Mexidol® Safety and Efficacy in Treatment of Hyperacute and Acute Ischemic Stroke

Prior treatment

• Hypersensitivity to ethylmethylhydroxypyridine succinate or any other components of the investigational product.
• Inability to take oral medications.
• Patients who have received or are scheduled to receive thrombolytic therapy or thrombectomy for the current episode of ischemic stroke.
• Traumatic brain injury (TBI) within 6 months prior to screening.
• History of brain or spinal cord surgery within 5 years prior to study enrollment.
• Need for surgical intervention during participation in the clinical study.
• Myocardial infarction within 3 months prior to screening.
• Acute infectious diseases (influenza, upper respiratory tract infections, etc.) within 4 weeks prior to screening.
• 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.
• Use of medications based on ethylmethylhydroxypyridine succinate for 3 or more consecutive days within 2 weeks prior to randomization.
• Systemic autoimmune diseases or vascular collagenoses requiring prior or current treatment with systemic corticosteroids, cytostatics, or other immunosuppressants.
• Participation in another clinical trial within 3 months prior to study enrollment.
• Blood donation or blood loss (≥ 450 mL of blood or plasma) within 3 months prior to screening.
• Any surgical procedures performed within 30 days prior to screening or planned during the study period.
• Acute infectious diseases, as well as fungal infections, within 4 weeks prior to the start of screening.
• Vaccination planned during the study or administered within 14 days prior to the start of screening.
• Regular use of medications, including herbal and homeopathic remedies, vitamins, and/or dietary supplements, within 4 weeks prior to the start of screening.
• Alcohol consumption within 72 hours prior to the start of screening.
• Use of medications with a significant effect on hemodynamics and/or liver function (e.g., barbiturates, omeprazole, cimetidine, etc.), injectable or oral hormonal contraceptives, subcutaneous hormonal implants, or intrauterine systems within 2 months prior to screening procedures.
• Adherence to a specific diet (e.g., vegetarian, vegan, or low-salt diet) within 2 months prior to the start of screening.
• Specific lifestyle factors (e.g., night-shift work, extreme physical exertion) within 2 months prior to the start of screening.
• Piercing, tattoos, or permanent makeup performed within 1 month prior to screening or planned during the study.
• Participation in another clinical trial within 3 months prior to the start of screening.

Other illness

• 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).
• Recurrent ischemic stroke.
• 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).
• 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).
• Any suspicion of subarachnoid hemorrhage (SAH) in the medical history or at the time of screening.
• History of hemorrhagic stroke or stroke of unspecified nature.
• Any known history of conditions associated with a bleeding tendency.
• Deep vein thrombosis (DVT) or pulmonary embolism (PE), or detection of a floating thrombus.
• History of epilepsy.
• History of severe cognitive impairment, including dementia.
• Parkinson's disease.
• History of hereditary degenerative diseases of the Central Nervous System (CNS).
• History of demyelinating diseases of the nervous system.
• History of severe or global aphasia and/or clinical evidence of these conditions at screening.
• NYHA Class III-IV chronic heart failure at the time of screening.
• Unstable angina pectoris at the time of screening.
• History of Stage III-IV Chronic Obstructive Pulmonary Disease (COPD).
• Uncontrolled diabetes mellitus.
• History of HIV, syphilis, hepatitis B, and/or hepatitis C.
• 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.
• 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.
• History of alcoholism, drug addiction, or substance abuse and/or presence of these conditions at screening.
• History of schizophrenia, schizoaffective disorder, bipolar disorder, or other psychiatric disorders.
• Any other conditions that, in the investigator's opinion, preclude the patient's inclusion in the study.
• Acute or chronic diseases of the cardiovascular, bronchopulmonary, endocrine, and nervous systems, including organic central nervous system (CNS) disorders, as well as gastrointestinal (GI), hepatic, renal, and hematological diseases.
• History of intracranial hemorrhage of any etiology.
• Hemophilia or other blood clotting disorders (including hypocoagulation states) and hemorrhagic diatheses.
• Active bleeding of any etiology at the time of screening.
• History of alcohol consumption exceeding 10 units per week (1 unit is equivalent to 500 mL of beer, 200 mL of wine, or 50 mL of spirits), or a medical history of alcoholism, drug addiction, or substance abuse.

Lab values

• Galactose intolerance, lactase deficiency, or glucose-galactose malabsorption.
• Renal impairment (creatinine clearance \< 50 mL/min calculated by the Cockcroft-Gault formula) at the time of screening.
• Hepatic impairment (AST and/or ALT ≥ 2 × ULN and/or total bilirubin ≥ 1.5 × ULN) at the time of screening.
• Galactose intolerance, lactase deficiency, or glucose-galactose malabsorption.
• Any deviations from normal values during laboratory and/or instrumental examinations.

Other

• Inability to undergo contrast-enhanced imaging for any reason.
• Absence of neuroimaging signs of acute ischemic brain injury.
• Lesion in the vertebrobasilar system.
• SBP ≥ 200 mmHg and/or DBP ≥ 100 mmHg at the time of screening.
• Life expectancy of less than 6 months.
• Unwillingness or inability of the patient to comply with the study protocol procedures (in the investigator's opinion).
• Pregnancy or breastfeeding (for women).
• Inability to undergo blood sampling (e.g., due to compromised skin integrity at venipuncture sites).
• Decreased circulating blood volume (due to a salt-free diet, vomiting, or diarrhea).
• Smoking at the time of the screening visit.
• Mental, physical, or other reasons preventing the volunteer from adequately assessing their behavior and correctly following the Study Protocol requirements.
• Inability or unwillingness to comply with required contraceptive measures.
• Pregnancy (confirmed by a positive pregnancy test) or breastfeeding at the time of screening25.
• Other reasons that, in the investigator's opinion, preclude the volunteer's participation in this study.

• 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.
• Men and women aged 18 to 90 years (inclusive) at the time of signing the ICF or Decision of the Medical Board.
• First-ever hemispheric ischemic stroke (ICD-10 codes: I63.0-I63.9), confirmed by neuroimaging (CT or MRI).
• 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.
• 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.
• 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)).
• 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\. 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.
• White male and female participants aged 18 to 45 years inclusive at the time of signing the Informed Consent Form (ICF).
• Verified "healthy" status based on standard clinical, laboratory, and instrumental examination methods.
• 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.
• 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.
• Body Mass Index (BMI) from 18.5 to 30 kg/m² inclusive.
• Willingness to abstain from alcohol throughout the entire study period.
• 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.