Clinical trial NCT05054114
Conditions: COVID-19 Respiratory Infection Acute Respiratory Disease
Keywords: COVID-19 prevention, interferon gamma, nasal drops
Sponsor: SPP Pharmaclon Ltd.
Start date: 2020-12-21; Completion date: 2021-09-02
Enrollment: 630 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
It is known that the pretreatment with exogenous interferon blocks SARS-CoV-2 infection, but intervention is much more effective if administered prior to infection. In this study the primary aim is to investigate 28-day regime of nasal interferon gama use in healthy participants for COVID-19 and other respiratory infections prevention.

Detailed description:
The tissues of the upper respiratory tract: the mucous membrane of the oropharynx, nose, - as well as the lung parenchyma are identified as the main targets of SARS-CoV-2. Previously published data from studies describe that in vitro and in vivo observations SARS-CoV-2 replicates exponentially during the first few days after infection to the peak of the host's antiviral response. It is assumed that it is the violation of the antiviral immunity of the nasal epithelium that may underlie the development of a severe form of the disease. The significance of interferon protection proven in early studies supposes that it can reduce peak viral load and viral reproduction index.

To confirm the efficacy and safety of nasal interferon gama use in healthy participants for COVID-19 and other respiratory infections prevention there is a need of interventional study. Interferon gamma has many years of clinical experience in the prevention and treatment of various viral infections, including coronavirus nature, flu and pneumonia.

After participant enrollment, comprehensive baseline documentation of anamnestic, clinical and allergy data is collected on the same day if possible. For participants who develops acute respiratory symptoms or recieve positive PCR test for SARS-CoV-2, all parameters are collected that may be necessary to assess the type and severity of acute respiratory disease. Furthermore, data is collected that may be suitable for an assessment of the safety profile. In particular, questions are asked about known infection risks, lifestyle, alternative prevention methods, immune competence, rate of acute respiratory infections, the history of symptoms and tests relating to COVID-19, preexisting medication, as well as ethnicity.

On the day of inclusion (day -3-1) routine clinical values, safety-relevant data, WHO scale score, concomitant medication and anamnesis, as well as study criteria analysis are documented.

On the day 0 (randomization visit) and at termination visit (up to 90 days) repeated routine clinical values, safety-relevant data, WHO scale score, and concomitant medication are collected. If the patient falls ill, the necessary disease information is documented. If the patient dies, the date and cause of death are documented.

On days 24-30 after randomization, a follow-up call takes place with particular attention to the health-related events such as respiratory diseases or other changes in health and vital status and drug compliance. If the participant cannot be reached for the follow-up call, the including study center will attempt to reach the participant, otherwise exclude the participant.

A nasopharynx swab is obtained on days 0 to exclude asymptomatic patients before the randomisation. If possible, sputum is obtained for termination visit and during the acute respiratory symproms manifestation to confirm COVID-19.

Arms: arm 1: IFN-G administered for 2 10-day courses with a 1-week pause between the courses. arm 2: Any preventive method including a variety of pharmacologic therapies against COVID-19, alongside the use of antiviral and immunomodulating agents, with the exception of drugs prescribed off-label or for research purposes, and IFN-G as well.
Interventions: intervention 1: Interferon gamma human recombinant (IFN-G)
Intervention descriptions: intervention 1: nasal form

Protocol documents:
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LLC "NPP "Pharmaclon" 
 
 
Protocol of post-marketing non-interventional study 
 
 
"Prospective randomized open-label comparative study of the use of the 
intranasal form of human recombinant interferon gamma for the prevention of 
acute respiratory viral infections, including diseases caused by coronavirus 
infection 2019 (COVID-19)" 
 
 
RAIN-2020 (NCT05054114) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL 
Moscow – 202 1 
 


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PROTOCOL SIGNATURE PAGE (EXAMPLE) 
 
 
«Prospective randomized open-label comparative study of the use of the intranasal form of 
human recombinant interferon gamma for the prevention of acute respiratory viral 
infections, including diseases caused by coronavirus infection 2019 (COVID-19)" 
Protocol Version 2 dated February 17, 2021 
 
Sponsor: LLC "NPP "PHARMACLON" 
 
 
 
Signature: ________________________________________ Date:______/______/______ 
      day/month/year 
 
 
_______________________________ 
Full name 
 
 
_______________________________ 
Post 
 
 
Address: _________________________ 
 
 
Phone number:__________________ 
 
 
 
 


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CONTENT 
 
SYNOPSIS 
4 
ABBREVIATIONS 
7 
ETHICAL AND LEGAL ASPECTS 
8 
INTRODUCTION 
10 
OBJECTIVES OF NON-INTERVENTIONAL RESEARCH 
12 
DESIGN OF A NON-INTERVENTIONAL STUDY 
12 
METHODOLOGY OF NON-INTERVENTIONAL RESEARCH 
14 
STUDY POPULATION 
19 
STUDY THERAPY 
22 
STUDY PARAMETERS OF EFFICIENCY AND SAFETY 
24 
URGENT EVENT: 
30 
QUALITY CONTROL 
32 
DIRECT ACCESS TO PRIMARY DATA/DOCUMENTATION 
32 
INSPECTION 
32 
ACCOUNTING OF DRUGS 
33 
RESEARCH DOCUMENTATION 
33 
STORAGE OF DOCUMENTATION 
33 
STATISTICAL METHODS 
33 
RESEARCH REPORT 
34 
REFERENCES TO LITERATURE 
35 
APPENDIXES 
37 
 


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SYNOPSIS 
 
Title 
study 
Protocol of post-marketing non-interventional study "Prospective 
randomized open-label comparative study of the use of the intranasal 
form of Interferon gamma human recombinant in patients for the 
prevention of acute respiratory viral infections, including coronavirus 
infection disease 2019 (COVID-19)" 
Protocol of post-marketing non-interventional study "Prospective 
randomized open-label comparative study of the use of intranasal form 
of interferon gamma human recombinant in patients for the prevention of 
acute respiratory viral infections, including coronavirus infection disease 
2019 (COVID-19)" 
RAIN-2020 
Design 
study 
Post-marketing non-interventional prospective randomized open-label 
comparative study 
Purpose of the study 
Primary objective 
Evaluation of the effectiveness of the prophylactic use of Ingaron (INN: 
human recombinant interferon gamma, lyophilizate for the preparation of 
a solution for intranasal administration of 100,000 IU) in regimen of 3 
drops in each nasal passage intranasally every other day for 10 days with 
a break of 7 days (two 10-day cycles) in adult volunteers. 
Secondary objectives 
Safety assessment of the prophylactic use of Ingaron (INN: human 
recombinant interferon gamma; lyophilizate for the preparation of a 
solution for intranasal administration of 100,000 IU), applied 3 drops 
into each nasal passage intranasally every other day for 10 days with a 
break of 7 days (two 10-day cycles) in adult volunteers.  
Study 
drug 
Trade name: Ingaron® 
International Nonproprietary Name: interferon gamma human 
recombinant 
Product license number – 001330 
Pharmaceutical dosage form: Lyophilizate for preparation of a solution 
for intranasal administration of 100,000 IU 
Composition: 
Drug substance: interferon gamma – 100,000 IU. 
Excipients: mannitol 14.5 mg. 
Pharmacotherapeutic group: immunomodulatory agent 
ATX Code: [L03AB03] 
Ingaron® is a recombinant human gamma interferon, consists of 144 
amino-acid residues, deprived of the first three amino-acid residues Cys-
Tyr-Cys, replaced by Met. Molecular weight is 16.9 kDa. Obtained by 
microbiological synthesis in a recombinant strain of Escherichia coli and 
purified by column chromatography.  
Interferon gamma (immune interferon) is the most important anti-


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inflammatory cytokine, the producers of which in the human body are 
natural killer cells, CD4 Th1 cells and CD8 cytotoxic suppressor cells.  
Macrophages, neutrophils, natural killer cells, cytotoxic T-lymphocytes 
have receptors for interferon gamma. Activates the effector functions of 
these cells, their bactericidal activity, cytotoxicity, production of 
cytokines, superoxide and nitrous oxide radicals (thereby causing the 
death of intracellular parasites). Cancels the suppressive effect of 
interleukin-4 on interleukin-2-dependent proliferation and generation of 
lymphokine-activated killers. Activates the production of proteins of the 
acute phase of inflammation, enhances the expression of genes C2 and 
C4 components of the complement system. 
Unlike other interferons, it increases the expression of major 
histocompatibility complex (MHC) antigens of both classes I and II on 
different cells and induces the expression of these molecules even on 
those cells that do not express them constitutively. This increases the 
efficiency of antigen presentation and the ability of their recognition by 
T-lymphocytes. 
Interferon gamma blocks the synthesis of β-TGF, which is responsible 
for the development of lung and liver fibrosis. 
Release form: Lyophilizate for the preparation of a solution for 
intranasal administration in vials of 100,000 IU per 1 vial. 1 vial of drug, 
1 vial of water for injection (5 ml) and 1 cap-dropper made of 
polyethylene in packaging of polyethylene or medical dropper in contour 
cellular package or in cassette contour package. 
Method of administration and dosage: Intranasally. 2–3 drops in each 
nasal passage every other day 30 minutes before breakfast for 10 days. 
After instillation, it is recommended to massage the wings of the nose 
with your fingers for several minutes to evenly distribute the drug in the 
nasal cavity. Preparation: The contents of the vial are dissolved in 5 ml 
of water for injection. 
Effects on ability to drive and use machines: Not studied. 
Manufacturing enterprise/organization accepting consumer claims: 
LLC "NPP "Pharmaclon", Russia.  
Legal address: 142279, Moscow region, Serpukhovskii district, 
Obolensk workers settlement, Obolenskoe highway industrial zone, 
building 5A, office 312. 
The address of the place of manufacture: 143422, Moscow region, 
Krasnogorskii district, Petrovo-Dalnee village, J.S.C. “Biomed”-
 Mechnikov Tel/fax (4967) - 36-07-71, (495) – 120-12-47  
E-mail: info@pharmaclon.ru Internet: www.pharmaclon.ru  
Sample Size 
630 adult volunteers randomized into 2 parallel groups with a 1:1 
distribution, considering a possible 10% premature exclusion and 
withdrawal of informed consent during the study. The population for 
analysis will be at least 572 participants: 286 in each group. 


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Selection criteria 
Eligible volunteers can participate in the study. 
Inclusion criteria 
1. Volunteers of both genders over 18 years old. 
2. Obtaining a written form of informed consent. 
3. Ability and consent to participate in this study. 
4. No symptoms of respiratory infection. 
5. A negative result of a PCR study for the presence of SARS-CoV-
2 RNA according to the biomaterial obtained by nasopharyngeal 
1smear. 
Non-inclusion criteria 
1. Any other concomitant diseases or conditions that, in the opinion 
of the research doctor, may distort the results of the study, restrict 
the rights of the volunteer, or put him at greater risk. 
2. Contraindications to the use of the study drug. 
3. Individual intolerance of the ingredients included in the 
composition of the study drug. 
4. Pregnancy or breast-feeding. 
5. Controversial result of PCR test for the presence of SARS-CoV-2 
RNA according to the biomaterial obtained by nasopharyngeal 
smear. 
6. Participation in a clinical trial using the investigated therapy for 
30 days prior to inclusion in this study.  
7. Disagreement on following reliable contraceptive measures 
within the study (sexual abstinence; or a combination of 2 
different methods: for example, barrier and spermicides, or 
barrier and intrauterine device, or barrier and hormonal, etc.) – 
for participants with preserved childbearing potential. 
Effectiveness criteria 
Primary effectiveness criteria: 
The proportion of patients with acute respiratory viral infections, 
including COVID-19, at the end of the period of preventive 
administration of the drug (measurement time: 28 days). 
Secondary effectiveness criteria:  
1. 
The proportion of patients with confirmed COVID-19 at the 
end of the period of preventive treatment of the drug (measurement 
period: 28 days). 
2. 
The proportion of patients with acute respiratory viral 
                                                 
1 It is permissible to accept the results of a nasal or pharyngeal smear, as well as the results of studies performed 
before inclusion in the study for no more than 72 hours. 


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infections, including COVID-19, at the end of the follow-up period 
(change period: 2 months). 
3. 
The proportion of patients with confirmed COVID-19 at the 
end of the follow-up period (change period: 2 months). 
4. 
Frequency of development of complicated course of ARVI. 
5. 
The proportion of participants with each of the scores (0–8) on 
World 
Health 
Organization 
(WHO) 
Ordinal Scale for Clinical 
Improvement (change period: 28 days). 
6. 
The proportion of participants with each of the scores (0–8) on 
World 
Health 
Organization 
(WHO) 
Ordinal Scale for Clinical 
Improvement (change period: 2 months). 
7. 
The duration of the symptoms of the disease of the study 
participants who fell ill with ARVI, including COVID-19 (change 
period: 2 months). 
8. 
The duration of the symptoms of the disease of the study 
participants who fell ill with ARVI, including COVID-19 
(measurement period: 28 days). 
Safety criteria 
The assessment of the safety of treatment will be carried out based on the 
registration of adverse events by analyzing complaints and subjective 
symptoms, as well as analyzing their severity using the CTCAE scale 
version 4.03 from 2010. 
Financing and 
insurance 
Financial support for this non-interventional post-marketing study will 
be provided at the expense of the manufacturing company in accordance 
with contracts with research centers. Additional payments and insurance 
of participants are not provided. 
 
ABBREVIATIONS 
 
ATC – Anatomical Therapeutic Chemical Classification System 
VI – viral infections 
CI – confidence interval 
IU – international unit 
BMI – body mass index 
INN – international nonproprietary name 
IEC – Independent Ethics Committee 
AE – adverse event 
ARVI – acute respiratory viral infection 
ARD – acute respiratory disease 
SAR – serious adverse reaction 
SARS – severe acute respiratory syndrome 
COVID-19 – coronavirus disease 2019 (coronavirus disease 2019) 


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CTCAE – Toxicity Scale (Common Terminology Criteria for Adverse Events) 
SARS-CoV-2 – type 2 coronavirus that causes severe acute respiratory syndrome (SARS) 
M – arithmetic mean 
Max – Maximum value 
Me – Median 
Min – minimum value 
N – number of values 
SD – standard deviation 
 
ETHICAL AND LEGAL ASPECTS 
 
This study will be conducted in accordance with the Research Program, the Helsinki Declaration 
(ICH Harmonized Tripartite Guideline for GCP) and current local regulatory requirements 
(GOST R 52379-2005 "Good Clinical Practice", Order of the Ministry of Health of the Russian 
Federation No. 200n dated 01.04.2016 "On approval of the rules of good clinical practice"),The 
Rules of Good Clinical Practice of the Eurasian Economic Union (approved by the Decision of 
the Council of the Eurasian Economic Commission No. 79 of November 03, 2016), as well as 
according to the principles of the Independent Ethical Committee (IEC) accompanying this 
study. The research protocol, informed consent, participant diaries and the list of researchers 
must be submitted to the IEC before the start of the study and the inclusion of the first 
participant. 
 
Informed consent 
Each potential participant of the study will be informed about the study drug, objectives, and 
essence of the study, expected benefits, degree of risk and the requirements that he/she must 
fulfill during the study.  
The participant's information sheet with the informed consent form will be signed and dated by 
both the volunteer and the researcher in two copies. One copy is transferred to the participant, 
and the other remains in the file of the research center. Each volunteer will receive information 
about the study in writing on hand. Information about the study is presented in Russian. 
 
Risks and benefits for the study participant 
The study drug has a low degree of toxicity and possible efficacy in relation to the prevention of 
COVID-19. All information that will be provided to the volunteer to decide on participation, 
including information about potential risks, is indicated in the participant's information sheet 
with an informed consent form.  
Possible risks 
The following side effects have been registered for the injectable dosage form of the drug 
(lyophilizate for the preparation of solution for intramuscular and subcutaneous administration). 
The appearance of these effects during intranasal administration of the drug Ingaron® is not 
expected. 
It is noted that the use of the drug Ingaron® may be accompanied by the development of side 
effects, represented mainly by manifestations of flu-like syndrome: fever, chills, headache, 


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muscle pain, joint pain, weakness, which develop after the first injections of the drug and are 
amenable to correction with drugs with antipyretic and analgesic effects, without requiring 
withdrawal of the drug. In most cases, fever did not rise above 37.5 °C and was controlled 
independently.  
Basically, registered side effects were reversible and easily controlled by the appointment of 
concomitant therapy (antidepressants for depression; antiallergic agents for skin rash): 
thrombocytopenia2*, neutropenia3*, anemia2*, lymphopenia4; autoimmune thyroiditis, allergic 
reactions5; vomiting 2*, nausea2; weight loss, anorexia3; depression; general malaise, 
headaches3, dizziness; rhinorrhea; allergic rash, alopecia6**; myalgia3; increased concentration 
of liver enzymes 3**, increased concentration of bilirubin 3*, creatinine3*, urea 3*, glucose 3**.  
Risks from the use of the studied drug Ingaron® for the course of pregnancy, fetal development 
or for a breastfed child has not been sufficiently studied. In this regard, pregnant and lactating 
women, as well as women capable of childbearing and unwilling to follow reliable methods of 
contraception, as indicated in the inclusion/non-inclusion criteria, are not allowed to participate 
in this study. If a case of a participant's pregnancy is detected during the study, she is excluded 
from the study ahead of schedule and is subject to medical supervision during the entire period 
of pregnancy, as well as within 6 months after the birth period to assess the condition of the 
woman and the born child (observation is carried out if possible and only if she has her desire 
and consent to such observation). 
Risk/benefit ratio 
Considering the above, as well as the satisfactory study of the drug Ingaron® for intranasal 
administration when used in clinical practice, including for preventive purposes, the risk/benefit 
ratio in this study can be considered acceptable. 
 
Benefit 
Participation in the study does not imply receiving monetary, other material compensation, or 
any other direct benefit for the subject. However, the participant will have the opportunity to 
receive the study drug Ingaron®, registered for medical use in the Russian Federation for 
indications of prevention and treatment of acute respiratory viral infections. During the study, 
study group participants will receive 2 vials of the drug based on 2 cycles of 10-day prevention. 
Participants of the control group will have the opportunity to receive 1 bottle of the drug upon 
                                                 
2 It was noted in patients receiving complex therapy for hepatitis B, C, as well as in the treatment 
of oncological diseases 
3 It was noted in patients who received the drug as part of chemotherapy for oncological diseases 
4 It was noted in patients receiving the drug with disseminated melanoma of the skin  
5 It was noted in patients receiving complex therapy for hepatitis B, C, as well as in the treatment 
of disseminated melanoma 
6 It was noted in patients receiving complex therapy for hepatitis C, as well as in the treatment of 
oncological diseases 
* It was noted with the same frequency in patients who received the drug as part of 
chemotherapy or who received only chemotherapy 
** It was noted with a lower frequency in patients who received the drug as part of 
chemotherapy, compared with patients who received only chemotherapy 


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completion of participation in the study for self-use within the instructions for medical use if 
they express a desire.  
 
