Ischemic Stroke
Conditions
Keywords
Ischemic Stroke, Hyperacute Stroke, Acute Stroke, Cerebral Stroke, Acute Cerebrovascular Accident, ACVA, Acute cerebral failure, Cerebral Infarction, Neuroprotection, Mexidol, Ethylmethylhydroxypyridine Succinate, Antioxidants
Brief summary
The primary objective of this study is to further define the mechanisms of action of Mexidol® (solution for intravenous and intramuscular injection, 50 mg/ml) and Mexidol® FORTE 250 (film-coated tablets, 250 mg) in the hyperacute and acute periods of ischemic stroke, and to evaluate their impact on clinical and neuroimaging outcomes of the disease.
Detailed description
This is a pilot, randomized, multicenter, comparative, open-label study designed to evaluate the clinical, laboratory, and instrumental efficacy and safety of sequential Mexidol® therapy in patients during the hyperacute and acute periods of ischemic stroke. The study will include 100 patients with acute ischemic stroke and 20 healthy volunteers to establish baseline biomarker values. Patients with ischemic stroke will be randomized in a 1:1 ratio to one of two treatment arms. Group 1 (Experimental) will receive Mexidol® solution (500 mg twice daily, IV drip) for the first 10 days, followed by Mexidol® FORTE 250 tablets (250 mg three times daily) for 60 days. This therapy is administered on top of standard background treatment. Group 2 (Active Comparator) will receive Glycine sublingual tablets (1 g daily) for 5 days on top of standard background treatment. A separate non-randomized healthy volunteer reference group will be enrolled for assessment of normal biomarker levels and will not receive study treatment.
Interventions
DRUGMexidol
Phase 1 (Days 1-10): Mexidol® solution, 500 mg (10 ml) twice daily (total daily dose 1000 mg) administered via IV infusion in 100-200 ml of 0.9% NaCl solution for 10 days. Infusion rate: 40-60 drops per minute. Phase 2 (Days 11-70): Mexidol® FORTE 250 film-coated tablets, 250 mg three times daily (total daily dose 750 mg) for 60 days. Administered on top of standard background therapy in accordance with the 2024 Clinical Guidelines of the Ministry of Health of the Russian Federation for Ischemic Stroke and TIA.
DRUGGlycine
Glycine, 100 mg sublingual tablets, 1 g (10 tablets) daily for 5 days. Administered on top of standard background therapy in accordance with the 2024 Clinical Guidelines of the Ministry of Health of the Russian Federation for Ischemic Stroke and TIA.
Sponsors
Pharmasoft
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 90 Years
Healthy volunteers
Yes
Inclusion criteria
for Patients: 1. Signed and dated Informed Consent Form (ICF) by the patient or their legal representative (in case of physical inability to sign), and/or a Decision of the Medical Board. 2. Men and women aged 18 to 90 years (inclusive) at the time of signing the ICF or Decision of the Medical Board. 3. First-ever hemispheric ischemic stroke (ICD-10 codes: I63.0-I63.9), confirmed by neuroimaging (CT or MRI). 4. Presence of occlusion in the internal carotid artery (ICA) system at any level, including the middle cerebral artery (MCA) and anterior cerebral artery (ACA) (anterior circulation) and/or presence of neuroimaging signs, characteristic of acute cerebral ischemia (based on CT perfusion and/or MRI data in accordance with current Clinical Guidelines). Note: Presence of internal carotid artery (ICA) occlusion is not a mandatory criterion; neuroimaging signs of acute cerebral ischemia (CT perfusion/MRI) are sufficient for inclusion. 5. Time from the onset of acute ischemic stroke symptoms or the time the patient was last known to be well (last known well, LKW) to randomization is no more than 36 hours. 6. No significant pre-stroke disability (the patient is able to carry out all daily activities and duties without assistance, a score of 0-1 on the modified Rankin Scale (mRS)). 