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

A Pilot, Randomized, Multicenter, Comparative, Open-label Study to Evaluate the Clinical, Laboratory, and Instrumental Efficacy and Safety of Mexidol® Solution for Intravenous and Intramuscular Administration, 50 mg/mL (LLC RPC "PHARMASOFT", Russia), and Mexidol® FORTE 250 Film-coated Tablets, 250 mg (LLC RPC "PHARMASOFT", Russia), in the Treatment of Ischemic Stroke in Hyperacute and Acute Periods

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.

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.

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.

Exclusion Criteria for Healthy Volunteers:

1. 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.
2. Galactose intolerance, lactase deficiency, or glucose-galactose malabsorption.
3. Any deviations from normal values during laboratory and/or instrumental examinations.
4. Inability to undergo blood sampling (e.g., due to compromised skin integrity at venipuncture sites).
5. History of intracranial hemorrhage of any etiology.
6. Hemophilia or other blood clotting disorders (including hypocoagulation states) and hemorrhagic diatheses.
7. Active bleeding of any etiology at the time of screening.
8. Decreased circulating blood volume (due to a salt-free diet, vomiting, or diarrhea).
9. Blood donation or blood loss (≥ 450 mL of blood or plasma) within 3 months prior to screening.
10. Any surgical procedures performed within 30 days prior to screening or planned during the study period.
11. Acute infectious diseases, as well as fungal infections, within 4 weeks prior to the start of screening.
12. Vaccination planned during the study or administered within 14 days prior to the start of screening.
13. Regular use of medications, including herbal and homeopathic remedies, vitamins, and/or dietary supplements, within 4 weeks prior to the start of screening.
14. Alcohol consumption within 72 hours prior to the start of screening.
15. 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.
16. Adherence to a specific diet (e.g., vegetarian, vegan, or low-salt diet) within 2 months prior to the start of screening.
17. Specific lifestyle factors (e.g., night-shift work, extreme physical exertion) within 2 months prior to the start of screening.
18. 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.
19. Smoking at the time of the screening visit.
20. Piercing, tattoos, or permanent makeup performed within 1 month prior to screening or planned during the study.
21. Mental, physical, or other reasons preventing the volunteer from adequately assessing their behavior and correctly following the Study Protocol requirements.
22. Inability or unwillingness to comply with required contraceptive measures.
23. Pregnancy (confirmed by a positive pregnancy test) or breastfeeding at the time of screening25.
24. Participation in another clinical trial within 3 months prior to the start of screening.
25. Other reasons that, in the investigator's opinion, preclude the volunteer's participation in this study.