Introduction 
 
The first coronavirus was isolated back in 1965 from a patient with SARS. But it has been of 
particular interest since the early 2000s, when the first outbreaks of coronavirus infections with 
fatal outcomes began. To date, science knows 37 types of RNA-containing coronaviruses.  
A new coronavirus infection COVID-19 has been observed in the human population since the 
end of 2019. The characteristic symptoms of the disease are fever, cough, shortness of breath, 
myalgia. According to computed tomography (CT), in most cases, bilateral lung damage of the 
"ground-glass opacity" type is registered. Histological examination reports of patients' lungs 
indicate bilateral diffuse alveolar and bronchial [1] damage, pulmonary edema, hyaline 
membrane formation, false respiratory distress syndrome, accumulation of neutrophils, 
macrophages, and lymphocytes [2][3]. A characteristic feature is the presence of synth [4][5]. In 
addition to acute respiratory symptoms, weight loss may be observed [6][7]. 
The first stage of the SARS-CoV-2 life cycle is the adsorption of the viral particle by the target 
cell through ACE2, a receptor different from other types of coronaviruses for introduction into 
the host cell. After receptor binding, the stages of the SARS-CoV-2 viral cycle are similar for all 
coronaviruses [8][9][2 6]. 
The initial outbreak in China was represented in every fifth case by a severe form of the disease. 
The severe course of COVID-19 is associated with the high tropicity of the SARS-CoV-2 virus 
to the lung tissue, which determines its similarity to the pathogenesis of severe acute respiratory 
syndrome (SARS), registered in 2003. Since the beginning of the spread of COVID-19, quite a 
lot of reports have been received about a mild and even asymptomatic form of the disease 
without affecting the lower respiratory tract [1]. 
There is limited information about the systemic and local immune response of the body to the 
SARS-CoV-2 virus and the localization of virus replication in the tissues of the respiratory tract. 
Single scientific works on the study of this problem indicate the activity of replication in the 
tissues of the upper respiratory tract, including the nasal cavity, bronchi, bronchioles and alveoli, 
and the important role of the respiratory organs as "site of entry" for SARS-CoV-2. An important 
difference between SARS-CoV-2 and other epidemiologically important coronavirus strains was 
established, which consisted in the detection of the virus antigen in the ciliated epithelium of the 
nasal mucosa, which was combined with a high risk of transmission of the viral agent, as in cases 
of influenza infections [1]. The condition of a patient with active replication of the virus in the 
upper respiratory tract is of great epidemiological importance, posing a threat of spread [10], but 
may be reversible in terms of the development of subsequent complications and damage to the 
underlying respiratory tract [11]. 
The SARS-CoV-2 virus persists in the pharynx, throat, and lungs during the first week of 
infection and is well detected in a smear from the throat during this time period. At the same 
time, with age, there is a longer release of the virus in the upper respiratory tract [1], which was 
also noted in patients infected with SARS-CoV [12][13]. The detection limit is maximum at the 
beginning of infection. Unlike MERS-CoV, but just as in cases of SARS-CoV, SARS-CoV-2 
infects both type I and type II pneumocytes, which explains the similarity of the histological 


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picture and explains pulmonary edema and the formation of hyaline membranes. Active 
replication of the virus in the lower respiratory tract is associated with the development of 
complications and lung damage [1][2 6]. Viral RNA can be detected in sputum within a month 
from 
the 
moment 
of 
manifestation 
of 
symptoms 
of 
the 
disease.  
SARS-CoV-2 is also identified in intestinal tissues [14]. Blood and urine samples do not give a 
positive result for the presence of viral RNA [11]. 
By the 14th day of the disease, seroconversion, and an increase in the concentration of IgG and 
IgM antibodies occur in all patients against the background of the remaining viral load [11].  
However, it should be noted that acquired immunity against coronavirus infections is not 
persistent and does not protect against re-infection. Although the severity of the disease is 
associated with age and the presence of concomitant pathologies [1][26], susceptibility to SARS-
CoV-2 is high in all population groups [8][15][16]. 
The interferon system is the most important and integral part of the body's immune system, 
which is responsible for the formation of an immune response, to produce specific antibodies and 
the activation of individual clones of immune system cells responsible for the detection and 
destruction of infectious pathogens: viruses and bacteria. It has been proven that it plays a key 
role in triggering the cellular immune response against any viral expansion, including lethal 
viruses (Ebola, SARS-CoV, MERS-CoV, hepatitis, etc.), which opens promising opportunities 
for the safe use of interferon-based drugs to provide preventive and therapeutic care. 
[18][19][20][21] 
Studies on the role of interferons of different classes in the immune response processes have 
shown that interferons alpha and beta have their own antiviral activity, and interferon gamma is a 
powerful endogenous regulatory cytokine that activates the antiviral immune response, while it 
also has its own antiviral activity.  
One of the unique manifestations of immune influence is the ability of interferon gamma to 
stimulate other cells of the immune system using the mechanism of "antigen presentation". This 
is a process in which phagocytes "place" fragments of pathogen proteins on the surface of their 
cells, thereby presenting these fragments are used by other cells of the immune system to 
develop an antigen-specific response. This mechanism significantly increases the ability of the 
immune system to target respond to a virus or any other intracellular pathogen.  
Drug product called Ingaron (human recombinant interferon gamma), presented in two dosage 
forms: lyophilizate for the preparation of solution for intranasal administration, as well as 
intramuscular or subcutaneous administration, have many years of clinical experience in the 
prevention and treatment of viral infections, including coronavirus, influenza, and pneumonia. 
Efficacy and safety have been demonstrated in randomized controlled and placebo-controlled 
clinical trials [2 2][2 3][2 4]. 
A drug for intranasal administration based on recombinant interferon gamma was studied to 
assess the effectiveness of preventive administration during the epidemic rise in the incidence of 
influenza and ARVI. According to the results of a placebo-controlled randomized trial, the 
incidence during the prevention period and within 1 month after two 10-day cycles of using the 
drug decreased by more than 2 times. Among those who did get sick, a complicated course of 
infection was observed 2 times less often [2-4]. 
The nasal form of the drug has additional advantages. Firstly, a more favorable safety profile was 
noted with intranasal use. Secondly, the form is convenient for use, does not require a violation 


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of the skin, does not have an irritating effect on the gastrointestinal tract. But one of the main 
advantages should be noted that the intranasal route of administration contributes to the 
protection of cells, primarily the epithelium of the nasal mucosa, and performs the function of an 
additional mechanical barrier, which can contribute to a more rapid elimination of the virus from 
the upper respiratory tract, prevent its penetration into the lower respiratory tract and provide 
effective preventive protection. 
The drug was included in the training manual "New coronavirus infection COVID-19: etiology, 
epidemiology, clinic, diagnosis, treatment and prevention" [8] and recommended by the Expert 
Council on Science by the Department of Health of the City of Moscow as a preventive measure 
to prevent infection with COVID-19 [15]. 
It is worth paying attention to the fact that during clinical studies to evaluate the antiviral 
efficacy of Ingaron 100,000 IU, a lyophilizate for the preparation of a solution for intranasal 
administration, therapeutic efficacy of the drug was noted in patients with coronavirus infection 
[2 5]. 
In this regard, the following tasks were set in this study: 
• 
to evaluate the effectiveness of the proposed scheme of preventive therapy with Ingaron 
(INN: human recombinant interferon gamma, lyophilizate for the preparation of solution for 
intranasal administration of 100,000 IU) in adult volunteers. Effectiveness includes evaluation 
according to primary and secondary effectiveness criteria. 
• 
to evaluate the safety of the proposed regimen of preventive therapy with Ingaron (INN: 
human recombinant interferon gamma, lyophilizate for the preparation of solution for intranasal 
administration of 100,000 IU) in adult volunteers. Safety is assessed based on adverse events, 
clinically significant changes in laboratory parameters during the study, taking into account the 
assessment of severity according to the STCAE 4.03 scale. 
 
OBJECTIVES OF NON-INTERVENTIONAL RESEARCH 
 
Primary objective 
To evaluate the effectiveness of the prophylactic use of Ingaron (INN: human recombinant 
interferon gamma, lyophilizate for the preparation of solution for intranasal administration of 
100,000 IU) in the mode of 3 drops in each nasal passage intranasally every other day for 10 
days with break of 7 days (2 10-day cycles) in adult volunteers. 
 
Secondary objectives 
Safety assessment of the prophylactic use of Ingaron (INN: human recombinant interferon 
gamma; lyophilizate for the preparation of a solution for intranasal administration of 100,000 
IU), applied 3 drops into each nasal passage intranasally every other day for 10 days with break 
of 7 days (two 10-day cycles) in adult volunteers.  
 
Efficacy and safety include evaluation based on epidemiological, anamnestic, and clinical data, 
as well as laboratory studies and specialized scales. 
 
DESIGN OF A NON-INTERVENTIONAL STUDY 
 


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Post-marketing prospective randomized open-label comparative non-interventional study in 
parallel groups.  
A total of 4 visits are planned (0–3). Visit 0 and 1 can be combined.  
 
Main stages of the study 
1. Visit 0. Conducted in person7. Screening: informed consent, inclusion of volunteers and 
distribution into groups (Day -3-1) 
2. Visit 1. Conducted in person. Randomization. Delivery of the investigated drug and the 
diary of the researcher participant (Day 0) 
3. Visit 2. It is carried out remotely (by phone). Completion of a preventive course, 
evaluation of preventive efficacy and safety during the period of drug administration. The 
beginning of the observation period. (Day 28–30) 
4. Visit 3. Conducted in person. Completion of the observation and research period. (Day 
56–62) 
The main procedures and stages of the study are reflected in the Schedule of research 
procedures. 
The total duration of participation is about 2 months (56–62 days). 
For participants who have a case of ARVI (COVID-19), visit 3 can be carried out earlier or later, 
but the total duration of the study should not be more than 90 days. Up to this point, medical 
researcher should try to collect the most complete information about the patient's condition. If it 
is not possible to conduct a face-to-face visit, final visit is conducted remotely.  
Schedule of research procedures 
 
Visit number 
0 
1 
2 
3 
Setting  
In person 
In person 
Phone call 
In person 
Visit name 
Screening 
 
 
Randomization 
 
The end of the 
course of 
prevention 
Beginning of the 
observation 
period 
End of the 
observation period  
Completion of the 
study 
Study days 
-3-1(0) 
0 
27 (+/-3) 
56-62* 
Informed consent 1 
+ 
 
 
 
Anamnesis 2 
+ 
 
 
 
Complaints 
+ 
+ 
+ 
+ 
Physical examination 3 
+ 
+ 
 
+ 
Pregnancy test  
+ 
 
 
 
Safety assessment 
+ 
+ 
+ 
+ 
Analysis for RNA to SARS-CoV-2 4 
+ 
 
 
+6 
Checking the inclusion/non-inclusion criteria 
+ 
+ 
 
 
Checking exclusion criteria 
 
 
+ 
 
                                                 
7 A full-time visit can be carried out both at the research center and at home 


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Randomization 
 
+ 
 
 
Delivery of the study drug 5 
 
+ 
 
+ 
Compliance assessment 
 
 
+ 
+ 
Issue of the participant's diary 
 
+ 
 
 
Effectiveness evaluation 
 
 
+ 
+ 
Assessment of the participant's condition 
according to the WHO scale 
+ 
+ 
+ 
+7 
Return of study drug and diary 
 
 
 
+ 
*  
For patients with a registered case of ARVI, duration of participation in the study may be longer, but not exceed 90 days 
1 
All research procedures, except routine laboratory and instrumental studies, the data of which are used to assess the condition of the 
study participant, are performed after the procedure of signing the informed consent of the patient 
2 
The study should indicate the epidemiological history of respiratory viral diseases, status of vaccination (influenza, pneumonia, 
COVID-19), use of means of nonspecific protection and prevention of acute respiratory viral infections, including COVID-19 
3 
It includes a standard examination by a doctor, including: thermometry, assessment of visible mucous membranes of the upper 
respiratory tract, auscultation and percussion of the lungs, palpation of lymph nodes, examination of abdominal organs with 
determination of the size of the liver and spleen, assessment of the level of consciousness; clinical history; measurement of height, 
weight, respiratory rate, heart rate, blood pressure, pulse oximetry with measurement SpO2   
4 
Within the framework of this study, results of tests performed no later than 72 hours before screening can be accepted at the screening 
visit; if the PCR test is received as "controversial", patient excluded of the study according to non-inclusion criterion No. 5 and cannot 
be re-screened further. 
5 
At the randomization visit, drug is given to participants assigned to the study group immediately for 2 courses (2 vials) with 
instructions for use and preparation. Upon completion of the study, participants of the control group can also optionally receive 1 vial 
of the study drug as a means of preventing acute respiratory viral infections for use as part of the instructions for medical use. 
6 
If performed as part of a routine practice 
7 
In case of registration of ARVI at the final visit 3, in parallel with the current assessment of the participant's condition, an additional 
assessment of the case is carried out according to the WHO scale, reflecting the maximum clinical manifestation of the disease.      
 
Rules for stopping research 
The sponsor has the right to stop the research at any time. Also, the study may be stopped 
prematurely by the decision of the IEC or regulatory authorities.  
In case of early closure of the research center, all research documentation (except for the one that 
should remain in storage at the center) must be returned to the sponsor. Research documents, 
including primary medical records, must be kept at the center for at least 15 years after the 
completion of the study. 
 
METHODOLOGY OF NON-INTERVENTIONAL RESEARCH 
 
Randomization of study participants 
 
During randomization, patients are randomly distributed in a 1:1 ratio into two groups:  
Group I (main) and Group II (control). 


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According to the methodology approved by this protocol, the participant must use (Group I) or 
not use (Group II) study drug (depending on the distributed randomization number at Visit 1) for 
27 days of the preventive course (10 days + 7 days + 10 days).  
Randomization of the study participants is carried out on the same day or the next day after 
signing the informed consent, but no later than 3 days from the date of material sampling to the 
PCR test. 
Randomization is carried out according to the Randomization List version 1.00 from 16.11.2020.  
To randomize a participant into a study, a research physician must contact the employee 
responsible for randomization (instructions for randomization are provided by the sponsor to the 
center before the start of the study) by phone and provide the study code and the researcher's full 
name for identification, as well as the data of the randomized participant: screening number, 
initials, date of birth. The researcher is informed of the assigned randomization number of the 
participant and the number of the prevention group (I or II). After the call, a Randomization 
Form is sent to the researcher's email as confirmation. The form must be printed out, signed by 
the researcher, and attached to the primary documentation of the participant.  
The intake of the study drug is carried out independently by the participant at home, with the 
Diary of the participant of the study. 
 
Other preventive measures 
 
Any non-specific measures for the prevention of a new coronavirus infection COVID-19 are 
allowed, including personal protective equipment (respirators, glasses, gloves, protective suits). 
 
Previous therapy 
 
As a previous therapy, it is prohibited to take any drug with test status 1 month before 
participating in this study. 
 
Concomitant therapy  
 
According to the design of the non-interventional study, participants can receive any 
concomitant therapy for concomitant chronic diseases, except medications prescribed off-label or 
for research purposes. 
 
Prohibited therapy 
 
For the study group: use of any medications that may or may have preventive effects against 
ARVI, including COVID-19, is prohibited; use of non-specific methods of preventive protection 
is not prohibited. 
For the control group: use of interferon gamma is prohibited; use of any medications that may or 
may have preventive effects against ARVI, including COVID-19, as well as the use of non-
specific methods of preventive protection is not prohibited. 
All preventive measures, including pharmacotherapeutic ones, should be indicated in the diary 
filled in by the participant. 


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Exclusion criteria 
A participant should be excluded from the study if at least one of the following criteria is met: 
1. 
The use of the prohibited therapy indicated above, specific to each of the groups. 
2. 
Withdrawal of informed consent. 
3. 
Compliance to the study therapy is 50% or less. 
4. 
Systematic non-compliance with protocol procedures by the participant. 
5. 
Development of individual intolerance to the study drug (for the study group). 
6. 
The development of concomitant diseases or conditions that, according to the researcher, 
may distort the results of the study, restrict the rights of the volunteer or put him at greater risk. 
7. 
The appearance of contraindications to the use of the study drug in the period before the 
last intake of the second 10-day cycle (for the study group). 
8. 
Participation in a clinical trial using a different therapy. 
9. 
Disagreement on following reliable contraceptive measures (sexual abstinence; or a 
combination of 2 different methods: for example, barrier and spermicides, or barrier and 
intrauterine device, or barrier and hormonal, etc.) – for participants with preserved childbearing 
potential in the period before the last intake of the second 10-day cycle (for the study group). 
10. 
Pregnancy. 
A woman who excluded from the study due to the onset of pregnancy during the clinical trial is 
subject to medical supervision during the entire period of pregnancy, as well as for 6 months 
postpartum period to assess the condition of the woman and the born child (observation is carried 
out if possible and only if her desire and consent to such observation is mandatory). Information 
about the course of pregnancy and its outcome is entered in the primary documentation (with the 
consent of the woman). During the entire period of pregnancy, together with an obstetrician-
gynecologist (with the consent of the pregnant woman and, if possible, contact with a doctor), 
observing a woman, her general condition, data reflecting the nature of the course of pregnancy, 
results of laboratory and instrumental examination methods, including ultrasound, are analyzed. 
Monitoring of the born child is carried out with the consent of the woman together with the 
district pediatrician (if possible, contact with him) until the child is 6 months old to analyze the 
clinical status of the child, data from laboratory and instrumental research methods. 
 
There are no procedures for replacing excluded participants.  
 
Diaries of participants 
 
The diaries of the participants (study groups and control groups) are presented in Appendices 1 
and 2. The diaries include 2 blocks to be filled in by the research participant: 1) initial 
information about the participant: initials, gender, date of birth, presence of smoking experience; 
2) information about compliance with the accepted therapy, about the tolerability of preventive 
therapy, cases of ARVI incidence, severity and duration of symptoms, treatment methods. 
To reduce the risk of violation of the dosage regimen, participant diary in the study group 
provides detailed instructions on the preparation, administration and features of the use of the 
drug under study, as well as the diary will contain a calendar for registering the days of 


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instillations. In addition, when issuing a diary to a participant, it indicates the contact details of 
the doctor for direct communication with the researcher in case of symptoms of acute respiratory 
viral infections during the study period. 
 
Nasopharyngeal smear 
 
Prior to the start of preventive observation, the participant must take a smear from the mucous 
membranes of the upper respiratory tract (nasopharyngeal8). It is allowed to use the results of a 
PCR test before inclusion in the study, but no later than 3 days. If the study is completed with the 
registration of a confirmed case of COVID-19, PCR test is not performed at visit 3, the results of 
the tests performed to confirm the patient's recovery are accepted. 
 
The procedure for working with biological material: 
1. 
The biomaterial is taken on an empty stomach or not earlier than 2 hours after 
eating and drinking; before rinsing, irrigation with medicines.  
2. 
The study is conducted before the start of treatment with antibiotics, antiseptics, 
antifungal and antiviral drugs.  
3. 
Caution should be exercised in the presence of pronounced inflammatory processes 
in the pharynx. In case of severe edema, the material is not taken.  
4. 
The material is taken before carrying out hygienic procedures. 
 
