Conditions: COVID-19
Keywords: SARS-CoV-2 Severe acute respiratory syndrome coronavirus 2 2019-nCoV 2019 novel coronavirus Respiratory disease lung disease COVID-19 coronavirus
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 372
Healthy volunteers: no

Brief summary:
The primary objective of the study was to evaluate the efficacy and safety of a single dose of RPH-104 (80 mg) or OKZ (64 mg) compared to placebo in addition to standard therapy in patients with severe SARS-CoV-2 infection (COVID-19) at Day 15 of the study.

Detailed description:
The study consisted of two phases:

* Pilot phase: the first 189 patients were randomized in three groups to receive OKZ, RPH-104 (63 patients per group), followed by an interim analysis of efficacy and safety data.
* The main phase was the conduct of all procedures prespecified in the protocol. Based on results of interim analysis no changes were made regarding the sample size or primary efficacy endpoint.

For each patient the study included the following periods:

* Screening period for no more than 48 hours before the start of the day of randomization (Day 1). During the screening period, an assessment was performed to determine whether the patient met the eligibility criteria;
* Treatment period lasting from the end of the screening (considered as the beginning of the Day 1) to 23:59 of the Day 1, including randomization of the patients in the treatment groups and then a single administration of the study drug;
* Follow-up period lasting from 00:00 of the Day 2 to 23:59 of the Day 29, including an assessment of the efficacy and safety after administration of the study drug.

Eligible patients were randomized to one of three treatment groups to receive a single subcutaneous injection: RPH-104 80 mg, OKZ 64 mg or placebo in addition to standard care for patients with COVID-19 as per the routine practice in participating facilities. Further, during the term of hospitalization, the clinical observation was performed (Day 1 - Day 15 of the Last Hospitalization Day (LHD), whichever comes first). This was followed by a follow-up period from the from Day 15 or LHD (whichever comes first) to Day 29.

Standard COVID-19 therapy, as per the institution routine practice, was permitted during the study, except the prohibited protocol medication (during the whole period of the study) and tocilizumab and sarilumab (during the first 24 hours after the study treatment administration).

In the absence of positive dynamics in the patient's condition (as per Investigator's judgement), it was possible to administrate a single dose of tocilizumab or sarilumab (in accordance with the actual recommendations), after the 24 hours from one of the study drug's administration.

On Day 15 primary endpoint of patient's clinical status (response to the study therapy) was assessed. The response to the therapy was considered as improvement of the patient's clinical status by at least 1 point on a 6-point COVID-19 scale in the absence of tocilizumab or sarilumab administration.

The last patient's visit in the study was the visit on Day 29. If the patient was discharged from the hospital earlier than Day 15 or Day 29, patient's clinical status at these visits were assessed by phone call.

The total expected duration of the study for each patient was not more than 31 days, including 48 hours of screening, 1 day of the study drug administration and 28 days of observation.

Arms:
arm 1: Subject randomized to receive subcutaneous single injection of 2 ml solution of RPH-104 on Day 1, in addition to standard therapy arm 2: Subject randomized to receive subcutaneous single injection of 0,4 ml solution of Olokizumab on Day 1, in addition to standard therapy arm 3: Subject randomized to receive subcutaneous single injection of 2 ml solution of Placebo on Day 1, in addition to standard therapy

Interventions: intervention 1: RPH-104 80 mg intervention 2: Olokizumab 64 mg intervention 3: Placebo
Intervention descriptions: intervention 1: solution for subcutaneous administration 40 mg/mL, 2 mL in the 4-mL glass vial intervention 2: solution for subcutaneous administration 160 mg/mL, in the 2-mL glass vial (target volume 0,4 ml) intervention 3: Normal Saline (0.9% Sodium Chloride solution for Injection), in the market package

Protocol document:
Prot_SAP_000.pdf: 
Clinical Study Protocol 
Protocol Number: CL04041078 
Sponsor: R-Pharm International LLC, Russia  
 
CONFIDENTIAL 
Version 3.0 dated April 26, 2020 
Page 1 of 78 
 
CLINICAL STUDY PROTOCOL 
Protocol Title: 
 
