Clinical trial NCT03485495
Conditions: Cerebral Atherosclerosis
Sponsor: Materia Medica Holding
Start date: 2018-04-12; Completion date: 2019-04-11
Enrollment: 124 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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".

Arms: arm 1: 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 2: 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.
Interventions: intervention 1: Divaza intervention 2: Placebo
Intervention descriptions: intervention 1: Oral administration. intervention 2: Oral administration.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
 
 
 
 
 
 
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 
 
 
 
 
Phase IV 
 
 
 
 
 
 
 
 
 
 
Sponsor 
OOO «NPF «MATERIA MEDICA HOLDING» 
Protocol number 
MMH-DV-010 
Version date: 
December 05, 2017 


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ClinicalTrials.gov Id: 
NCT03485495 
 
Protocol Summary 
 
This document represents the protocol summary for the study on human subjects. The study will 
be carried out in accordance with ICH GCP, National Standard of the Russian Federation GOST 
52379-2005 "Good Clinical Practice", Helsinki Declaration of World Medical Association, 
relevant requirements of the regulatory authorities as well as the study procedures. 
Title of Study 
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 
Phase: IV 
Sponsor: OOO "NPF "MATERIA MEDICA HOLDING", Moscow, Russia 
Protocol No. MMH-DV-010 
 
Objective of the study 
 To obtain additional data on efficacy and safety of Divaza for adjustment of oxidative 
disorders in patients with cerebral atherosclerosis. 
Endpoints  
Primary endpoint 
 Change in mean value of lipoprotein resistance to LP after 12-week therapy vs. baseline. 
Secondary endpoint 
 Proportion of patients with improved cognitive function (MoCA score + 1 or more) after 12-
week therapy versus baseline. 
Exploratory endpoints 
 Change in mean level of preformed LP products, predominantly lipid hydroperoxides after 
12-week therapy versus baseline. 
 Change in mean value of lipoprotein ability for oxidation after 12-week therapy versus 
baseline. 
 Change in mean value of NO product serum concentration after 12-week therapy versus 
baseline. 
 Change in mean value of platelet aggregation after 12-week therapy versus baseline. 
 Change in mean IMCT value after 12-week therapy versus baseline. 


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Safety assessment  
 Occurrence and nature of adverse events during the therapy, their intensity (severity), causal 
relationship to the study drug, and outcome. 
Study design  
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 
mRs1.  
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 
with2: 
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. 
                                                 
1 If applicable. 
2 Will be performed in FSBRI Research Center of Neurology only.  


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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". 
Inclusion and exclusion 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. 


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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) > 13. 
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. 
                                                 
3 If the patient did not have a stroke, this scale will not be filled. 


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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). 
Criteria for Withdrawal or Termination 
1. Screening failure.  
2. Acute or exacerbated chronic infectious or inflammatory disease with the symptoms 
persisting for more than 7 days. 
3. Modification of the dose and/or combination of basic products. 
4. Patient's inability or refusal to follow protocol requirements. 
5. Necessity in medical products prohibited within the study. 
6. Development of adverse event requiring cancellation of the study drug. 
7. Incorrect inclusion of ineligible patient. 
8. Pregnancy. 
9. Desire of patient to complete the study ahead of schedule for any reason. 
10. Participation in another clinical study. 
11. Cases not specified by the protocol where the investigator decides that further participation 
may harm the patient. 
12. Unblinding. 
Number of subjects 
It is planned to include 124 subjects which is expected to allow completion of all protocol 
procedures by at least 98 subjects (49 in each group). 
Interim analysis 
The protocol does not schedule any unblinded interim analyses, however, at the sponsor’s 
decision a blinded interim analysis may be carried out to specify population parameters and 
potential further specification of sample size (increase only).  