Taking a nasopharyngeal smear for the presence of SARS-CoV-2 RNA is carried out as 
follows:  
1. Scraping of epithelial cells from the oropharynx is carried out with a dry probe, rotational 
movements from the surface of the tonsils, palatine arches and posterior wall of the oropharynx.  
2. Scraping of epithelial cells from the nasopharynx, a smear is taken with a dry sterile probe. 
The probe is inserted with a gentle motion along external wall of the nasal cavity to a depth of 2–
3 cm to the inferior nasal concha. Then the probe is slightly lowered to the bottom, inserted into 
the inferior nasal meatus under the inferior nasal concha and removed along external wall of the 
nasal cavity, producing rotational movements (3–4 cm in children and 5–6 cm in adults).  
3. After taking the material, the tampon should be placed in a sterile disposable tube of the type 
"Eppendorf" with 500 ml of transport medium, mix with a few neat movements, squeeze the 
tampon on the inside "Eppendorf", remove the probe and the working part of the tampon – do 
not leave it in Eppendorf. Next, close the cap of the test tube tightly, sterilize with a disposable 
alcohol wipe, wait for drying and label. 
4. The probe and its working part must be disposed of immediately after inoculation in 
Eppendorf according to the rules for the disposal of potentially infected material (Class B 
waste). 
Scraping from the oropharynx is performed with the maximum possible pressure. At the same 
time, the participant should not experience pain or discomfort, but it is necessary to press cotton 
swab as tightly as possible. 
                                                 
8 It is permissible to accept the results of a nasal or pharyngeal smear, as well as the results of studies performed 
before inclusion in the study for no more than 72 hours. 


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Both smears are placed in the same test tube to create the highest possible concentration of the 
virus (if present). 
 
Labeling and packaging: 
1. A test tube of the type "Eppendorf" should be treated with an alcohol wipe (after taking 
the biomaterial and closing cap Eppendorf, let it dry (2-3 seconds) and stick-on 1st 
barcode; 
2. Eppendorf with the taken material should be placed in a packaging bag with zip lock. It is 
allowed to place material from only one patient in one packaging bag.  
3. Place the sealed bag inside a plastic sterile sputum container (with a red cap). Paste the 
2nd barcode on the sputum container. It is allowed to place material from only one 
patient in one container. 
4. Put the prepared containers in a large zip package (up to 5 containers are included). 
5. To transport the biomaterial, use a separate shipping container. It is necessary to attach 
the "Transfer Acceptance Certificate" (Number of samples. Inscription: to the PCR 
department URGENTLY!). 
      
Transportation: 
1. Transportation of samples is carried out in compliance with the requirements of SP 1.2.036-
95 "Procedure for accounting, storage, transfer and transportation of microorganisms of 
pathogenicity groups I - IV" by employees trained in the practice of safe handling of 
biomaterials, in compliance with precautionary measures and the use of personal protective 
equipment (PPE). 
2. The biomaterial is transported to the laboratory at a temperature of +2 ... +8 °C, and if it is 
impossible to deliver the biomaterial to the laboratory within 48 hours, biomaterial should be 
frozen at -20 °C. 
It is allowed to use eppendorfs only with locking systems. Eppendorfs without locking system 
cannot be used since they can open spontaneously. When taking the biomaterial and closing the 
Eppendorf, precautions must be taken especially carefully to prevent the biomaterial from 
entering the environment, because after placing the probe in the Eppendorf and at the time of its 
closure, a slight shaking of the eppendorf and spilling from the test tube is possible. 
 
The study of the nasopharyngeal smear for the presence of SARS-CoV-2 RNA during screening 
is carried out with the support of DiaLab LLC Plus." 
 
Used process aids and personal protective equipment (PPE): 
1. Urogenital disposable sterile probe type A "Universal" (provided by DiaLab LLC Plus"). 
2. Eppendorf with transport environment (provided by DiaLab LLC Plus"). 
3. Package with zip lock (provided by DiaLab LLC Plus"). 
4. Personal protection kit. 
 
The collection of clinical material is carried out with the mandatory use of personal protective 
equipment.  
 


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Medical waste management: 
1. Medical waste generated when working with biological material belongs to class "B" – 
epidemiologically hazardous waste. 
2. Personal protective equipment is required for medical workers engaged in the collection and 
disposal of Class B medical waste.  
3. Work on the treatment of medical waste of class "B" is organized in accordance with the 
requirements of Sanitary Regulations and Norms - SanPiN 2.1.7.2790-10 "Sanitary and 
epidemiological requirements for the treatment of medical waste" and SanPiN 2.1.3.2630-10 
"Sanitary and epidemiological requirements for organizations engaged in medical activities". 
 
In case of a positive PCR test before the start of the drug, volunteer is not included in the study, 
is isolated and falls under the supervision of a district doctor. In case of a positive PCR test 
during or after the preventive course, volunteer continues to participate in the study, is isolated 
under observation and, if possible, comes to visit 3 after the quarantine is lifted (at least 14 days 
from the date of signing Consent for the treatment of a new coronavirus infection COVID-19 in 
outpatient conditions (at home) and observing the isolation regime or discharge from the hospital 
in case of laboratory confirmation of COVID-19) with the provision of data on their condition to 
the researcher coordinator.  
 
STUDY POPULATION 
 
Adult volunteers who do not have clinical symptoms of ARVI. 
 
Inclusion criteria 
1. Volunteers of both genders over 18 years old. 
2. Obtaining a written form of informed consent. 
3. Ability and consent to participate in this study. 
4. No symptoms of respiratory infection. 
5. A negative result of a PCR study for the presence of SARS-CoV-2 RNA according to the 
biomaterial obtained by nasopharyngeal 9smear. 
Non-inclusion criteria 
1. Any other concomitant diseases or conditions that, in the opinion of the research doctor, 
may distort the results of the study, restrict the rights of the volunteer, or put him at 
greater risk. 
2. Contraindications to the use of the study drug. 
3. Individual intolerance of the ingredients included in the composition of the study drug. 
4. Pregnancy or breast-feeding. 
5. Controversial result of PCR test for the presence of SARS-CoV-2 RNA according to the 
biomaterial obtained by nasopharyngeal smear. 
6. Participation in a clinical trial using the investigated therapy for 30 days prior to 
inclusion in this study.  
7. Disagreement on following reliable contraceptive measures in the framework of the study 
                                                 
9 It is permissible to accept the results of a nasal or pharyngeal smear, as well as the results of studies performed 
before inclusion in the study for no more than 72 hours. 


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(sexual abstinence; or a combination of 2 different methods: for example, barrier and 
spermicides, or barrier and intrauterine device, or barrier and hormonal, etc.) – for 
participants with preserved childbearing potential. 
 
Number of participants 
In this study, the main parameter of effectiveness is the proportion of patients with acute 
respiratory viral infections, including COVID-19, at the end of the period of preventive 
administration of the drug. The study is planned to show that in the study group, the number of 
patients with acute respiratory viral infections, including COVID-19, will be significantly less 
compared to the control group.  
The efficiency parameter was selected based on international recommendations for 
manufacturers of medicines and biological products [28]. 
 
The null hypothesis will be tested by comparing the number of cases in the two groups at the end 
of the period of preventive administration of the drug. It is expected that at least 90% of 
randomized patients will be suitable for inclusion in the population of the primary analysis (PP). 
The statistical purpose of the study is a comparative study of the effectiveness of the preventive 
regimen of the drug. In the main group of study I, study drug Ingaron 100,000 IU, lyophilizate, 
will be used to prepare a solution for intranasal administration, 1 time a day every other day for 
10 days with a repeat of the 10-day course of preventive administration after 7 days of 
interruption.  
To estimate the sample size in this study, an 80% power level was taken (P – probability of not 
missing the present effect is 0.8) and a one-sided level of statistical significance of 5% (α – the 
probability of making an erroneous decision about the presence of an effect is less than 0.05). 
The statistical criteria used are one-sided due to the availability of information about the 
superiority of the effect of the study drug over the lack of preventive measures against the 
nosology being studied [28]. 
Thus, the sample size was calculated based on the following parameters: 
● at the required significance level α= 0.05, the value of Z = 1.96; 
● level of statistical power is assumed to be 80%, the value of Z = 0.84; 
● method of sample formation – randomization using random elements. 
The primary criterion of effectiveness is the proportion of patients with acute respiratory viral 
infections, including COVID-19, at the end of the period of preventive administration of the drug 
(measurement time: 28 days). Secondary efficacy criteria: proportion of patients with confirmed 
COVID-19 at the end of the period of preventive administration of the drug (measurement 
period: 28 days); proportion of patients with acute respiratory viral infections, including COVID-
19, at the end of the follow-up period (change period: 2 months); proportion of patients with 
confirmed COVID-19 at the end of the follow-up period (period of change: 2 months); and the 
frequency of development of complicated course of ARVI.  
The literature analysis conducted on similar studies of the effectiveness and safety of the use of 
interferon-gamma shows that the incidence of ARVI can be observed in 2% of cases in the main 
group of patients taking interferon gamma, as well as in 14% of the control group taking 
alternative methods of protection and representing medical workers working in the "red zone" 
and those at high risk through frequent and prolonged contact with infected patients (p<0.05). 


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Provided incidence in the control group is from 1 to 5% (taking into account the assumption that 
the incidence in the control group will be approximately equal to the average incidence of the 
general population) [29], and incidence in the study group will be at least 3% lower (which can 
already be considered a minimally clinically significant decrease in incidence in the absence of 
preventive measures with proven effectiveness, which could be taken as a standard), minimum 
sample size should be 630 patients (taking into account 10% of early retirement). Such a sample 
size will also make it possible to establish a decrease in incidence by 4% or more when incidence 
is set at up to 8% in the control group and a decrease in incidence by 6% or more when the 
incidence is set at up to 18% in the control group (Table 1 – Dependence of the sample size on 
various parameters). 
The calculation of the required sample size was performed using a formula for calculating the 
sample size for a qualitative sign [30]: 
 
n 
= 
P1 * Q1 * t2 + P2 * 
Q2 * t2 
(P1− P2)2 
 
Note to the formula:  
P – proportion of cases in which the study sign occurs, 
Q – proportion of cases in which the study sign does not occur, 
t – critical value of the Student's t-test at the appropriate level of significance.  
 
Considering the ratio of the distribution of patients into groups 1:1 with the above parameters, 
the study should complete at least 572 patients: 286 in each group. Considering the possible 10% 
premature exclusion and withdrawal of informed consent, it is necessary to randomize 630 
patients (315 in each group).  
Below is the dependence of the sample size on the parameters of the magnitude of the expected 
effect and the minimum difference that needs to be detected (Table 1 – Dependence of the 
sample size on various parameters).  
Thus, the sample size in each group with a random distribution method will be10: 
 
Table 1 – Dependence of the sample size on various parameters 
The proportion of sick 
patients in the control 
group, % 
Decreased proportion of cases compared to the control group, % 
2 
3 
4 
6 
8 
10 
12 
14 
2 
207 
- 
- 
- 
- 
- 
- 
- 
3 
411 
136 
- 
- 
- 
- 
- 
- 
4 
613 
227 
101 
- 
- 
- 
- 
- 
5 
809 
315 
151 
- 
- 
- 
- 
- 
6 
1001 
400 
200 
66 
- 
- 
- 
- 
8 
1373 
526 
295 
109 
48 
- 
- 
- 
10 
1728 
686 
386 
151 
72 
37 
- 
- 
12 
2066 
840 
473 
189 
95 
53 
31 
- 
14 
2387 
988 
556 
228 
117 
67 
41 
25 
                                                 
10 The calculation is given for a power of 80%, a one-sided significance level of 0.05 and taking into account 10% of the early exclusion of 
patients from the study 


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16 
2692 
1126 
634 
263 
136 
80 
51 
33 
18 
2979 
1257 
707 
297 
156 
92 
59 
40 
20 
3249 
1382 
777 
329 
175 
106 
68 
46 
22 
3502 
1498 
843 
359 
193 
117 
76 
53 
24 
3739 
1607 
904 
387 
209 
128 
84 
58 
 
Thus, in the present study, taking into account the possible 2% exclusion of patients at the 
screening stage due to non-compliance with the inclusion/non-inclusion criteria, it is planned to 
include up to 642 volunteers with a 1:1 distribution in each of the 2 parallel groups (study and 
control), of which up to 321 people will use study drug Ingaron with preventive objective, up to 
321 people, will not use the study drug and will form a control comparison group. 
 
The screening number of the participant is assigned in the order of inclusion of participants in 
the study and consists of numerical character corresponding to the number of the research center 
and three numerical characters of the serial number of the participant in this center. That is, the 
screening number of the first participant in the first center should look like this: 1-001, 
following: 1-002, etc. The screening number of the three hundred and twenty-fourth participant 
of the third center will look like this: 3-324. It is prohibited to re-assign a screening number to a 
participant. The number is unique. 
 
Research hypothesis  
Preventive administration of Ingaron will not lead to a decrease in the incidence of acute 
respiratory viral infections, including COVID-19, among adult volunteers.  
 
STUDY THERAPY 
 
Trade Name: INGARON® 
 
International nonproprietary or generic name: Interferon gamma human recombinant 
 
Registration number: LS – 001330 
 
Dosage form: Lyophilizate for the preparation of solution for intranasal administration. 
 
Drug form: Lyophilizate for the preparation of solution for intranasal administration in vials of 
100,000 IU per 1 vial. 1 vial of drug, 1 vial of water for injection (5 ml) and 1 cap-dropper made 
of polyethylene in packaging of polyethylene or medical dropper in contour cellular package or 
in cassette contour package. 
 
Shelf life: 2 years. After the preparation of the solution for 10 days. 
 
Method of administration and dosage: 
Intranasally. 2–3 drops in each nasal passage every other day 30 minutes before breakfast for 10 
days. After instillation, it is recommended to massage the wings of the nose with your fingers for 


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several minutes to evenly distribute the drug in the nasal cavity. Preparation: The contents of the 
vial are dissolved in 5 ml of water for injection. 
 
Overdose: Overdose cases are not known. 
 
Effects on ability to drive and use machines: Not studied. 
 
Storage conditions: The drug should be stored in a dry place, protected from light, at 
temperature not higher than + 25 ° C. The solution of the drug should be stored for no more than 
10 days in the refrigerator (do not freeze). Keep out of reach of children.  
 
Manufacturing enterprise/organization accepting consumer claims: 
LLC "NPP "Pharmaclon", Russia.  
Legal address: 142279, Moscow region, Serpukhovskii district, Obolensk workers settlement, 
Obolenskoe 
highway 
industrial 
zone, 
building 
5A, 
office 
312. 
Address of the place of manufacture: 143422, Moscow region, Krasnogorskii district, Petrovo-
Dalnee village, J.S.C. “Biomed”-Mechnikov Tel/fax (4967) - 36-07-71, (495) – 120-12-47  
E-mail: info@pharmaclon.ru Internet: www.pharmaclon.ru 
 
Labelling: The inscription "For post-marketing research RAIN-2020" is applied to the primary 
packaging and secondary (consumer) packaging of the study drug product, the inscription "Not 
for sale" is additionally applied to the secondary (consumer) packaging in accordance with the 
requirements of the Federal Law "On Circulation of Medicines" dated 12.04.2010 N 61-FZ as 
amended Federal Law No. 429-FZ from 22.12.2014.      
      
Compliance assessment 
Assessment of compliance with study preventive therapy is evaluated on the basis of data 
recorded in the participant's diary, on visit 3, as well as in advance as part of an oral survey of 
the participant on a phone call visit after the end of preventive use of the drug. Compliance is 
assessed on a 100% scale, where: 
100% – participant completed 2 cycles of 10-day courses without violating the dosage regimen 
and the frequency of admission 
90% – participant completed 2 cycles of 10-day courses with a single violation of dosage 
regimen or dosage frequency 
80% – participant completed 1 cycle of the 10-day course without violating dosage regimen or 
dosage frequency  
70% – participant completed 2 cycles of 10-day courses with a double violation of dosage 
regimen or dosage frequency (single violation of each course) 
60% – participant completed 1 cycle of 10-day course with a single violation of dosage regimen 
or dosage frequency 
50% or less – participant completed 1 or 2 cycles of 10-day courses with a systematic (twofold 
or more) violation of the dosage regimen or dosage frequency in each of the courses (non-
compliance with a single dose, frequency of use and/or its duration). 
Compliance of 50% or less is the criterion for excluding a participant from the study. 


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STUDY PARAMETERS OF EFFICIENCY AND SAFETY 
 
Effectiveness criteria 
Effectiveness criteria will be evaluated according to the data recorded in the participants' diaries, 
in primary medical documentation.  
 
Primary effectiveness criterion: 
The proportion of patients with acute respiratory viral infections, including COVID-19, at the 
end of the period of preventive administration of the drug (measurement time: 28 days). 
 
Secondary effectiveness criterion: 
1. 
The proportion of patients with confirmed COVID-19 at the end of the period of 
preventive treatment of the drug (measurement period: 28 days). 
2. 
The proportion of patients with acute respiratory viral infections, including COVID-19, at 
the end of the follow-up period (change period: 2 months). 
3. 
The proportion of patients with confirmed COVID-19 at the end of the follow-up period 
(change period: 2 months). 
4. 
Frequency of development of complicated course of ARVI. 
5. 
The proportion of participants with each of the scores (0-8) according to the WHO 
Clinical Improvement Scale (change period: 28 days). 
6. 
The proportion of participants with each of the scores (0-8) according to the WHO 
Clinical Improvement Scale (change period: 2 months). 
7. 
Duration of symptoms of the disease of study participants who had acute respiratory viral 
infections, including COVID-19 (change period: 2 months). 
8. 
The duration of the symptoms of the disease of the study participants who were infected 
with ARVI, including COVID-19 (measurement period: 28 days). 
Confirmation of clinical cases of ARVI, including COVID-19: 
In the following cases: 
1) a positive result of PCR on SARS-CoV-2 RNA, regardless of the presence of clinical 
symptoms;  
2) appearance of clinical symptoms of ARVI in the absence of a PCR result on SARS-CoV-
2 RNA or in the case of a negative result on SARS-CoV-2 RNA, - 
at any stage during participation in the study, a completion visit (Visit 3) is conducted at the end 
of the quarantine period (at least 14 days from the date of signing Consent for the treatment of a 
new COVID-19 coronavirus infection in outpatient settings (at home) and compliance with the 
isolation regime or discharge from the hospital in case of laboratory confirmation of COVID-
19), at which the patient returns the participant's diary and reports his condition to the doctor-
researcher, transmits information about hospitalization, duration of symptoms, results of tests 
and performed studies.  


