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Clinical Trial of Efficacy and Safety of Divaza for Adjustment of Oxidative Disorders in Patients With Cerebral Atherosclerosis

Primary Purpose

Cerebral Atherosclerosis

Status
Completed
Phase
Phase 4
Locations
Russian Federation
Study Type
Interventional
Intervention
Divaza
Placebo
Sponsored by
Materia Medica Holding
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Cerebral Atherosclerosis

Eligibility Criteria

40 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Patients of both genders aged 40-75 years old inclusive.
  2. Diagnosis of cerebral atherosclerosis verified by all three signs:

    • underlying vascular disease (atherosclerosis and/or hypertension) and focal neurological symptoms combined with cerebral symptoms (headache, dizziness, tinnitus, impaired memory, working capacity);
    • ultrasound signs of atherosclerotic cerebrovascular lesions (according to MAH duplex scanning within 6 months preceding the patient enrollment into the study);
    • signs of morphological changes in the brain based on neuroimaging (CT/MRI 1.0-1.5 T) (subcortical and periventricular leukoaraiosis and/or focal changes in grey matter and white matter in the form of postischemic cysts and/or lacunar strokes and/or diffuse atrophic changes in the form of dilated cardiovascular system or subarachnoidal spaces).
  3. Cognitive disorders (MoCa <26).
  4. Patients with unchanged dose and combination of basic therapy of cerebral atherosclerosis and hypertension during the previous month.
  5. Patients who gave their consent to use reliable contraception during the study.
  6. Availability of signed patient information sheet and informed consent form for participation in the clinical trial.

Exclusion Criteria:

  1. History of subarachnoidal/parenchymatous/ventricular hemorrhage, cerebral tumour or another disease resulting in neurological disorders.
  2. Ischemic-type stroke or any other acute cerebrovascular accident less than 6 months prior to the study with Modified Rankin Scale (mRs) > 1 .
  3. Cardiac sources of high risk or medium risk embolism (TOAST criteria).
  4. Signs of acute or exacerbated chronic infectious diseases at or less than 2 weeks prior to screening.
  5. History of CNS diseases including:

    • Inflammatory CNS diseases (G00-G09)
    • Systemic Atrophies Primarily Affecting the CNS (G10-G13)
    • Other degenerative diseases of the nervous system (G30-G32)
    • Demyelinating diseases of the CNS (G35-G37).
  6. Dementia (F00-F03).
  7. Previously diagnosed cardiovascular diseases with functional class III or IV (according to New York Heart Association, 1964).
  8. Hypothyroidism, diabetes mellitus and other somatic diseases at decompensation stage.
  9. Uncontrollable hypertension: SBP > 180 mm Hg and/or DBP > 110 mm Hg.
  10. Diseases of lower limb veins (lower limb varicose veins, deep venous thrombosis, etc.) at decompensation stage.
  11. Any other severe concomitant pathology which, according to the investigator, may interfere with the patient's participation in the study.
  12. History/suspicion of oncology of any location (except for benign neoplasms).
  13. Allergy/intolerance of any component of the drug products used in the therapy.
  14. Hereditary lactose intolerance.
  15. Malabsorption syndrome, including congenital or acquired lactase deficiency (or any other disaccharidase deficiency) and galactosemia.
  16. Pregnancy, breast-feeding.
  17. History of treatment non-compliance, psychiatric disorders, alcoholism or drug abuse which, according to the investigator, may interfere with the study procedures.
  18. Use of any medicine indicated in the section "Prohibited concomitant treatment" within 1 month prior to enrollment.
  19. Participation in other clinical trials in the previous 3 months.
  20. Patients who are related to any of the on-site research personnel directly involved in the study or are an immediate relative of the study investigator, or has another conflict of interests. 'Immediate relative' means husband, wife, parent, son, daughter, brother, or sister (regardless of whether they are natural or adopted).
  21. Patients who work for OOO "NPF "MATERIA MEDICA HOLDING" (i.e. the company's employees, temporary contract workers, appointed officials responsible for carrying out the research or immediate relatives of the aforementioned).

Sites / Locations

  • Limited Liability Company "Family policlinic no. 4"
  • Moscow City Clinical Hospital after V.M. Buyanov
  • State Budgetary Institution of Healthcare of the City of Moscow City Clinical Hospital No. 1 named after. N.I. Pirogov Moscow Department of Health
  • Federal State Budgetary Institution Federal Research and Clinical Center of Physical-Chemical Medicine Federal Medical Biological Agency
  • Federal State Autonomous Educational Institution of Higher Education I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation
  • Federal State Budget Scientific Institution "Scientific Center of Neurology"
  • The state budgetary health care institution of the Vladimir region "Regional Clinical Hospital"
  • Federal State Budgetary Educational Institution of Higher Education "Yaroslavl State Medical University" of the Ministry of Healthcare of the Russian Federation
  • State Institution of Health of the Yaroslavl Region Clinical Hospital No. 8
  • State budgetary institution of health care of the Yaroslavl region "Regional Clinical Hospital"

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Divaza

Placebo

Arm Description

Tablet for oral use. Two tablets per intake 3 times a day (approximately at the same time), outside of meal (between meals or 15 minutes before eating or drinking). The tablets should be held in mouth until completely dissolved.

