Clinical Trial of Efficacy and Safety of MMH-MAP in the Treatment of Cognitive Disorders in Patients With Ischemic Stroke in the Carotid Arteries

Study Overview
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Brief Summary
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The clinical trial to valuate efficacy and safety of MMH-MAP in the treatment of cognitive disorders in patients with ischemic stroke in the carotid arteries.

Detailed Description
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Design: double-blind, randomized, parallel group placebo-controlled clinical study of efficacy and safety of MMH-MAP in the treatment of cognitive disorders in patients with ischemic stroke in the carotid arteries. The study will enroll hospitalized subjects of either gender aged 40-75 years old with verified diagnosis of ischemic stroke in the carotid arteries within 72 hours post debut having moderate cognitive disorders, moderate neurological deficit. At Visit 1 (day 1) the subject's complaints and medical history will be collected, objective examination, safety laboratory tests (hematology, serum chemistry, urinalysis) will be performed. The investigator will evaluate the patient's level of consciousness using The Glasgow Coma Scale, intensity of cognitive disorders using The Montreal Cognitive Assessment (МоСА), condition using National Institute of Health Stroke Scale (NIHSS) and The Modified Rankin Scale (mRs). Concomitant therapy will be recorded and changes in cerebral CT/MRI will be evaluated. If the subject meets inclusion criteria and has no exclusion criteria, he/she will be randomized to MMH-MAP or Placebo group. The first dose of the study product should be taken within 72 hours post stroke debut. At Visit 2 (day 12±3, end of hospitalization period - the last day of hospitalization due to the current stroke) complaints will be collected, objective examination findings will be recorded, monitoring of the prescribed and concomitant therapy will be performed, treatment safety, compliance and stroke severity according to NIHSS will be evaluated. By the end of hospital therapy the subject will be switched to outpatient therapy with continuation of IMP and medical assistance designed for the treatment of stroke and its sequelae. At Visit 3 (day 45±7 days) the investigator will make a phone call to the subject evaluating the treatment safety. At final Visit 4 (day 90±7 days) complaints will be collected, objective examination findings will be recorded, monitoring of the prescribed and concomitant therapy will be performed, treatment safety, compliance, condition according to NIHSS will be evaluated, mRs, Clinical Global Impression Efficacy Index (CGI-EI) will be filled. The investigator will perform MoCA testing. Safety laboratory tests (hematology, serum chemistry, urinalysis) will be carried out. Throughout the study the patient will receive the treatment approved by the decree of the RF Ministry of Health dated 29.12.2012 No. 740n On approval of standard of special care in cerebral infarction except for the products specified in section Forbidden concomitant therapy.

Official Title
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A Multicenter, Double-blind, Randomized, Parallel Group Placebo-controlled Clinical Trial of Efficacy and Safety of MMH-MAP in the Treatment of Cognitive Disorders in Patients With Ischemic Stroke in the Carotid Arteries

Conditions
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Cognitive Disorders

Intervention / Treatment
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* Drug: MMH-MAP
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age between 40 and 75 years old inclusively. Ischemic stroke in the carotid arteries (I 63) within 72 hours post debut. Moderate cognitive disorders (MoCA < 26). Normal consciousness (Glasgow score 15) Stroke severity 8-12 according to NIHSS. Disability mRs score 2-3. Availability of cerebral CT/MRI within 72 hours post stroke debut. Patients who agreed to use a reliable method of contraception during the study. Patients who have signed the Participant Information Sheet and Informed Consent. Exclusion Criteria: Current or previous subarachnoidal/parenchymatous/ventricular hemorrhage, cerebral infarction, cerebral tumour. Cerebral CT/MRI findings suggesting cerebral hemorrhage, tumour within 72 hours post stroke debut. Scheduled or completed thrombolytic therapy for the treatment of the current cerebral infarction. Central nervous system (CNS) diseases including: Inflammatory diseases of the central nervous system (G00-G09); Systemic atrophies primarily affecting the central nervous system (G10-G13); Extrapyramidal and movement disorders (G20-G26); Other degenerative diseases of the nervous system (G30-G32); Demyelinating diseases of the CNS (G35-G37); Episodic and paroxysmal disorders (G40-G47); Polyneuropathies and other disorders of the peripheral nervous system (G60-64), with marked movement and/or sensory impairments that cause movement disorders; Hydrocephalus (G91). (History of) injuries to the head (S00-S09) associated with impaired consciousness, cerebral contusion or open craniocerebral trauma. Musculoskeletal disorders causing motor disturbances. (History of) dementia (F00-F03). Malignant neoplasms. Patients previously diagnosed with class IV heart failure (1964 New York Heart Association functional classification), hypothyroidism, or poorly treated diabetes mellitus. Patients having unstable angina or myocardial infarction in the past 6 months. Allergy/ intolerance to any of the components of medications used in the treatment. Malabsorption syndrome, including congenital or acquired lactase deficiency (or any other disaccharidase deficiency) and galactosemia. Any conditions which, according to the investigator opinion, may interfere with the subject's participation in the study. Prior history of non-adherence to a drug regimen, a psychiatric disorder, alcoholism or drug abuse, which, in the opinion of the investigator, can compromise compliance with study protocol. Pregnancy, breast-feeding; childbirth less than 3 months prior to the inclusion in the trial, unwillingness to use contraceptive methods during the trial. Participation in other clinical studies within 3 month prior to enrollment in the study. Patients who are related to any of the on-site research personnel directly involved in the conduct of the trial or are an immediate relative of the study investigator. 'Immediate relative' means husband, wife, parent, son, daughter, brother, or sister (regardless of whether they are natural or adopted). Patients who work for OOO NPF Materia Medica Holding (i.e. the company's employees, temporary contract workers, designated officials responsible for carrying out the research or any immediate relatives of the aforementioned).

