Clinical trial NCT04552041
Conditions: Vascular Dementia
Sponsor: Materia Medica Holding
Start date: 2020-12-03; Completion date: 2022-09-22
Enrollment: 406 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Study purpose:

\- evaluate clinical efficacy ands afety of Prospekta in the treatment of cognitive, behavioral and psychiatric disorders in patients with vascular dementia.

Study objectives:

* evaluate and compare changes in cognitive functions, in behavioral and in psychiatric dementia symptoms in Prospekta and Placebo groups after 24-weeks of treatment
* evaluate and compare the frequency, severity and causal relationship of adverse events (AEs) with the type of therapy in Prospekta and Placebo groups (including central nervous system AEs during therapy, their relationship with the study drug and other characteristics).

Detailed description:
Design: double-blind placebo-controlled randomized parallel-group clinical trial. The study will enroll male and female patients aged 60-85 years inclusively diagnosed with vascular dementia verified at Visit 1 according to the criteria of The National Institute of Neurological Disorders and Stroke National Institute of Neurological Disorders and Stroke-Association Internationale pour la Recherche et l'Enseignement en Neurosciences - NINDS-AIREN. Severity of vascular dementia should be moderate or mild (10-24 points according to Mini-Mental State Examination - MMSE), without signs of depression (total Cornell Scale for Depression in Dementia (CSDD) score ≤10).

After signing patient information sheet (informed consent form) to participate in the study, at Visit 1 (from day -14 to day 1) complaints and medical history will be collected, objective examination, recording vital signs (BP, RR, HR) will be performed and compliance of the subject's diagnosis with NINDS-AIREN vascular dementia criteria will be evaluated. The study investigator will assess cognitive disorders using Mini-Mental State Examination (MMSE) and Montreal Сognitive Assessment (МоСА). The investigator and the patient's caregiver will fill Neuropsychiatric Inventory Сlinician (NPI-С), and СSDD scales. The patient will undergo brain MRI (in the absence of brain MRI data within the previous 12 months before inclusion in the study).

Concomitant therapy and concomitant diseases and conditions will be recorded. If inclusion/exclusion criteria are met, the patient will be randomized to one of the two groups: group 1 will receive Prospekta 2 tablets twice daily; group 2 will receive Placebo using the study drug dosing regimen.

Treatment duration will be 24 weeks during which 6 Visits will be made. At visits 2 and 3 (week 4±3 days and week 8±3 days) the study investigator will make a phone call and collect the complaints, monitor the prescribed and concomitant therapy, evaluate therapeutic safety.

At visit 4 (week 12±7 days) the study investigator will collect complaints, record objective examination findings and vital signs, monitor the prescribed and concomitant therapy, evaluate therapeutic safety and compliance, dispense the study drug until the next visit. The study investigator and caregiver will fill NPI-C.

At visits 5 and 6 (week 16±3 days and week 20±3 days) the study investigator will make a phone call and collect the complaints, monitor the prescribed and concomitant therapy, evaluate therapeutic safety.

At visit 7 (week 24±7 days) the study investigator will collect complaints, perform objective examination, record vital signs, monitor the prescribed and concomitant therapy, evaluate therapeutic safety, evaluate compliance. The study investigator will fill MоСА and Clinical Global Impression Efficacy Index (CGI-EI). The study investigator and caregiver will fill NPI-C.

During the study the treatment for concomitant diseases will be allowed with the exception of the drugs specified in the section "Prohibited concomitant therapy".

Arms: arm 1: Two tablets per intake 2 times a day (approximately at the same time), outside of meal (between meals or 15 minutes prior to meal or drinking). The tablets should be held in mouth until completely dissolved. The overall duration of treatment is 24 weeks. arm 2: Two tablets per intake 2 times a day (approximately at the same time), outside of meal (between meals or 15 minutes prior to meal or drinking). The tablets should be held in mouth until completely dissolved. The overall duration of treatment is 24 weeks.
Interventions: intervention 1: Prospekta 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 Prospekta in the treatment of cognitive 
behavioral and psychiatric disorders in subjects with vascular dementia 
 
 
 
Phase III 
 
 
 
 
 
 
 
 
 
 
 
Sponsor 
OOO «NPF «MATERIA MEDICA HOLDING» 
Protocol number 
MMH-MAP-003 
Version 1 date: 
Version 2 date: 
April 06, 2020 
February 08, 2021 
ClinicalTrials.gov Id: 
NCT04552041 
 


