Clinical trial NCT02793687: Study of Efficacy and Safety of MEXIDOL® in Ischemic Stroke Therapy
Official title: Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel-group Study of Efficacy and Safety of Mexidol® in Long-term Sequential Treatment of Patients in the Acute and Early Recovery Periods of Hemispheric Ischemic Stroke (EPICA)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Ischemic Stroke
Keywords: Stroke
Ischemic Stroke
Neuroprotective Agents
Nootropic Agents
Antioxidants
Randomized Controlled Trials as Topic
Recovery of Function
Mexidol
Ethylmethylhydroxypyridine Succinate
Brain Ischemia
Acute Stroke
Acute Cerebrovascular Accident
Cerebral Stroke
Neuroprotection
Lead sponsor: Pharmasoft
Sponsor class: INDUSTRY
First posted: 2016-06-08
Enrollment: 150
Sex: ALL
Minimum age (years): 40
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to evaluate the efficacy and safety of long-term sequential therapy with Mexidol® in long-term sequential treatment of patients in the acute and early recovery periods of hemispheric ischemic stroke (IS). This is superiority trial that investigates whether Mexidol® better than placebo.

Detailed description: In the course of a clinical study involving patients, the efficacy and safety of prolonged sequential therapy with Mexidol® (solution for intravenous and intramuscular administration / coated tablets) were evaluated compared to placebo in patients with hemispheric ischemic stroke during the acute and early recovery periods. The use of Mexidol® (solution for intravenous and intramuscular administration / coated tablets) and placebo (solution for intravenous and intramuscular administration / coated tablets) was conducted against the background of standard baseline therapy.

Throughout the study, both the investigational drug Mexidol® and the placebo, used alongside baseline therapy, were tolerated satisfactorily. In this clinical study, 37 cases of adverse events (AEs) not meeting the criteria for severity were recorded in 28 patients, along with 4 AEs that were categorized as serious adverse events (SAEs) in 4 patients. Most of the registered AEs required appropriate corrective therapy but did not necessitate other medical interventions and resolved by the end of the patient's participation in the study. According to the researchers, in the majority of recorded AEs, the relationship with the investigational drugs was determined to be absent (no relationship).

When comparing the frequency of registration of both individual AEs and SAEs, no statistically significant differences (p \< 0.05) were found in the frequency of AEs/SAEs in patients after taking the investigational drug (Mexidol®) and the comparison drug (placebo). According to the conducted clinical study, the safety profile of Mexidol® remained unchanged and favorable. No new safety signals were recorded during the course of the study.

The primary endpoint is the results of testing using the modified Rankin Scale (mRS) at the end of the therapy course (in both the investigational and control groups). In the overall population of patients included in the efficacy analysis, positive dynamics were observed in both the Mexidol® group and the placebo group (p \< 0.001): a decrease in the mean scores on the scale throughout the study; a statistically significant difference was also identified between the mean scores on the mRS at visit 5 compared to baseline values (visit 1) in both groups. Additionally, at visit 5, a statistically significant difference was observed between the treatment groups (p = 0.04) regarding the total scores on the modified Rankin Scale: the average score for the Mexidol® group was 1.098 points, while for the placebo group, it was 1.46 points. No statistically significant differences between the groups were found at other visits. The assessment of the change in mRS score from baseline (visit 1) to the end of therapy (visit 5) showed statistically significant differences (p = 0.04) between the treatment groups: in the Mexidol® group, the value was 1.098; in the placebo group, it was 1.460.

Thus, Mexidol® demonstrated greater efficacy compared to placebo when used alongside baseline therapy in patients with hemispheric ischemic stroke during the acute and early recovery period based on the primary efficacy criterion, which is the results of testing using the modified Rankin Scale (mRS) at the end of the therapy course.

Furthermore, the study demonstrated the efficacy of Mexidol® therapy concerning several secondary efficacy endpoints. Mexidol® showed greater efficacy in treating hemispheric ischemic stroke compared to placebo when using the specialized scale for this condition-the NIHSS (National Institutes of Health Stroke Scale). In testing using the Beck Depression Inventory (BDI), the efficacy of Mexidol® regarding cognitive disorders in patients who suffered strokes with concurrent diabetes was also identified.

Eligibility criteria: Inclusion Criteria:

1. Clinical diagnosis of first-ever hemispheric ischemic stroke (codes ICD-10: I63.0 - I63.9).
2. Age 18-80 years
3. The ability to understand the purpose of research, risks associated with the research intervention, obligations and consequences of research participation and their right of withdrawing consent any time during the study.
4. The time from onset of a stroke \<72 hours.
5. The Modified Rankin Scale (mRS) score ≥3.
6. The National Institutes of Health Stroke Scale (NIHSS) score from 5 to 15 points.
7. The Beck Depression Inventory (BDI) score \<19 points.
8. The written informed consent form (ICF) is signed and personally dated by the participant or by an impartial witness (by a person who is independent of the trial and cannot be unduly influenced by the people involved with the trial and who attends the informed consent process).
9. Negative pregnancy test for women of childbearing age.
10. Willingness to use reliable methods of contraception, and/or abstinence, for the duration of therapeutic product exposure.

