Clinical trial NCT03815292
Conditions: Mild Cognitive Impairment Ischemic Stroke
Sponsor: Materia Medica Holding
Start date: 2018-10-19; Completion date: 2020-01-27
Enrollment: 276 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is:

* to evaluate efficacy of MMH-MAP in the treatment of mild cognitive impairment in subjects in early rehabilitation period of ischemic stroke
* to evaluate safety of MMH-MAP in the treatment of mild cognitive impairment in subjects in early rehabilitation period of ischemic stroke

Detailed description:
A double-blind, placebo-controlled randomized clinical trial in parallel groups.

The study patients are subjects of either gender, aged 45-80 years old, after an ischemic stroke within 3-6 months prior to enrollment and confirmed by neuroimaging, having mild cognitive impairment.

After the patients provide signed Participant Information Sheet and Informed Consent, they will be interviewed for complaints and medical history and undergo physical examination and laboratory tests. The doctor will rate the severity of patients' cognitive impairments on the Mini Mental State Examination (MMSE) scale and Montreal Cognitive Assessment (MoCA) scale, assess their performance in activities of daily living on the Barthel Index scale \[Collin C, Wade DT, Davies S, Horne V. "The Barthel ADL Index: a reliability study." Int Disability Study.1988;10:61-63.\], and administer the Stroke Specific Quality of Life Scale (SS-QOL) questionnaire \[Williams LS, Weinberger M, Harris LE, Clark DO, Biller J. Development of a stroke-specific quality of life scale. Stroke 1999 Jul;30(7):1362-9\]. Eligible participants will have to have moderate cognitive impairments (MMSE score - at least 21 and MoCA - less than 26). Therapy received by patients for their co-morbidities and primary diagnosis will be recorded. All women of childbearing potential will be administered pregnancy tests.

If a patient meets all inclusion criteria and does not have any exclusion criteria at Visit 1, he/she is randomized to one of the two groups: group 1 will receive MMH-MAP at 2 tablets twice daily; group 2 will receive Placebo using the study product dosing regimen. The total duration of follow-up and treatment will be 28 weeks, which will include 5 additional visits.

At Visit 2 (Week 4±7 days), the doctor records patients' complaints and physical examination data, reviews the progress of study and basic and concomitant therapy, and assesses treatment safety and patient compliance with treatment.

At Visit 3 (Week 8±7 days), Visit 4 (Week 16±7 days), and Visit 5 (Week 24±7 days), the doctor assesses patients' cognitive impairments (MoCA) and performance in activities of daily living (the Barthel Index). The patients complete the SS-QOL questionnaire.

At Visit 5 (Week 24±7 days), the doctor will additionally complete the Clinical Global Impression Efficacy Index (CGI-EI) scale \[Guy W, editor. ECDEU Assessment Manual for Psychopharmacology. 1976 Rockville, MD, U.S. Department of Health, Education, and Welfare\] and collect samples for laboratory testing. The patient stops taking the study drug.

After four weeks following the end of study therapy patients complete a follow-up visit -Visit 6 (Week 28±7 days). The patients are interviewed for complaints and undergo physical examination, with a check on their concomitant and primary therapies as well as on the safety of study treatment. The doctor assesses patients' cognitive impairments (MoCA) and performance in activities of daily living (the Barthel Index) and administers the SS-QOL questionnaire.

The total length of the observation period will be 28 weeks. During the study, symptomatic therapy and therapy for underlying chronic conditions are allowed with the exception of the drugs indicated in the section "Prohibited Concomitant Treatment".

Arms: arm 1: Tablet for oral use. Dose per administration: 2 tablets. 2 tablets twice daily (4 tablets/day). The tablets should be held in mouth without chewing until complete dissolution. The duration of treatment will be 24 weeks. arm 2: Placebo for 24 weeks, according to the MMH-MAP dosing regimen.
Interventions: intervention 1: MMH-MAP 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 MMH-MAP in the treatment of mild 
cognitive impairment in subjects in early rehabilitation period of ischemic 
stroke 
 
 
 
 
Phase III 
 
 
 
 
 
 
 
 
 
 
Sponsor 
OOO «NPF «MATERIA MEDICA HOLDING» 
Protocol number 
MMH-MAP-001 
Version date: 
August 29, 2018 
ClinicalTrials.gov Id: 
NCT03815292 
 