An International Multicenter Randomized Double-
blind Adaptive Placebo-controlled Study of the Efficacy 
and Safety of a Single Administration of Olokizumab 
and RPH-104 with Standard Therapy in Patients with 
Severe SARS-CoV-2 Virus Infection (COVID-19) 
Protocol ID: 
CL04041078  
 
Date of the Report: 
April 26, 2020 
Protocol amendment No: 
2 
Date of Protocol amendment 
issue: 
April 26, 2020 
Protocol version: 
Version 3.0 
Name and address of the clinical 
study Sponsor: 
 
R-Pharm International LLC, Russia  
Legal address and physical location: 123154, Russian Federation, 
Moscow, 19 Berzarina str., bldg. 1, floor 1, office V, room 9 
TIN 7734406215 
Phone: +7 (495) 956-79-37  
 
Full name, position of persons 
authorized on behalf of the 
Sponsor to sign the protocol and 
amendments to the protocol: 
 
Mikhail Samsonov, MD PhD. 
Chief Medical Officer, R-Pharm JSC 
Address: Moscow, Leninsky 111 bldg.1 
Phone: +74 959 567 937  
Email: samsonov@rpharm.ru 
Full name, position, address and 
telephone number of the medical 
experts appointed by the Sponsor 
for this study: 
Boris Berezhanskiy, 
Senior Medical Advisor of Medical Affairs Group,  R-Farm JSC 
Address: 119421 Moscow, 111 Leninsky Prospekt bldg. 1  
Phone: +7 (968) 776-81-37 
Email: berezhanskiy@rpharm.ru  
 
 
CONFIDENTIALITY STATEMENT 
 
The confidential information in this document is provided to you as an Investigator, member of 
the applicable Institutional Review Board/Independent Ethics Committee or Heath Authority 
Officer. The acceptance of this document constitutes agreement that you will not disclose the 
information contained herein to others without written authorization from R-Pharm International, 
unless it is necessary to obtain the consent of patients to participate in the study. 


Clinical Study Protocol 
Protocol Number: CL04041078 
Sponsor: R-Pharm International LLC, Russia  
 
CONFIDENTIAL 
Version 3.0 dated April 26, 2020 
Page 2 of 78 
 
These requirements come into force upon signing this protocol. 
 


Clinical Study Protocol 
Protocol Number: CL04041078 
Sponsor: R-Pharm International LLC, Russia  
 