7. Total National Institutes of Health Stroke Scale (NIHSS) score of 6 to 20 (inclusive) at screening, provided that the score for item 5a/b (Motor Arm: Left/Right) is at least 2 points on the paretic side and/or item 6a/b (Motor Leg: Left/Right) is at least 2 points on the paretic side. 8. 8\. Agreement to use highly effective methods of contraception throughout the study and for 3 weeks after study completion. Eligible participants include: women of childbearing potential, who must have a negative pregnancy test and agree to use the following contraceptive methods: a barrier method (condom or occlusive cap \[diaphragm or cervical/vault cap\]) or a double-barrier method (condom or occlusive cap \[diaphragm or cervical/vault cap\] plus spermicide \[foam/gel/film/cream/suppository\]); women of non-childbearing potential with documented history of hysterectomy, tubal ligation, infertility, or postmenopausal status (at least 1 year of amenorrhea); fertile men who must agree to use barrier contraception; men with documented infertility or prior vasectomy. Inclusion Criteria for Healthy Volunteers: 1. White male and female participants aged 18 to 45 years inclusive at the time of signing the Informed Consent Form (ICF). 2. Verified "healthy" status based on standard clinical, laboratory, and instrumental examination methods. 3. Ability to provide written informed consent prior to any screening procedures, and the ability, in the investigator's opinion, to comply with all study protocol requirements. 4. Hemodynamic parameters: systolic blood pressure (SBP) within 100-130 mmHg, diastolic blood pressure (DBP) within 60-90 mmHg, heart rate (HR) 60-90 bpm, and respiratory rate (RR) 16-20 breaths per minute. 5. Body Mass Index (BMI) from 18.5 to 30 kg/m² inclusive. 6. Willingness to abstain from alcohol throughout the entire study period. 7. Agreement to use highly effective methods of contraception throughout the entire study. Eligible participants include: women of childbearing potential, who must have a negative pregnancy test and agree to use the following contraceptive methods: a barrier method (condom or occlusive cap \[diaphragm or cervical/vault cap\]) or a double-barrier method (condom or occlusive cap \[diaphragm or cervical/vault cap\] plus spermicide \[foam/gel/film/cream/suppository\]); women of non-childbearing potential with documented history of hysterectomy, tubal ligation, infertility, or postmenopausal status (at least 1 year of amenorrhea); fertile men who must agree to use barrier contraception; men with documented infertility or prior vasectomy.
Exclusion criteria
for Patients: 1. Hypersensitivity to ethylmethylhydroxypyridine succinate or any other components of the investigational product. 2. Galactose intolerance, lactase deficiency, or glucose-galactose malabsorption. 3. Inability to take oral medications. 4. Contraindications or inability to undergo CT/MRI procedures (including, but not limited to: permanent cardiac pacemakers/neurostimulators; inner ear prosthesis, ferromagnetic or electronic middle ear implants, hemostatic clips, cardiac valve prostheses, or any other metal-containing structures; ferromagnetic fragments; insulin pumps; severe claustrophobia). 5. Inability to undergo contrast-enhanced imaging for any reason. 6. Patients who have received or are scheduled to receive thrombolytic therapy or thrombectomy for the current episode of ischemic stroke. 7. Recurrent ischemic stroke. 8. Direct signs of irreversible total occlusion of the internal carotid artery (ICA) system at the relevant level within the current episode of ischemic stroke (based on CT/MRI data). 9. Absence of neuroimaging signs of acute ischemic brain injury. 10. Presence of any of the following neuroimaging (CT/MRI) findings: * Intracranial hemorrhage; * Hemorrhagic transformation of the cerebral infarction; * Subarachnoid hemorrhage; * Brain tumor; * Arteriovenous malformation (AVM); * Brain abscess; * Cerebral aneurysm; * Edema of the infarct zone leading to brain structure displacement (malignant cerebral infarction). 11. Lesion in the vertebrobasilar system. 