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Definition of the COVID-19 case: 
Suspicious case of COVID-19 
Body temperature above 37.5° in addition to one or more of the following signs (in the absence 
of other known causes that explain the clinical picture, regardless of the epidemiological 
history): 
● Cough (dry or with scant sputum) 
● Shortness of breath 
● Feeling of congestion in the chest 
● SpO 2 no more than 95% 
● Sore throat 
● Nasal stuffiness or moderate rhinorrhea 
● Smell disorders or anosmia 
● Ageusia 
● Conjunctivitis 
● Fatigue 
● Myalgia 
● Headache 
● Vomiting 
● Diarrhea 
● Skin rash 
Probable case of COVID-19 
Body temperature above 37.5° in addition to one or more of the following signs: 
● Cough (dry or with scant sputum) 
● Shortness of breath 
● Feeling of congestion in the chest 
● SpO 2 no more than 95% 
● Sore throat 
● Nasal stuffiness or moderate rhinorrhea 
● Smell disorders or anosmia 
● Ageusia 
● Conjunctivitis 
● Fatigue 
● Myalgia 
● Headache 
● Vomiting 
● Diarrhea 
● Skin rash 
In the presence of at least one of the epidemiological signs: 
● Return from cross-border travel 14 days before the onset of symptoms 
● The presence of close contacts over the past 14 days with a person under surveillance for 
COVID-19, who subsequently became ill 
● The presence of close contacts over the past 14 days with a person who has laboratory 
confirmed diagnosis of COVID-19 


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● The presence of professional contacts with persons who have a suspected or confirmed 
case of COVID-19 
Or in combination with characteristic changes in the lungs according to computed tomography 
(CT), regardless of the results of a single laboratory test for the presence of SARS-CoV-2 RNA 
and an epidemiological history. 
Also, a possible case of COVID-19 should include a clinical case in the presence of the clinical 
manifestations described above (fever in combination with one or more signs) with characteristic 
changes in the lungs according to imaging studies if it is impossible to conduct a laboratory 
study for the presence of SARS-CoV-2 RNA. 
 
Confirmed case of COVID-19  
A positive result of laboratory test for the presence of SARS-CoV-2 RNA using nucleic acid 
amplification methods or SARS-CoV-2 antigen using immunochromatographic assay regardless 
of clinical manifestations, or a positive result for IgA, IgM and/or IgG antibodies in patients with 
clinically confirmed COVID-19 infection. 
 
In the case of ARVI symptoms characteristic of a suspicious case of COVID-19, accompanied 
by a negative result of PCR test, registered during or after a preventive course (during the period 
of participation in the study after randomization until the end of the observation period), the 
patient may additionally undergo a quantitative test for the presence of IgM and IgG antibodies 
to SARS-CoV-2 by the ELISA method for the purpose of additional verification and detection of 
COVID-19 cases. An additional quantitative test for antibodies to SARS-CoV-2 can be 
performed from the 10th to the 21st day after the appearance of the first symptom of ARVI to 
register the immune response of the acute phase of infection at the beginning of its development 
(increased IgM levels) or during high-grade response (increased IgM and IgG), considering the 
seronegative the period of the disease (5-7 days). The analysis is taken only in the absence of 
fever and a satisfactory general condition of the patient, accompanied by a favorable recovery 
dynamics. When interpreting the results, it is necessary to consider the probability of obtaining 
false positive results (for example, the presence of "cross-reacting" antibodies). If the 
interpretation of the results is difficult, it is allowed to conduct a repeated ELISA study using the 
same test systems after 5-7 days to assess the dynamics of indicators. Quantitative determination 
of IgM and IgG antibodies in the blood by the ELISA method will be carried out with the 
support of DiaLab LLC Plus." 
 
The condition of the study participant is assessed according to the WHO standard scale of 
clinical improvement from 0 to 8 points at each visit, including a phone call visit. In case of 
registration of ARVI at the final visit 3, in parallel with the current assessment of the 
participant's condition, an additional assessment of the case is carried out according to the WHO 
scale, reflecting the maximum clinical manifestation of the disease. 
 
 
 
 


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WHO Clinical Improvement Scale 
Assessme
nt on the 
WHO 
scale 
0 
1 
2 
3 
4 
5 
6 
7 
8 
Select the 
appropriat
e 
score 
from 0 to 
8 
Not 
infected 
Outpatient 
Hospitalized with mild 
form 
Hospitalized with severe form 
D
ie
d 
 
there 
are 
no clinical 
or 
virological 
signs 
of 
infection 
no 
activity 
restricti
ons 
activity 
restricti
ons 
hospitalize
d, 
no 
oxygen 
therapy 
hospitalize
d, oxygen 
therapy 
through 
a 
mask 
or 
nasal 
cannula 
non-
invasive 
lung 
ventilati
on or 
high-
flow 
oxygen 
therapy  
endotrach
eal 
intubation 
and 
mechanic
al 
ventilatio
n 
ventilatio
n 
+ 
additional 
organ 
support – 
pressor 
drugs, 
renal 
replacem
ent 
therapy, 
extracorp
oreal 
membran
e 
oxygenati
on 
(ECMO) 
deat
h 
 
Safety criteria 
 
The assessment of the safety of treatment will be carried out based on registration of adverse 
events by analyzing complaints and subjective symptoms, comparative analysis of clinically 
significant changes in laboratory parameters, as well as the severity of these changes, using the 
CTCAE scale version 4.03 from 2010. 
 
Each participant should be monitored by a researcher for the occurrence of adverse events, which 
should be classified according to the severity and connection with the drug under study during 
the entire period of participation in the study. 
 
Adverse events: 
 
Adverse reaction (AR) – an unintentional adverse reaction of the body associated with the use 
of a drug and suggesting the presence, at least, of a possible relationship with the use of a 
suspected medicinal product. 
 
Adverse event (AE) – any adverse change in the state of health of the patient or the subject of a 
clinical trial to whom the drug (study) product was prescribed, regardless of the causal 
relationship with its use. AE may represent any adverse and unintended change (including 
deviation of the laboratory indicator from the norm), symptom or disease, the time of occurrence 


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of which does not exclude a causal relationship with the use of drug product, regardless of the 
presence or absence of a relationship with the use of drug product11. 
Symptoms of acute respiratory infection: fever, manifestations of general infectious intoxication, 
signs of respiratory damage are not considered as adverse event, however, they are recorded 
during the study and analyzed as data for evaluating effectiveness. 
 
Assessment of the causal relationship: 
Methods for assessing the degree of causal relationship are based on the following criteria: 
● the presence of a reliable temporary association of the AE with the use of the study drug 
(AE are registered after the start of the use of the study drug before the completion of 
participation in the study); 
● presence of a direct temporary connection of AE with specific administration of the drug 
(for example, development of AE during instillation); 
● possibility of explaining the development of AE by the pharmacological effect of the 
drug; 
● availability of information about such AE as a possible side effect in Clinical 
Investigation Brochure/guidelines for medical use; 
● description of similar cases in the literature; 
● presence of additional specific data indicating the association of AE with the drug (for 
example, the presence of specific antibodies, positive result of allergological tests); 
● positive test with the withdrawal of the study drug (AE was resolved or its severity 
decreased after the drug was discontinued); 
● positive test with repeated administration of the drug under study (AE reappeared or its 
severity worsened with repeated administration of the drug after withdrawal); 
● presence of other reasons for the development of this AE (manifestations of the 
underlying disease, concomitant diseases and conditions, concomitant therapy, food, 
lifestyle, etc.). 
The association of adverse events with the study drug will be evaluated based on the following 
principles in accordance with the WHO classification: 
● reliable – clinical manifestations, including violations of laboratory parameters 
that occur during the period of taking drug s and which cannot be explained by the 
presence of existing diseases and the influence of other factors and chemical compounds. 
Manifestations of an adverse reaction regress after the drug is discontinued and occur 
when it is re-prescribed; 
● probable – clinical manifestations, including changes in laboratory parameters 
associated with the instillation of the drug, which are unlikely to be related to 
concomitant diseases or other factors and which regress with the withdrawal of the drug. 
The response to the rechallenge is unknown; 
● possible – clinical manifestations, including changes in laboratory parameters 
associated with the use of the drug, but which can be explained by the presence of 
                                                 
11 Due to statistical necessity, adverse events are recorded both in the study group and in the control group. 
Evaluation and registration of adverse events begins from the moment of signing the informed consent form. 


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concomitant diseases or taking other drugs and chemical compounds. Information about 
the reaction to drug withdrawal is unclear; 
● questionable – clinical manifestations, including changes in laboratory 
parameters, which occur in the absence of a clear temporal connection with taking 
medication; there are other factors (drugs, diseases, chemicals) that may be the cause of 
their occurrence; 
● conditional – clinical manifestations, including violations of laboratory 
parameters attributed to "adverse reactions" that need additional data (for an accurate 
assessment) or these obtained data are currently being analyzed; 
● unclassifiable – reports of a suspected adverse reaction cannot be evaluated 
because there is not enough information or it is contradictory. 
● unrelated – clinical manifestations are not associated with the use of the drug. 
 
Serious adverse reaction (SAE) – AE, which leads to death12, poses life threatening13, requires 
hospitalization of the patient or its extension14, leads to persistent or severe disability, to 
congenital anomalies or malformations15, requires medical intervention to prevent the 
development of these conditions. 
 
Unlabeled adverse reaction (unlabeled AE) – an undesirable reaction, nature, severity or 
outcome of which does not correspond to the information in the current instructions for the 
medical use of the drug or in investigator's brochure for unapproved drug. 
All unexpected serious adverse events (unexpected SAE) those recognized by the researcher 
as related to the drug are classified as unexpected serious adverse drug reactions (unexpected 
SAE). Serious adverse drug reaction report form is presented in Appendix 3. 
 
Persistent AE – AE, lasting for a long time, including between cycles of therapy. Persistent AE 
is registered once. If there were no AE symptoms at the visit before the first use of the study 
drug, time of AE completion is the moment when AE is completely stopped. If AE symptoms 
were registered at the visit before the first use of the study drug, time of AE completion is the 
moment when the values of the deviated indicators/severity of AE symptoms (degree according 
to CTCAE) return to the basic (initial) values, i.e., before the use of the product under study. If 
AE symptoms continue at the time of completion of the study, AE registration form is marked 
"ongoing". If AE changes the degree to a higher one (for example, from 1 to 3 degrees), a note 
about the change in AE degree with the date is made in the same AE registration form. At the 
                                                 
12 Death is an outcome, not the SAE itself, so such a name should not appear as a name. If a case of death for an 
unknown reason is identified, researcher should make every effort to identify its suspected causes. SAE in such 
cases can be referred to as "Death by unexplained cause" only in cases where the causes of death are not known and 
cannot be clarified. In case of a fatal outcome due to COVID-19, the information is recorded in the primary medical 
documentation of the study participant without registration of the SAE.  
13 The term "Life threatening" in this context means that the volunteer participating in the study was at immediate 
risk of death during the occurrence of adverse event. This term does not apply to cases where adverse event could 
hypothetically cause the death of a participant if it were more intense in severity or longer in duration. 
14 Hospitalization for optional or pre-planned treatment of concomitant diseases that the participant had prior to 
inclusion in the study, the course of which did not worsen during participation in the study, is not considered to 
SAE, as well as being in a hospital for less than 24 hours or hospitalization for social reasons. 
15 Pregnancy cases in the participants of the clinical study are not subject to registration as AE, except in cases when 
the child has congenital anomaly or malformation (case is registered as AE). 


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same time, when closing AE registration form, maximum severity of AE is indicated, which was 
observed for the entire period of AE persistence as part of the subject's participation in the study. 
 
Recurrent AE – AE, which was completely resolved, for example, during one cycle of therapy, 
and then reappeared, for example, on the next cycle of therapy, while the participant is in the 
study. Each recurrent AE is registered separately. 
 
All AE are registered in the primary medical documentation of the participant based on physical 
examination, survey, and diary records. The following information must be recorded in the 
primary medical documentation (outpatient card) for each AE: 
- 
severity (mild, moderate, severe); 
- 
nature of adverse event; 
- 
relationship with study drug; 
- 
duration (date of occurrence and end date), preferably with an indication of the time interval 
(hours) from the moment of administration of the study drug; 
- 
whether adverse event is serious. 
The severity is assessed using the CTCAE scale version 4.03 from 2010. The CCAE scale 
contains a list of the most frequent AE recorded in clinical study, in tabular format, indicating 
criteria of various degrees of severity (from 1 to 5, where 5 is death as a result of AE). For AE 
that are not in the tabulated list, the severity is determined in accordance with the textual 
description of the degrees of severity. 
The terms "serious" and "severe" are not synonymous. The term "severe" is often used to 
describe the intensity (severity) of a particular event (for example, anemia of severe, moderate or 
mild severity); however, the event itself may be clinically insignificant (for example, severe 
headache). 
The concept of "severe" is not equivalent to the concept of "serious". The criteria of the latter are 
the outcome of the event or the measures, which are usually associated with the elimination of 
life threatening or severe disorders of vital activity. The criterion of seriousness, and not the 
severity of adverse event, should be guided when determining the need for expedited safety 
report of LLC "NPP "Pharmaclon" and authorized agencies. 
The AE notification form is presented in Appendix 4. 
 
Urgent event: 
Urgent events include all serious adverse events. 
All SAE detected during the period from the moment of signing the informed consent, even 
before the application of the first dose of the product under study until the end of the study, are 
subject to registration. The researcher has the right to provide reports on the development of a 
disease that has developed at any time after the established mandatory observation period, but it 
is necessary to provide an appropriate justification for the presence of a causal relationship. 
In the event of a serious adverse event, researcher is obliged to: 
● 
provide (if necessary) the study participant with appropriate qualified medical care, 
including laboratory tests and/or instrumental examinations; 


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● 
within 24 hours from the moment when the researcher became aware of the occurrence of 
adverse event, send the data to LLC NPP Pharmaclon (contact information: tel.: 8 800 777 
86 04; e-mail: adversereaction@drugsafety.ru ); 
● 
provide a detailed written report as soon as possible; 
● 
continue monitoring the participant until the full resolution of the SAE. 
Any additional information and supporting documentation (blinded copies of the results of 
laboratory tests, procedures, pathologist's report or postmortem epicrisis in case of death, etc.) 
will be provided by the Researcher in additional written messages of LLC NPP Pharmaclon. In 
case of death of a participant, the Researcher is obliged to provide any additional information at 
the request of LLC NPP Pharmaclon. 
The initial report (completed form of notification of AR) and subsequent detailed and additional 
reports should identify the subjects of the study by the unique numbers assigned to them, not by 
the names of the subjects or their addresses and other personal data.  
In connection with the occurrence of serious adverse events, the researcher is obliged to notify 
the ethics committee. The Ethics Committee may, if necessary, discontinue or cancel the study. 
The minimum information that should be included in the initial notification of the occurrence of 
an urgently reported event should contain the identification data of the participant under which he 
passes in the study, identification data of the person reporting the occurrence of this phenomenon 
(full name of the chief researcher or authorized employee), characteristics of the event that 
occurred and its causal relationship with the use of the investigated drug. 
Except those cases when the urgently reported event was sufficiently documented in the initial 
message about its occurrence, the researcher must provide all additional information available to 
him in subsequent messages about the urgently reported event using the same form, the same 
ways of its transmission and the time frame as established for the initial message about the 
urgently reported event. These procedures should continue until AE has been fully documented 
and reported.  
After sending by e-mail the completed SAE notification, researcher must place the originals of 
the initial and subsequent messages about urgently reported events in investigator file. 
Events deemed NOT to require urgent notification include: 
● hospitalization for optional or pre-planned treatment of concomitant diseases that the 
participant had prior to inclusion in the study, the course of which did not worsen during 
participation in the study; 
● hospitalization, death, or life threatening due to the development of complications of 
ARVI (COVID-19) – however, this information is necessarily recorded and analyzed to 
assess effectiveness.      
      
Features of AE registration in some cases: 
      
Lack of preventive effect 
Absence of preventive effect of therapy should not be registered as AE. 
 
Pregnancy 


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All cases of pregnancy that developed in the participants of the clinical trial against the 
background of the study therapy during the period of participation in the study are subject to 
mandatory registration in the Pregnancy Registration Form and are not accompanied by the 
registration of AE/SAE. The signed and dated pregnancy form is sent to LLC "NPP 
"Pharmaclon" by e-mail: medical@pharmaclon.ru , - within 5 working days from the date of 
notification of the research doctor. 
 
AE in the period before taking study drug 
In the presence of deviations of laboratory, physiological and/or instrumental indicators at the 
screening or randomization visit before the first use of the drug, in the future, the following are 
subject to registration as AE: 
● all deviations accompanied by an increase in severity according to the version used; 
● deviations that are not associated with a change in severity, but have, from the 
researcher's point of view, clinical significance. 
If the participant had deviations of laboratory, physiological and/or instrumental indicators at the 
visit before the first use of the study drug, after which the indicators during the study normalized 
or the severity of the deviation changed for the better, and then changed again for the worse, but 
the values of the indicators remained within the same severity according to If the patient was on 
a visit before the first use of the study drug, the phenomenon should not be registered as AE, 
except in cases where it is clinically significant from the point of view of the research physician. 
 
Registration of a disease/syndrome characterized by several symptoms 
In case of registration of a disease accompanied by various symptoms, registration of individual 
symptoms as AE is not required, however, it is recommended to list all the symptoms of the 
disease in the note to the description of the AE. 
 
For more detailed information on the procedures for registration and evaluation of adverse events 
under this Protocol, see the Guide on Adverse Events Version 2 of 17/02/2021. 
 
QUALITY CONTROL 
 
Direct access to primary data/documentation 
The researcher/research center is obliged to provide direct access to primary 
data/documentation for examination by the Ethics Council under the Ministry of Health of the 
Russian Federation, an Independent Ethics Committee, as well as inspections by authorized 
bodies. Ethics Council/The Independent Ethics Committee, the authorized bodies, and the 
sponsor of this study, to the extent permitted by law, will have direct access to the original 
medical records of the participant to verify the procedures and/or research data, without 
violating the confidentiality of the participant's data. By signing the Information Sheet with 
the informed consent form, the Participant gives permission for such access. 
 
Inspection 
National regulatory authorities may conduct inspections during and after the study.  
 


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Accounting of drugs 
The researcher or other responsible persons will keep records of the study drug. 
The researcher is responsible for the fact that the study drugs: 
− stored in proper conditions in a lockable and safe place; 
− scheduled, and the registration of drugs is documented with the indication of the number of 
the participant to whom the drug was issued. 
The control of the study drugs should be documented throughout the study. 
 
Storage of drugs 
The Ingaron® preparation should be stored in a dry place protected from light, at temperature no 
higher than +25 ° C. Ingaron® solution should be stored for no more than 10 days in the 
refrigerator (do not freeze). 
All participants will be instructed by the researcher about the required storage conditions when 
receiving study drug at visit 1. 
 
RESEARCH DOCUMENTATION 
 
Storage of documentation 
The researcher undertakes to keep all documentation on the study, including the original medical 
documentation of the participants (outpatient records, diaries) for 15 years after the completion of 
the study. This documentation regarding the ongoing research should be available for audits and 
inspections by regulatory authorities. 
 
STATISTICAL METHODS 
 
Populations for analysis 
During the statistical analysis, the following populations of participants will be studied: 
❖ All participants included in the study (FAS, Full Analysis Set). This population will be 
used to describe basic characteristics, including demographic and anthropometric 
indicators, data on concomitant diseases, and will also be used as the main population to 
assess performance parameters. In this case, the participant's group will be determined by 
the "intention to treat" (ITT Analysis). 
❖ Auxiliary analysis of effectiveness parameters is planned for all subjects who completed 
the study without significant deviations from the study protocol (PP, Per Protocol).  
 
