- A multicenter study - a study that is carried out in a large number of specialized clinical centers;
- Randomized - a study in which patients are randomly assigned to groups.
- Double-blind, placebo-controlled - a study in which the allocation of patients to groups (receiving the drug or placebo) is concealed from both the participants and the investigators.
MIR study in ischemic stroke
The international multicenter, randomized, double-blind, placebo-controlled MIR study, conducted in accordance with GCP standards, demonstrated the high therapeutic value of the strategy of sequential use of Mexidol® and Mexidol® FORTE 250 (ethylmethylhydroxypyridine succinate) in the acute and early recovery periods of ischemic stroke (IS), which confirmed its clinical validity, demonstrating convincing efficacy and a high safety profile [1][2].
Research design
A total of 304 patients (ITT population/group) (Intention to Treat) aged 40-75 years were randomized in the study. The study groups did not differ in gender, age, height, body weight, or body mass index. The Per Protocol (Per Protocol) population/group, according to the study protocol, was the primary one for efficacy evaluation and included 279 randomized patients: 141 in the main group (Group 1 or Mexidol® group) and 138 in the placebo group (Group 2 or comparison group). The Per Protocol population for calculating some secondary efficacy endpoints consisted of 276 patients, as the methodology of these scales does not include the assessment of mortality. Patients in the first group received sequential therapy with Mexidol® solution, 500 mg twice daily intravenously by drip for 10 days, followed by Mexidol® FORTE 250 tablets, 1 tablet (250 mg) 3 times daily for 60 days. Patients in the comparison group received placebo according to a similar regimen. The duration of treatment in both groups was 70 (10 + 60) days.
-
The study scheme included 5 control stages of examination and two phone calls to observed patients:
- Visit 1 (1st day of research),
- Visit 2 (Day 11, completion of injection course, start of oral therapy),
- Visit 3 (day 40),
- Visit 4 (study day 71, completion of oral therapy),
- Active telephone calls (televisits) to patients were made between the 2nd and 3rd, 3rd and 4th visits.
Efficiency criteria
The primary efficacy criterion was the magnitude of change in the patient's condition assessment results (Δ) using the modified Rankin Scale (mRS) (which allows for the assessment of the degree of disability, independence, and rehabilitation outcomes) at the end of therapy relative to the baseline level.
When analyzing secondary efficacy criteria, the results of testing on scales at the end of the parenteral stage and the entire course of therapy were taken as a basis:
- Δ on the mRS scale at the end of the parenteral course of therapy relative to the baseline level;
- The proportion of disabled patients (3 points or more on the mRS scale) at the end of the parenteral course of therapy;
- The proportion of disabled patients (3 points or more on the mRS scale) at the end of therapy;
- The proportion of patients with a score of 0–1 on the mRS scale at the end of the parenteral course of therapy;
- The proportion of patients with a score of 0–1 on the mRS scale at the end of therapy;
- Δ on the NIHSS scale at the end of the parenteral course of therapy relative to the baseline level;
- Δ according to the National Institutes of Health Symptoms Scale (NIHSS) (characterizes the severity of neurological deficit) at the end of therapy relative to the baseline level;
- Δ according to the Rivermead mobility index at the end of the parenteral course of therapy;
- Δ according to the Rivermead Mobility Index (assesses the mobility indicators of patients after a stroke) at the end of therapy relative to the baseline level;
- Δ on the MoCA scale at the end of the parenteral course of therapy relative to the baseline level;
- Δ on the MoCA scale at the end of therapy relative to the baseline level;
- Δ on the HADS scale at the end of the parenteral course of therapy relative to the baseline level;
- Δ on the anxiety and depression scale (HADS) at the end of therapy relative to the baseline level.
Treatment safety: safety and tolerability were assessed throughout the study (from the first administration of the study drugs/placebo) based on physical examination data; general clinical and biochemical blood tests, coagulogram, general urine analysis, ECG, frequency and severity of adverse events.
Results
The magnitude of change in the patient's condition assessment results (∆) on the mRS scale at the end of therapy relative to the baseline
(Visit 4)
Δ on the mRS scale
Mexidol®
Placebo
n=279
When analyzing the results for the primary efficacy criterion, it was found that in the group treated with Mexidol® and Mexidol® FORTE 250, a significant improvement in life activity and a reduction in functional impairment was demonstrated compared to placebo.
The average change in the indicator by the end of therapy in the Mexidol® group was –2.45 (95% CI –2.698 – –2.323) points, and in the placebo group –2.01 (95% CI –2.246 – –1.869) points.
The difference between the groups was -0.432 (p=0.003), which confirmed the superiority in the effectiveness of therapy using drugs
Mexidol® and Mexidol® FORTE 250 over placebo in terms of Δ on the mRS scale at the end of the study by patients.
Mexidol® is 21% superior to placebo in reducing limitations in life activities and the degree of disability.
Long-term sequential therapy with Mexidol® and Mexidol® FORTE 250 significantly improves functional outcomes and reduces disability in patients after ischemic stroke.