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Treatment 
 
Group 1 
Name of the medicinal product: Divaza 
Active ingredient: Affinity purified antibodies to brain-specific S-100 protein - 0.006 g*; 
affinity purified antibodies to endothelial NO synthase - 0.006 g* 
Excipients: Lactose monohydrate (lactose) - 0.267g; microcrystalline cellulose - 0.03 g;               
magnesium stearate - 0.003 g  
Method of 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.    
Dosage form: Tablets 
Description: Scored and beveled flat cylindrical tablets, white to off-white 
Storage conditions: Store at a temperature not exceeding 25° C. 
Group 2 
Name of the medicinal product: Placebo 
Active ingredient: NA 
 
Excipients: Lactose monohydrate (lactose) - 0.267 g, microcrystalline cellulose - 0.03 g;               
magnesium stearate - 0.003 g 
Method of 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.    
Dosage form: Tablets 
Description: Scored and beveled flat cylindrical tablets, white to off-white 
Storage conditions: Store at a temperature not exceeding 25° C.  
Prohibited concomitant therapy 
One month prior to enrollment and during the study (beginning from signing informed consent 
form and initiation of screening) it is prohibited to administer any therapy affecting neurological 
and oxidative status of the patient: 
1. Products manufactured by OOO "NPF "Materia Medica Holding": Tenoten, Kolofort, 
Brizantin, Proproten, Afalaza, Impaza. 
2. Antihypoxants and antioxidants including: 
• vitamin Е and its derivatives – α-tocopherol acetate, etc. 
• vitamin C and its derivatives – ascorbic acid, ascovit, etc. 


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• vitamin А and its derivatives – retinol etc. 
• glutathione 
• deproteinized fetal hemoderivative - actovegin 
• dihydroquercetin 
• dimethyloxobutylphosphonyldimethylate derivative – dimephosphon 
• carnitine and its derivatives - carnitine chloride 
• oxygen 
• levocarnitine and its derivatives – carniten, carnifit, levocarnil, elcar 
• methylethylpyridinol and its derivatives – vixipin, cardioxipin, emoxipin, etc. 
• morpholinyl-methyl-triazolyl thioacetate derivatives – thiotriazoline 
• meldonium derivatives - mildronate 
• sodium oxybutyrate 
• sodium fumorste derivatives - confumin 
• oxyethylammonium methylfenoxyacetate deritvatives – trecresan 
• pentahydroxyethylnaftoquinone derivativrs – histochrome, echinochrome 
• polydihydroxyphenylene thiosulfonate sodium – hypoxen, olifen, etc 
• superoxide dismutase – rexod etc. 
• thioctic acid derivatives – neurolipon, octolipen, polition, thiogamma, espalipon 
• trimethazine and its derivatives – preductal, rimecod, trimectal, triducard, etc. 
• pumpkin-seed oil – peponen, etc. 
• ubidecarenone and its derivatives – kudesan, kudevita, etc. 
• phenazone acid 
• cytochrome C 
• ethylmethyhydroxypyridine malate derivatives – ethoxydol 
• ethylmethylhydroxypyridine succinate and its derivatives – mexidol, mexicor, mexiprim, 
neurox, cerecard, etc. 
• ethylthiobenzimidazole hydrobromide. 
3. Other antioxidants including: 
• acetylcysteine and its derivatives – fluimucil, mucobene, etc. 
4. Peripheral vasodilating agents (ATC group C04) including nicotinic acid and its derivatives; 
purines (xanthinol nicotinate, pentoxyphylline), ergot alkaloids (nicergoline, α-
dihydroergocriptine + caffeine), other vasodilating agents (vincamine, bencyclane, 
naftidrofuryl), papaverine, etamivan + etophylline + hexobendine. 
5. Calcium channel blockers − nimodipine (С08СА06), instenone(С01ЕХ). 
6. Anticholinergic agents (N04A). 


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7. Dopaminergic agents (N04B). 
8. Psycholeptics (N05) including anxiolytics (tranquilizers), hypnotics and sedative agents. 
9. Psychoanaleptics (N06) including antidepressants, psychostimulants and nootropic agents 
including: 
• pyrrolidine derivatives (racetams) – piracetam, etiracetam, aniracetam, etc. 
• dimethylaminoethanol derivatives (acetylcholine precursors) – deanol aceglumate, 
meclofenoxate 
• pyridoxine derivatives – pyritinol, biotredin 
• derivatives and analogues of GABA – gamma-aminobutyric acid, nicotinoyl γ-
aminobutyric acid, γ-amino-beta-phenylbutyric acid hydrochloride, hopantenic acid, 
calcium γ-hydroxybutyrate 
• ginkgo biloba 
• neuropeptides and their analogues - methyonyl-glutamyl-histidyl-phenylalanyl-prolyl-
glycyl-proline 
• amino acids and substances affecting the system of excitatory amino acids – glycine, 
pyridoxine+threonine 
• derivatives of 2-mercaptobenzimidazole – ethylthiobenzimidazole hydrobromide 
• idebenone 
• vinpocetine derivatives - cavinton 
• choline alfoscerate derivatives - cerepro 
• popypeptides and organic composites - polypeptides of the cerebral cortex of cattle, 
cerebrolysin 
• cytoflavin. 
10. Other products for the treatment of nervous system diseases (N07) including: 
• parasimpathomimetics (N07A) 
• antivertigo preparations (N07C) 
• other nervous system drugs (N07X). 
11. The substances from other pharmacological groups with nootropic effect including: 
• general tonic agents and adaptogens – ginseng, melatonin, lecithin, acetylaminoauccinic 
acid, etc. 
• metabolic agents. 
12. Corticosteroids for systemic use (Н02А). 
13. Corticosteroids for systemic use, combinations (H02B). 
14. Homeopathic agents. 
15. Any unregistered product and/or vaccine.. 


