Multicenter, Double-blind, Placebo-controlled, Randomized, Parallel-group Clinical Trial to Evaluate the Efficacy and Safety of Ergoferon as Non-specific COVID-19 Prevention During Vaccination Against SARS-CoV-2
Phase: PHASE3
Conditions: Immunization Against COVID-19
Sponsor: Materia Medica Holding

 
 
 
 
 
 
 
 
 
 
 
 
 
Multicenter, Double-blind, Placebo-controlled, Randomized, Parallel-group 
Clinical Trial to Evaluate the Efficacy and Safety of Ergoferon as Non-specific 
COVID-19 Prevention During Vaccination Against SARS-CoV-2  
 
Phase III 
 
 
 
 
 
 
 
 
 
 
 
 
Sponsor 
OOO «NPF «MATERIA MEDICA HOLDING» 
Protocol number 
MMH-ER-010 
Version date: 
July 19, 2021 
ClinicalTrials.gov Id: 
NCT05069649 
 

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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, Good Clinical Practice, approved by order of the 
Ministry of Health of the Russian Federation dated April 1, 2016 N 200n, Helsinki Declaration 
of World Medical Association, relevant requirements of the regulatory authorities as well as the 
study procedures.  
Title of Study 
A Multicenter, Double-blind, Placebo-controlled, Randomized, Parallel-group Clinical Trial to 
Evaluate the Efficacy and Safety of Ergoferon as Non-specific COVID-19 Prevention During 
Vaccination Against SARS-CoV-2. 
Phase: III 
Sponsor: OOO "NPF "Materia Medica Holding", Moscow, Russia 
Protocol No. MMH-ER-010 
 
Objective of the study 
• To evaluate the efficacy and safety of Ergoferon as a non-specific COVID-19 prevention 
during vaccination against sars-cov-2.   
Endpoints  
Primary endpoint 
• To evaluate and compare in two groups (Ergoferon and Placebo) the number of laboratory-
confirmed cases of SARS-CoV-2 infections1 (with or without symptoms) in vaccinated 
individuals during their participation in the study.  
Exploratory endpoints 
• To evaluate and compare in two groups (Ergoferon and Placebo) the proportions of 
hospitalized participants with COVID-19. 
Safety assessment  
• To evaluate and compare in two groups (Ergoferon and Placebo) the occurrence and nature 
of adverse events, their intensity (severity), causal relationship to the study drug, and 
outcomes.    
Study design  
Study design: double-blind randomized placebo-controlled parallel-group trial.  
 
1 A positive reverse transcription polymerase chain reaction (RT-PCR) test result for SARS-CoV-2. 

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The study will enroll adult participants of either gender aged ≥18 years who receive a COVID-19 
vaccine. A participant signs a participant information sheet (Informed Consent Form) to 
participate in the clinical trial on the day of administration the first dose of the Gam-COVID-Vac 
(Sputnik-V) vaccine. The physician evaluates the participant's eligibility for inclusion in the 
study. A rapid test for SARS-CoV-2 (BIOCREDIT COVID-19 Ag)2 is carried out. 
If the participant meets all inclusion criteria and does not have any non-inclusion criteria, then he 
is included in the study, the doctor fills out the primary medical documentation. 
After inclusion in the study (Day 1, Visit 1), the participant is randomized into one of two 
groups: participants in group 1 receive Ergoferon according to a preventive regimen for three 
weeks, participants in group 2 receive Placebo for three weeks.  
On a day of administration of the second Gam-COVID-Vac dose3 (Day 22, Visit 2 + 3 days), a 
rapid SARS-CoV-2 test (BIOCREDIT COVID-19 Ag) is performed.  
After administration of the second dose of the vaccine, the participant is observed for 2 weeks. 
After 2 weeks, Visit 3 (telephone visit) is conducted to interview the participant about their 
health status (absence/presence of ARVI symptoms). 
All participants are provided with classic axillary temperature thermometers. The study uses an 
electronic diary to record any possible deterioration in the participant's condition (if applicable) 
to assess efficacy, safety and reporting of adverse events. The investigator instructs the 
participant to complete the diary. Each participant will receive an SMS reminder once a week: 
“If you have any symptoms of the disease, record them in the diary. The investigator will contact 
you.” 
If within five weeks of observation the participant develops symptoms of acute respiratory viral 
infection (increased body temperature to febrile/subfebrile values, weakness, headache, chills, 
cough, sore throat, other symptoms), then the study investigator performs an unscheduled visit, 
during which swabs are taken from the nasopharyngeal and oropharyngeal mucosa for PCR (RT-
PCR) test (in the central laboratories). 
If at Visits 1 or 2 a participant without ARVI symptoms has a positive rapid test result for 
SARS-CoV-2, his/her oropharyngeal and nasopharyngeal swabs are also collected for PCR 
testing (in the central laboratory). 
 
