in accordance with the applicable ethics committee requirements prior to study procedures.
3. A stroke is ischemic in origin that is diagnosed clinically and/or radiologically confirmed by 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 within 24 hours after the onset of symptoms with NIHSS score of ≥8 and \<20, NIHSS Level of Consciousness (1A) score \<2 at the time of screening. This includes cerebral ischemic stroke patients who completely recovered from earlier episodes before having a new or fresh stroke having a pre-stroke historical measure of mRS score of 0-2.
5. The patient is \<24 hours from the time of stroke onset when the first dose of sovateltide 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.
6. Reasonable expectation of availability to receive the full sovateltide/placebo course of therapy and to be available for subsequent follow-up visits.

Exclusion Criteria:

A patient will not be eligible for inclusion in this study if they meet any of the following exclusion criteria:

1. 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.
2. 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).
3. 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.
4. Known pregnancy and lactating women.
5. Known medical history of neurological (other than current acute ischemic stroke) or psychiatric condition that, in the investigator's opinion, would confound the neurological and functional evaluations, lead to further deterioration of neurological status, or interfere with participation in this study.
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 sovateltide therapy would be contraindicated or might cause harm to the patient.

Primary outcomes:
measure: Determine the efficacy of sovateltide in patients with acute cerebral ischemic stroke assessed by modified Rankin Scale (mRS) score of 0-2 at day 90 post-randomization.
timeFrame: Day 1 through Day 90
Secondary outcomes:
measure: Determine a good functional outcome in patients with acute cerebral ischemic stroke assessed by the National Institute of Health Stroke Scale (NIHSS) score of <6 at day 90 post-randomization.
timeFrame: Day 1 through Day 90
measure: Determine a good functional outcome in patients with acute cerebral ischemic stroke assessed by the Barthel Index (BI) score of ≥90 at day 90 post-randomization.
timeFrame: Day 1 through Day 90
measure: Determine an excellent functional outcome in patients with acute cerebral ischemic stroke assessed by a modified Rankin Scale score of 0-1 at day 90 post-randomization.
timeFrame: Day 1 through Day 90
measure: Determine a change in Quality-of-life (QoL) as assessed by EuroQol-EQ-5D-5L and Stroke-Specific Quality of Life (SS-QOL) at days 30, 60, and 90 post-randomization.
timeFrame: Day 1 through Day 90
measure: Determine the incidence of recurrent cerebral ischemic stroke within 90 days post-randomization.
timeFrame: Day 1 through Day 90
measure: Determine the incidence of mortality within 90 days post-randomization.
timeFrame: Day 1 through Day 90
measure: Determine the incidence of symptomatic Intracerebral Hemorrhage (ICH) within 24 (± 6) hours of randomization.
timeFrame: Day 1 through Day 90
measure: Determine the incidence of radiographic Intracerebral Hemorrhage (ICH) within 24 (± 6) hours of randomization.
timeFrame: Day 1 through Day 90
measure: Determine alteration in cognition at days 30 and 90 measured by Montreal Cognitive Assessment (MoCA) Test.
timeFrame: Day 1 through Day 90
measure: Determine any adverse events (AE) or serious adverse events (SAEs) are associated with sovateltide.
timeFrame: Day 1 through Day 90
Other outcomes:
measure: Determine a good functional outcome in patients with acute cerebral ischemic stroke assessed by mRS score of 0-2 at day 30 post-randomization.
timeFrame: Day 1 through Day 30
measure: Determine a good functional outcome in patients with acute cerebral ischemic stroke assessed by the NIHSS score of <6 at day 30 post-randomization.
timeFrame: Day 1 through Day 30
measure: Determine a good functional outcome in patients with acute cerebral ischemic stroke assessed by the BI score of ≥90 at day 30 post-randomization.
timeFrame: Day 1 through Day 30
measure: Determine Alberta Stroke Program Early CT (ASPECT) Score for stroke severity at baseline and identify sites of ischemic lesions.
timeFrame: Day 1 through Day 90
measure: Determine the subtype of acute cerebral ischemic stroke according to TOAST classification at day 30 post-randomization.
timeFrame: Day 1 through Day 30
Locations:
city: Chattanooga
country: United States
facility: CHI Memorial Neuroscience Institute
state: Tennessee
city: Altenburg
country: Germany
facility: Klinikum Altenburger Land GmbH
city: Bad Neustadt a.d. Saale
country: Germany
facility: Rhon-Klinikum Campus Bad Neustadt
city: Tübingen
country: Germany
facility: Universitatsklinikum Tubingen
city: Valencia
country: Spain
facility: Hospital Clinico Universitario de Valencia
city: Zaragoza
country: Spain
facility: Hospital Universitario Miguel Servet
Study officials:
affiliation: Pharmazz, Inc.
name: Anil Gulati, MD, PhD
role: STUDY_CHAIR
References:
citation: Gulati A, Adwani SG, Vijaya P, Agrawal NR, Ramakrishnan TCR, Rai HP, Jain D, Sundarachary NV, Pandian JD, Sardana V, Sharma M, Sidhu GK, Anand SS, Vibha D, Aralikatte S, Khurana D, Joshi D, Karadan U, Siddiqui MSI. Efficacy and Safety of Sovateltide in Patients with Acute Cerebral Ischaemic Stroke: A Randomised, Double-Blind, Placebo-Controlled, Multicentre, Phase III Clinical Trial. Drugs. 2024 Dec;84(12):1637-1650. doi: 10.1007/s40265-024-02121-5. Epub 2024 Nov 15.
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