The proportion of disabled patients (3 points or more on the mRS scale) at the end of therapy
NNT = 17.9
NNT = 7.9
OR = 0.79
OR = 0.47
Mexidol®
Placebo
At visit 2, the number of disabled patients was 81 (57%) in the main group and 87 (63%) in the placebo group (p=0.4), while by visit 4 the number of disabled patients decreased in the main group to 22 (16%) and in the placebo group to 39 (28%) (p=0.016).
The differences identified at visit 4 were also confirmed by the NNT values for disability, which at visits 2 and 4 were 17.9 and 7.9, respectively, and the OR was 0.79 and 0.47, respectively.
The positive impact of sequential therapy with Mexidol® and Mexidol® FORTE 250 on patients' functional status, as assessed by the mRS scale, was confirmed compared to placebo. This therapy significantly reduces limitations in daily activities and the degree of disability in patients after ischemic stroke.
The risk of moderate and severe disability in the main group, with the use of sequential therapy with Mexidol® and Mexidol® FORTE 250, is 53% lower compared to placebo.
Notes:
▼
NNT (Number Needed to Treat) shows the average number of patients who need to be treated to prevent one adverse outcome or achieve one favorable outcome compared to the control group. The ideal NNT value is 1, which means the treatment is absolutely effective (every patient benefits), and the higher the NNT, the less effective the treatment. An NNT in the range of 5 to 15 is a sign of a positive impact of treatment on human health.
The odds ratio (OR) is the ratio of the occurrence of an event in one group to the chances of its occurrence in the other group; odds were defined as the ratio of the probability of an event to the probability of its absence. If the OR is > 1, this indicates a positive association; if the OR is
Long-term sequential therapy with Mexidol® and Mexidol® FORTE 250 reduces the risk of disability by 2.2 times compared to placebo.
Proportion of patients with mRS score of 0-1 at completion of therapy
NNT = 5.3
OR = 2.2
0 - 1 points on the mRS scale
2 or more points on the mRS scale
In clinical practice, information on the frequency of favorable functional outcomes of IS at the end of follow-up (MSR score 0–1) is extremely important. In the study group, the proportion of such cases was 60.3% (n = 85), while in the placebo group it was only 41.3% (n = 57). The differences between the groups were statistically significant (p = 0.002).
The determination of the OR shows that the administration of the study drugs increases the odds of a favorable outcome after ischemic stroke by 2.2 times compared to placebo (OR 2.157, 95% CI 1.337 - 3.479, p <0.001).
In addition, the NNT- 5.3 indicator indicates that with long-term sequential therapy with Mexidol® and Mexidol® FORTE 250, approximately every fifth patient with a moderate stroke can achieve high functional independence (0–1 point on the MSHR) by the end of therapy.
Long-term sequential therapy with Mexidol® and Mexidol® FORTE 250 leads to a significant decrease in the proportion of patients with disabilities and an increase in the proportion of patients without limitations in life activities, compared with placebo.
Proportion of patients with different degrees of functional impairment (according to mRS)
No limitations in life activity mRS 0 - 1
Mild limitations of life activities mRS 2
Significant degree of disability mRS ≥ 3
Distribution of the proportions of disabled and self-sufficient patients (≥3 and 0-1 points on the mRs scale, respectively) at the beginning of therapy and after the end of a long-term sequential therapy course with Mexidol® and Mexidol® FORTE 250.
The proportion of patients with no neurological deficit according to the NIHSS scale at the end of therapy
NNT = 8.2
OR = 3.88
0 points on the NIHSS scale
1 or more points on the NIHSS scale
At visit 4, the number of patients who had no clinical signs of stroke (0 points on the NIHSS scale) was 24 (17%) in the main group and 7 (5.1%) in the placebo group (the differences are statistically significant).
Long-term sequential therapy with Mexidol® and Mexidol® FORTE 250 increases by 3.9 times the chances of complete recovery of neurological status and the absence of neurological deficit by the end of therapy compared to placebo (OR 3.876, 95% CI 1.610 - 9.331, p = 0.001).
The NNT indicator was 8.2, which corresponds to a complete regression of neurological symptoms according to the NIHSS scale in every eighth patient with an initially moderate and moderate degree of neurological deficit.
The results of the study on the NIHSS scale allow us to conclude that the use of a sequential treatment regimen with Mexidol® and Mexidol® FORTE 250 in patients in combination with standard therapy in the acute and early recovery periods of ischemic stroke can reliably reduce the severity of neurological deficit.
Long-term sequential therapy with Mexidol® and Mexidol® FORTE 250 significantly increases the proportion of patients without neurological deficit compared to placebo.
Median change in Rivermead Index scores
Number of patients without mobility impairment (Rivermead Index score of 14 or more)
NNT = 4.6
OR = 2.51
Mexidol®
Placebo
The median increase in the Rivermead Index score at the end of parenteral therapy compared with baseline was 6 points in the study group and 5 in the placebo group (p=0.3), and after completion of the full course of therapy, it was 10 and 9 points, respectively (p=0.014). The use of sequential therapy with Mexidol® and Mexidol® FORTE 250 leads to a statistically significant improvement in patient mobility.