Methods of descriptive statistics 
For numerical indicators, such as demographic and anthropometric data (body weight, age, 
height, BMI), as well as numerical performance parameters will be calculated: 
• 
Number of missing values (N); 
• 
Minimum value (Min); 
• 
Maximum value (Max); 
• 
Arithmetic Mean (M); 
• 
Standard Deviation (SD); 
• 
95 % confidence interval (CI) for the mean; 


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• 
Median (Me). 
For qualitative variables (frequency of AE/SAE development, for example), absolute number in 
the n/N format will be given, as well as the percentage (%). 
 
Analysis of basic characteristics 
The distribution of subjects, demographic and baseline characteristics will be presented using 
descriptive statistics methods for all subjects included in the study (FAS-population). An 
intergroup comparison of the basic quantitative characteristics will be carried out using the t-test 
(or the Mann-Whitney test), depending on the type of data distribution. For categorical data, the 
2-criterion or Fisher's exact test will be applied if the expected frequency in any of the cells is 
less than 5.  
Standard methods available in the XLSTAT 2020.3 program will be used for data analysis. 
When analyzing numerical data, preliminary testing of variables for the normality of the 
distribution will be carried out using Shapiro-Wilk's test, as well as a test for asymmetry and 
kurtosis with an indication of the p value when testing the null hypothesis of the normal 
distribution of the variable. In the case of a normal distribution, an intra-group comparison of 
parameter changes is carried out using a paired t-test. For a comparative evaluation, the χ2-
criterion or the exact Fisher test will be used if the expected frequency in any of the cells is less 
than 5. 
 
Significance level 
A significance level of 0.05 will be used in all tests. Correction for the multiplicity of 
comparison is not introduced. 
 
Handling missing data and significance level 
There are no plans to use data reconstruction methods in this study. The probability of a type I 
error (two-way significance level) will be set at 5% for all comparisons. Correction for the 
multiplicity of comparison is not carried out. 
 
Research Report 
The report will be prepared based on the results obtained at the research center. 
The submitted report should have the character of a full-fledged reasoned scientific research with 
a clear description of the amount of work carried out, research methods, principles of the 
detectable preventive effect of the study drug. 
The final report should reflect the number of participants, their characteristics, method, dose and 
duration of use of the study drugs, tolerability and preventive effect when using them. 
The report should reflect the condition of the participants before the appointment of the study 
drug and the dynamics of their condition under the influence of preventive administration, 
occurrence of adverse events, etc. 
Conclusions should be clear and specific, followed by reasonable practical recommendations 
reflecting the expediency of the use of the study drug. 
The report must be approved by the sponsor of the study and certified with the seal of the 
organization. 
 


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FINANCING AND INSURANCE 
 
Financing 
Financial support for this non-interventional post-marketing study will be provided at the 
expense of the manufacturing company in accordance with contracts with research centers.  
 
Insurance 
Additional payments and insurance of participants are not provided. 
 
REFERENCES TO LITERATURE 
 
[1] 
B. Rockx et al., “Comparative pathogenesis of COVID-19, MERS, and SARS in a 
nonhuman primate model,” Science, vol. 368, no. 6494, pp. 1012–1015, May 2020, doi: 
10.1126/science.abb7314. 
[2] 
H. Shi et al., “Radiological findings from 81 patients with COVID-19 pneumonia in 
Wuhan, China: a descriptive study,” Lancet Infect. Dis., vol. 20, no. 4, pp. 425–434, Apr. 
2020, doi: 10.1016/S1473-3099(20)30086-4. 
[3] 
L. B. Ware and M. A. Matthay, “The acute respiratory distress syndrome,” New England 
Journal of Medicine, vol. 342, no. 18. N Engl J Med, pp. 1334–1349, May 04, 2000, doi: 
10.1056/NEJM200005043421806. 
[4] 
Z. Xu et al., “Pathological findings of COVID-19 associated with acute respiratory 
distress syndrome,” Lancet Respir. Med., vol. 8, no. 4, pp. 420–422, Apr. 2020, doi: 
10.1016/S2213-2600(20)30076-X. 
[5] 
S. Tian, W. Hu, L. Niu, H. Liu, H. Xu, and S. Y. Xiao, “Pulmonary Pathology of Early-
Phase 2019 Novel Coronavirus (COVID-19) Pneumonia in Two Patients With Lung 
Cancer,” J. Thorac. Oncol., vol. 15, no. 5, pp. 700–704, May 2020, doi: 
10.1016/j.jtho.2020.02.010. 
[6] 
L. Bao et al., “Reinfection could not occur in SARS-CoV-2 infected rhesus macaques,” 
bioRxiv, p. 2020.03.13.990226, Mar. 2020, doi: 10.1101/2020.03.13.990226. 
[7] 
V. J. Munster et al., “Respiratory disease and virus shedding in rhesus macaques 
inoculated with SARS-CoV-2,” bioRxiv, p. 2020.03.21.001628, Mar. 2020, doi: 
10.1101/2020.03.21.001628. 
[8] 
“New coronavirus infection (COVID-19): etiology, epidemiology, clinic, diagnosis, 
treatment and prevention. Guidance manual.” 
[9] 
A. E. Gorbalenya et al., “Severe acute respiratory syndrome-related coronavirus: The 
species and its viruses – a statement of the Coronavirus Study Group,” bioRxiv, 2020. 
[10] A. Kimball et al., “Asymptomatic and presymptomatic SARS-COV-2 infections in 
residents of a long-term care skilled nursing facility - King County, Washington, March 
2020,” Morbidity and Mortality Weekly Report, vol. 69, no. 13. Department of Health and 
Human Services, pp. 377–381, Apr. 03, 2020, doi: 10.15585/MMWR.MM6913E1. 
[11] R. Wölfel et al., “Virological assessment of hospitalized patients with COVID-2019,” 
Nature, vol. 581, no. 7809, pp. 465–469, May 2020, doi: 10.1038/s41586-020-2196-x. 
[12] L. Zou et al., “SARS-CoV-2 viral load in upper respiratory specimens of infected 
patients,” New England Journal of Medicine, vol. 382, no. 12. Massachussetts Medical 


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Society, pp. 1177–1179, Mar. 19, 2020, doi: 10.1056/NEJMc2001737. 
[13] J. S. M. Peiris et al., “Clinical progression and viral load in a community outbreak of 
coronavirus-associated SARS pneumonia: A prospective study,” Lancet, vol. 361, no. 
9371, pp. 1767–1772, May 2003, doi: 10.1016/S0140-6736(03)13412-5. 
[14] F. Xiao, M. Tang, X. Zheng, Y. Liu, X. Li, and H. Shan, “BRIEF COMMUNICATIONS 
Evidence for Gastrointestinal Infection of SARS-CoV-2,” Gastroenterology, vol. 158, pp. 
1831-1833.e3, 2020, doi: 10.1053/j.gastro.2020.02.055. 
[15] S. V. Smetanina V V Nikiforov, L V Kolobukhina,New coronavirus infection (COVID-
19): etiology, epidemiology, clinic, diagnosis, treatment and prevention. Moscow: 
Moscow Government Department of Health of the City of Moscow, 2020. 
[16] N. Chen et al., “Epidemiological and clinical characteristics of 99 cases of 2019 novel 
coronavirus pneumonia in Wuhan, China: a descriptive study,” Lancet, vol. 395, no. 
10223, pp. 507–513, Feb. 2020, doi: 10.1016/S0140-6736(20)30211-7. 
[17] H. Lu, “Drug treatment options for the 2019-new coronavirus (2019-nCoV),” Biosci. 
Trends, vol. 14, no. 1, pp. 69–71, Jan. 2020, doi: 10.5582/BST.2020.01020. 
[18] L. Zhang and Y. Liu, “Potential interventions for novel coronavirus in China: A 
systematic review,” Journal of Medical Virology, vol. 92, no. 5. John Wiley and Sons 
Inc., pp. 479–490, May 01, 2020, doi: 10.1002/jmv.25707. 
[19] A. P. Costa-Pereira, T. M. Williams, B. Strobl, D. Watling, J. Briscoe, and I. M. Kerr, 
“The Antiviral Response to Gamma Interferon,” J. Virol., vol. 76, no. 18, pp. 9060–9068, 
Sep. 2002, doi: 10.1128/jvi.76.18.9060-9068.2002. 
[20] A. J. Lee and A. A. Ashkar, “The dual nature of type I and type II interferons,” Frontiers 
in Immunology, vol. 9, no. SEP. Frontiers Media S.A., Sep. 11, 2018, doi: 
10.3389/fimmu.2018.02061. 
[21] L. Shan et al., “Interferon gamma inhibits transmissible gastroenteritis virus infection 
mediated by an IRF1 signaling pathway,” Arch. Virol., vol. 164, no. 11, pp. 2659–2669, 
Nov. 2019, doi: 10.1007/s00705-019-04362-2. 
[22] B. A. Rhein et al., “Interferon-γ Inhibits Ebola Virus Infection,” PLoS Pathog., vol. 11, 
no. 11, Nov. 2015, doi: 10.1371/journal.ppat.1005263. 
[23] T. V. Sologub, G. S. Golobokov, V. V. Tsvetkov, and I. I. Tokin, “Interferon-gamma in 
the treatment of influenza and other respiratory viral infections,” Medical Council, No. 7, 
2015, 
Accessed: 
Jun. 
23, 
2020. 
[Online]. 
Available: 
https://cyberleninka.ru/article/n/interferon-gamma-v-terapii-grippa-i-drugih-respiratornyh-
virusnyh-infektsiy. 
[24] V. V. Nikiforov, T. V. Sologub, I. I. Tokin, V. V. Tsvetkov, M. K. Erofeeva, and V. V. 
Zarubaev, “The possibility of using interferon-y for influenza infection,” Epidemiology 
and Infectious Diseases, vol. 20, No. 3, 2015, Accessed: Jun. 23, 2020. [Online]. 
Available: https://cyberleninka.ru/article/n/vozmozhnost-ispolzovaniya-interferona-u-pri-
grippoznoy-infektsii. 
[25] “THE 
EFFECTIVENESS 
AND 
RATIONALE 
DOCUMENT 
OF 
USING 
RECOMBINANT INTERFERON-GAMMA IN THE COMPLEX THERAPY OF 
PATIENTS 
WITH 
INFLUENZA 
A 
(H1N1) 
PDM09.” 
https://elibrary.ru/item.asp?id=29008943 (accessed Jun. 23, 2020). 
[26] I. Tokin, V. Nikiforov, P. Shabalkin, P. Pimanchev, J. Isakova, and V. Tsvetkov, 


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“Randomized Controlled Parallel-Design Clinical Study of the Efficacy and Safety of 
Intranasal Interferon gamma in Treatment of Influenza-Like Infections,” Int. J. Biomed., 
vol. 8, no. 4, pp. 327–332, Dec. 2018, doi: 10.21103/article8(4)_oa12. 
[27] “Temporary guidelines ‘Prevention, diagnosis, and treatment of new coronavirus infection 
(COVID-19). Version 9 (10/26/2020)’ (approved Ministry of Health of the Russian 
Federation) (together with the "Instructions for conducting etiological laboratory 
diagnostics 
/ 
ConsultantPlus.” 
http://www.consultant.ru/document/cons_doc_LAW_354163/ (accessed Jun. 23, 2020). 
[28]    Guidance for Industry “COVID-19: Developing Drugs and Biological Products for 
Treatment or Prevention” FDA (February 2021).    
 
Appendixes 
 
Appendix 1 
 
Participant's diary (study group)   
 
LLC "NPP "Pharmaclon" 
 
Medical 
Researcher:__________________________________________________________________ 
Contact details:_________________________________________________ 
Research Center: 
__________________________________________________________________ 
__________________________________________________________________ 
__________________________________________________________________ 
__________________________________________________________________ 
 
Research participant's diary 
Protocol of post-marketing non-interventional study 
"A prospective randomized open-label comparative study of the use of the intranasal form of 
human recombinant interferon gamma for the prevention of acute respiratory viral infections, 
including diseases caused by coronavirus infection 2019 (COVID-19)" 
RAIN-2020 
 
Study Group 
 
 
Participant screening number: ǀ__ǀ-ǀ__ǀ__ǀ__ǀ 
Randomization number of the participant: ǀ________ 
Date of signing informed consent: ǀ__ǀ__ǀ ǀ__ǀ__ǀ ǀ__ǀ__ǀ__ǀ__ǀ 
                                                                                                           day month year       
The start date for the diary: ǀ__ǀ__ǀ ǀ__ǀ__ǀ ǀ__ǀ__ǀ__ǀ__ǀ 
                                                                         day month year       
The end date for the diary: ǀ__ǀ__ǀ ǀ__ǀ__ǀ ǀ__ǀ__ǀ__ǀ__ǀ 
                                                                                 day month year       
Participant's signature____________________ 
Signature of the medical researcher____________________ 


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Participant ǀ________ 
(randomization number) 
Initial data 
Date ǀ__ǀ__ǀ ǀ__ǀ__ǀ ǀ__ǀ__ǀ__ǀ__ǀ 
                      day month year 
 
1. 
Initials 
 
2. 
Date of birth 
 
3. 
Gender 
male / female 
4. 
Smoking, 
history 
yes (___ pack/day for ___ years)               no 
 
 
 


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Instructions for the preparation of the drug INGARON 
1. Gently pull the plastic nozzle on the glass vial, following the direction of the arrows on the aluminum 
guard. 
2. The plastic cap along with part of the aluminum guard will be removed. 
3. In a circular motion, remove the remaining part of the aluminum guard.  
Remove the rubber stopper from the glass vial. 
 
 
4. Open the vial of 
water for injection by breaking off its upper part. 
5. Pour 5 ml of water for injection into glass vial with a dry substance. 
6. Remove the dropper cap from the package and fix it on the neck of the bottle. 
 
 
Due to the need to store the active substance in a full vacuum, the aluminum cap must be hermetic and durable. 
Slowly remove the aluminum guard of the bottle, avoid cuts. If the cap breaks off during removal, you can remove 
the rest of the metal cap with scissors.   
Take vial with Ingaron with liquid inside with both hands and turn it over 10–15 times.  
Put the vial with Ingaron with the liquid inside in the refrigerator and store there for 10 days. For the second course 
of prevention (after 1 week), use the second vial.  
Return the empty ampoules of water for injection together with the used glass vials to the researcher at the next visit. 
Administration 
Course 1. The drug is applied 3 drops in each nasal passage every other day 30 minutes before breakfast for 10 days 
(total of 5 instillations). The use of the drug is carried out according to the following regimen: 
o 
Course 1. Day 1 – mark administration time in your diary 
o 
Course 1. Day 3 – mark administration time in your diary 
o 
Course 1. Day 5 – mark administration time in your diary 
o 
Course 1. Day 7 – mark administration time in your diary 
o 
Course 1. Day 9 – mark administration time in your diary 
This is 1 preventive cycle. Then a break of 7 days. 
Course 2. Drug administration is carried out similarly to Course 1. Preparation of the drug is carried out similarly to 
the algorithm described earlier. Dosage regimen is the same: 
o 
Course 2. Day 1 – mark administration time in your diary 
o 
Course 2. Day 3 – mark administration time in your diary 
o 
Course 2. Day 5 – mark administration time in your diary 
o 
Course 2. Day 7 – mark administration time in your diary 
o 
Course 2. Day 9 – mark administration time in your diary 
If you missed drug administration, mark the day in your diary with a "check mark" and take the next dose the next 
morning 30 minutes before breakfast and then continue using it every other day. Remember that the finished 
solution of the drug is stored for no more than 10 days in the refrigerator. Do not use it after the expiration date. For 
Course 2, use the second bottle, do not use the first bottle, even if the drug is not fully used.


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Course 1 
Day 1 
Date ǀ__ǀ__ǀ ǀ__ǀ__ǀ ǀ__ǀ__ǀ__ǀ__ǀ 
                      day month year 
Administration of study drug 
 
Time of administration: ǀ_____:ǀ__ǀ__ǀ 
In case of complaints, symptoms of ARVI, please fill out the table below: 
Start date 
End date 
Complaints 
Therapy (if taken) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Course 1 
Day 2 
Date ǀ__ǀ__ǀ ǀ__ǀ__ǀ ǀ__ǀ__ǀ__ǀ__ǀ 
                      day month year 
In case of complaints, symptoms of ARVI, please fill out the table below: 
Start date 
End date 
Complaints 
Therapy (if taken) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Course 1 
Day 3 
Date ǀ__ǀ__ǀ ǀ__ǀ__ǀ ǀ__ǀ__ǀ__ǀ__ǀ 
                      day month year 
 
Time of administration: ǀ_____:ǀ__ǀ__ǀ 
In case of complaints, symptoms of ARVI, please fill out the table below: 
Start date 
End date 
Complaints 
Therapy (if taken) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Course 1 
Day 4 
Date ǀ__ǀ__ǀ ǀ__ǀ__ǀ ǀ__ǀ__ǀ__ǀ__ǀ 
                      day month year 
 
In case of complaints, symptoms of ARVI, please fill out the table below: 
Start date 
End date 
Complaints 
Therapy (if taken) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Course 1 
Day 5 
Date ǀ__ǀ__ǀ ǀ__ǀ__ǀ ǀ__ǀ__ǀ__ǀ__ǀ 
                      day month year 
 
Time of administration: ǀ_____:ǀ__ǀ__ǀ 
In case of complaints, symptoms of ARVI, please fill out the table below: 
Start date 
End date 
Complaints 
Therapy (if taken) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Course 1 
Date ǀ__ǀ__ǀ ǀ__ǀ__ǀ ǀ__ǀ__ǀ__ǀ__ǀ 


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Day 6 
                      day month year 
 
In case of complaints, symptoms of ARVI, please fill out the table below: 
Start date 
End date 
Complaints 
Therapy (if taken) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Course 1 
Day 7 
Date ǀ__ǀ__ǀ ǀ__ǀ__ǀ ǀ__ǀ__ǀ__ǀ__ǀ 
                      day month year 
 
Time of administration: ǀ_____:ǀ__ǀ__ǀ 
In case of complaints, symptoms of ARVI, please fill out the table below: 
Start date 
End date 
Complaints 
Therapy (if taken) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Course 1 
Day 8 
Date ǀ__ǀ__ǀ ǀ__ǀ__ǀ ǀ__ǀ__ǀ__ǀ__ǀ 
                      day month year 
In case of complaints, symptoms of ARVI, please fill out the table below: 
Start date 
End date 
Complaints 
Therapy (if taken) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Course 1 
Day 9 
Date ǀ__ǀ__ǀ ǀ__ǀ__ǀ ǀ__ǀ__ǀ__ǀ__ǀ 
                      day month year 
 
Time of administration: ǀ_____:ǀ__ǀ__ǀ 
In case of complaints, symptoms of ARVI, please fill out the table below: 
Start date 
End date 
Complaints 
Therapy (if taken) 
 
 
 
 
 
 
 
 
 
 
 