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16.  The products to which the patient had previously an allergic reaction. 
Study design scheme 
 
 
 
 
 
 
 
 
 
 
 
 
Schedule of study procedures  
Visit 
 
Procedure 
 
Visit 1 
(from day  -5 to 
day 0) 
Screening 
Visit 24 
(Day 0) 
Randomization 
Visit 3 
(Week 4  ± 5 
days) 
Visit 4 
(phone call) 
(Week 8 ± 5 days) 
Visit 5 
(Week 12 ± 5 
days) 
Informed consent 
+ 
 
 
 
 
Study subject registration in 
IVRS and assignment of a 
personal code 
+ 
 
 
 
 
Collection of complaints 
+ 
+ 
+ 
+ 
+ 
Medical history 
+ 
 
 
 
 
Recording concomitant 
conditions and diseases 
+ 
+ 
 
 
 
Objective examination 
+ 
+ 
+ 
 
+ 
Vital signs (HR, BR, BP) 
+ 
+ 
+ 
 
+ 
Concomitant therapy 
+ 
+ 
+ 
+ 
+ 
Inclusion/exclusion criteria 
+ 
 
 
 
 
Appointment of visit 
+ 
+ 
+ 
+ 
 
Randomization 
 
+ 
 
 
 
Study drug supply 
 
+ 
+ 
 
 
Study drug accountability 
and return, compliance 
assessment 
 
 
+ 
 
+ 
Evaluation of treatment 
safety 
 
+ 
+ 
+ 
+ 
Completing the Montreal 
Cognitive Assessment Scale 
+ 
 
+ 
 
+ 
                                                 
4 If Visit 1 and Visit 2 procedures are performed on the same day, repeated procedures are not required. 
SCREENING
12 weeks 
Visit 5 
(Week 12 ± 5 days) 
 
Group 2: Placebo 2 tablets 3 times a day for 12 weeks. 
RANDOMIZATION
 
Group 1: Divaza 2 tablets 3 times a day for 12 weeks. 
STUDY 
COMPLETION 
Visit 3 
(Week 4 ± 5 days) 
Vist 4 (phone call) 
(Week 8 ± 5 days) 
Visit 2 
(Day 0) 
Visit 1 
(Day -5 - 0) 


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(MoCA) 
Completing the Modified 
Rankin Scale (mRs)5 
+ 
 
 
 
 
Venous blood sampling for 
testing: 
 
+ 
 
 
+ 
- levels of preformed LP 
products, predominantly 
lipid hydroperoxides 
 
+ 
 
 
+ 
- low and very low-density 
lipoprotein resistance to LP 
 
+ 
 
 
+ 
- lipoprotein ability for 
oxidation 
 
+ 
 
 
+ 
- serum levels of NO 
products  
 
+ 
 
 
+ 
- platelet aggregation with 
bandage sign6 
 
+ 
 
 
+ 
Duplex MAH scanning7 
 
+ 
 
 
+ 
Pregnancy test 8 
+ 
 
 
 