Protocol No. MMH-MAP-001 
29-Aug-2018 
CONFIDENTIAL  
 
Page 2 of 14 
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", World Medical Association Declaration of Helsinki, 
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 MMH-MAP in the treatment of mild cognitive impairment in subjects in early 
rehabilitation period of ischemic stroke. 
Phase: III 
Sponsor: Company «MATERIA MEDICA HOLDING», Moscow, Russia 
Protocol No. MMH-MAP-001 
Objective of the study 
 To evaluate efficacy of MMH-MAP in the treatment of mild cognitive impairment in subjects 
in early rehabilitation period of ischemic stroke. 
 To evaluate the safety of MMH-MAP in the treatment of mild cognitive impairment in 
subjects in early rehabilitation period of ischemic stroke.   
Endpoints  
Primary endpoint 
1. Proportion of subjects with improved cognitive functions (MoCA ≥ +1) after 24-week therapy 
compared to baseline. 
Secondary endpoints 
1. Change in MoCA scores after 24 weeks of treatment. 
2. Percentage of patients with improved performance in activities of daily living (total Barthel 
Index score + 5 or more) after 24 weeks of treatment. 
3. Changes in Barthel index for activities of daily living after 24 weeks of treatment. 
4. Change in SS-QOL total score after 24 weeks of therapy. 
5. Therapeutic effect and adverse event values and CGI-EI scores after 24 weeks of treatment. 
6. Changes in intensity of cognitive disorders (MoCA) in follow-up period (24–28 weeks). 
7. Changes in Barthel index for activities of daily living in follow-up period (24−28 weeks). 
8. Changes in SS-QOL in follow-up period (24−28 weeks). 


Protocol No. MMH-MAP-001 
29-Aug-2018 
CONFIDENTIAL  
 
Page 3 of 14 
Safety assessment  
 Presence and nature of adverse events during the therapy, their intensity (severity), relation to 
the product, outcome. 
 Changes in vital signs. 
 Percentage of patients with clinically relevant laboratory abnormalities. 
Study design  
Design – multicenter double blind placebo-controlled randomized parallel-group clinical study. 
The study patients are subjects of either gender, aged 45-80 years old, after an ischemic stroke 
within 3-6 months prior to enrollment and confirmed by neuroimaging, having mild cognitive 
impairment. 
After the patients provide signed Participant Information Sheet and Informed Consent, they will 
be interviewed for complaints and medical history and undergo physical examination and 
laboratory tests. The doctor will rate the severity of patients’ cognitive impairments on the Mini 
Mental State Examination (MMSE) scale and Montreal Cognitive Assessment (MoCA) scale, 
assess their performance in activities of daily living on the Barthel Index scale, and administer 
the Stroke Specific Quality of Life Scale (SS-QOL) questionnaire. Eligible participants will have 
to have moderate cognitive impairments (MMSE score - at least 21 and MoCA - less than 26). 
Therapy received by patients for their co-morbidities and primary diagnosis will be recorded. All 
women of childbearing potential will be administered pregnancy tests. 
If a patient meets all inclusion criteria and does not have any exclusion criteria at Visit 1, he/she 
is randomized to one of the two groups: group 1 will receive MMH-MAP at 2 tablets twice daily; 
group 2 will receive Placebo using the study product dosing regimen. The total duration of 
follow-up and treatment will be 28 weeks, which will include 5 additional visits. 
At Visit 2 (Week 4±7 days), the doctor records patients' complaints and physical examination 
data, reviews the progress of study and basic and concomitant therapy, and assesses treatment 
safety and patient compliance with treatment.  
At Visit 3 (Week 8±7 days), Visit 4 (Week 16±7 days), and Visit 5 (Week 24±7 days), the doctor 
assesses patients' cognitive impairments (MoCA) and performance in activities of daily living 
(the Barthel Index). The patients complete the SS-QOL questionnaire.  
At Visit 5 (Week 24±7 days), the doctor will additionally complete the Clinical Global 
Impression Efficacy Index (CGI-EI) scale and collect samples for laboratory testing. The patient 
stops taking the study drug. 
After four weeks following the end of study therapy patients complete a follow-up visit –Visit 6 
(Week 28±7 days). The patients are interviewed for complaints and undergo physical 