12. Any suspicion of subarachnoid hemorrhage (SAH) in the medical history or at the time of screening. 13. History of hemorrhagic stroke or stroke of unspecified nature. 14. Any known history of conditions associated with a bleeding tendency. 15. Deep vein thrombosis (DVT) or pulmonary embolism (PE), or detection of a floating thrombus. 16. Traumatic brain injury (TBI) within 6 months prior to screening. 17. History of brain or spinal cord surgery within 5 years prior to study enrollment. 18. Need for surgical intervention during participation in the clinical study. 19. History of epilepsy. 20. History of severe cognitive impairment, including dementia. 21. Parkinson's disease. 22. History of hereditary degenerative diseases of the Central Nervous System (CNS). 23. History of demyelinating diseases of the nervous system. 24. History of severe or global aphasia and/or clinical evidence of these conditions at screening. 25. Myocardial infarction within 3 months prior to screening. 26. NYHA Class III-IV chronic heart failure at the time of screening. 27. Unstable angina pectoris at the time of screening. 28. SBP ≥ 200 mmHg and/or DBP ≥ 100 mmHg at the time of screening. 29. History of Stage III-IV Chronic Obstructive Pulmonary Disease (COPD). 30. Uncontrolled diabetes mellitus. 31. Renal impairment (creatinine clearance \< 50 mL/min calculated by the Cockcroft-Gault formula) at the time of screening. 32. Hepatic impairment (AST and/or ALT ≥ 2 × ULN and/or total bilirubin ≥ 1.5 × ULN) at the time of screening. 33. History of HIV, syphilis, hepatitis B, and/or hepatitis C. 34. Acute infectious diseases (influenza, upper respiratory tract infections, etc.) within 4 weeks prior to screening. 35. Use of prohibited medications or other drugs that, in the investigator's opinion, may interfere with the study results within 30 days prior to screening, or the anticipated need for such medications during the patient's participation in the study. 36. Use of medications based on ethylmethylhydroxypyridine succinate for 3 or more consecutive days within 2 weeks prior to randomization. 37. Systemic autoimmune diseases or vascular collagenoses requiring prior or current treatment with systemic corticosteroids, cytostatics, or other immunosuppressants. 38. History of malignant neoplasms, except for patients who have been disease-free for the past 5 years, or those with completely cured basal cell carcinoma of the skin, or completely cured carcinoma in situ. 39. Other severe, decompensated, or unstable medical conditions that, in the investigator's opinion, are life-threatening, adversely affect the patient's prognosis, or preclude safe participation in the study. 40. Life expectancy of less than 6 months. 41. Unwillingness or inability of the patient to comply with the study protocol procedures (in the investigator's opinion). 42. Pregnancy or breastfeeding (for women). 43. History of alcoholism, drug addiction, or substance abuse and/or presence of these conditions at screening. 44. History of schizophrenia, schizoaffective disorder, bipolar disorder, or other psychiatric disorders. 45. Participation in another clinical trial within 3 months prior to study enrollment. 46. Any other conditions that, in the investigator's opinion, preclude the patient's inclusion in the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Infarct Volume at Visit 2 (Day 11) | Day 11 (Visit 2). | Evaluation of the ischemic lesion volume using Diffusion-Weighted Imaging (DWI). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Infarct Volume from Baseline to Visit 2 (Day 11) | Baseline (Visit 0) and Day 11 (Visit 2) | Assessment of ischemic lesion dynamics measured by Diffusion-Weighted Imaging (DWI). |
| Incidence of Symptomatic Hemorrhagic Transformation (sHT) by Visit 2 (Day 11) | Up to Day 11 (Visit 2) | Number of participants with new intracranial hemorrhage associated with any of the following, according to the Heidelberg Criteria: * Increase in NIHSS total score by ≥ 4 compared to the score immediately prior to deterioration; OR * Increase in any single NIHSS subscale score by ≥ 2; OR * Need for intubation, hemicraniectomy, or ventricular drainage; OR * No other clinical explanation for the patient's deterioration. |