Protocol No. MMH-MAP-003 
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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 Prospekta in the treatment of cognitive, behavioral and psychiatric disorders in 
subjects with vascular dementia. 
Phase: III 
Sponsor: Company «MATERIA MEDICA HOLDING», Moscow, Russia 
Protocol No. MMH-MAP-003 
Study purposes  
 To evaluate efficacy of Prospekta in the treatment of cognitive, behavioral and psychiatric 
disorders in vascular dementia. 
 To evaluate the safety of Prospekta in the treatment of cognitive, behavioral and psychiatric 
disorders in vascular dementia.   
Study objectives 
 Evaluate and compare changes in cognitive functions in two groups (Prospekta and Placebo) 
after 24-weeks of treatment. 
 Evaluate and compare changes in behavioral and psychiatric dementia symptoms in two 
groups (Prospekta and Placebo) after 24-weeks of treatment. 
 Evaluate and compare the presence and nature of adverse events (AEs) in two groups 
(Prospekta and Placebo), including central nervous system AEs during therapy, their 
relationship with the study drug and other characteristics. 
Endpoints  
Primary endpoint 
1. Change in mean MoCA score after 24-week therapy (vs. baseline). 
Secondary endpoints 
1. Change in mean NPI-С score after 24-week therapy (vs. baseline). 
Additional endpoints 
1. Change in mean MoCA score after 12-week therapy. 
2. Change in mean NPI-С score after 12-week therapy. 


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3. Mean СGI-EI score after 24-week therapy. 
Safety assessment  
 Changes in vital signs during the study. 
 Occurrence and nature of adverse events (AEs) during the treatment, their intensity (severity), 
relation to the study drug, outcome. 
Study design  
Design: double-blind placebo-controlled randomized parallel-group clinical trial. The study will 
enroll male and female patients aged 60-85 years inclusively diagnosed with vascular dementia 
verified at Visit 1 according to the criteria of The National Institute of Neurological Disorders 
and Stroke National Institute of Neurological Disorders and Stroke-Association Internationale 
pour la Recherche et l’Enseignement en Neurosciences - NINDS-AIREN. Severity of vascular 
dementia should be moderate or mild (10-24 points according to Mini-Mental State Examination 
- MMSE), without signs of depression (total Cornell Scale for Depression in Dementia (CSDD) 
score ≤10). 
After signing patient information sheet (informed consent form) to participate in the study, at 
Visit 1 (from day -14 to day 1) complaints and medical history will be collected, objective 
examination, recording vital signs - blood pressure (BP), respiration rate (RR), heart rate (HR) 
will be performed and compliance of the patient's diagnosis with NINDS-AIREN vascular 
dementia criteria will be evaluated. The study investigator will assess cognitive disorders using 
MMSE and Montreal Сognitive Assessment (МоСА). The study investigator and the patient's 
caregiver will fill Neuropsychiatric Inventory Сlinician (NPI-С), and СSDD scales. The patient 
will undergo brain MRI (in the absence of brain MRI data within the previous 12 months before 
inclusion in the study). 
Concomitant therapy and concomitant diseases and conditions will be recorded.  
If inclusion/exclusion criteria are met, the patient will be randomized to one of the two groups: 
group 1 will receive Prospekta 2 tablets twice daily; group 2 will receive Placebo using the study 
drug dosing regimen. 
Treatment duration will be 24 weeks during which 6 Visits will be made. At visits 2 and 3 (week 
4±3 days and week 8±3 days) the study investigator will make a phone call and collect the 
complaints, monitor the prescribed and concomitant therapy, evaluate therapeutic safety. 
At visit 4 (week 12±7 days) the study investigator will collect complaints, record objective 
examination findings and vital signs, monitor the prescribed and concomitant therapy, evaluate 
therapeutic safety and compliance, dispense the study drug until the next visit. The study 
investigator and caregiver will fill NPI-C. 