Protocol No. MMH-MAP-001 
29-Aug-2018 
CONFIDENTIAL  
 
Page 4 of 14 
examination, with a check on their concomitant and primary therapies as well as on the safety of 
study treatment. The doctor assesses patients' cognitive impairments (MoCA) and performance 
in activities of daily living (the Barthel Index) and administers the SS-QOL questionnaire. 
The total length of the observation period will be 28 weeks. 
During the study, symptomatic therapy and therapy for underlying chronic conditions are 
allowed with the exception of the drugs indicated in the section “Prohibited Concomitant 
Treatment”. 
Inclusion and exclusion criteria 
Inclusion criteria 
1. Patients of either sex, aged 45 to 80 years old inclusively. 
2. Patients with a history of one stroke sustained 3 to 6 months prior to study entry and 
confirmed by neuroimaging.  
3. Patients with cognitive impairment (MoCA score < 26).  
4. Patients with moderate performance in activities of daily living (Barthel score = 61-80). 
5. Agreement to use a reliable method of birth control for the duration of the study (men and 
women of reproductive potential) 
6. Availability of signed patient information sheet (Informed Consent form) for participation in 
the clinical trial. 
Exclusion criteria 
1. Patients with a history of subarachnoid/parenchymatous/ventricular hemorrhage, brain 
neoplasm, or any other condition which has caused neurological dysfunction. 
2. History of central nervous system (CNS) disorders, including:  
•   inflammatory diseases of the CNS (G00-G09) 
•   systemic atrophies primarily affecting the CNS (G10-G13) 
•   extrapyramidal and movement disorders (G20-G26) 
•   other degenerative diseases of the nervous system (G30-G32) 
•   demyelinating diseases of the CNS (G35-G37) 
•   epilepsy (G40–41) 
• polyneuropathies and other disorders of the peripheral nervous system (G60-64), with 
marked movement and/or sensory impairments that cause movement disorders 
•   diseases of neuromuscular junction and muscle (G70-73) 
•   hydrocephalus (G91) 
•   compression of brain (G93.5). 
3. Dementia (20 or less on the MMSE score). 


Protocol No. MMH-MAP-001 
29-Aug-2018 
CONFIDENTIAL  
 
Page 5 of 14 
4. Speech disorders affecting investigator-patient communication. 
5. Prior diagnosis of heart failure defined by the New York Heart Association classification 
(1964) as IV Functional Classification or poorly treated hypothyroidism or diabetes mellitus. 
6. Patients having unstable angina or myocardial infarction in the past 6 months. 
7. History/suspicion of oncology of any location (except for benign neoplasms). 
8. Any other co-morbidity which, in the opinion of the investigator, may affect patient 
participation in the clinical trial. 
9. Patients allergic to/intolerant of any components of the study treatment. 
10. Patients with hereditary lactose intolerance. 
11. Malabsorption syndrome, including congenital or acquired lactase deficiency (or any other 
disaccharidase deficiency) and galactosemia. 
12. Pregnancy, breast-feeding or unwillingness to use birth control during the study. 
13. Patients who, from the investigator’s point of view, will not comply with the observation 
requirements of the study or adhere to study drug dosing regimens. 
14. Patients with a history of non-adherence to medication; mental disorder (except for 
cognitive deficits); or alcoholism or abuse of psychoactive substances, which, in the 
investigator’s opinion, will compromise compliance with study procedures. 
15. Patients who have used medications listed in ‘Prohibited Concomitant Treatment’ in the past 
week. 
16. Participation in other clinical trials in the previous 3 months. 
17. Patients who are related to any of the on-site research personnel directly involved in the 
conduct of the trial or are an immediate relative of the study investigator. ‘Immediate 
relative’ means husband, wife, parent, son, daughter, brother, or sister (regardless of whether 
they are natural or adopted). 
18. Patients who work for 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. Inability or patient’s refusal to comply with the protocol requirements. 
3. Necessity in medications prohibited within the study. 
4. An adverse event requiring discontinuation of the study product. 
5. Eligibility error. 
6. Pregnancy. 