 


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Participant ǀ________ 
(randomization number) 
Break between preventive courses 
The break between preventive courses is 7 days 
In case of complaints, symptoms of ARVI, please fill out the table below: 
Start date 
End date 
Complaints 
Therapy (if taken) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Course 2 
Day 1 
Date ǀ__ǀ__ǀ ǀ__ǀ__ǀ ǀ__ǀ__ǀ__ǀ__ǀ 
                      day month year 
Administration of study drug 
 
Time of administration: ǀ_____:ǀ__ǀ__ǀ 
In case of complaints, symptoms of ARVI, please fill out the table below: 
Start date 
End date 
Complaints 
Therapy (if taken) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Course 2 
Day 2 
Date ǀ__ǀ__ǀ ǀ__ǀ__ǀ ǀ__ǀ__ǀ__ǀ__ǀ 
                      day month year 
In case of complaints, symptoms of ARVI, please fill out the table below: 
Start date 
End date 
Complaints 
Therapy (if taken) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Course 2 
Day 3 
Date ǀ__ǀ__ǀ ǀ__ǀ__ǀ ǀ__ǀ__ǀ__ǀ__ǀ 
                      day month year 
 
Time of administration: ǀ_____:ǀ__ǀ__ǀ 
In case of complaints, symptoms of ARVI, please fill out the table below: 
Start date 
End date 
Complaints 
Therapy (if taken) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Course 2 
Day 4 
Date ǀ__ǀ__ǀ ǀ__ǀ__ǀ ǀ__ǀ__ǀ__ǀ__ǀ 
                      day month year 
 
In case of complaints, symptoms of ARVI, please fill out the table below: 
Start date 
End date 
Complaints 
Therapy (if taken) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Course 2 
Day 5 
Date ǀ__ǀ__ǀ ǀ__ǀ__ǀ ǀ__ǀ__ǀ__ǀ__ǀ 
                      day month year 
 
Time of administration: ǀ_____:ǀ__ǀ__ǀ 
In case of complaints, symptoms of ARVI, please fill out the table below: 
Start date 
End date 
Complaints 
Therapy (if taken) 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Course 2 
Day 6 
Date ǀ__ǀ__ǀ ǀ__ǀ__ǀ ǀ__ǀ__ǀ__ǀ__ǀ 
                      day month year 
 
In case of complaints, symptoms of ARVI, please fill out the table below: 
Start date 
End date 
Complaints 
Therapy (if taken) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Course 2 
Day 7 
Date ǀ__ǀ__ǀ ǀ__ǀ__ǀ ǀ__ǀ__ǀ__ǀ__ǀ 
                      day month year 
 
Time of administration: ǀ_____:ǀ__ǀ__ǀ 
In case of complaints, symptoms of ARVI, please fill out the table below: 
Start date 
End date 
Complaints 
Therapy (if taken) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Course 2 
Day 8 
Date ǀ__ǀ__ǀ ǀ__ǀ__ǀ ǀ__ǀ__ǀ__ǀ__ǀ 
                      day month year 
In case of complaints, symptoms of ARVI, please fill out the table below: 
Start date 
End date 
Complaints 
Therapy (if taken) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Course 2 
Day 9 
Date ǀ__ǀ__ǀ ǀ__ǀ__ǀ ǀ__ǀ__ǀ__ǀ__ǀ 
                      day month year 
 
Time of administration: ǀ_____:ǀ__ǀ__ǀ 
In case of complaints, symptoms of ARVI, please fill out the table below: 
Start date 
End date 
Complaints 
Therapy (if taken) 
 
 
 
 
 
 
 
 
 
 
 
 


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Participant ǀ________ 
(randomization number) 
Observation period 
Follow-up period 1 month 
In case of complaints, symptoms of ARVI, please fill out the table below: 
Start date 
End date 
Complaints 
Therapy (if taken) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Participant ǀ________ 
(randomization number) 
Observation period 
 
Start date 
End date 
Complaints 
Therapy (if taken) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix 2 
 
Participant's diary (control group) 
 
 
 
 
LLC "NPP "Pharmaclon" 
 
Medical 
Researcher:__________________________________________________________________ 
Contact details:_________________________________________________ 
Research Center: 
__________________________________________________________________ 
__________________________________________________________________ 
__________________________________________________________________ 
__________________________________________________________________ 
 
Research participant's diary 
Protocol of post-marketing non-interventional study 
"A prospective randomized open-label comparative study of the use of the intranasal form of 
human recombinant interferon gamma for the prevention of acute respiratory viral infections, 
including diseases caused by coronavirus infection 2019 (COVID-19)" 
RAIN-2020 
 
Control Group 
 
Participant screening number: ǀ__ǀ-ǀ__ǀ__ǀ__ǀ 
Randomization number of the participant: ǀ________ 
Date of signing informed consent: ǀ__ǀ__ǀ ǀ__ǀ__ǀ ǀ__ǀ__ǀ__ǀ__ǀ 
                                                                                                           day month year       
The start date for the diary: ǀ__ǀ__ǀ ǀ__ǀ__ǀ ǀ__ǀ__ǀ__ǀ__ǀ 
                                                                         day month year       
The end date for the diary: ǀ__ǀ__ǀ ǀ__ǀ__ǀ ǀ__ǀ__ǀ__ǀ__ǀ 
                                                                                 day month year       
Participant's signature____________________ 
Signature of the medical researcher____________________ 
 
Participant ǀ________ 
(randomization number) 
Initial data 
Date ǀ__ǀ__ǀ ǀ__ǀ__ǀ ǀ__ǀ__ǀ__ǀ__ǀ 
                      day month year 
 
1. 
Initials 
 
2. 
Date of birth 
 
3. 
Gender 
male / female 
4. 
Smoking, 
history 
yes (___ pack/day for ___ years)               no 
 
 


 
VERSION 1.01 
 
November 17, 2020 
The observation period is 2 months 
If you are taking medications to prevent ARVI, please fill out the table below: 
Drugs taken for 
prevention16 
Drug name 
Dosage regimen17 
On-treatment 
period 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Participant ǀ________ 
(randomization number) 
Observation period 
Participant ǀ________ 
(randomization number) 
Observation period 
In case of complaints, symptoms of ARVI, please fill out the table below: 
Start date 
End date 
Complaints 
Therapy (if taken) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                                 
16 Before using the drug, it is necessary to familiarize yourself with the current instructions for medical use to 
exclude contraindications 
17 A single dose and the frequency of dosing are indicated 


 
 
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2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
VERSION 1.01 
 
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3 
 
 
Appendix 3 
 
Form for reporting unlabeled serious adverse reaction 
 
Reporting of unlabeled serious reaction to a drug being studied in a clinical trial 
 Research protocol No. 
 
Name of the research protocol 
 
Name of study drug 
 
Study phase 
 
The name of the medical 
institution in which the SAE 
was detected 
 
Information about the SAE 
1. Initials of the 
patient 
2. Date of 
birth 
3. Age 
4. Gender 
5. Start 
date of the 
SAE 
6.Mark everything that 
corresponds to the SAE 
 
 
 
 
 
• Death 
• Hospitalization or its 
prolongation 
• Involved persistence of 
significant disability or 
incapacity 
• Life threatening 
7. Description of the SAE, including data from laboratory and instrumental 
studies 
 
Information about suspected medicinal product 
8. Suspected medicinal product, including international non-
proprietory name or generic name 
9. Has SAE resolved after drug 
withdrawal 
 
• Yes 
• No 
• Not applicable 
10. Daily dose 
11. Administration route 
12. Did the reaction occur again 
after repeated use of the drug 
 
 
• Yes 
• No 
• Not applicable 
13. Indications 
14. Dates of treatment 
15. Duration of therapy 
 
from                   
to 
 
Concomitant drug therapy and anamnesis 
16. Concomitant medications and dates of administration (except those used for the treatment of SAE 
 
17. Other relevant anamnesis data (for example, diagnoses, allergies, pregnancy with indication of the 
time of the last menstruation, etc.) 
 
Other information 
18. Name and address of the manufacturer 
 
19. Case identification number 
20. Date of receipt of the SAE 


 
 
VERSION 1.01 
 
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4 
 
 
information by the manufacturer 
 
 
21. Source of information about the SAE 
• Research • Literature • Healthcare Specialist • Regulatory authorities.  • Other 
___________________________________________________________________ 
22. Date of this report 
 
23. Type of report 
• Initial report    
• Follow-up report 
 
 
 


 
 
VERSION 1.01 
 
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5 
 
 
Appendix 4 
 
ADVERSE DRUG REACTION REPORT FORM 
MEDICINAL PRODUCT 
 
 
Primary 
Additional information to the message 
No.___________ from_________________ 
 
Patient data 
Patient initials (patient code)*___________________________________      Gender   □ M  □ F    Weight__________ kg 
Age___________________ Pregnancy  □, gestational age _____ weeks 
Allergy    □ No    □ Yes ______________________________________  
Treatment    □    outpatient     □    inpatient    □    self-treatment             
Medications suspected of causing AR 
 
Name of the drug (trade 
name)* 
Manufacturer 
Batch 
number 
Dose, route 
of 
administrati
on 
Therapy 
starting date 
Therapy end 
date 
Indication 
1 
 
 
 
 
 
 
 
2 
 
 
 
 
 
 
 
3 
 
 
 
 
 
 
 
Adverse reaction 
AR initial 
date__________ 
Description of the reaction* (specify all details, including laboratory data) 
 
 
 
 
 
 
 
 
 
 
Date of AR resolving_________________________________ 
Criteria for AR severity:    
□   Death 
□   Life threatening 
- Hospitalization or its 
extension 
□   Disability 
□    Congenital anomalies 
□   Clinically significant 
event 
□   Not applicable   
Interventions 
 □  Without treatment     □  Withdrawal of suspected medicinal product  □  Drug dose tapering 
 □  Non-drug therapy (including surgical intervention)  
 □  Drug therapy_________________________________________________________________ 
Outcome 
 □    Recovery without complications    □  Recovering or resolving    □  Condition without changes 
 □   Recovery with complications (specify)___________________________________________ 
 
 □   Death  □ Unknown   □ Not applicable 
 
Was drug withdrawal accompanied by AR resolving? 
□ No  □ Yes  □ No drug withdrawal □ Not applicable 
Has medicinal product been prescribed repeatedly?   □ No  □ Yes 
Result___________________ □ Not applicable 
Other medications taken during the last 3 months, including drugs taken by the patient independently (at his own 
request) 
 
Name of the drug (trade 
name) 
Manufacturer 
Batch 
number 
Dose, route 
of 
administrati
on 
Therapy 
starting date 
Therapy end 
date 
Indication 
1 
 
 
 
 
 
 
 
2 
 
 
 
 
 
 
 
3 
 
 
 
 
 
 
 
4 
 
 
 
 
 
 
 


 
 
VERSION 1.01 
 
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6 
 
 
5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Data of the reporting person 
□  Physician    □  Other healthcare system specialist    □   Patient    □  Other 
 
Contact phone/e-mail:*________________________________________________________________     
Full name_____________________________________________________________________________________ 
Position and place of work____________________________________________________________________ 
Report Date _____________________________________________________________________________ 
   
 
* Required fields 
 
 
The message can be sent: 
 
NPP Pharmaclon LLC 
 
e-mail: adversereaction@drugsafety.ru  
tel. 24 hours: 8-800-777-8-604, 
you can download the form on the website www.pharmaclon.ru  
postal address: Moscow, Presnenskii val str., 17c.1 
 
 
 
 
 
 
 

SAP_001.pdf: 
INGARON LLC "NPP "PHARMACLON" 
12.10.2021 
 
RAIN-2020 
SAP v.1 
 
1 
 
STATISTICAL ANALYSIS PLAN 
 
Protocol 
RAIN-2020 (NCT05054114) version 2.0 from 17.02.2021 
Date 
12/10/2021 
Version 
2 
Protocol 
Prospective randomized open-label comparative study of the use of the intranasal form of human 
recombinant interferon gamma for the prevention of acute respiratory viral infections, including 
diseases caused by coronavirus infection 2019 (COVID-19) 
Implementor 
Head of Clinical Research Organization Department 
Signature 
                                                                                       Yu.A. Isakova 
 
 


INGARON LLC "NPP "PHARMACLON" 
12.10.2021 
 
RAIN-2020 
SAP v.1 
 
2 
CONTENT 
Abbreviations ....................................................................................................................................... 4 
1. 
Purposes and objectives .............................................................................................................. 5 
1.1. 
Purpose of the study .......................................................................................................................... 5 
1.2. 
Research objectives ............................................................................................................................ 5 
2. 
Clinical trial design ....................................................................................................................... 6 
2.1. 
Design ................................................................................................................................................. 6 
2.2. 
Randomization ................................................................................................................................... 6 
2.3. 
Blinding procedure ............................................................................................................................. 6 
3. 
Evaluation of effectiveness parameters ...................................................................................... 7 
3.1. 
Endpoints of the study ....................................................................................................................... 7 
3.2. 
Registration, analysis and evaluation of effectiveness parameters ................................................... 7 
4. 
Assessment of safety parameters ............................................................................................. 11 
4.1. 
Safety Endpoints............................................................................................................................... 11 
4.2. 
Registration, analysis and evaluation of safety parameters ............................................................ 11 
Adverse event (AE) ............................................................................................................................................ 11 
Adverse reaction (AR) ....................................................................................................................................... 11 
Determination of a serious adverse event (SAE) ............................................................................................. 11 
Intensity of adverse event ................................................................................................................................ 12 
Criteria for assessing the association of adverse event with the intake of study drug .................................. 12 
5. 
Statistical data processing ......................................................................................................... 14 
5.1. 
Statistical methods of analysis ......................................................................................................... 14 
Analysis of the source data ............................................................................................................................... 14 
Primary Endpoint Analysis ................................................................................................................................ 15 
Secondary Endpoint analysis ............................................................................................................................ 15 
Analysis of safety parameters........................................................................................................................... 16 
5.2. 
The size of the sample under study ................................................................................................. 16 
5.3. 
Missing / incorrect data ................................................................................................................... 16 
5.4. 
Deviations from the protocol and the original statistical plan ........................................................ 16 
5.5. 
Populations of participants for analysis ........................................................................................... 17 
5.6. 
Interim analysis ................................................................................................................................ 18 
6. 
Table patterns ............................................................................................................................ 19 
 
 
 
 
 
 
 


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VERSION HISTORY 
Version 
Reason for amendment 
Date 
1 
Final version 
08.09.2021 
2 
Supplemented version 
12.10.2021 
 
 
 


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ABBREVIATIONS 
ATC – Anatomical Therapeutic Chemical Classification System 
VI – viral infections 
CI – confidence interval 
IU – international unit 
BMI – body mass index 
INN – international nonproprietary name 
IEC – Independent Ethics Committee 
AE – adverse event 
ARVI – acute respiratory viral infection 
ARD – acute respiratory disease 
SAR – serious adverse reaction 
SARS – severe acute respiratory syndrome 
COVID-19 – coronavirus disease 2019 (coronavirus disease 2019) 
CTCAE – Toxicity Scale (Common Terminology Criteria for Adverse Events) 
SARS-CoV-2 – type 2 coronavirus that causes severe acute respiratory syndrome (SARS) 
M – arithmetic mean 
Max – Maximum value 
Me – Median 
Min – minimum value 
N – number of values 
SD – standard deviation 
ATC – Anatomical Therapeutic Chemical Classification System 
VI – viral infections 
CI – confidence interval 
IU – international unit 
BMI – body mass index 
INN – international nonproprietary name 
IEC – Independent Ethics Committee 
AE – adverse event 
ARVI – acute respiratory viral infection 
ARD – acute respiratory disease 
SAR – serious adverse reaction 
SARS – severe acute respiratory syndrome 
COVID-19 – coronavirus disease 2019 (coronavirus disease 2019) 
CTCAE – Toxicity Scale (Common Terminology Criteria for Adverse Events) 
SARS-CoV-2 – type 2 coronavirus that causes severe acute respiratory syndrome (SARS) 
M – arithmetic mean 
Max – Maximum value 
Me – Median 
Min – minimum value 
N – number of values 
SD – standard deviation 
ATC – Anatomical Therapeutic Chemical Classification System 
VI – viral infections 
CI – confidence interval 
IU – international unit 
BMI – body mass index 
INN – international nonproprietary name 
IEC – Independent Ethics Committee 
AE – adverse event 
ARVI – acute respiratory viral infection 
ARD – acute respiratory disease 
SAR – serious adverse reaction 
SARS – severe acute respiratory syndrome 
COVID-19 – coronavirus disease 2019 (coronavirus disease 2019) 
CTCAE – Toxicity Scale (Common Terminology Criteria for Adverse Events) 
SARS-CoV-2 – type 2 coronavirus that causes severe acute respiratory syndrome (SARS) 
M – arithmetic mean 
 
 


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1. PURPOSES AND OBJECTIVES 
1.1. 
Purpose of the study 
Evaluation of the efficacy and safety of the prophylactic use of Ingaron (INN: human recombinant interferon gamma, 
lyophilizate for the preparation of a solution for intranasal administration of 100 000 IU) in the mode of 3 drops in 
each nasal passage intranasally every other day for 10 days with a break of 7 days (two 10-day cycles) in adult 
volunteers.  
1.2. 
Research objectives 
Evaluation of the effectiveness and safety of the proposed regimen of preventive therapy with Ingaron (INN: human 
recombinant interferon gamma, lyophilizate for the preparation of a solution for intranasal administration of 100 000 
IU) in adult volunteers.  
 
 


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2. CLINICAL TRIAL DESIGN 
2.1. 
Design 
Post-marketing non-interventional prospective randomized open-label comparative study. 
A total of 4 visits are planned (0–3). Visit 0 and 1 can be combined. 
During randomization, participants are randomly distributed in a 1:1 ratio into two groups:  
Group I (main) and Group II (control). 
According to the methodology approved by this protocol, the participant must use (Group I) or not use (Group II) 
study drug (depending on the distributed randomization number at Visit 1) for 27 days of the preventive course (10 
days + 7 days + 10 days).  
The effectiveness of preventive therapy will be recorded. The presence and severity of any adverse events and events 
will also be evaluated, regardless of the alleged connection with the use of the study drug Ingaron®. 
The schedule of visits and procedures is identical for all study participants. A detailed description of the research 
procedures is provided in the Protocol. 
The schedule of research procedures is presented in the section DESIGN of NON-INTERVENTIONAL RESEARCH 
Protocol. The study periods with the planned time are shown in the diagram below: 
PREVENTION PERIOD 
 
OBSERVATION PERIOD 
 
 
 
Main group 
 
 
 
GROUP I 
 
 
 
 
 
 
 
 
Ingaron  
 
В0_В1  
 
30 days  
     
        B2_X 
30 days        
 
B3_X 
 
 
 
 
Without Ingaron 
 
 
 
GROUP II 
 
 
 
 
 
 
 
 
 
Control group 
 
X – effectiveness evaluation 
Scheme 1. Design 
 
 
2.2. 
Randomization 
The methodology of the study involved the use of randomization to distribute participants into groups. Randomization 
was block-based. All blocks were balanced, i.e., each block should have an equal number of participant numbers with 
2 types of preventive treatment. 
2.3. 
Blinding procedure 
This study is open-label.  