Tablet for oral use. Two tablets per intake 3 times a day (approximately at the same time), outside of meal (between meals or 15 minutes before eating or drinking). The tablets should be held in mouth until completely dissolved.

Outcomes

Primary Outcome Measures

Change in Mean Value of Lipoprotein Resistance to LPO.
Based on laboratory evaluation. Change in the mean resistance of lipoprotein (LP) to lipid peroxidation (LPO) after 12-week therapy versus baseline.

Secondary Outcome Measures

Percentage of Patients With Improved Cognitive Function.
MoCA (Montreal Cognitive Assessment) score +1 and over after 12-week therapy versus baseline. Minimum score is 0, maximum score is 30. Higher values represent a better outcome.

Full Information

First Posted
March 26, 2018
Last Updated
August 25, 2021
Sponsor
Materia Medica Holding
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1. Study Identification

Unique Protocol Identification Number
NCT03485495
Brief Title
Clinical Trial of Efficacy and Safety of Divaza for Adjustment of Oxidative Disorders in Patients With Cerebral Atherosclerosis
Official Title
Multicenter Double-blind Placebo-controlled Randomized Parallel-group Clinical Study of Efficacy and Safety of Divaza for Adjustment of Oxidative Disorders in Patients With Cerebral Atherosclerosis
Study Type
Interventional

2. Study Status

Record Verification Date
August 2019
Overall Recruitment Status
Completed
Study Start Date
April 12, 2018 (Actual)
Primary Completion Date
April 11, 2019 (Actual)
Study Completion Date
April 11, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Materia Medica Holding

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No

5. Study Description

Brief Summary
The purpose of this study is to obtain additional data on efficacy and safety of Divaza for adjustment of oxidative disorders in patients with cerebral atherosclerosis. It is assumed that the inclusion of the drug Divaza in the basic therapy will help reduce the severity of cognitive disorders, other clinical symptoms of cerebral atherosclerosis, reduce the impact of the disease on the quality of life of the patient. Participate in the study may be patients with a diagnosis of "cerebral atherosclerosis", which, against the backdrop of basic therapy with constant doses of drugs (within the last 4 weeks), to achieve a stable course of cerebral atherosclerosis, cognitive disorders without significant disability are detected.
Detailed Description
Design - a multicenter randomized double-blind placebo-controlled parallel-group clinical trial. The study will enroll the patients of either gender aged 40-75 years old inclusively with verified atherosclerotic cerebrovascular lesions (ICD-10 code - "Cerebral atherosclerosis" [I67.2]), with cognitive disorders (МоСА<26), without relevant incapacity (mRs≤1). At screening visit (Visit 1, from day - 5 to day 0), after signing patient information sheet (informed consent form) for participation in the clinical study the patient's complaints and medical history will be collected and objective examination will be carried out. The investigator will assess intensity of cognitive disorders using MoCA, extent of functional capacity using mRs . If the patient meets inclusion criteria and has no exclusion criteria at Visit 2 (Day 0) he/she will be randomized to one of two groups: group 1 will receive Divaza at 2 tablets 3 times a day; group 2 - placebo using study drug scheme. Laboratory examination will be performed. oxidant and antioxidant systems (Fe2+-induced chemoluminescence method, ELISA) defining: 1.1. level of preformed LP products, predominantly lipid hydroperoxides; 1.2. low and very low density lipoprotein resistance to LP; 1.3. lipoprotein potential for oxidation; 1.4. serum NO product concentration (Griess reaction). compensatory potential of endothelium and its ability for adequate regulation of vascular tone with : 2.1. determination of platelet aggregation with bandage sign; 2.2. MAH duplex scanning. Procedures of Visit 2 may be performed on day of Visit 1 if general rules for blood collection are met, at that previously performed procedures will not be repeated. The first administration of Divaza or Placebo will be performed at Visit 2 at medical site in the investigator's presence. The patient monitoring and therapy will last for 12 weeks during which 3 additional visits will be made. At Visit 3 (Week 4±5 days) the investigator will collect the complaints, perform objective examination, evaluate intensity of cognitive disorders (MoCA). The investigator will monitor the prescribed, basic and concomitant therapy, evaluate therapeutic safety. At Visit 4 (Week 8±5 days) the investigator will make a phone call to the patient to evaluate safety of the treatment. At the final Visit 5 (Weeks 12±5 days) the investigator will evaluate intensity of cognitive disorders (MoCA). Laboratory examination of oxidant and antioxidant systems, compensatory potential of endothelium and its potential for adequate vascular tone regulation. The investigator will monitor the prescribe, basic and concomitant therapy, evaluate therapeutic safety and treatment compliance. During the study basic, concomitant therapy will be allowed except for the products indicated in the section "Prohibited concomitant therapy".