Protocol No. MMH-MAP-001 
29-Aug-2018 
CONFIDENTIAL  
 
Page 6 of 14 
7. Patient’s decision to complete the study ahead of schedule due to lack of the therapy efficacy 
or any reasons. 
8. Enrollment of the subject into another clinical study. 
9. Cases not stipulated in the protocol where the investigator decides that further participation 
may harm the patient.   
10. Unblinding. 
Number of subjects 
It is planned to include 276 subjects, which is expected to yield at least 220 patients completing 
all protocol procedures. 
Interim analysis 
Two interim analyses are scheduled in the study: involving 15% and 30% subjects recruited. 
Type 1 error distribution is in accordance with O'Brien-Fleming alpha spending function,        
type II - according to Pocock test.  Early study termination is possible both due to acceptance 
and rejection of null hypothesis.  
Treatment 
Group 1 
Name of the medicinal product: MMH-MAP 
Active ingredient: Affinity purified antibodies to S-100 brain protein – 0.006 g, modified. С200 
dilution. 
Excipients: Lactose monohydrate - 0.267g  
 Microcrystalline cellulose - 0.030 g  
                    Magnesium stearate - 0.003 g  
Method of administration: Tablet for oral use. Dose per administration: 2 tablets. 2 tablets 
twice daily (4 tablets/day). The tablets should be held in mouth without chewing until complete 
dissolution.    
Dosage form: Tablets. 
Description: Flat cylinder-shaped scored beveled edge white to off-white tablets. 
Storage conditions: At temperature ≤ 25 ºС. 
Group 2 
Name of the medicinal product: Placebo 
Active ingredient: No 
Excipients: Lactose monohydrate - 0.267 g  
                    Microcrystalline cellulose - 0.030 g  
                    Magnesium stearate - 0.003 g  


Protocol No. MMH-MAP-001 
29-Aug-2018 
CONFIDENTIAL  
 
Page 7 of 14 
Method of administration: Tablet for oral use. Dose per administration: 2 tablets. 2 tablets 
twice daily (4 tablets/day). The tablets should be held in mouth without chewing until complete 
dissolution.    
Dosage form: Tablets. 
Description: Flat cylinder-shaped scored beveled edge white to off-white tablets. 
Storage conditions: At temperature ≤ 25 ºС. 
Treatment duration 
MMH-MAP/Placebo treatment duration is 24 weeks.  
Observation period 
The total length of patient observation is 28 weeks (screening + randomization ‒ up to 1 day, 
treatment – 24 weeks, follow-up ‒ 4 weeks).  
Symptomatic (Standard) treatment  
Throughout the study the subject will receive therapy for the underlying disease including 
therapy designed for secondary prevention of stroke and other vascular events except for the 
medicinal products referred to in "Prohibited concomitant therapy''. 
1. Antihypertensive products. 
2. Angiotensin-converting enzyme (ACE) inhibitors. 
3. Angiotensin II receptor antagonists. 
4. β-adrenoblockers or α- and β-adrenoblockers. 
5. Calcium antagonists (except for nimodipine). 
6. Diurectics (thiazide, aldosterone receptor antagonist). 
7. Antiplatelets (acetylsalicylic acid, clopidogrel, dipyridamol, ticlopidine, ticagrelor). 
8. Anticoagulants. 
9. Statins. 
10. Antidiabetic drugs. 
11. Other agents except for those referred to as prohibited ones.  
Prohibited concomitant therapy 
Within 1 week prior to enrollment and during the study (beginning from signing patient 
information sheet and informed consent form and initiation of screening) subjects are not 
allowed to receive any medications that may affect mental and emotional status (parenthesized is 
the ATC group): 
1. Peripheral vasodilators (ATC group – C04) including nicotinic acid and its derivatives; 
purines (xantinol nicotinate, pentoxifylline), ergot alkaloids (nicergoline, alpha-


Protocol No. MMH-MAP-001 
29-Aug-2018 
CONFIDENTIAL  
 
Page 8 of 14 
dihidroergocryptine + caffeine), other vasodilators (vincamine, bencyclane, naftidrofuryl), 
papaverine, etamivan+etophylline+hexobendine. 
2. Calcium channel blockers − nimodipine (С08СА06), instenon (С01ЕХ). 
3. Muscle relaxants (M03). 
4. Anticholinergic agents (N04A). 
5. Dopaminergic agents (N04В). 
6. Actovegin (В06). 
7. Psycholeptics (N05), including anxiolytics (tranquilizers), hypnotics and sedatives. 
8. Psychoanaleptics (N06), including antidepressants, psychostimulants and nootropics 
including: 
 pyrrolidine derivatives (racetams) – piracetam, etiracetam, aniracetam, etc.; 
 dimethylaminoethanol derivatives (acetylcholine precursors) - deanol aceglumate, 
meclofenoxate;  
 pyridoxine derivatives - pyritinol, biotredin; 
 GABA derivatives and analogues – gamma-aminobutyric acid, nicotinoyl gamma-
aminobutyric acid, gamma-amino-beta-phenylbutyric acid hydrochloride, hopantenic 
acid, calcium gamma-hydroxybutirate; 
 gingko biloba; 
 neuropeptides and their analogues - methionyl-glutamyl-histidyl-phenylalanyl-propyl-
glycyl-proline; 
 aminoacids and substances affecting excitatory amino acid system – glycine, 
pyrodoxine+threonine; 
 derivatives of 2-mercantobenzimidazole – ethylthiobenzymidazole hydrobromide; 
 idebenon; 
 vinpocetine; 
 polypeptides and organic composites - bovine cortical polypeptides, cerebrolysin; 
 memantine (N06DX01). 
9. Other nervous system drugs (N07) including: 
    parasympathomimetics (N07A); 
   antivertigo preparations (N07C); 
   other nervous system drugs (N07X). 
10. Substances of other pharmacological group with a nootropic ingredient including: 
   general tonic agents and adaptogens – ginseng, melatonin, lecithin, acetylaminosuccinic 
acid etc.; 