 
End of patient participation 
in the study 
+ 
+ 
+ 
+ 
+ 
 
Statistical Analyses 
Samples  
Total set includes all the patients who have signed ICF. This sample will consider all adverse 
events throughout the study, including those occurred prior to the study therapy.  
The sample including all patients who received at least one dose of the study drug to be used for 
analysis of the study treatment safety and tolerability (Safety population), as all adverse events 
identified after the study drug administration will be recorded.  
Full Analysis Set This sample will consist of all enrolled patients, except for those who met at 
least one of the following criteria:  
1) noncompliance with inclusion/exclusion criteria;  
2) patient failing to take any dose of the study drug; 
3) lack of any data on the patient after the study drug administration.  
This was the best set for the Intention-to-treat method, so it will be used in the Intention-to-treat 
efficacy analysis of the study therapy. 
Per Protocol set. This sample includes all patients who completed the therapy as per the study 
protocol, without any missing visits or major protocol deviations. This set will be used in the Per 
Protocol efficacy analysis of the test therapy.  
                                                 
5 If applicable. 
6 Will be performed for the patients in FSBRI Research Center of Neurology only. 
7 Will be performed for the patients in FSBRI Research Center of Neurology only. 
8 If applicable. 


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Per Protocol set will not include the subjects whose data are fully or partially invalid for analysis 
due to a protocol deviation. 
Protocol deviations resulting in full or partial data invalidity. 
1. Violation of visit schedule. 
2. Inappropriate supply of the study drug. 
3. Prescription of prohibited therapy. 
4. ≥ 25% increase or reduction in the amount of the study therapy administered. 
5. Inability to assess the subject's compliance using the formula (e.g. loss of pack with the 
product). 
6. Major discrepancies between source documents and CRF detected during monitoring or 
another authorized check.  
7. Violation of the procedure for obtaining Informed consent.  
8. Non-compliance with the clinical study protocol procedures. 
9. Inability to collect all subject's data used for evaluation of the study endpoints (e.g. lack of 
entries in source documents required for verification of inclusion/exclusion criteria, safety 
and efficacy criteria). 
10. Other protocol deviations resulting in full or partial data invalidity. 
Data treatment and all statistical calculations under the protocol will be made using SAS-9.4 
statistical software.9 
Evaluation of sample size 
The sample size was assessed in accordance with the following rules and assumptions: 
1. Statistical assumptions 
1.1 the power of statistical tests 'P = (1 − β)' is 80% (the probability of correct rejection of 
the null hypothesis is 0.8) 
1.2 the probability of type I error ' α ' is less that 5% (the probability of false acceptance of 
the alternative hypothesis is less than 0.05); 
1.3 statistical criteria will be two-sided;  
1.4 calculation of sample size will be based on the assumptions on the expected effect 
declared in the primary and secondary endpoints of the protocol; 
1.5 ratio between Divaza and Placebo sample sizes is 1:1 (1 Divaza subject per 1 Placebo 
subject); 
1.6 statistical hypotheses will be as follows:  
 Binary values: 
                                                 
9 Holder of license: ООО "NPF "MATERIA MEDICA HOLDING", No. 70100045. 


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null and alternative hypotheses on superiority of the study product under the dosing scheme 
used: 
                                  H0: p1=p2 
                                  Ha: p1≠p2 
p1  –  proportion of patients in Divaza group with ≥ 1 improvement 
p2  –  proportion of patients in Placebo group with ≥ 1 improvement 
 Interval values 
null and alternative hypotheses on superiority of the study product under the dosing scheme 
used: 
H0: Δµ1=Δµ2 
Ha: Δµ1≠Δµ2 
where      Δµ1 – mean reduction (initial – final score) in Divaza group 
Δµ2 – mean reduction (initial – final score) in Placebo group; 
1.7 calculation of sample size for statistical criteria will be made using the following 
formulas:  
 Binary values: 
n1 = kn2 
              
 
 
where         n1, n2 are sample sizes for Divaza and Placebo groups 
= p1-p2 – expected difference between proportions of subjects with improvement in 
Divaza and Placebo groups 
k – ratio of sample sizes (in this study equal to 1) 
zα/2 – tabular value of two-sided z-criterion for α  
\zβ – tabular value of one-sided z-criterion for β; 
 Interval values:  
n1 = kn2 
 
 where         n1, n2 are sample sizes for Divaza and Placebo groups, respectively  
ε = Δµ1-Δµ2 – expected difference between mean reductions of value between Divaza 
and Placebo groups 