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MMH-MAP<br>Oral administration. 2 tablets twice daily (approximately at the same time). The drug is taken outside a meal (between the meals or 15 min prior to meal or fluid intake). Tablets should be held in the mouth until completely dissolved. The overall duration of treatment is 90 months. | Drug: MMH-MAP<br>* Oral administration.<br>|
| Placebo Comparator: Placebo<br>Oral administration. For 90 days according to MMH-MAP dosing regimen. | Drug: Placebo<br>* Oral administration.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Average MoCA score. | Montreal Cognitive Assessment Scale (The Montreal Cognitive Assessment, MoCA) will be used to identify moderate cognitive impairment, as well as to assess changes in cognitive functions during therapy. The time for MoCA is approximately 10 minutes. The maximum possible number of points is 30; 26 points or more is considered normal. | On the 90th day of the treatment period. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in NIHSS score. | NIHSS Scale (National Institutes of Health Stroke Scale) is a scale for assessing the severity of neurological disorders of the acute period of ischemic stroke. The NIHSS scale involves the assessment of a neurological condition by generally accepted methods of clinical examination of reflexes, sensory organs, and the patient's level of consciousness. The results range from minimum indicators - normal or close to normal, to maximum - reflect the degree of neurological damage. | On the days 12, 90 of the treatment period. | 
| Percentage of patients with no significant disabilities. | The modified Rankin scale (mRs 0-1) allows to assess the grade of disability after a stroke. The scale includes five grades of disability: from 0 to 5: 0 - no symptoms, 5 - gross disability; bedridden, fecal and urinary incontinence, need for constant assistance by medical staff. | On the 90th day of the treatment period. | 
| Therapeutic and side effects, efficacy index. | According to Clinical Global Impression Efficacy Index (CGI-EI).CGI-EI is filled out by an investigator. It is necessary to indicate the level of efficacy of the therapy and the grade of safety of the therapy and circle the index values at the intersection of the selected lines. | On the 90th day of the treatment period. | 
| Occurrence and nature of adverse events (AEs). | Based on medical records. Occurrence, nature, severity, causality and outcome of adverse events (AEs). | For 90 days of the treatment period. | 
| Percentage of patients with сomplication of cerebral infarction. | Based on medical records. The sequelae of cerebral infarction (severe infections - hospital-acquired pneumonia, uroinfection; deep venous thrombosis, PATE; epileptic episodes). | For 90 days of the treatment period. | 
| Death rate. | Based on medical records. Frequency of all-cause mortality outcomes. | For 90 days of the treatment period. | 
| Changes in vital signs (pulse rate (heart rate)). | Based on medical records. Vital signs will be measured in a medical setting. | For 90 days of the treatment period. | 
| Changes in vital signs (respiration rate (breathing rate)). | Based on medical records. Vital signs will be measured in a medical setting. | For 90 days of the treatment period. | 
| Changes in vital signs (blood pressure). | Based on medical records. Vital signs will be measured in a medical setting. | For 90 days of the treatment period. | 
| Percentage of patients with clinically significant abnormal laboratory data. | Based on medical records. | For 90 days of the treatment period. | 
| Percentage of patients with recurring cerebral infarction. | Based on medical records. | For 90 days of the treatment period. |