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At visits 5 and 6 (week 16±3 days and week 20±3 days) the study investigator will make a phone 
call and collect the complaints, monitor the prescribed and concomitant therapy, evaluate 
therapeutic safety. 
At visit 7 (week 24±7 days) the study investigator will collect complaints, perform objective 
examination, record vital signs, monitor the prescribed and concomitant therapy, evaluate 
therapeutic safety, evaluate compliance. The study investigator will fill MоСА and Clinical 
Global Impression Efficacy Index (CGI-EI). The study investigator and caregiver will fill NPI-C. 
During the study the treatment for concomitant diseases will be allowed with the exception of the 
drugs specified in the section "Prohibited concomitant therapy". 
Inclusion and exclusion criteria 
Inclusion criteria 
1. Subjects aged 60-85 years old inclusively. 
2. Subjects with verified diagnosis of vascular dementia. 
3. Presence of all the vascular dementia criteria according to NINDS-AIREN: 
A. Presence of dementia, which is defined as a decline in cognitive function relative to the 
previous level of functioning, manifested by impairments in memory and two or more 
cognitive domains (orientation, attention, language, visuospatial functions, executive 
functions, motor control and praxis), preferably established during a clinical trial and 
confirmed by neuropsychological testing. 
The cognitive impairment must be so severe that it affects daily activity, reducing it 
independently of the physical consequences of the stroke. 
B. The presence of cerebrovascular disease, confirmed by signs of focal damage on 
neurological examination, such as hemiparesis, lower facial weakness, Babinski sign, 
sensory deficit, hemianopsia or dysarthria associated with stroke (either a history of 
stroke or absence of such anamnestic information), and neuroimaging (CT or MRI) signs 
of cerebrovascular disease, including multiple infarcts in the territory of large vessels, or 
a single infarction in a strategically important area (angular gyrus, thalamus, basal 
ganglia, or the territory of the anterior or posterior cerebral arteries), as well as multiple 
lacunae in the region of the basal ganglia or white matter, or significant damage to the 
periventricular white matter, or a combination of the above lesions. 
C. There is an association between dementia and cerebrovascular disease as follows:  
a) onset of dementia within 3 months of stroke;  
b) sharp deterioration of cognitive functions; or fluctuating, stepwise progression of 
cognitive impairment. 
 


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4. Availability of permanent caregiver throughout the study (nurse or relatives). 
5. Total Mini-Mental State Examination (MMSE) score - 10-24. 
6. Total MoCA score <26. 
7. Total NPI-C aggression and agitation domain score ≥14. 
8. Аbsence of depression (total Cornell Scale for Depression in Dementia (CSDD) score ≤10). 
9. Brain MRI confirming the diagnosis of vascular dementia within 1 year prior to enrollment 
(or brain MRI performed at enrollment visit). 
10. Patients giving their consent to use reliable contraception throughout the study (for males). 
11. Availability of signed patient information sheet and informed consent form for participation 
in the clinical trial. 
Exclusion criteria 
1.   Signs of intracerebral hemorrhage, brain tumours causing dementia. 
2.  Alzheimer's disease, Parkinson disease, Lewy body dementia, multiple system atrophy, 
Jacob-Creutzfeld disease, Pick's disease, corticobasal degeneration. 
3.  Injuries of head (S00-S09) associated with impaired consciousness, cerebral contusion or 
open craniocerebral traumas. 
4.  Toxicity-related dementia (including drug-induced), multiorgan failure or metabolic and toxic 
disorders (chronic hypothyroidism, decompensated diabetes mellitus, avitaminoses, etc.). 
5.   Other psychiatric diseases besides dementia: mental disorders and behavioral disorders due 
to use of psychoactive substances (F10-19) schizophrenia, schizotypal and delusional 
disorders (F20-29). 
6.   Mental retardation (F70-79). 
7.   Inflammatory lesions of the brain with persistent neurological deficit. 
8.   Malignant neoplasms. 
9.  Previously diagnosed cardiovascular diseases with functional class IV (according to New 
York Heart Association, 1964). 
10. Unstable angina pectoris, myocardial infarction or ischemic stroke within the last 6 months. 
11. Female patients with childbearing potency. 
12. Allergy/intolerance of any of the study drugs components including secondary to lactase 
deficiency.  
13. Any conditions which, according to the investigator opinion, may interfere with the patient's 
participation in the study. 
14. History of treatment noncompliance, mental diseases, alcoholism or drug abuse which will 
prevent from following the study procedures, according to investigator's opinion. 