| Change in laboratory biomarkers (TNF-α, BDNF, NSE, GFAP, MMP-9, Caspase-3, VCAM-1, MBP, fibronectin) | Baseline (Visit 0) and Day 11 (Visit 2) | Evaluation of the dynamics of laboratory markers to clarify the mechanism of action. |
| Assessment of coagulation parameters (D-dimer, fibrinogen). | Baseline (Visit 0) and Day 11 (Visit 2) | Evaluation of blood coagulation dynamics |
| Metabolomic assessment (lactate, pyruvate, succinate, malate, fumarate, oxoglutarate, ATP, AMP, ADP, MDA, glutamate, GABA, glycine). | Baseline (Visit 0) and Day 11 (Visit 2) | Evaluation of the dynamics of key metabolites and energy metabolism markers |
| Mean modified Rankin Scale (mRS) score at Visit 2 (Day 11), Visit 3 (Day 30±2), Visit 4 (Day 70±2), and Visit 5 (Day 90±2). | Day 11 (Visit 2), Day 30±2 (Visit 3), Day 70±2 (Visit 4), and Day 90±2 (Visit 5) | The Modified Rankin Scale (mRS) is used to measure the degree of disability in patients who have had a stroke. Possible scores range from 0 (no symptoms at all) to 6 (death) \[6 point scale: min value 0, max value 6, higher scores mean a worse outcome\]. |
| Change from baseline (Visit 0) in the total NIHSS score (The National Institutes of Health Stroke Scale) at Visit 2 (Day 11). | Baseline (Visit 0) and Day 11 (Visit 2) | The National Institutes of Health Stroke Scale (NIHSS) is a 15-item neurologic examination stroke scale used to evaluate the effect of acute cerebral infarction on the levels of consciousness, language, neglect, visual-field loss, extraocular movement, motor strength, ataxia, dysarthria, and sensory loss. Ratings for each item are scored with 3 to 5 grades with 0 as normal, and there is an allowance for untestable items. The individual scores from each item are summed in order to calculate a patient's total NIHSS score. The maximum possible score is 42 (severe stroke), with the minimum score being a 0 (no stroke symptoms) \[43 point scale: min value 0, max value 42, higher scores mean a worse outcome\]. |
| Mean total NIHSS score at Visit 2 (Day 11). | Day 11 (Visit 2) | The National Institutes of Health Stroke Scale (NIHSS) is a 15-item neurologic examination stroke scale used to evaluate the effect of acute cerebral infarction on the levels of consciousness, language, neglect, visual-field loss, extraocular movement, motor strength, ataxia, dysarthria, and sensory loss. Ratings for each item are scored with 3 to 5 grades with 0 as normal, and there is an allowance for untestable items. The individual scores from each item are summed in order to calculate a patient's total NIHSS score. The maximum possible score is 42 (severe stroke), with the minimum score being a 0 (no stroke symptoms) \[43 point scale: min value 0, max value 42, higher scores mean a worse outcome\]. |
| All-cause mortality rate by Visits 2, 3, 4, and 5. | Up to Day 11 (Visit 2), Day 30 (Visit 3), Day 70 (Visit 4), and Day 90 (Visit 5). | The proportion of participants with a fatal outcome (all-cause mortality). |
| Assessment of MRI parameters at Visit 2 (Day 11) | Day 11 (Visit 2) | Evaluation of brain structural parameters using Magnetic Resonance Imaging (MRI) |
| Assessment of CT parameters at Visit 2 (Day 11) | Day 11 (Visit 2) | Evaluation of brain structural parameters using Computed Tomography (CT) |
| Assessment of Safety and Tolerability | From Day 1 (Visit 1) to Day 90 (Visit 5) | Total number of adverse events (AEs), stratified by severity and frequency; Incidence of adverse drug reactions (ADRs); Incidence of serious adverse events (SAEs) related to the investigational or comparator products; Proportion of participants with at least one reported AE; Proportion of participants who discontinued treatment due to AEs. |
Countries
Russia
Contacts
CONTACTYuriy E. Meshcherskiy, Medical Director, LLC "RPC "PHARMASOFT", Medical Director
Outcome results
None listed