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Cerebral Atherosclerosis

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
124 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Divaza
Arm Type
Experimental
Arm Description
Tablet for oral use. Two tablets per intake 3 times a day (approximately at the same time), outside of meal (between meals or 15 minutes before eating or drinking). The tablets should be held in mouth until completely dissolved.
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Tablet for oral use. Two tablets per intake 3 times a day (approximately at the same time), outside of meal (between meals or 15 minutes before eating or drinking). The tablets should be held in mouth until completely dissolved.
Intervention Type
Drug
Intervention Name(s)
Divaza
Intervention Description
Oral administration.
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Oral administration.
Primary Outcome Measure Information:
Title
Change in Mean Value of Lipoprotein Resistance to LPO.
Description
Based on laboratory evaluation. Change in the mean resistance of lipoprotein (LP) to lipid peroxidation (LPO) after 12-week therapy versus baseline.
Time Frame
12 weeks of the observation period.
Secondary Outcome Measure Information:
Title
Percentage of Patients With Improved Cognitive Function.
Description
MoCA (Montreal Cognitive Assessment) score +1 and over after 12-week therapy versus baseline. Minimum score is 0, maximum score is 30. Higher values represent a better outcome.
Time Frame
12 weeks of the observation period.
Other Pre-specified Outcome Measures:
Title
Change in Mean Level of Preformed LP Products (Mainly Lipid Hydroperoxides).
Description
Based on laboratory evaluation. Change in mean level of preformed LP products, predominantly lipid hydroperoxides after 12-week therapy versus baseline. The following kinetic parameters of chemiluminescence were measured: rapid chemiluminescence flare amplitude reflecting the stationary level of lipid hydroperoxides.
Time Frame
12 weeks of the observation period
Title
Change in Mean Value of Lipoprotein Ability for Oxidation.
Description
Based on laboratory evaluation. Change in mean value of lipoprotein ability for oxidation after 12-week therapy versus baseline. For plasma, draw blood into an EDTA tube and gently invert the tube 8 to 10 times to mix the anticoagulant. Centrifuge the tube, remove the stopper and draw off approximately 2/3 of the upper plasma layer into a labeled transfer tube using a transfer pipet bulb. Plasma must be separated from cells within 45 minutes of venipuncture. Measurement of oxidized LDL (oxLDL) has been incorporated into clinical practice in the diagnosis and treatment of lipid disorders (such as diabetes mellitus), atherosclerosis, and various liver and renal diseases, especially as it pertains to the evaluation of oxidative stress. Oxidized LDL-particles are considered to be an important driving factor in the pathophysiology of atherosclerosis and oxLDL measurement has been used to test the efficacy of CVD drugs (eg, statins) to reduce oxidative stress.
Time Frame
12 weeks of the observation period.
Title
Change in Mean Value of NO Products Serum Concentration.
Description
Based on laboratory evaluation. Change in the mean concentration of nitrites and nitrates in serum after 12-week therapy versus baseline. Griess Reaction assay. In the Griess reaction, first reported by Johann Peter Griess in 1879 as a method of analysis of nitrite (NO2-), nitrite reacts under acidic conditions with sulfanilic acid (HO3SC6H4NH2) to form a diazonium cation (HO3SC6H4-Ntriple bondN+) which subsequently couples to the aromatic amine 1-naphthylamine (C10H7NH2) to produce a red-violet coloured (λmax ≈ 540 nm), water-soluble azo dye (HO3SC6H4-Ndouble bondN-C10H6NH2).
Time Frame
12 weeks of the observation period.
Title
Change in Mean Value of Platelet Aggregation.
Description
Based on laboratory evaluation. Change in mean platelet aggregation after 12-week therapy versus baseline.
Time Frame
12 weeks of the observation period.

10. Eligibility

Sex
All
Minimum Age & Unit of Time
40 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patients of both genders aged 40-75 years old inclusive. Diagnosis of cerebral atherosclerosis verified by all three signs: underlying vascular disease (atherosclerosis and/or hypertension) and focal neurological symptoms combined with cerebral symptoms (headache, dizziness, tinnitus, impaired memory, working capacity); ultrasound signs of atherosclerotic cerebrovascular lesions (according to MAH duplex scanning within 6 months preceding the patient enrollment into the study); signs of morphological changes in the brain based on neuroimaging (CT/MRI 1.0-1.5 T) (subcortical and periventricular leukoaraiosis and/or focal changes in grey matter and white matter in the form of postischemic cysts and/or lacunar strokes and/or diffuse atrophic changes in the form of dilated cardiovascular system or subarachnoidal spaces). Cognitive disorders (MoCa <26). Patients with unchanged dose and combination of basic therapy of cerebral atherosclerosis and hypertension during the previous month. Patients who gave their consent to use reliable contraception during the study. Availability of signed patient information sheet and informed consent form for participation in the clinical trial. Exclusion Criteria: History of subarachnoidal/parenchymatous/ventricular hemorrhage, cerebral tumour or another disease resulting in neurological disorders. Ischemic-type stroke or any other acute cerebrovascular accident less than 6 months prior to the study with Modified Rankin Scale (mRs) > 1 . Cardiac sources of high risk or medium risk embolism (TOAST criteria). Signs of acute or exacerbated chronic infectious diseases at or less than 2 weeks prior to screening. History of CNS diseases including: Inflammatory CNS diseases (G00-G09) Systemic Atrophies Primarily Affecting the CNS (G10-G13) Other degenerative diseases of the nervous system (G30-G32) Demyelinating diseases of the CNS (G35-G37). Dementia (F00-F03). Previously diagnosed cardiovascular diseases with functional class III or IV (according to New York Heart Association, 1964). Hypothyroidism, diabetes mellitus and other somatic diseases at decompensation stage. Uncontrollable hypertension: SBP > 180 mm Hg and/or DBP > 110 mm Hg. Diseases of lower limb veins (lower limb varicose veins, deep venous thrombosis, etc.) at decompensation stage. Any other severe concomitant pathology which, according to the investigator, may interfere with the patient's participation in the study. History/suspicion of oncology of any location (except for benign neoplasms). Allergy/intolerance of any component of the drug products used in the therapy. Hereditary lactose intolerance. Malabsorption syndrome, including congenital or acquired lactase deficiency (or any other disaccharidase deficiency) and galactosemia. Pregnancy, breast-feeding. History of treatment non-compliance, psychiatric disorders, alcoholism or drug abuse which, according to the investigator, may interfere with the study procedures. Use of any medicine indicated in the section "Prohibited concomitant treatment" within 1 month prior to enrollment. Participation in other clinical trials in the previous 3 months. Patients who are related to any of the on-site research personnel directly involved in the study or are an immediate relative of the study investigator, or has another conflict of interests. '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, appointed officials responsible for carrying out the research or immediate relatives of the aforementioned).
Facility Information:
Facility Name
Limited Liability Company "Family policlinic no. 4"
City
Korolev
ZIP/Postal Code
141060
Country
Russian Federation
Facility Name
Moscow City Clinical Hospital after V.M. Buyanov
City
Moscow
ZIP/Postal Code
115516
Country
Russian Federation
Facility Name
State Budgetary Institution of Healthcare of the City of Moscow City Clinical Hospital No. 1 named after. N.I. Pirogov Moscow Department of Health
City
Moscow
ZIP/Postal Code
119049
Country
Russian Federation
Facility Name
Federal State Budgetary Institution Federal Research and Clinical Center of Physical-Chemical Medicine Federal Medical Biological Agency
City
Moscow
ZIP/Postal Code
119435
Country
Russian Federation
Facility Name
Federal State Autonomous Educational Institution of Higher Education I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation
City
Moscow
ZIP/Postal Code
119992
Country
Russian Federation
Facility Name
Federal State Budget Scientific Institution "Scientific Center of Neurology"
City
Moscow
ZIP/Postal Code
1253678
Country
Russian Federation
Facility Name
The state budgetary health care institution of the Vladimir region "Regional Clinical Hospital"
City
Vladimir
ZIP/Postal Code
600023
Country
Russian Federation
Facility Name
Federal State Budgetary Educational Institution of Higher Education "Yaroslavl State Medical University" of the Ministry of Healthcare of the Russian Federation
City
Yaroslavl
ZIP/Postal Code
150000
Country
Russian Federation
Facility Name
State Institution of Health of the Yaroslavl Region Clinical Hospital No. 8
City
Yaroslavl
ZIP/Postal Code
150030
Country
Russian Federation
Facility Name
State budgetary institution of health care of the Yaroslavl region "Regional Clinical Hospital"
City
Yaroslavl
ZIP/Postal Code
150062
Country
Russian Federation

12. IPD Sharing Statement

Learn more about this trial

Clinical Trial of Efficacy and Safety of Divaza for Adjustment of Oxidative Disorders in Patients With Cerebral Atherosclerosis

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