2 If the participant tests positive for SARS-CoV-2, he/she is not enrolled in the study. The investigator’s approach 
should be in compliance with the current version of the guidelines “Prevention, diagnosis and treatment of a new 
coronavirus infection (COVID-19) by the Ministry of Health of the Russian Federation.  
3 Contraindications for the second dose of the vaccine: Severe post-vaccination adverse events (anaphylaxis, severe 
generalized allergic reactions, convulsive disorder, fever (≥40°C), etc.) following the injection of the first dose of 
the vaccine.  
 
 

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If a laboratory-confirmed case of SARS-CoV-2 infection (with or without symptoms) is 
detected, the participant prematurely completes the study as having reached the primary 
endpoint.  
If the PCR test for SARS-CoV-2 is positive, in accordance with the requirements of 
Rospotrebnadzor, the information is transferred to the health care facility to which the participant 
is attached, where he will be provided with the necessary medical care (according to current 
standards). Health care facility employees report data on COVID-19 cases (in accordance with 
the recommendations of the Ministry of Health of the Russian Federation and the rules of health 
care facilities). 
Possible post-vaccination symptoms; 
•    general (flu-like syndrome characterized by chills, fever, arthralgia, myalgia, asthenia, 
malaise, headache) and local (pain at the injection site, hyperemia, swelling) symptoms 
that develop on the first-second day and resolve within three days; 
•    nausea, dyspeptic disorder, loss of appetite;  
•    enlarged regional lymph nodes; 
•    allergic reactions; 
•    transient increase in serum levels of liver transaminases, creatinine, and creatine 
phosphokinase. 
These post-vaccination symptoms are not recorded as adverse events (either associated with the 
study product administration or developing after discontinuation); they are registered by the 
participant in a diary and assessed by the physician as post-vaccination complications.  
Transient flu-like syndrome should not be diagnosed as ARVI, in this case a PCR test for SARS-
CoV-2 is not carried out. 
If the participant develops COVID-19 or is hospitalized for COVID-19, then delayed telephone 
visit will be performed. The duration of the visit is determined by the study investigator on a 
case-by-case basis. 
During the study participants are allowed to take medications for the treatment of underlying 
(chronic) diseases, with the exception of the drugs specified in the section "Prohibited 
concomitant treatment." 
 

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Inclusion and exclusion criteria 
Inclusion criteria 
1. 
Adults of either gender aged ≥18 years. 
2. 
Participant has not had COVID-19 within the previous 6 months. 
3. 
The participant has not been vaccinated against COVID-19 or other viral infections within 
the previous 6 months. 
4. 
Negative result of the rapid test for SARS-CoV-2 (COVID-19 Ag). 
5. 
Absence of clinical manifestations of any infectious disease, but not earlier than 14 days 
from its debut. 
6. 
Consent to use reliable contraceptive methods during the study (for men and women of 
reproductive potential). 
7. 
Availability of a signed information sheet and informed consent form for participation in 
the clinical trial. 
Exclusion criteria 
 