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3. EVALUATION OF EFFECTIVENESS PARAMETERS 
3.1. 
Endpoints of the study 
The primary criterion of effectiveness is the proportion of patients with acute respiratory viral infections, including 
COVID-19, at the end of the period of preventive administration of the drug (measurement time: 28 days).  
The scientific hypothesis is that the prophylactic administration of Ingaron will lead to a decrease in the incidence of 
acute respiratory viral infections, including COVID-19, among adult volunteers. 
The preventive efficacy of the study drug will be evaluated by the following primary and secondary endpoints. 
Primary endpoint: 
The proportion of patients with acute respiratory viral infections, including COVID-19, at the end of the period of 
preventive administration of the drug (measurement time: 28 days). 
Secondary endpoints: 
1. 
The proportion of patients with confirmed COVID-19 at the end of the period of preventive treatment of the 
drug (measurement period: 28 days). 
2. 
The proportion of patients with acute respiratory viral infections, including COVID-19, at the end of the 
follow-up period (change period: 2 months). 
3. 
The proportion of patients with confirmed COVID-19 at the end of the follow-up period (change period: 2 
months). 
4. 
Frequency of development of complicated course of ARVI. 
5. 
The proportion of participants with each of the scores (0-8) according to the WHO Clinical Improvement Scale 
(change period: 28 days). 
6. 
The proportion of participants with each of the scores (0-8) according to the WHO Clinical Improvement Scale 
(change period: 2 months). 
7. 
Duration of symptoms of the disease of study participants who had acute respiratory viral infections, 
including COVID-19 (change period: 2 months). 
8. 
The duration of the symptoms of the disease of the study participants who were infected with ARVI, including 
COVID-19 (measurement period: 28 days). 
3.2. 
Registration, analysis and evaluation of effectiveness parameters 
The effectiveness will be evaluated based on the data obtained during the study visits. The effectiveness assessment 
will include the presence of a case of ARVI, including COVID-19. 
Confirmation of clinical cases of ARVI, including COVID-19: 
In the following cases: 
1) a positive result of PCR on SARS-CoV-2 RNA, regardless of the presence of clinical symptoms;  
2) appearance of clinical symptoms of ARVI in the absence of a PCR result on SARS-CoV-2 RNA or in the case of a 
negative result on SARS-CoV-2 RNA, - 
at any stage during participation in the study, a completion visit (Visit 3) is conducted at the end of the quarantine 
period (at least 14 days from the date of signing Consent for the treatment of a new COVID-19 coronavirus infection in 


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outpatient settings (at home) and compliance with the isolation regime or discharge from the hospital in case of 
laboratory confirmation of COVID-19), at which the patient returns the participant's diary and reports his condition to 
the doctor-researcher, transmits information about hospitalization, duration of symptoms, results of tests and 
performed studies.  
Definition of the COVID-19 case: 
Suspicious case of COVID-19 
Body temperature above 37.5 ° in addition to one or more of the following signs (in the absence of other known 
causes that explain the clinical picture, regardless of the epidemiological history): 
● 
Cough (dry or with scant sputum) 
● 
Shortness of breath 
● 
Feeling of congestion in the chest 
● 
SpO 2 no more than 95% 
● 
Sore throat 
● 
Nasal stuffiness or moderate rhinorrhea 
● 
Smell disorders or anosmia 
● 
Ageusia 
● 
Conjunctivitis 
● 
Fatigue 
● 
Myalgia 
● 
Headache 
● 
Vomiting 
● 
Diarrhea 
● 
Skin rash 
Probable case of COVID-19 
Body temperature above 37.5° in addition to one or more of the following signs: 
● 
Cough (dry or with scant sputum) 
● 
Shortness of breath 
● 
Feeling of congestion in the chest 
● 
SpO 2 no more than 95% 
● 
Sore throat 
● 
Nasal stuffiness or moderate rhinorrhea 
● 
Smell disorders or anosmia 
● 
Ageusia 
● 
Conjunctivitis 
● 
Fatigue 
● 
Myalgia 
● 
Headache 
● 
Vomiting 
● 
Diarrhea 
● 
Skin rash 
In the presence of at least one of the epidemiological signs: 
● 
Return from cross-border travel 14 days before the onset of symptoms 


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● 
The presence of close contacts over the past 14 days with a person under surveillance for COVID-19, who 
subsequently became ill 
● 
The presence of close contacts over the past 14 days with a person who has laboratory confirmed diagnosis 
of COVID-19 
● 
The presence of professional contacts with persons who have a suspected or confirmed case of COVID-19 
Or in combination with characteristic changes in the lungs according to computed tomography (CT), regardless of the 
results of a single laboratory test for the presence of SARS-CoV-2 RNA and an epidemiological history. 
Also, a possible case of COVID-19 should include a clinical case in the presence of the clinical manifestations described 
above (fever in combination with one or more signs) with characteristic changes in the lungs according to imaging 
studies if it is impossible to conduct a laboratory study for the presence of SARS-CoV-2 RNA. 
Confirmed case of COVID-19  
A positive result of laboratory test for the presence of SARS-CoV-2 RNA using nucleic acid amplification methods or 
SARS-CoV-2 antigen using immunochromatographic assay regardless of clinical manifestations, or a positive result for 
IgA, IgM and/or IgG antibodies in patients with clinically confirmed COVID-19 infection. 
In the case of ARVI symptoms characteristic of a suspicious case of COVID-19, accompanied by a negative result of PCR 
test, registered during or after a preventive course (during the period of participation in the study after randomization 
until the end of the observation period), the patient may additionally undergo a quantitative test for the presence of 
IgM and IgG antibodies to SARS-CoV-2 by the ELISA method for the purpose of additional verification and detection of 
COVID-19 cases. An additional quantitative test for antibodies to SARS-CoV-2 can be performed from the 10th to the 
21st day after the appearance of the first symptom of ARVI to register the immune response of the acute phase of 
infection at the beginning of its development (increased IgM levels) or during high-grade response (increased IgM and 
IgG), considering the seronegative the period of the disease (5-7 days). The analysis is taken only in the absence of 
fever and a satisfactory general condition of the patient, accompanied by a favorable recovery dynamic. When 
interpreting the results, it is necessary to consider the probability of obtaining false positive results (for example, the 
presence of "cross-reacting" antibodies). If the interpretation of the results is difficult, it is allowed to conduct a 
repeated ELISA study using the same test systems after 5-7 days to assess the dynamics of indicators. Quantitative 
determination of IgM and IgG antibodies in the blood by the ELISA method will be carried out with the support of 
DiaLab LLC Plus." 
The condition of the study participant is assessed according to the WHO standard scale of clinical improvement from 0 
to 8 points at each visit, including a phone call visit. In case of registration of ARVI at the final visit 3, in parallel with 
the current assessment of the participant's condition, an additional assessment of the case is carried out according to 
the WHO scale, reflecting the maximum clinical manifestation of the disease. 
WHO Clinical Improvement Scale 
Assessm
ent 
on 
the WHO 
scale 
0 
1 
2 
3 
4 
5 
6 
7 
8 
Select 
the 
appropri
ate score 
from 0 to 
8 
Not 
infected 
Outpatient 
Hospitalized with mild 
form 
Hospitalized with severe form 
D
i
e
d 
 
there 
are 
no clinical 
no 
activit
activity 
restrict
hospitalize
d, 
no 
hospitalize
d, oxygen 
non-invasive 
lung 
endotr
acheal 
ventilation + 
additional 
deat
h 


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or 
virological 
signs 
of 
infection 
y 
restri
ctions 
ions 
oxygen 
therapy 
therapy 
through a 
mask 
or 
nasal 
cannula 
ventilation 
or high-flow 
oxygen 
therapy  
intubat
ion and 
mecha
nical 
ventilat
ion 
organ 
support 
– 
pressor 
drugs, renal 
replacement 
therapy, 
extracorpore
al 
membrane 
oxygenation 
(ECMO) 
 
 
 


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4. ASSESSMENT OF SAFETY PARAMETERS 
4.1. 
Safety Endpoints 
The assessment of the safety of treatment was carried out based on registration of adverse events by analyzing 
complaints and subjective symptoms, comparative analysis of clinically significant changes in laboratory data, as well 
as the severity of these changes, using the CTCAE scale version 4.03 from 2010. 
The study will evaluate the following safety variables:  
• 
frequency of AE/SAE registration in treatment groups (in general and by organ systems); 
• 
changes in vital signs (heart rate, blood pressure, body temperature, respiration rate and SpO2) during the 
study (by visits and groups). 
4.2. 
Registration, analysis, and evaluation of safety parameters 
Adverse events were recorded from the moment of signing the informed consent until the end of the study. The 
safety analysis of the drug will consider the data of physical examination, diaries of participants, laboratory tests or 
other assessments. The study will analyze the frequency of occurrence and the nature of AE and SAE. The safety 
assessment was carried out throughout the study. 
Adverse event (AE)  
Adverse event (AE) – any adverse change in the state of health of the patient or the subject of a clinical trial to whom 
the drug (study) product was prescribed, regardless of the causal relationship with its use. AE may represent any 
adverse and unintended change (including deviation of the laboratory indicator from the norm), symptom or disease, 
the time of occurrence of which does not exclude a causal relationship with the use of drug product, regardless of the 
presence or absence of a relationship with the use of drug product1. 
Symptoms of acute respiratory infection: fever, manifestations of general infectious intoxication, signs of respiratory 
damage are not considered as adverse event, however, they are recorded during the study and analyzed as data for 
evaluating effectiveness. 
Adverse reaction (AR)  
Adverse reaction (AR) – an unintentional adverse reaction of the body associated with the use of a drug and 
suggesting the presence, at least, of a possible relationship with the use of a suspected medicinal product. 
Determination of a serious adverse event (SAE) 
Serious adverse event (SAE) – AE that leads to death2, poses a threat to life3, requires hospitalization of the patient or 
its prolongation4, leads to persistent or severe uncapacity or disability, to congenital anomalies or malformations5, 
requires medical intervention to prevent the development of these conditions. 
                                                          
1 Due to statistical necessity, adverse events are recorded both in the study group and in the control group. Evaluation and registration of adverse 
events begins from the moment of signing the informed consent form. 
2 Death is an outcome, not the SAE itself, so such a name should not appear as a name. If a case of death for an unknown reason is identified, researcher should make every effort to 
identify its suspected causes. SAE in such cases can be referred to as "Death by unexplained cause" only in cases where the causes of death are not known and cannot be clarified. In 
case of a fatal outcome due to COVID-19, the information is recorded in the primary medical documentation of the study participant without registration of the SAE.  
3 The term "Life threatening" in this context means that the volunteer participating in the study was at immediate risk of death during the occurrence of adverse event. This term does 
not apply to cases where adverse event could hypothetically cause the death of a participant if it were more intense in severity or longer in duration. 


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Unexpected adverse event (Unexpected AE) – adverse event, the nature, severity, or outcome of which does not 
correspond to the information in the current instructions for the medical use of the drug or in Clinical Investigation 
Brochure for an unapproved drug. 
All unexpected serious adverse events (unexpected SAE) those recognized by the researcher as related to the drug 
are classified as unexpected serious adverse drug reactions (unexpected SAE). Serious adverse drug reaction report 
form is presented in Appendix 3. 
Intensity of adverse event 
All AE are registered in the primary medical documentation of the participant based on physical examination, survey 
and diary records. The following information must be recorded in the primary medical documentation (outpatient 
card) for each AE: 
• 
severity (mild, moderate, severe); 
• 
nature of adverse event; 
• 
relationship with study drug; 
• 
duration (date of occurrence and end date), preferably with an indication of the time interval (hours) from 
the moment of administration of the study drug; 
• 
whether adverse event is serious. 
The severity is assessed using the CTCAE scale version 4.03 from 2010. The CCAE scale contains a list of the most 
frequent AE recorded in clinical study, in tabular format, indicating criteria of various degrees of severity (from 1 to 5, 
where 5 is death because of AE). For AE that are not in the tabulated list, the severity is determined in accordance 
with the textual description of the degrees of severity. 
The terms "serious" and "severe" are not synonymous. The term "severe" is often used to describe the intensity 
(severity) of a particular event (for example, anemia of severe, moderate, or mild severity); however, the event itself 
may be clinically insignificant (for example, severe headache). 
The concept of "severe" is not equivalent to the concept of "serious". The criteria of the latter are the outcome of the 
event or the measures, which are usually associated with the elimination of life threatening or severe disorders of vital 
activity. The criterion of seriousness, and not the severity of adverse event, should be guided when determining the 
need for expedited safety report of LLC "NPP "Pharmaclon" and authorized agencies. 
Criteria for assessing the association of adverse event with the intake of study drug 
Methods for assessing the degree of causal relationship are based on the following criteria: 
● 
the presence of a reliable temporary association of the AE with the use of the study drug (AE are registered 
after the start of the use of the study drug before the completion of participation in the study); 
● 
presence of a direct temporary connection of the AE with specific administration of the drug (for example, 
the development of AE during instillation); 
● 
possibility of explaining the development of AE by the pharmacological effect of the drug; 
● 
availability of information about such AE as a possible side effect in Clinical Investigation Brochure/guidelines 
for medical use; 
● 
description of similar cases in the literature; 
                                                                                                                                                                                                
4 Hospitalization for optional or pre-planned treatment of concomitant diseases that the participant had prior to inclusion in the study, the course of which did not worsen during 
participation in the study, is not considered to SAE, as well as being in a hospital for less than 24 hours or hospitalization for social reasons. 
5 Pregnancy cases in the participants of the clinical study are not subject to registration as AE, except in cases when the child has formed a congenital anomaly or malformation (the 
case is registered with SAE). 


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● 
presence of additional specific data indicating the association of AE with the drug (for example, the presence 
of specific antibodies, positive result of allergological tests); 
● 
positive test with the withdrawal of the study drug (AE was resolved or its severity decreased after the drug 
was discontinued); 
● 
positive test with repeated administration of study drug (AE reappeared or its severity worsened with 
repeated administration of the drug after withdrawal); 
● 
presence of other reasons for the development of this AE (manifestations of the underlying disease, 
concomitant diseases and conditions, concomitant therapy, food, lifestyle, etc.). 
The association of adverse events with the study drug will be evaluated based on the following principles in 
accordance with the WHO classification: 
● reliable – clinical manifestations, including violations of laboratory parameters that occur during the 
period of taking drug s and which cannot be explained by the presence of existing diseases and the influence 
of other factors and chemical compounds. Manifestations of an adverse reaction regress after the drug is 
discontinued and occur when it is re-prescribed; 
● probable – clinical manifestations, including changes in laboratory parameters associated with the 
instillation of the drug, which are unlikely to be related to concomitant diseases or other factors and which 
regress with the withdrawal of the drug. The response to the rechallenge is unknown; 
● possible – clinical manifestations, including changes in laboratory parameters associated with the use 
of the drug, but which can be explained by the presence of concomitant diseases or taking other drugs and 
chemical compounds. Information about the reaction to drug withdrawal is unclear; 
● questionable – clinical manifestations, including changes in laboratory parameters, which occur in 
the absence of a clear temporal connection with taking medication; there are other factors (drugs, diseases, 
chemicals) that may be the cause of their occurrence; 
● conditional – clinical manifestations, including violations of laboratory parameters attributed to 
"adverse reactions" that need additional data (for an accurate assessment) or these obtained data are 
currently being analyzed; 
● unclassifiable – reports of a suspected adverse reaction cannot be evaluated because there is not 
enough information or it is contradictory. 
● unrelated – clinical manifestations are not associated with the use of the drug. 
In order to determine the unambiguous connection of AE with the intake of the study drug, an approach will be used 
in which the presence of at least a possible relationship is assumed. 
 


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5. STATISTICAL DATA PROCESSING 
5.1. 
Statistical methods of analysis 
To create conditions for an independent evaluation of the results obtained, statistical data processing at the end of 
the study will be carried out by employees who are not related to the management of the subjects participating in the 
study. The primary data base was created in Excel when processing registration cards received from the clinical center. 
Data processing will be performed in the software environment of the R package (R: A language and environment for 
statistical computing. R Core Team. R Foundation for Statistical Computing, Vienna, Austria)6 version 4.1.0 using "A 
Guidance Document for the Use of R in Regulated Clinical Trial Environments"7.  
Descriptive statistics are presented for all baseline indicators collected during the study for all subjects included in the 
study (safety-population). The distribution of subjects, demographic and initial characteristics are presented using 
descriptive statistics methods.  
For numerical indicators, such as demographic and anthropometric data (body weight, age, height, BMI), as well as 
numerical performance parameters will be calculated: 
• 
Number of missing values (N); 
• 
Minimum value (Min); 
• 
Maximum value (Max); 
• 
Arithmetic Mean (M); 
• 
Standard Deviation (SD); 
• 
Median (Me). 
For qualitative variables (frequency of AE/SAE development, for example), absolute number in the n/N format will be 
given, as well as the percentage (%). 
Verification of the normality of the distribution will be carried out by one of the generally accepted methods 
(visualization of data in a dot diagram in combination with the calculation of the Kolmogorov-Smirnov test, as well as 
the test for asymmetry and kurtosis).  
In the case of a normal distribution, an intergroup comparison of quantitative characteristics will be carried out using 
the t-test (or the Mann-Whitney test otherwise). For categorical data, the χ2-criterion or the exact Fisher test will be 
applied if the expected frequency in any of the cells is less than 5.  
If statistically significant differences between the groups are found, the magnitude of the differences between the 
study groups will be estimated using confidence intervals. Significance levels and confidence intervals will be 
calculated as two-sided, and the statistical significance of the differences is by default two-sided and refers to a 
significance level of 0.05. 
Correction for multiple comparisons is not required. 
Analysis of the source data 
Demographic characteristics, baseline, and follow-up characteristics such as anamnesis, comorbidities and 
medications used will be described by treatment groups for the ITT population and then safety, if they differ.  
                                                          
6 URL https://www.R-project.org/ 
7 https://www.r-project.org/doc/R-FDA.pdf 


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Primary Endpoint Analysis 
The main parameter of the effectiveness of the preventive use of Ingaron® is the proportion of patients with acute 
respiratory viral infections, including COVID-19, at the end of the period of preventive administration of the drug 
(measurement time: 28 days).  
In accordance with the purpose and objectives of the study, the null and alternative hypotheses are formulated as 
follows: 
• 
Null hypothesis (H 0) consists in the assumption that the prophylactic administration of Ingaron will not lead 
to a change in the incidence of acute respiratory viral infections, including COVID-19, among adult volunteers; 
• 
Alternative hypothesis (H a) is that in the study group, the proportion of ARVI cases, including COVID-19, 
will differ from the control group. 
H0: µ1 = µ2 
Ha: µ1 ≠ µ2, 
where µ is the fraction of the main variable for the corresponding group. 
To test these hypotheses, the method of a two-way variant of the Fisher's exact test (with expected frequencies less 
than 5) or the Pearson's chi-squared test (2) (with the Yates correction for expected frequencies more than 5, but less 
than 10) will be used. 
In all cases, the significance level (α is the probability of an error of the first kind) 0.05 will be used. 
The analysis of the primary efficiency parameter will be carried out on the ITT population (main analysis), as well as – 
additionally – on the PP population (additional analysis). 
Data on the case of ARVI (COVID-19) is collected during the entire study by filling out a form on the registration of a 
case of ARVI. 
Secondary Endpoint analysis 
The following secondary efficacy parameters in this study are quantitative indicators that will be compared between 
treatment groups: 
• 
proportion of patients with confirmed COVID-19 at the end of the period of preventive administration of the 
drug (measurement period: 28 days);  
• 
proportion of patients with acute respiratory viral infections, including COVID-19, at the end of the 
observation period (change period: 2 months);  
• 
percentage of patients with confirmed COVID-19 at the end of the follow-up period (change period: 2 
months);  
• 
Frequency of development of complicated course of ARVI. 
The proportion of patients will be presented as a frequency, a percentage in % indicating a bilateral 95% CI, measured 
according to the data recorded at the time of the corresponding measurement period. For a comparative analysis of 
the proportions between the groups, method of a two-sided version of the Fisher's exact test (with expected 
frequencies less than 5) or the Pearson chi-squared test (2) (with the Yates correction for expected frequencies more than 5, but less than 10) will be 
used.  
The analysis of secondary performance parameters will be carried out both on the ITT population (main analysis) and 
on the PP population (additional analysis). 