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15. Participation in clinical trials for 3 months prior to enrollment in this study. 
16. Use of any medications specified in "Prohibited concomitant medications" within 1 month 
before enrollment. 
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 OOO "NPF "Materia Medica Holding" (i.e. the company's employees, 
temporary contract workers, designated officials responsible for carrying out the research or 
any immediate relatives of the aforementioned). 
Criteria for Withdrawal or Termination 
1. Screening failure.  
2. Inability or refusal of the patient/caregiver to comply with the protocol requirements. 
3. Necessity in medications prohibited within the study. 
4. An adverse event requiring discontinuation of the study drug. 
5. Eligibility error.  
6. Patient's/caregiver's desire to complete the study early for any reason. 
7. Participation in any other clinical trial. 
8. Cases not specified by the protocol when, according to the investigator’s opinion, further 
participation in the study harms the patient.   
9. Unblinding. 
Number of subjects 
It is planned to include 406 patients (203 per group), which is expected to yield at least 324 
patients (162 in Prospekta and Placebo groups) completing all protocol procedures. 
Interim analysis 
Unblinded interim analysis is preplanned in the study: at the 30% of enrolled patient. Type 1 
error at the analyses is in governed by O'Brien-Fleming spending function, for type II error – the 
Pocock spending function is selected. Early study termination is planned due to both acceptance 
and rejection of null hypothesis. Interim analysis will be carried out on the data from the number 
of completing subjects established by the protocol. Number of subjects for interim analysis: 98 
subjects (Prospekta – 49, Placebo – 49). Number of subjects for final analysis: 324 subjects 
(Prospekta – 162, Placebo – 162). 


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Treatment 
Group 1 
Name of the medicinal product: Prospekta 
Active ingredient: Affinity purified antibodies to brain-specific protein S-100, modified – 
10 000 MAU* 
* MAU – modifying action units 
Excipients: Lactose monohydrate (Ph.Eur., USP1 NF, BP2) - 0.267 g  
 Microcrystalline cellulose (Ph. Eur., USP NF, BP) - 0.030 g  
                    Magnesium stearate (Ph.Eur., USP NF, BP) - 0.003 g  
Method of administration: Tablet for oral use. 2 tablets twice daily (approximately at the same 
time), outside the meal (between meals or 15 minutes before meals or fluids). Keep the tablets in 
mouth until completely dissolved.    
Dosage form: Tablets. 
Description: Flat cylinder-shaped scored beveled edge white to off-white tablets with a smooth, 
uniform surface. 
Storage conditions: Store at a temperature not exceeding 25°С. 
Group 2 
Name of the medicinal product: Placebo 
Active ingredient: No 
Excipients: Lactose monohydrate (Ph.Eur., USP NF, BP) - 0.267 g  
                    Microcrystalline cellulose (Ph. Eur., USP NF, BP) - 0.030 g  
                    Magnesium stearate (Ph.Eur., USP NF, BP) - 0.003 g  
Method of administration: Tablet for oral use. 2 tablets twice daily (approximately at the same 
time), outside the meal (between meals or 15 minutes before meals or fluids). Keep the tablets in 
mouth until completely dissolved.    
Dosage form: Tablets. 
Description: Flat cylinder-shaped scored beveled edge white to off-white tablets with a smooth, 
uniform surface. 
Storage conditions: Store at a temperature not exceeding 25°С. 
Treatment duration 
Prospekta/Placebo treatment duration is 24 weeks.  
Observation period 
In total the patients will be monitored for 24-26 weeks (screening up to 2 weeks, therapy - 24 
weeks).  
                                                 
1 USP – current US Pharmacopoeia. 
2 BP – current British Pharmacopoeia. 


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Symptomatic (Standard) treatment  
During the study, the patient may receive therapy for concomitant diseases and conditions, with 
the exception of medications specified in the section “Prohibited Concomitant Treatments.” 
Prohibited concomitant therapy 
One month prior to the enrollment as well as during the study (from signing of informed consent 
form and screening) any therapy affecting cognitive and mental status of the subject the 
following products will not be allowed (ATC group is indicated in brackets): 
1. Anchicnolonergic agents (N04A). 
2. Psycholeptics (N05) including: 
 antipsychotics (N05A) 
 anxiolytics (N05B) 
 hypnotic and sedative drugs (N05C) 
    other hypnotics and sedatives (N05CM) including those of herbal origin. 
3. Psychoanaleptics (N06) including: 
 antidepressants (N06A) 
 psychostimulants and nootropics (N06B) including other psychostimulants and 
nootropics (N06BX) 
 anti-dementia drugs (N06D). 
4. Other nervous system drugs (N07) including: 
 
parasympathomimetics (N07A) 
   antivertigo preparations (N07C) 
   other nervous system drugs (N07X). 
5. Heme products (B06AB): Actovegin. 
6. Purine derivatives (C04AD): Pentoxifylline. 
7. Dihydropyridine derivatives (C08CA): Nimodipine. 
8. Substances of other pharmacological group with a nootropic ingredient including: 
 
general tonic agents and adaptogens – herbal; melatonin, lecithin, acetylaminosuccinic 
acid etc. 
 