1. 
Presence of contraindications to vaccination: 
• 
hypersensitivity to any component of the vaccine or a vaccine containing similar 
components; 
• 
history of severe allergic reactions; 
• 
acute infectious and non-communicable diseases, exacerbation of chronic diseases. 
2. 
Severe chronic hepatic and renal disorders, severe thyroid dysfunction, decompensated 
diabetes mellitus, severe disorders of the hematopoietic system, epilepsy and other CNS 
diseases, acute coronary syndrome, cerebrovascular accident, myocarditis, endocarditis, 
pericarditis, autoimmune diseases, or immunodeficiency. 
3. 
Malabsorption syndrome, including congenital or acquired lactase or other disaccharidase 
deficiency, galactosemia.. 
4. 
Hypersensitivity to any components of study drug used in the treatment. 
5. 
Pregnancy, breast-feeding; childbirth less than 3 months prior to the inclusion in the study.  
6. 
Patients, who, from the investigator's point of view, will not comply with study observation 
requirements or study drug administration procedures. 
7. 
Failure to observe the participant during the study period. 
8. 
History of mental illness, alcoholism or drug abuse that the investigator's opinion will 
interfere with successful study procedures. 
9. 
Participation in other clinical trials within 3 months prior to enrollment in the study. 

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10. 
Use of any medications listed in "Prohibited concomitant medications" within 4 weeks 
before enrollment. 
11. 
Patient belongs to the study site personnel directly involved in the study or is the closest 
relative of the study investigator. "Immediate relative" means husband, wife, parent, son, 
daughter, brother, or sister (regardless of whether they are natural or adopted). 
12. 
Patient who works for OOO “NPF “MATERIA MEDICA HOLDING” (i.e. i.e. they are 
employees of the Company, temporary employees on a contract basis or appointed officials 
responsible for conduction of the study or their immediate family members). 
 
Criteria for Withdrawal or Termination 
1. 
Screening failure.  
2. 
Laboratory-confirmed case of SARS-CoV-2 infection (with or without symptoms). 
3. 
Inability or refusal of the patients to comply with the protocol requirements. 
4. 
Use of any medication listed in the section "Prohibited concomitant medications”. 
5. 
An adverse event requiring discontinuation of the study. 
6. 
Participant’s decision to complete the study early due to lack of the therapy efficacy or any 
other reasons. 
7. 
Pregnancy. 
8. 
Cases not specified by the protocol when, according to the investigator’s opinion, further 
participation in the study harms the patient. 
9. 
Eligibility error. 
10. 
Participation in any other clinical trial. 
11. 
Unblinding.  
Number of subjects 
Study stage before adaptation: 
1268 participants will sign the informed consent.  
At least 1206 participants will be randomized. 
Study stage after adaptation4: 
Additional 0 to 2332 participants will sign the informed consent. 
Therefore, additional 0 to at least 2214 participants will be randomized. 
The total maximum sample size will be: 3600 participants will sign the ICF, n=3420 of which 
will be randomized. 
 
4 Refer to the section Statistical Methods 

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Interim analysis 
An "unblinded" interim analysis for 85% of the sample (0.85 information, 485 PP participants 
each) is planned in the protocol. It is assumed that the study can be stopped due to the rejection 
of the null hypothesis with the O’Brien-Fleming type I error spending function. Based on the 
results of this analysis (if the stopping parameters are not achieved), it is assumed that the study 
will be adapted to determine the required additional sample size. 
Treatment 
 