Protocol No. MMH-MAP-001 
29-Aug-2018 
CONFIDENTIAL  
 
Page 9 of 14 
   antihypoxants and antioxidants – ethylmethylhydroxypyridine succinate, citicoline, 
vitamin E, etc.; 
   metabolic agents. 
11. Any unauthorized product and/or vaccine. 
12.   Drugs that previously caused allergic reactions in patient. 
Study design scheme 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Schedule of study procedures  
Procedure/Visit 
Visit 1 
Screening, 
Randomization 
(Day 1) 
Visit 2 
(Week 
4±7 
days) 
Visit 3 
(Week 
8±7 
days) 
Visit 4 
(Week 
16±7 
days) 
Visit 5 
(Week 
24±7 
days) 
Visit 6 
(Week 
28±7 
days) 
Informed consent 
+ 
 
 
 
 
 
Registration patient in 
IVRS and assignment 
of a personal code 
+ 
 
 
 
 
 
Collection of 
complaints 
+ 
+ 
+ 
+ 
+ 
+ 
Medical history 
+ 
 
 
 
 
 
Concomitant 
conditions and diseases 
+ 
 
 
 
 
 
Physical examination 
+ 
+ 
+ 
+ 
+ 
+ 
Evaluation of vital 
signs (HR, RR, BP) * 
+ 
+ 
+ 
+ 
+ 
+ 
Recording therapy for 
concomitant diseases 
+ 
+ 
+ 
+ 
+ 
+ 
RANDOMIZATION
MMH-MAP 2 tablets twice daily for 24 weeks 
SCREENING
Visit 4 
(Week 16±7 
days) 
28 weeks 
Placebo 2 tablets twice daily for 24 weeks  
Visit 2  
(Week 4±7 
days) 
Study completion 
Visit 3  
(Week 8±7 
days) 
Visit 1 
(Screening, 
randomization 
Day 1) 
Visit 5 
(Week 
24±7 days) 
Visit 6 
(Week 28±7 
days) 
Follow-up 


Protocol No. MMH-MAP-001 
29-Aug-2018 
CONFIDENTIAL  
 
Page 10 of 14 
Recording basic 
therapy 
+ 
+ 
+ 
+ 
+ 
+ 
Inclusion/exclusion 
criteria 
+ 
 
 
 
 
 
Randomization 
+ 
 
 
 
 
 
Filling MMSE 
+ 
 
 
 
 
 
Filling MoCA 
+ 
 
+ 
+ 
+ 
+ 
Filling Barthel scale 
+ 
 
+ 
+ 
+ 
+ 
Filling SS-QOL 
+ 
 
+ 
+ 
+ 
+ 
Laboratory tests1 
+ 
 
 
 
+ 
 
Pregnancy test 
+ 
 
 
 
 
 
Drug issue 
+ 
+ 
+ 
+ 
 
 
Study drug 
accountability, 
compliance assessment 
 
+ 
+ 
+ 
+ 
 
Clinical Global 
Impression assessment 
(CGI-EI) 
 
 
 
 
+ 
 
Evaluation of treatment 
safety 
+ 
+ 
+ 
+ 
+ 
+ 
Visit completion 
+ 
+ 
+ 
+ 
+ 
+ 
Suggested duration of 
the subject's 
participation in the 
study 
 
 
 
 
 