antihypoxants and antioxidants – ethylmethylhydroxypyridine succinate, citicoline, all 
vitamins, etc. 
      metabolic agents. 
9. Drugs that previously caused allergic reactions in patient. 
10. Products containing ultrahigh dilutions (Tenoten, Proproten-100, Divaza, etc.). 
11. Homeopathic products with nootropic or psychoactive effect. 
12. Any unauthorized product and/or vaccine. 


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Study design scheme 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Schedule of study procedures  
Procedure/ 
visit 
Visit 1 
From day -
14 to day 1 
Visit 2 
Week 4 
±3 days 
(phone) 
Visit 3 
Week 8± 
3 days 
 (phone) 
Visit 4 
 Week 12 
± 7 days 
Visit 5 
Week 16 
±3 days 
(phone) 
Visit 6 
Week 20 
±3 days 
(phone) 
 
Visit 7 
Week 24 
±7 days  
Informed consent 
+ 
 
 
 
 
 
 
Patient 
registration in 
IVRS and 
assignment of a 
personal code 
+ 
 
 
 
 
 
 
Demographics 
+ 
 
 
 
 
 
 
Collection of 
complaints 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
Medical history 
+ 
 
 
 
 
 
 
Concomitant 
conditions and 
diseases 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
Physical 
examination 
+ 
 
 
+ 
 
 
+ 
Vital signs (HR, 
RR, BP)  
+ 
 
 
+ 
 
 
+ 
Matching 
vascular 
dementia 
diagnosis with 
NINDS-AIREN 
criteria 
+ 
 
 
 
 
 
 
Visit 3 
(Week 8±3 
days) phone 
call 
Visit 5  
(Week 16±3 
days) 
phone call 
Prospekta 2 tablets twice daily for 24 weeks 
 
SCREENING 
RANDOMIZATION 
Visit 1 
(from day -
14 to day 1) 
Placebo 2 tablets twice daily for 24 weeks 
 
Visit 2  
(Week 4±3 
days) 
phone call 
Visit 4  
(Week 12±7 
days) 
24 - 26 weeks 
Visit 6 
(Week 20±3 
days) 
phone call 
Visit 7  
(Week 24±7 
days) 
STUDY 
TERMINATION 


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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 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 AEs 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) non-compliance with inclusion/exclusion criteria;  
2) patient did not take any dose of study drug; 
                                                 
3 In case of early discontinuation the procedure may be performed at visits 1-7. 
 
Head MRI or 
analysis of 
findings of MRI 
made within 1 
year prior to 
enrollment 
+ 
 
 
 
 
 
 
Concomitant 
therapy 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
Filling MoCA  
+ 
 
 
+ 
 
 
+ 
Filling MMSE 
+ 
 
 
 
 
 
 
Filling NPI-C 
+ 
 
 
+ 
 
 
+ 
Filling CSDD 
+ 
 
 
 
 
 
 
Inclusion/exclusi
on criteria 
+ 
 
 
 
 
 
 
Randomization 
+ 
 
 
 
 
 
 
Dispensing of 
study drug 
+ 
 
 
+ 
 
 
 
Study drug 
accountability 
and return 
 
 
 
+ 
 
 
+ 
Treatment 
compliance 
 
 
 
+ 
 
 
+ 
Evaluation of 
study treatment 
safety 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
Filling CGI-EI 
scale 
 
 
 
 
 
 
+ 
Visit completion 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
Study completion 
 
 
 
 
 
 
+3 


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3) absence of any patient data after administration of study drug.  
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 study therapy. 
Per Protocol set. This sample includes all patients who received full protocol therapy and 
completed all scheduled visits. This set will be used for Per Protocol analysis (PP analysis) of 
efficacy of study therapy. Per Protocol set will not include the patients 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 drug. 
3. Prescription of prohibited therapy. 
4. Increase or decrease of 25% or more in the amount of study therapy received. 
5. Inability to assess patient's objective compliance (adherence to therapy) according to the 
formula (e.g. loss of packaging). 
6. Major discrepancies between source documents and CRF detected during monitoring or 
other authorized inspection.  
7. Violations of the Informed consent procedure. 
8. Non-compliance with the clinical study protocol procedures. 
9. Inability to collect all patient'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.4 
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 a type I error is less that 5% (the probability of false acceptance of the 
alternative hypothesis is less than 0.05) 
1.3 
type 1 error is distributed between the primary and secondary criteria in 1:1 ratio 
1.4 
statistical criteria of comparisons will be two-sided, unless specified otherwise  
                                                 