Group 1 
Name of the medicinal product: Ergoferon 
Active ingredient:  affinity purified antibodies to human gamma interferon – 0.006 g* 
affinity purified antibodies to histamine – 0.006 g* 
affinity purified antibodies to CD4 – 0.006 g* 
* applied onto lactose powder as a mixture of three active ethanol-water solutions of the drug substance diluted 
10012, 10030, 10050 times, respectively   
Excipients:  lactose monohydrate, microcrystalline cellulose – 0.03 g, magnesium stearate – 
0.003 g. 
Method of administration: For oral administration. One tablet twice daily. The drug is taken 
outside the meal (between meals or 15-30 minutes before meals). Keep the tablet in the mouth, 
without swallowing, until completely dissolved.  
Dosage form: Tablets. 
Description: White to almost white, flat- faced tablets with a score and a chamfer. 
Storage conditions: At a temperature not higher than 25°C. Keep out of the reach of children. 
 
Group 2 
Name of the medicinal product: Placebo 
Active ingredient: NA 
Excipients: lactose monohydrate, microcrystalline cellulose, magnesium stearate. 
Method of administration: For oral administration. One tablet twice daily. The drug is taken 
outside the meal (between meals or 15-30 minutes before meals). Keep the tablet in the mouth, 
without swallowing, until completely dissolved.  
Dosage form: Tablets. 
Description: White to almost white, flat- faced tablets with a score and a chamfer.  
Storage conditions: At a temperature not higher than 25°C. Keep out of the reach of children. 

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Treatment duration 
Ergoferon/Placebo treatment duration is 3 weeks.  
Observation period 
Generally, patients will be monitored for 5 weeks (screening, randomization, start of treatment - 
Day 1, treatment − 3 weeks, follow-up period − 2 weeks).  
Concomitant medications 
During the study, the patient may receive therapy for concomitant diseases and conditions that 
are not criteria for non-inclusion in this study, except for medicinal products specified in the 
section "Prohibited concomitant treatment." 
Prohibited concomitant therapy 
4 weeks prior to enrollment and during the study the following drugs are not allowed: 
1. 
Antivirals (J05).  
2. 
Immunostimulants, including: 
• 
interferon inducers (acridonoacetic acid, meglumine acridone acetate/cycloferon®, 
umifenovir/arbidol®, kagocel®, tiloron/amixin®, lavomax®, tilaxin®, polyadenyl 
acid + polyuridylic acid complex/poludan®, sodium deoxyribonucleate/derinat, etc.)  
• 
interferons;  
• 
bacterial immunomodulators (including ribomunyl®, IRS-19, imudon®, broncho-
munal®, etc.); 
• 
pidotimod/immunorix;   
• 
interleukins;  
• 
synthetic immunostimulants (levamisole, alpha-glutamyl-tryptophan/thymogen, etc.);  
• 
drug products with thymus hormones; 
• 
herbal immunostimulants (immunal®, etc.). 
3. 
Immunosuppressants (L04). 
4. 
Antitumor drugs (L01) and antitumor hormonal drugs (L02). 
5. 
Immune sera and immunoglobulins (J06). 
6. 
Vaccines (J07).  
7. 
Corticosteroids for systemic use (H02AB). 
8. 
Any unapproved medicinal product. 
9. 
Drugs that previously caused hypersensitivity/allergic reactions in patient.   
 
 
 
 

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Study design scheme 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Schedule of study procedures  
Procedure/ Visit 
Visit 1 
(Day 1) 
Visit 2 
(Day 22 +  
3 days) 
Unscheduled 
visit* 
Visit 3 
«phone» ▲ 
(Day 35 + 
3 days) 
Informed consent  
+ 
 
 
 
Registration in the IVRS and 
assignment of a personal code 
+ 
 
 
 
Rapid test for SARS-CoV-2 
(COVID-19 Ag) 
+ 
+ 
 
 
Demographics 
+ 
 
 
 
Medical history   
+ 
 
 
 
Concomitant diseases and 
conditions 
+ 
+ 
+ 
+ 
Concomitant therapy   
+ 
+ 
+ 
+ 
Nasopharyngeal and 
oropharyngeal (throat) swabs 
for PCR diagnostics 
+♥ 
+♥ 
+ 
 