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k – ratio of sample sizes (in this study k=1)  
ϭ – standard deviation of reduction 
zα/2 – tabular value of two-sided z-criterion for α  
zβ – tabular value of one-sided z-criterion for β; 
1.8 
the largest of the samples meeting the primary endpoint will be used for terminal PP 
sample size  
NPP=max (n1, n2, … , ni); 
1.9 
final sample size will be determined using the formula:  
NT=NPP/(1-Cw),  
where      NT – final sample size;  
NPP – result of calculation in cl. 1.7 – cl. 1.8, i.e. the scheduled number of the patients 
completing the study per protocol 
Cw – withdrawal coefficient. 
2. Assumptions on expected clinical study effects. 
Primary endpoint: difference in changes in activity of endogenous antioxidant protection 
between Divaza and Placebo groups will be no less than ε=20.36 s at standard deviation of 
σ=32.1. 
Secondary endpoint: Proportion of patients with reduced total MoCA score ≥ 1 in Divaza 
group will be no less than 82%, while in Placebo group the relevant value will be no more than 
50%. 
3. Total type I error is divided equally between the primary and secondary criteria. 
To evaluate superiority of Divaza over Placebo, group size will be (49, 42) patients for 
each group, respectively, for the primary and secondary criteria.  
Given potential withdrawal of at least 20% subjects (Rw=0.2) during the study for various 
reasons, at least 124 patients will be required to sign informed consent, with 62 patients per 
group. 
Statistical criteria  
All statistical calculations will be made using two groups of statistical criteria:  
 
parametric - to evaluate continuous and interval random values;  
 
nonparametric – to obtain: 
 evaluations of equality/inequality in the proportion of the patients upon their 
comparison for various visits,  
 analysis of frequencies of the features compared, 
and 


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 evaluation of continuous and interval random values in case of non-compliance with 
normal random distribution. 
Parametric criteria 
The application of parametric criteria will be accompanied by a check of models for applicability 
(e.g. Kolmogorov-Smirnov test, Shapiro-Wilk test). 
The following parameters and approaches are to be used: 
1. To evaluate the differences in continuous variables obtained in one group at two different 
visits – Student’s test for paired samples. 
2. To evaluate time changes in parameters compared - analysis of variance (ANOVA) or 
modified repeated measures covariance (ANCOVA).  
3. In case of multiple comparisons of the groups various adjustments for multiplicity will be 
used (Dunnett, Tukey, Scheffe, Holm adapted test), etc.  
4. Generalized Linear Models and/or Mixed Linear Models will be used in case of abnormal 
data distribution.  
5. Selection of the type of distribution, specification of factor and covariance structures of the 
model will be made using fit-statistics such as AIC (Akaike information criterion). 
The following SAS software programs are supposed to be applied to the above listed tests and 
techniques:  
 UNIVARIATE: normality verification of the distributions under comparison; 
 CORR, MEANS - calculation of descriptive statistics 
 TTEST – Student’s test with all modifications;  
 GLM – generalized linear models for analysis of time changes (ANOVA, ANCOVA); 
 GENMOD – generalized linear models. 
 MIXED – mixed linear models. 
Non-parametric criteria 
Below are potential types of comparisons with relevant criteria: 
1. To evaluate time changes in the parameters compared – Friedman test, nonparametric 
analogue of repeated measures analysis of variance. 
2. For frequency analysis of contingency tables 2×2 – χ2 (if the frequency under comparison > 
5) or exact Fisher’s test (if one of the frequencies under comparison < 5).  
3. Cochran-Mantel-Haenszel test (modified χ2 test for multiple comparisons) – to perform 
frequency analysis based on independent strata.  
4. For frequency analysis of data on presence/absence of an event or outcome during repeated 
measurements (contingency tables with dependent strata) – survival analysis.  


Protocol No. MMH-DV-010 
05-Dec-2017 
CONFIDENTIAL  
 
Page 16 of 16 
To perform the above-mentioned nonparametric statistical analysis the following SAS 
procedures are to be used:  
 FREQ – Friedman test, χ2 test and/or exact Fisher’s test; Cochran-Mantel-Haenszel test. 
 LIFETEST, PHREG – survival analysis.  
 NPAR1WAY - Mann-Whitney U-test. 
Safety parameters  
Adverse events recorded during the study will be grouped into frequency tables by severity, 
seriousness and relationship with the study drug. 
Data presentation 
Descriptive statistics will be provided for each study continuous / interval variable. Numerical 
data will be presented by mean, standard deviation, min and max values. Comparisons 
suggesting statistical conclusion will have the relevant confidence intervals. Outliers will be 
analyzed individually. The data will be grouped by visits. The categorical variables will be 
presented as frequency tables by visits.