+ 
*HR - heart rate; RR - respiration rate; BP - blood pressure 
 
Statistical Analyses 
Samples  
Total set includes all the subjects who have signed ICF. This sample will consider all adverse 
events (AEs) throughout the study, including those occurred prior to the study therapy.  
The sample including all subjects who received at least one dose of the study product to be used 
for analysis of the study treatment safety and tolerability (Safety population), as all AEs 
identified after the study product administration will be recorded.  
Full Analysis Set This sample will consist of all enrolled subjects, except for those who met at 
least one of the following criteria:  
1) non-compliance with inclusion/exclusion criteria;  
2) subject failing to take any dose of the study drug; 
3) lack of any data on the subject after the study drug administration.  
                                                 
1 Laboratory tests will be performed in central laboratory in subjects signing the relevant PIS and ICF. 


Protocol No. MMH-MAP-001 
29-Aug-2018 
CONFIDENTIAL  
 
Page 11 of 14 
This was the best set for the Intention-to-treat method, so it will be used in the Intention-to-treat 
efficacy analysis (ITT-analysis) of the test therapy. 
Per Protocol set. This set will comprise all the subjects receiving per protocol therapy in full and 
completing all the scheduled visits. This set will be used for efficacy Per Protocol analysis. 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 distribution/issue of the study product. 
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.2 
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 1 error 'a' is less that 5% (the probability of false acceptance of 
the alternative hypothesis is less than 0.05); 
1.3 statistical criteria of intergroup comparisons will be two-sided, equivalence criterion - 
one-sided;  
                                                 
2 Holder of license: ООО "NPF "Materia Medica Holding", No. 70100045. 


Protocol No. MMH-MAP-001 
29-Aug-2018 
CONFIDENTIAL  
 
Page 12 of 14 
1.4 calculation of sample size will be based on the assumptions on the expected effect 
declared in the primary efficacy criterion of the protocol; 
1.5 ratio between sample sizes of MMH-MAP and Placebo sample sizes is 1:1 (1 MMH-
MAP subject per 1 Placebo subject); 
1.6 
statistical hypotheses - null and alternative hypotheses on the difference between test 
product and placebo under the dosing regimen used: 
H0: Θ1- Θ 2 = 0 
Ha: Θ 1- Θ 2 ≠ 0 
where Θ1 is frequency of the claimed event in MMH-MAP group, а Θ 2 is frequency of 
the claimed event in Placebo group; 
1.7 
calculation of sample size for statistical criteria was made using the following program 
code: 
Proc seqdesign errspend 
 Design nstages = 3 
 Info = cum (0.15,0.3,1) 
 Method (alpha) = UNI (rho = 0.5 tau = 0) 
 Method (beta) = UNI (rho = 0 tau = 0) 
 Stop = both 
 Alpha = 0.05 
 Beta = 0.2 
 Samplesize model = twosamplefreq (test = PROP nullprop = 0.4 prop = 0.6) 
Run; 
1.8 
terminal sample size will be determined using the formula: 
 
where NT – terminal sample size; NPP – result of calculation in c. 1.7 i.e. 
scheduled number of subjects completing the study per protocol; Rw – withdrawal rate. 
2. Assumptions on expected clinical study effects: 
Proportion of subjects with improved cognitive function (MoCA ≥ +1) after 24-week therapy 
with MMH-MAP is expected to be no less than 60%, Placebo – no more than 40%. 
Therefore, group size needed to compare test product and placebo will be 110 subjects for 
each group. Given potential withdrawal of at least 20% subjects (Rw=0.2) during the study 
for various reasons, at least 276 subjects will be required to sign informed consent, with 138 
subjects per group (see cl. 1.8). 


Protocol No. MMH-MAP-001 
29-Aug-2018 
CONFIDENTIAL  
 
Page 13 of 14 
Statistical criteria  
All statistical calculations will be made using two groups of statistical criteria:  
 
parametric - to obtain effective estimates for random parameters in case the relevant 
conditions of method/model applicability are not violated (e.g. sphericity, normality, risk 
proportionality, etc.)  
 
nonparametric – in all other cases. 
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 matched 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 corrections for multiplicity will be 
used, e.g. 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).  


Protocol No. MMH-MAP-001 
29-Aug-2018 
CONFIDENTIAL  
 
Page 14 of 14 
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.  
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 test. 
Safety parameters  
Adverse events recorded during the study will be grouped into frequency tables by severity, 
seriousness and relationship with the study drug. At least 138 subjects evenly distributed to the 
study groups will participate in blood and urine sampling for adequate assessment of laboratory 
values. 
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.