Pregnancy test 
+ 
 
 
 
Inclusion/exclusion criteria 
+ 
 
 
 
Randomization and 
prescription of study therapy 
+ 
 
 
 
E-diary supply 
+ 
+ 
+ 
+ 
Study drug supply 
+ 
 
 
 
RANDOMIZATION 
Group 1: Ergoferon for 3 weeks  
SCREENING
Visit 1 
(Day 1) 
5 weeks + 3 days 
Group 2: Placebo for 3 weeks 
Visit 2 
(Day 22+3) 
STUDY  
TERMINATION 
Visit 3 “phone” 
(Day 35±3) 
Postponed Visit * 
(phone visit)  
(“follow-up”) 
* it is carried out if the participant has 
suffered COVID-19. The term is 
determined by the doctor-researcher in 
each case 
Unscheduled visit is 
carried out if the 
participant develops ARVI 
symptoms during the study 

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Study drug accountability, 
compliance assessment 
 
+ 
 
 
Evaluation of treatment safety 
+ 
+ 
+ 
+ 
Visit completion 
+ 
+ 
+ 
+ 
Study completion♦ 
 
 
 
 
 
* Conducted in case of a participant’s illness with COVID-19 
▲ If the participant has had COVID-19 or has been hospitalized for COVID-19, the timing of the visit is 
determined by the study investigator on a case-by-case basis. 
♥ Conducted with a positive rapid test for SARS-CoV-2 (COVID-19 Ag). 
♦ If a patient falls ill with COVID-19, he or she will terminate participation in the study early. 
 
Statistical Analyses 
Samples  
Total set: All subjects who signed Informed Consent Form (ICF). This sample will consider all 
adverse events (AEs) throughout the study, including those occurred prior to the study therapy.  
The sample including all enrolled and randomized 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. 
The AEs registered in patients of the Total set sample from the moment of signing the Informed 
Consent Form, but before the test drug administration will not be taken into account when 
analyzing the study therapy safety.    
Full Analysis Set. This sample includes all the enrolled patients, except for those who have 
experienced at least one of the following events: 
1) non-compliance with inclusion/exclusion criteria; 
2) patient did not take any dose of study drug; 
3) absence of any patient data after administration of study drug. 
Patients who had at least one of the listed events may be excluded from the analysis. 
This sample, the most consistent with the “Intention-to-treat” principle, will be used for 
the Intention-to-treat analysis (ITT analysis) of the the study therapy efficacy. 
Per protocol set. This sample includes all the patients who received full protocol therapy, 
completed all the scheduled visits. This sample will be used for Per Protocol analysis (PP-
 analysis) of the the study therapy efficacy. 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. 

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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. Any other protocol deviations that fall under definition of “significant deviation.” 
Data treatment and all statistical calculations under the protocol will be made using SAS-9.4 
statistical software.5 
Evaluation of sample size 
The sample size has been assessed on the basis of the following rules and assumptions: 
1. Statistical provisions. 
1.1 
the power of the statistical tests “P = (1 - β )” is assumed to be 80% (the 
probability of correct rejection of the null hypothesis is 0.8); 
1.2 
the probability of a type I error “α” is allowed to be less than 5% (the probability 
of the erroneous acceptance of an alternative hypothesis is less than 0.05); 
1.3 
statistical criteria of intergroup comparisons will be two-sided unless otherwise 
specified; 
1.4 
ratio between Ergoferon and Placebo sample sizes is 1:1 (1 Ergoferon patient per 
1 Placebo patient); 
1.5 
an "unblinded" interim analysis with possibility of early stopping due to the 
effectiveness on 85% of the sample is planned in the protocol. Error spending 
function - O’Brien-Fleming; 
1.6 
sample size can be adjusted after the interim analysis based on the estimated 
conditional power (at the same time as the interim analysis is conducted); 
1.7 
statistical null and alternative hypotheses regarding the superiority of Ergoferon 
over Placebo for the dosing regimen used: 
Primary endpoint: 
H0: OR1 2 = 1 
 