Exclusion Criteria:

1. No evidence of clinical diagnosis of first-ever hemispheric ischemic stroke (codes ICD-10: I63.0 - I63.9).
2. Age \<40 and \> 80 years.
3. The National Institutes of Health Stroke Scale (NIHSS) score is \<5 or \>15 points.
4. Hemorrhagic stroke confirmed with CT/MRI.
5. Hemorrhagic transformation of ischemic stroke.
6. Recurrent ischemic stroke.
7. Parkinson's disease.
8. Epilepsy.
9. Demyelinating diseases of central nervous system.
10. Hereditary and degenerative diseases of the central nervous system.
11. Infectious diseases of central nervous system in medical history.
12. Traumatic brain injury with severe neurocognitive impairment in medical history.
13. Unstable angina pectoris.
14. The participant had a heart attack within 3 months prior to enrollment.
15. Heart failure class IV (NYHA).
16. 2nd and 3rd-degree atrioventricular block.
17. Systemic connective tissue disorders.
18. Chronic obstructive pulmonary disease (stage III or IV).
19. Acute surgical pathology
20. Severe decompensated heart failure/liver disease/kidney disease (including acute or chronic kidney/hepatic failure).
21. Medical history of oncology diseases, tuberculosis, immunodeficiency disorders, mental disorders or alcohol/drug addiction.
22. The investigator's decision not to enroll participant due to any severe condition that can be issue of safety or treatment efficacy.
23. Acute infectious diseases (influenza, SARS, etc.) within 4 weeks prior to enrollment.
24. Evidence of lactose intolerance, galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption.
25. Pregnancy or breastfeeding.
26. Any reason (including mental or physical states) that can affect participant's capability to follow protocol procedures.
27. The participant (or their relative) is affiliated with the clinical site or Sponsor company.
28. Participation in another clinical trial within 3 months prior to enrollment.
29. Evidence of hypersensitivity reactions or intolerance associated with ethylmethylhydroxypyridine, succinate drugs or Vitamin B6.
30. Medical contraindications for Mexidol®.
31. The written informed consent form (ICF) is not signed and personally dated by the participant or by an impartial witness.

Primary outcomes:
measure: Mean Score of the 6-point Modified Rankin Scale (mRS) at Visit 5 After Completion of the Course of Therapy for Both Arms
timeFrame: Visit 5 (67-71 Day).
Secondary outcomes:
measure: Mean Score of the 15-item The National Institutes of Health Stroke Scale (NIHSS) at Visit 5 After Completion of the Course of Therapy for Both Arms
timeFrame: Visit 5 (67-71 Day)
measure: Mean Score of the 10-item Barthel Index (BI) at Visit 5 After Completion of the Course of Therapy for Both Arms
timeFrame: Time frame: Visit 5 (67-71 Day)
measure: Mean Score of the 21-item Beck Depression Inventory (BDI) at Visit 5 After Completion of the Course of Therapy for Both Arms.
timeFrame: Visit 5 (67-71 Day)
measure: Mean Score of on the EQ-5D-3L PRO Measure (VAS) at Visit 5 After Completion of the Course of Therapy for Both Arms.
timeFrame: Visit 5 (67-71 Day)
Other outcomes:
Locations:
city: Kazan
country: Russian Federation
facility: Tatarstan Republican Clinical Hospital
city: Kazan
country: Russian Federation
facility: Interregional Clinical Diagnostic Center
city: Kazan
country: Russian Federation
facility: Kazan Clinical Hospital № 7
city: Novosibirsk
country: Russian Federation
facility: Research Institute of Experimental and Clinical Medicine
city: Saint Petersburg
country: Russian Federation
facility: St. Petersburg Clinical Hospital № 26
city: Saint Petersburg
country: Russian Federation
facility: St. Petersburg Clinical Hospital № 2
city: Saint Petersburg
country: Russian Federation
facility: St. Petersburg "Nikolaevskaya" Hospital
city: Samara
country: Russian Federation
facility: Samara Regional Clinical Hospital n.a. V. D. Seredavin
city: Samara
country: Russian Federation
facility: Samara Clinical Hospital № 1 n.a. N. I. Pirogov
city: Sestroretsk
country: Russian Federation
facility: City Hospital № 40 of Kurortny District
city: Vsevolozhsk
country: Russian Federation
facility: Vsevolozhsk Clinical Interdistrict Hospital
Study officials:
References:
citation: Stakhovskaya LV, Shamalov NA, Khasanova DR, Melnikova EV, Agafiina AS, Golikov KV, Bogdanov EI, Yakupova AA, Roshkovskaya LV, Lukinykh LV, Lokshtanova TM, Poverennova IE, Shepankevich LA. [Results of a randomized double blind multicenter placebo-controlled, in parallel groups trial of the efficacy and safety of prolonged sequential therapy with mexidol in the acute and early recovery stages of hemispheric ischemic stroke (EPICA)]. Zh Nevrol Psikhiatr Im S S Korsakova. 2017;117(3. Vyp. 2):55-65. doi: 10.17116/jnevro20171173255-65. Russian.
citation: Stakhovskaya LV, Mkhitaryan EA, Tkacheva ON, Ostroumova TM, Ostroumova OD. [Efficacy and safety of mexidol across age groups in the acute and early recovery stages of hemispheric ischemic stroke (results of additional sub-analysis of a randomized double blind multicenter placebo-controlled study, in parallel groups trial EPICA)]. Zh Nevrol Psikhiatr Im S S Korsakova. 2020;120(8. Vyp. 2):49-57. doi: 10.17116/jnevro202012008249. Russian.