At visit 2, the number of patients without mobility impairments (14 points or more on the Rivermead Mobility Index) was 20 (14.2%) in the main group and 24 (17.4%) in the placebo group (p=0.478), and at visit 4, an assessment (14 points or more on the Rivermead Mobility Index) was present in 99 (70.2%) patients receiving Mexidol® and in 68 (49.3%) receiving placebo (p=0.002), which corresponds to NNT=4.6 and OR=2.51 (95% CI 1.53-4.15). Sequential therapy with the use of Mexidol® and Mexidol® FORTE 250.
Thus, long-term sequential therapy of AI with Mexidol® and Mexidol® FORTE 250 significantly increases the chances of regression of motor deficit and achievement of functional independence in post-stroke patients by 2.5 times compared to placebo.
Long-term sequential therapy with Mexidol® and Mexidol® FORTE 250 significantly increases activity and mobility compared to placebo.
Median change in MoCA scores
Median changes in the MoCA score at the end of parenteral therapy compared with the baseline level were 3 points in the main group and 2 points in the placebo group (p=0.2), and after completion of the full course of therapy – 4 and 3 points, respectively (p=0.052).
The results demonstrated a trend toward superiority of Mexidol® and Mexidol® FORTE 250 therapy over placebo in patients with ischemic stroke. Consequently, sequential therapy with Mexidol® and Mexidol® FORTE 250 positively impacts cognitive functioning in patients who have suffered ischemic stroke.
Long-term sequential therapy with Mexidol® and Mexidol® FORTE 250 reduces cognitive deficit in patients in the acute and early recovery periods of ischemic stroke.
Data on reported adverse events
Mexidol®
Placebo
Number of registered adverse events
1 - adverse events (AE)
2 - serious adverse events (SAE)
During the study, 85 adverse events (AEs) were registered, including 10 serious AEs (SAEs), of which 6 (60%) in the main group and 4 (40%) in the placebo group. AEs were detected in 35 (23%) patients in each group (main group - 42 AEs, placebo - 43 AEs), without statistically significant differences in the frequency of occurrence (p = 1.000). The relative risk of developing AEs in the main group compared to placebo was 1.00 (95% CI: 0.66; 1.51). Most AEs were mild (main group - 16 (38%), placebo - 18 (42%)) or moderate (main group - 21 (50%), placebo - 24 (56%)) severity. Good tolerability of long-term sequential therapy with Mexidol® and Mexidol® FORTE 250 and compatibility with basic therapy drugs have also been confirmed.
Sequential therapy with Mexidol® and Mexidol® FORTE 250 shows a favorable safety profile and good compatibility with basic therapy drugs.
Conclusions
A prospective, international, multicenter, randomized, double-blind, placebo-controlled study demonstrated the superiority of long-term sequential therapy with Mexidol® (solution for intravenous and intramuscular administration, 50 mg/ml) and Mexidol® FORTE 250 (film-coated tablets 250 mg) over placebo in patients in the acute and early recovery periods of ischemic stroke.
This sequential treatment regimen with Mexidol® and Mexidol® FORTE 250 in addition to basic therapy for ischemic stroke significantly improves functional outcomes, as confirmed by the following indicators:
- A significant reduction in life activity limitations and disability (according to the mRS scale).
- Significant reduction in the severity of neurological deficit (according to the NIHSS scale).
- Significant increase in mobility and motor activity (according to the Rivermead index).
- Positive impact on cognitive functions (according to the MoCA scale).
Long-term sequential therapy with Mexidol® and Mexidol® FORTE 250 in cerebral infarction (ischemic stroke) reliably reduces the degree of neurological deficit and improves the recovery of neurological functions, as well as improves functional outcome and reduces disability.
List of literature
- Shamalov N.A., Fedin A.I., Rakhimbaeva G.S., Nurguzhaev E.S., Khasanova D.R., Solovieva E.Yu., Melnikova E.V., Yanishevsky S.N., Mashin V.V., Pizova N.V., Poverennova I.E., Chuprina S.E., Agafyina A.S., Roshkovskaya L.V. Results of an international multicenter, randomized, double-blind, placebo-controlled study assessing the efficacy and safety of sequential therapy with ethylmethylhydroxypyridine succinate in patients in the acute and early recovery periods of ischemic stroke (MIR). Korsakov Journal of Neurology and Psychiatry. 2025;125(8 issue 2):40–53. https://doi.org/10.17116/jnevro202512508240
- Koltsov I.A., Shchukin I.A., Fidler M.S., Glukhareva A.P., Chubykin V.I. Multimodal antioxidant therapy for ischemic stroke: from the results of the MIR study to clinical practice. Korsakov Journal of Neurology and Psychiatry. 2025; 125(12 2): 64–71. https://doi.org/10.17116/jnevro202512512264
THE INFORMATION IS INTENDED FOR HEALTHCARE AND PHARMACEUTICAL PROFESSIONALS. THIS INFORMATION IS NOT INTENDED AS A SUBSTITUTE FOR MEDICAL ADVICE.
Source of photos and images Shutterstock.com