5 Holder of license: ООО "NPF "Materia Medica Holding", No. 70100045. 

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Ha: OR1 2 ≠ 1 
where OR12 – odds ratio of an event occurring between the Placebo and 
Ergoferon. 
The following SAS code was used to determine the required sample size6: 
proc seqdesign errspend; 
design nstages = 2 
info = cum (0.85 1) 
method (alpha) = obf 
alt = twosided 
stop = reject 
alpha = 0.05  
beta = 0.2 
samplesize model = twosamplefreq (nullprop=0.03 prop=0.0057) 
run 
1.8 
the final sample size is calculated with the following formula:  
N = NPP / (1 - Кв),  
where N – final sample size; NPP – sample size value in c. 1.7, i.e. scheduled number of 
patients completing the study per protocol; Кв – withdrawal rate. 
2. Assumptions about the expected effects of the clinical study: 
It is assumed that the odds ratio for the occurrence of an event will be not less than 0.162 
in favor8 of Ergoferon (as part of the adaptation process, a possible deterioration in the 
magnitude of the prediction of the effect is assumed to be up to 0.55). 
Population frequency: assumed to be 3%9. 
Therefore, the required size for each group is 57010 patients (PP sample). Considering the 
potential dropout of about 10% patients during the study for various reasons11, at least 1268 
patients (634 in each group) will be required to sign informed consent, of which 1206 patients 
will be randomized (603 in each group) (see cl. 1.8, the final total withdrawal rate will be         
(Кв = 0.1).  
 
6 Minimum size for this study. 
7 Equivalent to effect size OR=0.162 (smaller is better). 
8 OR = Oddtr/Oddpl – the higher, the greater the chance in Ergoferon group compared to the Placebo group. 
9 Rare event frequency assessment, is a population parameter and can be overestimated in a blinded interim analysis. 
10 Minimum size. 
11 Of them patients dropped out during the screening process (5%)  

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Sample Size Adaptation 
It is intended to adapt the sample size during the study in accordance with the following 
algorithm12: 
1) During the planned interim analysis (if the study was not completed due to rejection of the 
null hypothesis based on the interim analysis cutoff), the conditional power is calculated 
using the formula: 
 
where Z1 is the value of the Z-statistic obtained at the interim analysis on N1 of the first 
patients from Nmin (the minimum sample size of the study); 
Zα = 2.0255 (the value of statistics for the final analysis, taking into account the presence 
of an interim analysis); 
Φ(x) – the probability value of event X for the standard normal distribution (σ = 1, μ = 0). 
2) The maximum allowable increase in sample size is assumed to be no more than 324013. 
3) Taking into account the above, one of the adaptation scenarios will be selected. 
4) Optimistic scenario (conditional power CPower > 0.8, or equivalently Z1 > 2.168): 
sample size does not change (Nfinal = Nmin). 
5)  Medium scenario (conditional power 0.314 < CPower < 0.8, or equivalently value    
1.6815 < Z1 < 2.168): the sample size changes according to the formula: 
 
 
 
6)   Pessimistic scenario (conditional power CPower < 0.3, or, equivalently, value Z1 < 
1.6815): sample size does not change (Nfinal = Nmin). 
7)  The final statistical analysis is carried out with the critical statistical values obtained by 
estimating the minimum sample size (Zα = 2.0255). 
 