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Analysis of safety parameters 
The study plans to analyze the following security variables: 
• 
frequency of AE/SAE registration in treatment groups (in general and by organ systems); 
• 
changes in vital signs (heart rate, blood pressure, body temperature, respiration rate and SpO2) during the 
study (by visits and groups). 
For categorical safety indicators in each group and for each visit, according to the survey scheme of participants, 
frequency, percentage in% and bilateral 95% CI will be calculated. Comparing groups by categorical indicators with the 
number of categories less than 5, Fisher's exact test will be used, otherwise Pearson chi-squared test (2) will be used 
(with Yates correction for expected frequencies of more than 5, but less than 10). 
The results of measuring vital signs (assessment of heart rate, respiration rate, blood pressure, body temperature and 
SpO 2) will be presented by treatment groups using descriptive statistics. 
The analysis of safety parameters will be carried out on the safety population. 
5.2. 
The size of the sample under study  
The estimation of the sample size of subjects was based on the following parameters: 
• 
bilateral significance level α=0.05 Z value = 1.96; 
• 
statistical power level is 80%, Z-value = 0.84; 
• 
method of sample formation — randomization using elements of randomness; 
• 
statistical criteria used are two-sided due to the lack of aposteriori information about the superiority of the 
effect of the study drug over the placebo effect. 
Calculation results: 
• 
number of volunteers who must complete participation in the study in accordance with the protocol is 286 in 
the group or a total of 572 participants. 
• 
number of randomized participants is 315 in a group or total 630 people 
• 
number of screened volunteers – up to 642. 
5.3. 
Missing / incorrect data  
For all parameters, the analysis will be carried out only on the available information, without filling in the data. There 
are no plans to use data reconstruction methods in this study. 
5.4. 
Deviations from the protocol and the original statistical plan 
An additional analysis is planned for the sensitivity of the results of the evaluation of the primary endpoint, depending 
on the vaccination status. 
To maintain the balance and comparability of the groups, as well as to exclude the influence of the period of active 
antibody formation caused by the vaccine 8on the results, as part of an additional analysis, a subpopulation of 
participants vaccinated with at least one dose of the drug during participation in the study will be excluded from both 
groups.  
                                                          
8Due to the small proportion of vaccinated participants, the number of doses of the vaccine received by the participant and its type (trade name) will not be taken into account 


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Participants vaccinated prior to inclusion in the study will be included in a modified sample with the formation of a 
separate population "not vaccinated during the study" to achieve the necessary statistical power. 
The conditions for the uniform distribution of patients by vaccination status between groups will be checked 
beforehand. 
All changes in the initial statistical plan with their justification will be reflected in the final report on the clinical trial. 
5.5. 
Populations of participants for analysis  
The following populations will be formed for analysis: ITT, PP and safety; additionally: ITT_NV, PP_NV, ITT_NV_BE, 
PP_NV_BE.  
Statistical data analysis will be carried out in the following populations of participants:  
1. Population of all included and randomized participants (intention-to-treat, ITT): all randomized participants 
who were exposed to the study drug, regardless of the degree of protocol compliance during the study. This 
data set is the main one for the analysis of primary and secondary effectiveness parameters; 
2. Population of participants who completed the study according to the protocol (per protocol, PP): all 
randomized subjects who completed participation in the study in accordance with the protocol (completed 
the prescribed period of treatment and follow-up without significant deviations from the protocol). This data 
set is additional for the analysis of primary and secondary effectiveness parameters; 
3. Safety population: The data set analyzed for safety assessment is identical to the ITT data set. However, 
unlike the population depending on the prescribed treatment, participants are analyzed depending on the 
actual treatment (if it differs from the treatment that was prescribed by randomization). All types of safety 
analysis will be based on the use of a data set for security assessment; 
4. Modified population of all included and randomized participants (intention-to-treat, ITT) not vaccinated 
against COVID-19: ITT_NV. This data set is additional for the analysis of the primary efficiency parameter; 
5. Modified population of participants who completed the study according to the protocol (per protocol, PP), 
not vaccinated against COVID-19: PP_NV. This data set is additional for the analysis of the primary efficiency 
parameter; 
6. Modified population of all included and randomized participants (intention-to-treat, ITT) not vaccinated 
against COVID-19 or vaccinated before inclusion in the study: ITT_NV_BE. This data set is additional for the 
analysis of the primary efficiency parameter; 
7. Modified population of participants who completed the study according to the protocol (per protocol, PP), 
not vaccinated against COVID-19 or vaccinated before inclusion in the study: PP_NV_BE. This data set is 
additional for the analysis of the primary efficiency parameter. 
Thus, the safety population will be used to present demographic data about participants, as well as for safety 
assessment. ITT will be considered the main sample for comparative analysis of performance parameters. The PP 
population will include only participants who completed the study without critical deviations from the protocol and 
will be formed as an additional sample to evaluate the effectiveness parameters in order to analyze the sensitivity of 
the results obtained in the ITT population. The modified populations will be used to perform sensitivity analysis when 
evaluating the primary endpoint. 
The number of participants who must complete the study in accordance with the protocol is 286 in each group, or a 
total of 572 participants. 
The number of randomized participants is 315 in each group or total of 630 participants. 


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The number of screened participants is up to 642. 
5.6. 
Interim analysis 
Not applicable. 
 


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6. TABLE PATTERNS 
Table1. Distribution of subjects 
Distribution of subjects 
Group I (proportion, %) 
Group II (proportion, %) 
Included in the study (screened) 
n/N (%) 
Of these:  
Excluded at the screening stage: 
 
n/N (%) 
Randomized 
n/N (%) 
n/N (%) 
Prematurely excluded, out of them: 
n/N (%) 
n/N (%) 
 
Existence of exclusion criterion #X (description) 
n/N (%) 
n/N (%) 
Population safety 
n/N (%) 
n/N (%) 
ITT population 
n/N (%) 
n/N (%) 
Population PP 
n/N (%) 
n/N (%) 
 
Table2. Demographic and anthropometric characteristics of subjects at the time of inclusion (safety population) 
Group 
Parameter 
Age (years) 
Weight (kg) 
Height (cm) 
Smoking 
index (p/y) 
Frequency of 
acute 
respiratory 
infections 
(amount/g) 
GROUP I 
n 
 
 
 
 
 
M 
 
 
 
 
 
СО 
 
 
 
 
 
min. 
 
 
 
 
 
max. 
 
 
 
 
 
Me 
 
 
 
 
 
GROUP II 
n 
 
 
 
 
 
M 
 
 
 
 
 
СО 
 
 
 
 
 
min. 
 
 
 
 
 
max. 
 
 
 
 
 
Me 
 
 
 
 
 
p (between groups) 
 
 
 
 
 
 
Table3. Distribution of subjects by gender (safety population) 
Gender 
GROUP I 
GROUP II 
Male 
n/N (%) 
n/N (%) 
Female 
n/N (%) 
n/N (%) 
p (between groups) 
 
 
 
Table4. Distribution of subjects by race (safety population) 
Race 
GROUP I 
GROUP II 
Caucasian 
n/N (%) 
n/N (%) 
Mongoloid 
n/N (%) 
n/N (%) 
Negroid 
n/N (%) 
n/N (%) 
p (between groups) 
 
 
 


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Table5. Medical history (safety population) 
Parameter 
Value 
Group I (N =) 
Group II (N =) 
Diagnosis (chronic disease) 
… 
n/N (%) 
n/N (%) 
Diagnosis (according to anamnesis) 
… 
n/N (%) 
n/N (%) 
p (between groups) 
 
 
 
 
Table 6. Methods of nonspecific prevention (safety population) 
Type 
Frequency 
GROUP I 
GROUP II 
Total subjects 
 
N = 
N = 
Masks 
Yes 
n/N (%) 
n/N (%) 
No 
n/N (%) 
n/N (%) 
Sometimes 
n/N (%) 
n/N (%) 
Respirator 
Yes 
n/N (%) 
n/N (%) 
No 
n/N (%) 
n/N (%) 
Sometimes 
n/N (%) 
n/N (%) 
Gloves 
Yes 
n/N (%) 
n/N (%) 
No 
n/N (%) 
n/N (%) 
Sometimes 
n/N (%) 
n/N (%) 
Glasses 
Yes 
n/N (%) 
n/N (%) 
No 
n/N (%) 
n/N (%) 
Sometimes 
n/N (%) 
n/N (%) 
Surgical overalls 
Yes 
n/N (%) 
n/N (%) 
No 
n/N (%) 
n/N (%) 
Sometimes 
n/N (%) 
n/N (%) 
p (between groups) 
 
 
 
 
Table 7. Drug allergy (safety population) 
 
GROUP I 
GROUP II 
Total subjects 
N = 
N = 
No 
n/N (%) 
n/N (%) 
Yes 
n/N (%) 
n/N (%) 
p (between groups) 
 
 
 
Table 8. Results of the assessment of the incidence rate at the end of the prevention period 
(ITT/PP/ITT_NV/PP_NV/ITT_NV_BE/PP_NV_BE population) 
 
GROUP I 
GROUP II 
Total subjects 
N = 
N = 
ARVI 
n/N (%) 
n/N (%) 
Not sick 
n/N (%) 
n/N (%) 
p (between groups) 
 
 
 
Table 9. Results of the assessment of the incidence of COVID-19 at the end of the prevention period (ITT population, 
PP) 
 
GROUP I 
GROUP II 
Total subjects 
N = 
N = 
COVID-19 (total) 
n/N (%) 
n/N (%) 
Of these: COVID-19 confirmed 
n/N (%) 
n/N (%) 


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COVID-19 probable 
n/N (%) 
n/N (%) 
COVID-19 suspicious 
n/N (%) 
n/N (%) 
p (between groups) 
 
 
 
Table 10. Results of the assessment of the incidence rate at the end of the study (ITT population, PP) 
 
GROUP I 
GROUP II 
Total subjects 
N = 
N = 
ARVI 
n/N (%) 
n/N (%) 
Not sick 
 
 
p (between groups) 
 
 
 
Table 11. Results of the assessment of the incidence of COVID-19 at the end of the study (ITT population, PP) 
 
GROUP I 
GROUP II 
Total subjects 
N = 
N = 
COVID-19 (total) 
n/N (%) 
n/N (%) 
Of these: COVID-19 confirmed 
n/N (%) 
n/N (%) 
COVID-19 probable 
n/N (%) 
n/N (%) 
COVID-19 suspicious 
n/N (%) 
n/N (%) 
p (between groups) 
 
 
 
Table 12. Results of the assessment of the frequency of complicated course (ITT population, PP) 
 
GROUP I 
GROUP II 
Total subjects 
N = 
N = 
Complications (total) 
n/N (%) 
n/N (%) 
Of these: … 
n/N (%) 
n/N (%) 
… 
n/N (%) 
n/N (%) 
p (between groups) 
 
 
 
Table 13. Results of evaluation of the frequency of different scores on the WHO scale at the end of the prevention 
period (ITT population, PP) 
 
GROUP I 
GROUP II 
Total subjects 
N = 
N = 
0 
n/N (%) 
n/N (%) 
1 
n/N (%) 
n/N (%) 
2 
n/N (%) 
n/N (%) 
3 
n/N (%) 
n/N (%) 
4 
n/N (%) 
n/N (%) 
5 
n/N (%) 
n/N (%) 
6 
n/N (%) 
n/N (%) 
7 
n/N (%) 
n/N (%) 
8 
n/N (%) 
n/N (%) 
p (between groups) 
 
 
 


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Table 14. Results of evaluation of the frequency of different scores on the WHO scale at the end of the study (ITT 
population, PP) 
 
GROUP I 
GROUP II 
Total subjects 
N = 
N = 
0 
n/N (%) 
n/N (%) 
1 
n/N (%) 
n/N (%) 
2 
n/N (%) 
n/N (%) 
3 
n/N (%) 
n/N (%) 
4 
n/N (%) 
n/N (%) 
5 
n/N (%) 
n/N (%) 
6 
n/N (%) 
n/N (%) 
7 
n/N (%) 
n/N (%) 
8 
n/N (%) 
n/N (%) 
p (between groups) 
 
 
 
Table 15. Duration of symptoms of the disease (ITT population, PP) 
Evaluation period 
Parameter 
GROUP I 
GROUP II 
At the end of the prevention period 
(28 days) 
n 
  
 
M 
  
 
СО 
  
 
min. 
  
 
max. 
  
 
Me 
  
 
At the end of the study (2 months) 
n 
  
 
M 
  
 
СО 
  
 
min. 
  
 
max. 
  
 
Me 
  
 
p (between groups) 
 
 
 
 
Table 16. Distribution of the nature of the symptoms of the disease (ITT population, PP) 
Group 
Symptom 
Number of patients, percentage (%) 
GROUP I 
 
n/N (%)  
GROUP II 
 
n/N (%)  
p (between groups) 
 
 
 
Table 17. Assessment of vital signs (safety population) 
Visit 
Group 
Parameter 
SBP 
(mmHg) 
DBP 
(mmHg) 
HR 
(beats/min) 
RR 
(/min) 
Temperature 
(°C) 
Oxygenation 
(SpO 2) 
B0 
GROUP I 
n 
 
 
 
 
 
 
M 
 
 
 
 
 
 
СО 
 
 
 
 
 
 
min. 
 
 
 
 
 
 
max. 
 
 
 
 
 
 
Me 
 
 
 
 
 
 
GROUP II 
N 
 
 
 
 
 
 
M 
 
 
 
 
 
 
СО 
 
 
 
 
 
 


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Visit 
Group 
Parameter 
SBP 
(mmHg) 
DBP 
(mmHg) 
HR 
(beats/min) 
RR 
(/min) 
Temperature 
(°C) 
Oxygenation 
(SpO 2) 
min. 
 
 
 
 
 
 
max. 
 
 
 
 
 
 
Me 
 
 
 
 
 
 
p (between groups) 
 
 
 
 
 
 
B3 
GROUP I 
N 
 
 
 
 
 
 
M 
 
 
 
 
 
 
СО 
 
 
 
 
 
 
min. 
 
 
 
 
 
 
max. 
 
 
 
 
 
 
Me 
 
 
 
 
 
 
GROUP II 
N 
 
 
 
 
 
 
M 
 
 
 
 
 
 
СО 
 
 
 
 
 
 
min. 
 
 
 
 
 
 
max. 
 
 
 
 
 
 
Me 
 
 
 
 
 
 
p (between groups) 
 
 
 
 
 
 
 
Table 18. Total number of AE, SAE in groups (safety population) 
Group 
AE 
SAE 
GROUP I 
n/N (%) 
n/N (%) 
GROUP II 
n/N (%) 
n/N (%) 
p (between groups) 
 
 
 
Table 19. Number of subjects with reported adverse events (safety population) 
Group 
AE+ 
AE- 
GROUP I 
n/N (%) 
n/N (%) 
GROUP II 
n/N (%) 
n/N (%) 
p (between groups) 
 
 
 
Table 20. Adverse events that developed in the study group participants (safety population) 
N 
Mild AE 
Moderate AE 
Severe AE 
Total 
Total 
Organ system / AE 
С 
НС 
С 
НС 
С 
НС 
С 
НС 
С + НС 
Organ system x 
n/N 
(%) 
n/N 
(%) 
n/N 
(%) 
n/N (%) 
n/N 
(%) 
n/N 
(%) 
n/N 
(%) 
n/N 
(%) 
n/N 
(%) 
AE x 
NN1 
NN2 
NNX 
NN1 
NN2 
NNX 
NN1 
NN2 
NNX 
NN1 
NN2 
NNX 
NN1 
NN2 
NNX 
NN1 
NN2 
NNX 
NN1 
NN2 
NNX 
NN1 
NN2 
NNX 
NN1 
NN2 
NNX 
Note: the table shows all the AE that chronologically occurred in the group after at least one use of the study drug.  
C – related to the study drug 
HC – not related to the drug under study 
NNx – participant's number with the corresponding AE 
 
Table 21. Adverse events that have developed in the subjects of the control group (safety population) 
N 
Mild AE 
Moderate 
AE 
Severe AE 
Total 


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Organ 
system / 
AE 
С 
НС 
С 
НС 
С 
НС 
С + НС 
Organ 
system x 
n/N 
(%) 
n/N 
(%) 
n/N 
(%) 
n/N 
(%) 
n/N (%) 
n/N 
(%) 
n/N (%) 
AE x 
NN1 
NN2 
NNX 
NN1 
NN2 
NNX 
NN1 
NN2 
NNX 
NN1 
NN2 
NNX 
NN1 
NN2 
NNX 
NN1 
NN2 
NNX 
NN1 
NN2 
NNX 
Note: The table shows all AE that occurred in the control group at any time after randomization into the study.  
NNx – participant's number with the corresponding AE 
 
Table 22. Adverse events by nosology (safety population) 
SOC 
PT 
Group 1 
Group X 
Category SOC 1 
Category PT 1 
n/N (%) 
n/N (%) 
Category PT x 
n/N (%) 
n/N (%) 
Category SOC x 
Category PT 1 
n/N (%) 
n/N (%) 
Category PT x 
n/N (%) 
n/N (%) 
 
Table 23. Severity of AE (safety population) 
Group 
Mild 
Moderate 
Severe 
GROUP I 
n/N (%) 
n/N (%) 
n/N (%) 
GROUP II 
n/N (%) 
n/N (%) 
n/N (%) 
Table 24. Results of comparison of groups by vaccination status against COVID-19 
(ITT/PP/ITT_NV/PP_NV/ITT_NV_BE/PP_NV_BE population)  
 
GROUP I  
GROUP II  
Total subjects  
N 
N 
Not vaccinated  
n/N (%) 
n/N (%) 
Vaccinated  
n/N (%) 
n/N (%) 
p (between groups)