Clinical trial NCT03485495: 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
Overall status: COMPLETED
Phase: PHASE4
Conditions: Cerebral Atherosclerosis
Lead sponsor: Materia Medica Holding
Sponsor class: INDUSTRY
First posted: 2018-04-02
Enrollment: 124
Sex: ALL
Minimum age (years): 40
Maximum age (years): 75
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 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.

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".

Eligibility criteria: 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).

Primary outcomes:
measure: Change in Mean Value of Lipoprotein Resistance to LPO.
timeFrame: 12 weeks of the observation period.
Secondary outcomes:
measure: Percentage of Patients With Improved Cognitive Function.
timeFrame: 12 weeks of the observation period.
Other outcomes:
measure: Change in Mean Level of Preformed LP Products (Mainly Lipid Hydroperoxides).
timeFrame: 12 weeks of the observation period
measure: Change in Mean Value of Lipoprotein Ability for Oxidation.
timeFrame: 12 weeks of the observation period.
measure: Change in Mean Value of NO Products Serum Concentration.
timeFrame: 12 weeks of the observation period.
measure: Change in Mean Value of Platelet Aggregation.
timeFrame: 12 weeks of the observation period.
Locations:
city: Korolev
country: Russian Federation
facility: Limited Liability Company "Family policlinic no. 4"
city: Moscow
country: Russian Federation
facility: Moscow City Clinical Hospital after V.M. Buyanov
city: Moscow
country: Russian Federation
facility: 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
country: Russian Federation
facility: Federal State Budgetary Institution Federal Research and Clinical Center of Physical-Chemical Medicine Federal Medical Biological Agency
city: Moscow
country: Russian Federation
facility: 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
country: Russian Federation
facility: Federal State Budget Scientific Institution "Scientific Center of Neurology"
city: Vladimir
country: Russian Federation
facility: The state budgetary health care institution of the Vladimir region "Regional Clinical Hospital"
city: Yaroslavl
country: Russian Federation
facility: Federal State Budgetary Educational Institution of Higher Education "Yaroslavl State Medical University" of the Ministry of Healthcare of the Russian Federation
city: Yaroslavl
country: Russian Federation
facility: State Institution of Health of the Yaroslavl Region Clinical Hospital No. 8
city: Yaroslavl
country: Russian Federation
facility: State budgetary institution of health care of the Yaroslavl region "Regional Clinical Hospital"
Study officials:
References: