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

• Sponsor: Materia Medica Holding (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03485495
• Collaborator: (none)
• Enrollment: 124
• Locations: 10
• Arms: 2
• Actual Duration (Months): 12
• Patients Per Site: 12.4
• Patients Per Site Per Month: 1

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
Cerebral Atherosclerosis	Drug: Divaza; Drug: Placebo	Phase 4

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 Design

• Study Type: Interventional
• Actual Enrollment: 124 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: Apr 12, 2018
• Actual Primary Completion Date: Apr 11, 2019
• Actual Study Completion Date: Apr 11, 2019

Arms and Interventions

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.

Outcome Measures

Primary Outcome Measures

1. Change in Mean Value of Lipoprotein Resistance to LPO. [12 weeks of the observation period.]

   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

1. Percentage of Patients With Improved Cognitive Function. [12 weeks of the observation period.]

   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.

Other Outcome Measures

1. Change in Mean Level of Preformed LP Products (Mainly Lipid Hydroperoxides). [12 weeks of the observation period]

   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.

2. Change in Mean Value of Lipoprotein Ability for Oxidation. [12 weeks of the observation period.]

   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.

3. Change in Mean Value of NO Products Serum Concentration. [12 weeks of the observation period.]

   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).

4. Change in Mean Value of Platelet Aggregation. [12 weeks of the observation period.]

   Based on laboratory evaluation. Change in mean platelet aggregation after 12-week therapy versus baseline.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 40 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

1. (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).

1. Cognitive disorders (MoCa <26).

2. Patients with unchanged dose and combination of basic therapy of cerebral atherosclerosis and hypertension during the previous month.

3. Patients who gave their consent to use reliable contraception during the study.

4. 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).

1. Dementia (F00-F03).

2. Previously diagnosed cardiovascular diseases with functional class III or IV (according to New York Heart Association, 1964).

3. Hypothyroidism, diabetes mellitus and other somatic diseases at decompensation stage.

4. Uncontrollable hypertension: SBP > 180 mm Hg and/or DBP > 110 mm Hg.

5. Diseases of lower limb veins (lower limb varicose veins, deep venous thrombosis, etc.) at decompensation stage.

6. Any other severe concomitant pathology which, according to the investigator, may interfere with the patient's participation in the study.

7. History/suspicion of oncology of any location (except for benign neoplasms).

8. Allergy/intolerance of any component of the drug products used in the therapy.

9. Hereditary lactose intolerance.

10. Malabsorption syndrome, including congenital or acquired lactase deficiency (or any other disaccharidase deficiency) and galactosemia.

11. Pregnancy, breast-feeding.

12. History of treatment non-compliance, psychiatric disorders, alcoholism or drug abuse which, according to the investigator, may interfere with the study procedures.

13. Use of any medicine indicated in the section "Prohibited concomitant treatment" within 1 month prior to enrollment.

14. Participation in other clinical trials in the previous 3 months.

15. 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).

16. 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).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Limited Liability Company "Family policlinic no. 4"	Korolev		Russian Federation	141060
2	Moscow City Clinical Hospital after V.M. Buyanov	Moscow		Russian Federation	115516
3	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	119049
4	Federal State Budgetary Institution Federal Research and Clinical Center of Physical-Chemical Medicine Federal Medical Biological Agency	Moscow		Russian Federation	119435
5	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	119992
6	Federal State Budget Scientific Institution "Scientific Center of Neurology"	Moscow		Russian Federation	1253678
7	The state budgetary health care institution of the Vladimir region "Regional Clinical Hospital"	Vladimir		Russian Federation	600023
8	Federal State Budgetary Educational Institution of Higher Education "Yaroslavl State Medical University" of the Ministry of Healthcare of the Russian Federation	Yaroslavl		Russian Federation	150000
9	State Institution of Health of the Yaroslavl Region Clinical Hospital No. 8	Yaroslavl		Russian Federation	150030
10	State budgetary institution of health care of the Yaroslavl region "Regional Clinical Hospital"	Yaroslavl		Russian Federation	150062

Sponsors and Collaborators

• Materia Medica Holding

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Dec 5, 2017

More Information

Publications

None provided.

• Responsible Party: Materia Medica Holding
• ClinicalTrials.gov Identifier: NCT03485495
• Other Study ID Numbers: MMH-DV-010
• First Posted: Apr 2, 2018
• Last Update Posted: Aug 26, 2021
• Last Verified: Aug 1, 2019

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Intracranial Arteriosclerosis; Atherosclerosis

Study Results

Participant Flow

Arm/Group Title	Divaza	Placebo
Arm/Group 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. Divaza: Oral administration.	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. Placebo: Oral administration.
Period Title: Overall Study
STARTED	65	59
COMPLETED	64	59
NOT COMPLETED	1	0

Baseline Characteristics

Arm/Group Title	Divaza	Placebo	Total
Arm/Group 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. Divaza: Oral administration.	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. Placebo: Oral administration.	Total of all reporting groups
Overall Participants	65	59	124
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	61.4 (7.8)	59.8 (7.4)	60.7 (7.6)
Sex: Female, Male (Count of Participants)
Female	51 78.5%	40 67.8%	91 73.4%
Male	14 21.5%	19 32.2%	33 26.6%
Race and Ethnicity Not Collected (Count of Participants)
Count of Participants [Participants]	0 0%
Region of Enrollment (participants) [Number]
Russia	65 100%	59 100%	124 100%

Outcome Measures

1. Primary Outcome

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.

Outcome Measure Data

Analysis Population Description

1 patient in Divaza group had no laboratory data.

Arm/Group Title	Divaza	Placebo
Arm/Group 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. Divaza: Oral administration.	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. Placebo: Oral administration.
Measure Participants	63	59
Resistance of LP to LPO at baseline	42.4 (13.1)	42.9 (11.2)
Resistance of LP to LPO after 12 weeks	55.6 (12.5)	49.4 (14.3)
∆ between baseline and after 12 weeks	14.8 (14.7)	6.4 (16.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Divaza, Placebo
	Comments	This analysis applies to ∆ between baseline and after 12 weeks row.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.007
	Comments	A priori threshold for statistical significance is split evenly between primary and secondary endpoints. α=0.025.
	Method	t-test, 2 sided
	Comments

2. Secondary Outcome

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.

Outcome Measure Data

Analysis Population Description

8 patients in Divaza group and 2 patients in Placebo group had no data for week 12.

Arm/Group Title	Divaza	Placebo
Arm/Group 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. Divaza: Oral administration.	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. Placebo: Oral administration.
Measure Participants	56	57
Count of Participants [Participants]	56 86.2%	51 86.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Divaza, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0272
	Comments	A priori threshold for statistical significance is split evenly between primary and secondary endpoints. α=0.025.
	Method	Fisher Exact
	Comments

3. Other Pre-specified Outcome

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

Outcome Measure Data

Analysis Population Description

1 patient in Divaza group had no laboratory data.

Arm/Group Title	Divaza	Placebo
Arm/Group 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. Divaza: Oral administration.	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. Placebo: Oral administration.
Measure Participants	63	59
Level of preformed LPO products at baseline	72.5 (14.1)	72.8 (12.9)
Level of preformed LPO products after 12 weeks	67.7 (13.1)	69.9 (11.7)
∆ between baseline and after 12 weeks	-3.2 (9.6)	-2.9 (8.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Divaza, Placebo
	Comments	This analysis applies to ∆ between baseline and after 12 weeks row.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8762
	Comments
	Method	t-test, 2 sided
	Comments

4. Other Pre-specified Outcome

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.

Outcome Measure Data

Analysis Population Description

1 patient in Divaza group had no laboratory data.

Arm/Group Title	Divaza	Placebo
Arm/Group 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. Divaza: Oral administration.	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. Placebo: Oral administration.
Measure Participants	63	59
LP ability for oxidation at baseline	1027.3 (204.7)	993.8 (264.1)
LP ability for oxidation after 12 weeks	1024.1 (226.7)	1040.6 (217.7)
∆ between baseline and after 12 weeks	-12.1 (192.1)	57.0 (241.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Divaza, Placebo
	Comments	This analysis applies to ∆ between baseline and after 12 weeks row.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2082
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

5. Other Pre-specified Outcome

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.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Divaza	Placebo
Arm/Group 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. Divaza: Oral administration.	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. Placebo: Oral administration.
Measure Participants	7	8
NO-3 level at baseline	41.3 (14.9)	69.0 (28.9)
NO-3 level (after cuff test) at baseline	38.4 (16.5)	79.1 (33.5)
NO-3 level after 12 weeks	51.7 (23.9)	63.3 (36.8)
NO-3 level (after cuff test) after 12 weeks	64.0 (15.6)	61.1 (27.9)
NO-2 level at baseline	35.9 (16.0)	62.8 (28.0)
NO-2 level (after cuff test) at baseline	31.8 (16.1)	69.6 (32.3)
NO-2 level after 12 weeks	43.9 (22.2)	52.5 (35.9)
NO-2 level (after cuff test) after 12 weeks	57.0 (14.5)	51.0 (25.9)
NO level at baseline	5.4 (2.3)	6.3 (4.1)
NO level (after cuff test) at baseline	6.6 (1.8)	9.5 (4.0)
NO level after 12	7.8 (3.9)	10.7 (4.5)
NO level (after cuff test) after 12 weeks	7.0 (2.8)	10.1 (5.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Divaza, Placebo
	Comments	This analysis applies to NO-3 data.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0038
	Comments	The p-value associated with "treatment*visit" interaction between Divaza and Placebo treatment groups. Model includes cuff test status, treatment, visit and treatment*visit interaction.
	Method	Mixed Models Analysis
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Divaza, Placebo
	Comments	This analysis applies to NO-2 data.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0018
	Comments	The p-value associated with "treatment*visit" interaction between Divaza and Placebo treatment groups. Model includes cuff test status, treatment, visit and treatment*visit interaction.
	Method	Mixed Models Analysis
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Divaza, Placebo
	Comments	This analysis applies to NO data.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.46
	Comments	The p-value associated with "treatment*visit" interaction between Divaza and Placebo treatment groups. Model includes cuff test status, treatment, visit and treatment*visit interaction.
	Method	Mixed Models Analysis
	Comments

6. Other Pre-specified Outcome

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.

Outcome Measure Data

Analysis Population Description

ADP-AP - platelet aggregation (PA) induced by adenosine diphosphate (ADP) ADR-AP - platelet aggregation (PA) induced by adrenaline (ADR)

Arm/Group Title	Divaza	Placebo
Arm/Group 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. Divaza: Oral administration.	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. Placebo: Oral administration.
Measure Participants	7	8
ADP-PA at baseline	46.9 (13.8)	44.6 (14.1)
ADP-PA (after cuff test) at baseline	45.0 (14.0)	51.9 (15.7)
ADP-PA after 12 weeks	45.3 (12.5)	46.3 (9.4)
ADP-PA (after cuff test) after 12 weeks	49.7 (14.6)	52.5 (11.6)
ADR-PA at baseline	48.4 (12.2)	47.8 (16.4)
ADR-PA (after cuff test) at baseline	44.7 (13.3)	53.1 (16.8)
ADR-PA after 12 weeks	47.7 (11.8)	51.4 (11.3)
ADR-PA (after cuff test) after 12 weeks	54.1 (8.6)	57.4 (14.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Divaza, Placebo
	Comments	This analysis applies to ADP-PA data.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.88
	Comments	The p-value associated with "treatment*visit" interaction between Divaza and Placebo treatment groups. Model includes cuff test status, treatment, visit and treatment*visit interaction.
	Method	Mixed Models Analysis
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Divaza, Placebo
	Comments	This analysis applies to ADR-PA data.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.93
	Comments	The p-value associated with "treatment*visit" interaction between Divaza and Placebo treatment groups. Model includes cuff test status, treatment, visit and treatment*visit interaction.
	Method	Mixed Models Analysis
	Comments

Adverse Events

Time Frame	During the treatment period - 12 weeks (start after taking the first dose of the study drug, during the entire period of the study therapy and within 24 hours after the last dose of the study drug).
Arm/Group Title	Divaza		Placebo
Arm/Group 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. Divaza: Oral administration.		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. Placebo: Oral administration.
All Cause Mortality
	Divaza		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/64 (0%)		0/59 (0%)
Serious Adverse Events
	Divaza		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/64 (0%)		0/59 (0%)
Other (Not Including Serious) Adverse Events
	Divaza		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/64 (7.8%)		3/59 (5.1%)
Gastrointestinal disorders
Odinophagy	1/64 (1.6%)	1	0/59 (0%)	0
Infections and infestations
Nasopharyngitis	1/64 (1.6%)	1	0/59 (0%)	0
Respiratory tract infection	1/64 (1.6%)	1	1/59 (1.7%)	1
Injury, poisoning and procedural complications
Arthropod bite	1/64 (1.6%)	1	0/59 (0%)	0
Investigations
Increased blood pressure	0/64 (0%)	0	1/59 (1.7%)	1
Nervous system disorders
Headache	1/64 (1.6%)	1	0/59 (0%)	0
Respiratory, thoracic and mediastinal disorders
Nosebleed	0/64 (0%)	0	1/59 (1.7%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.