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

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

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.

Study Overview

• Status: Completed
• Conditions: Cerebral Atherosclerosis
• Intervention / Treatment: Drug: Placebo; Drug: Divaza

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.

1. 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).
2. 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".

• Study Type: Interventional
• Enrollment (Actual): 124
• Phase: Phase 4

Contacts and Locations

Study Locations

• Russian Federation
  • Korolev, Russian Federation, 141060
    • Limited Liability Company "Family policlinic no. 4"
  • Moscow, Russian Federation, 115516
    • Moscow city clinical Hospital after V.M. Buyanov
  • Moscow, Russian Federation, 119049
    • State Budgetary Institution of Healthcare of the City of Moscow City Clinical Hospital No. 1 named after. N.I. Pirogov Moscow Department of Health
  • Moscow, Russian Federation, 119435
    • Federal State Budgetary Institution Federal Research and Clinical Center of Physical-Chemical Medicine Federal Medical Biological Agency
  • Moscow, Russian Federation, 119992
    • 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
  • Moscow, Russian Federation, 1253678
    • Federal State Budget Scientific Institution "Scientific Center of Neurology"
  • Vladimir, Russian Federation, 600023
    • The state budgetary health care institution of the Vladimir region "Regional Clinical Hospital"
  • Yaroslavl, Russian Federation, 150062
    • State budgetary institution of health care of the Yaroslavl region "Regional Clinical Hospital"
  • Yaroslavl, Russian Federation, 150030
    • State Institution of Health of the Yaroslavl Region Clinical Hospital No. 8
  • Yaroslavl, Russian Federation, 150000
    • Federal State Budgetary Educational Institution of Higher Education "Yaroslavl State Medical University" of the Ministry of Healthcare of the Russian Federation

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Divaza; 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.	Drug: Divaza; Oral administration.
Placebo Comparator: Placebo; 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.	Drug: Placebo; Oral administration.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	12 weeks of the observation period.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	12 weeks of the observation period.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Mean Level of Preformed LP Products (Mainly Lipid Hydroperoxides).	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.	12 weeks of the observation period
Change in Mean Value of Lipoprotein Ability for Oxidation.	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.	12 weeks of the observation period.
Change in Mean Value of NO Products Serum Concentration.	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).	12 weeks of the observation period.
Change in Mean Value of Platelet Aggregation.	Based on laboratory evaluation. Change in mean platelet aggregation after 12-week therapy versus baseline.	12 weeks of the observation period.

Collaborators and Investigators

• Sponsor: Materia Medica Holding

Study record dates

Study Major Dates

• Study Start (Actual): April 12, 2018
• Primary Completion (Actual): April 11, 2019
• Study Completion (Actual): April 11, 2019

Study Registration Dates

• First Submitted: March 26, 2018
• First Submitted That Met QC Criteria: March 26, 2018
• First Posted (Actual): April 2, 2018

Study Record Updates

• Last Update Posted (Actual): August 26, 2021
• Last Update Submitted That Met QC Criteria: August 25, 2021
• Last Verified: August 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Intracranial Arterial Diseases; Atherosclerosis; Intracranial Arteriosclerosis
• Other Study ID Numbers: MMH-DV-010

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No