Statistical criteria  
All the statistical calculations will be performed using two groups of statistical criteria:  
 
12 Adaptive Increase in Sample Size when Interim Results are Promising: A Practical Guide with Examples Cyrus R. 
Mehta1,2, Stuart J. Pocock3 STATISTICS IN MEDICINE Statist. Med. 2000; 00:1–6 
13 Taking into account withdrawal - up to 3600 
14 This value is the minimum acceptable for the stated sample ratio for interim analysis, minimum and maximum 
samples (as well as statistical parameters of the study). Based on table 1 of the source. Adaptive Increase in Sample 
Size when Interim Results are Promising: A Practical Guide with Examples Cyrus R. Mehta1,2, Stuart J. Pocock3 
STATISTICS IN MEDICINE Statist. Med. 2000; 00:1–6 

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• parametric – to obtain effective estimates for the parameters of random variables, if the 
corresponding conditions of applicability of methods/models are not violated (for example, 
sphericity, normality, proportionality of risks, etc.); 
• non-parametric – in all other cases. 
Parametric criteria 
The application of parametric criteria will be accompanied by checking the models for 
applicability (for example, the Kolmogorov-Smirnov criterion, the Shapiro-Wilk criterion, etc.). 
The following parametric methods and approaches are supposed to be used: 
1. To assess the differences of continuous variables between two groups – Student t-test. 
2. To assess the dynamics of the compared indicators – analysis of variance (ANOVA) 
or covariance (ANCOVA) in the modification with repeated measures. 
3. In case of multiple comparisons between the groups will apply a variety of corrections 
for multiplicity (Dunnett), (Tukey), (Scheffe), Holm adaptive test, etc. 
4. In 
case 
of 
abnormal 
data 
distribution, 
approaches 
with 
the 
Generalized Linear Models and/or Mixed Linear Models will be used.  
5. Selection of the type of distribution, clarification of the factor and covariance 
structures 
of 
the 
model 
is 
carried 
out 
with fit statistics 
such 
as AIC (Akaike information criterion). 
To perform the above-mentioned statistical tests and techniques, it is assumed that the 
following SAS procedures are used:  
• 
UNIVARIATE – check for normality of the compared distributions; 
• 
CORR, MEANS – calculation of descriptive statistics; 
• 
TTEST – Student t-test with all the modifications; 
• 
GLM – analysis of Generalized Linear Models for studying temporal dynamics 
(ANOVA, ANCOVA); 
• 
GENMOD – analysis of Generalized Linear Models. 
MIXED – analysis of Mixed Linear Models. 
Non-parametric criteria 
Below, there are the main types of possible comparisons with the respective criteria: 
1. To evaluate the dynamics of the compared indicators – Friedman test, nonparametric 
analogue of repeated measures analysis of variance. 
 
2. For the frequency analysis of 2×2 cross tables – χ2-test (if the compared frequencies are 
greater than 5) or Fisher exact test (if one of the compared frequencies is less than 5). 

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3. For the frequency analysis of cross tables with independent strata – Cochran–Mantel–
Haenszel test (modification of the χ2-test for multiple comparisons). 
4. For the frequency analysis of data on the presence / absence of an event or outcome 
during repeated measures (cross tables with dependent strata) – survival analysis. 
To perform the above-mentioned non-parametric statistical analysis options, it is assumed 
that the following SAS procedures are used: 
• FREQ – Friedman test, χ 2-test and / or Fisher exact test; Cochran–Mantel–Haenszel test 
• LIFETEST – 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, as well as 1st, 2nd and 
3rd quartiles (other measures of central tendency and dispersion may be additionally provided if 
necessary). The categorical variables will be presented as frequency tables by visits. 
Comparisons suggesting statistical conclusion will have the relevant confidence intervals. 
Outliers will be analyzed individually. The data will be grouped by visits.  
Incomplete/missing data 
Missing data not requiring the patient exclusion from analysis will be processed as follows: 
1. For sections of descriptive statistics the missing/incomplete data will be ignored specifying 
the number of complete and incomplete data points. 
2. For efficacy criteria, if the type of gaps (MCAR, MAR, etc.) and the type of variable are 
acceptable, multiple imputation methods can be applied. Alternative methods: data will 
be populated according to the LOCF approach. 
3. For additional criteria - similar to descriptive statistics.