4 Holder of license: ООО "NPF "Materia Medica Holding", No. 70100045. 


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1.5 
calculation of the sample size will be based on the assumptions concerning the effect 
declared in the primary efficacy criterion of the protocol 
1.6 
ratio between Prospekta and Placebo sample sizes is 1:1 (1 Prospekta patient per 1 
Placebo patient) 
1.7 
statistical hypotheses - null and alternative hypotheses on the difference between study 
drug and placebo under the dosing regimen used: 
Primary endpoint: 
H0: μ1- μ2 = 0 
Ha: μ1- μ2 ≠ 0 
where μ1 - change in total MoCA score in Prospekta group, μ2 - change in total MoCA 
score in Placebo group 
Secondary endpoint: 
 H0: μ1- μ2 = 0 
 Ha: μ1- μ2 ≠ 0 
where μ1 - change in total NPI-C score in Prospekta group, μ2 - change in total NPI-C 
score in Placebo group 
1.8 
calculation of sample size for statistical criteria was made using the following program 
code: 
Proc seqdesign errspend; 
Design nstages = 2 
Info = cum (0.3,1) 
Method (alpha) = UNI (rho = 0.5 tau = 0) 
Method (beta) = UNI (rho = 0 tau = 0) 
Stop = both 
Alpha = 0.025 
Beta = 0.2 
Samplesize model = twosamplemean (meandiff = 1.3 stddev = 3.53) 
Run 
1.9 
Full  sample size will be determined using the formula: 
 
where NT – full sample size; NPP – result of calculation in c. 1.8, i.e. scheduled number 
of patients completing the study per protocol; Кв – withdrawal rate. 
2. Assumptions on expected treatment effects. 


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It is assumed that the difference between the changes in the mean total MoCA score in the 
Prospekta and Placebo after 24 weeks of treatment will be 1.3 points with a standard deviation 
of at least 3.535. 
Therefore, group size needed to compare Prospekta and Placebo will be 162 subjects for each 
group. Given potential withdrawal of at least 20% patients (Кв = 0.2) during the study for various 
reasons, at least 406 subjects will be required to sign informed consent, with 203 patients per 
group (see cl. 1.9).  
Minimum detectable effect for secondary criterion (change in total NPI-C score) at fixed sample 
size is supposed to be equal to: 7.36 (this being lower than clinically relevant change) at standard 
deviation of total score of 20 [13]6. 
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, etc.). 
The following parametric methods and approaches are supposed to be used: 
1. To evaluate the differences in continuous variables obtained in one group at two different 
visits – Student t-test for paired samples. 
2. To evaluate time changes in parameters compared - analysis of variance (ANOVA) or 
covariance (ANCOVA) modified with repeated measures. 
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). 
                                                 
5 The data were obtained from MMH-MAP-001trial blinded interim analysis. 
6 Assessment is based on bibliographic data in assumption, uniformity of mean change from time and reduction in correlation of 
measurements over time. 


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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 studying temporal dynamics (ANOVA, ANCOVA) 
 GENMOD – generalized linear models 
 MIXED – mixed linear models. 
Non-parametric criteria 
Below are the main potential types of comparisons with relevant criteria: 
1. To evaluate time changes in the parameters compared – Friedman test, non-parametric 
analogue of analysis of variance with repeated measures. 
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.  
To perform the above-mentioned non-parametric 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 treatment.  
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. 
Incomplete/missing data 
Missing data not requiring the patient exclusion from analysis will be processed as follows: 


Protocol No. MMH-MAP-003 
08-Feb-2021 
CONFIDENTIAL  
 
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1. For sections of descriptive statistics the missing/incomplete data will be ignored specifying 
the number of complete and incomplete data points. 
2. Efficacy criteria - after unblinding the interval data will be filled with the relevant group 
median value, categorical data - according to worst case approach. Prospekta group - worst 
outcome, Placebo group - best outcome. If allowed by the type of missing values (MCAR, 
MAR, etc.) and the type of variable, multiple imputation may be used.  
3. Additional criteria will be processed similar to descriptive statistics.