CONFIDENTIAL 
Version 3.0 dated April 26, 2020 
Page 3 of 78 
 
TABLE OF CONTENTS 
 
CONFIDENTIALITY STATEMENT ....................................................................................................... 1 
SIGNATURE PAGE 1 (PRINCIPAL INVESTIGATOR) ...................................................................... 6 
SIGNATURE PAGE 2 (SPONSOR) ......................................................................................................... 7 
LIST OF ABBREVIATIONS ..................................................................................................................... 8 
DOCUMENT HISTORY .......................................................................................................................... 10 
CONTACT INFORMATION .................................................................................................................. 12 
1. SYNOPSIS OF THE STUDY PROTOCOL CL04041078 ................................................................ 14 
2. 
STUDY RATIONALE ................................................................................................................. 21 
2.1. Overview of data on pathogenesis, epidemiology and current treatment options for the disease .. 21 
2.2. Background information on the study therapy ............................................................................... 23 
2.2.1. 
RPH-104 .................................................................................................................................. 23 
2.2.2. 
Olokizumab ............................................................................................................................. 24 
2.3. Summary of known and potential risks and benefits for clinical trial subjects (risk/benefit ratio) 24 
2.3.1. 
Benefit evaluation ................................................................................................................... 24 
2.3.2. 
Risk evaluation ........................................................................................................................ 24 
2.3.3. 
Conclusions ............................................................................................................................. 27 
2.4. Rationale for study design .............................................................................................................. 27 
2.5. Justification for the route of administration, dose, dosage regimen, and treatment course ............ 28 
2.6. Justification for placebo use ........................................................................................................... 30 
2.7. Rationale for the choice of study population .................................................................................. 31 
2.8. Clinical study compliance with standard regulatory requirements................................................. 31 
3. 
STUDY OBJECTIVES AND ENDPOINTS ................................................................................. 32 
3.1. Study goal ....................................................................................................................................... 32 
3.2. Study objectives and their corresponding endpoints ...................................................................... 32 
4. 
STUDY DESIGN ........................................................................................................................... 34 
4.1. Description of the study design ...................................................................................................... 34 
4.2. Study flow chart ............................................................................................................................. 36 
5. 
STUDY POPULATION ................................................................................................................. 38 
5.1. Inclusion criteria ............................................................................................................................. 38 
5.2. Non-inclusion criteria ..................................................................................................................... 38 
5.3. Restrictions for patients during the study ....................................................................................... 39 
5.4. Exclusion criteria (early study termination) ................................................................................... 39 
6. 
STUDY THERAPY ....................................................................................................................... 40 
6.1. Doses and dosing schedules of the study drugs .............................................................................. 40 
6.2. Preparation of the study drugs for administration and the administration procedures ................... 40 
6.3. Overdose ......................................................................................................................................... 41 
6.3.1. 
Olokizumab overdose .............................................................................................................. 41 
6.3.2. 
RPH-104 overdose .................................................................................................................. 41 
6.4. Treatment compliance .................................................................................................................... 41 
6.5. Concomitant therapies .................................................................................................................... 42 
6.5.1. 
Allowed concomitant therapies ............................................................................................... 42 
6.5.2. 
Prohibited concomitant therapies ............................................................................................ 42 
6.6. Dosage form, packaging and labeling of the study drugs............................................................... 43 
6.6.1. 
Olokizumab  ............................................................................................................................ 43 
6.6.2. 
RPH-104 .................................................................................................................................. 43 
6.6.3. 
Placebo .................................................................................................................................... 44 
6.6.4. 
Labeling ................................................................................................................................... 44 
6.7. Handling of study drugs ................................................................................................................. 45 
7. 
SUBJECTIVITY MINIMIZATION/EXCLUSION MEASURES ................................................ 45 
7.1. Patient disposition by study site ..................................................................................................... 45 


Clinical Study Protocol 
Protocol Number: CL04041078 
Sponsor: R-Pharm International LLC, Russia  
 
CONFIDENTIAL 
Version 3.0 dated April 26, 2020 
Page 4 of 78 
 
7.2. Assignment of screening numbers.................................................................................................. 45 
7.3. Randomization................................................................................................................................ 46 
7.4. Blinding .......................................................................................................................................... 46 
7.5. Compliance with study therapy ...................................................................................................... 46 
8. 
STUDY PROCEDURES ................................................................................................................ 46 
8.1. Procedures of individual visits ....................................................................................................... 50 
8.1.1. 
Screening period ...................................................................................................................... 50 
8.1.2. 
Treatment period ..................................................................................................................... 51 
8.1.3. 
Follow-up period ..................................................................................................................... 52 
8.1.4. 
End-of-study visit .................................................................................................................... 53 
8.1.5. 
Study withdrawal visit ............................................................................................................. 54 
8.1.6. 
Additional unscheduled visits ................................................................................................. 54 
8.2. Description of individual study procedures .................................................................................... 55 
8.2.1. 
Obtaining written informed consent for participation in the clinical study ............................. 55 
8.2.2. 
Medical Consilium .................................................................................................................. 56 
8.2.3. 
Collection of demographic data, life history, medical history, and prior therapy ................... 57 
8.2.4. 
Evaluation of the results of SARS-CoV-2 PCR analysis ........................................................ 57 
8.2.5. 
Anthropometric parameters ..................................................................................................... 58 
8.2.6. 
Physical examination ............................................................................................................... 58 
8.2.7. 
Vital signs ................................................................................................................................ 58 
8.2.8. 
Laboratory tests ....................................................................................................................... 59 
8.2.9. 
Electrocardiography ................................................................................................................ 61 
8.2.10. 
Assessment of chest CT findings ............................................................................................ 61 
8.2.11. 
Determination of oxygenation parameters .............................................................................. 61 
9. 
EFFICACY ASSESSMENT .......................................................................................................... 62 
9.1. Assessment of treatment response .................................................................................................. 62 
9.2. Assessment of the clinical status of the patient .............................................................................. 62 
9.3. NEWS2 score ................................................................................................................................. 62 
9.4. Assessment of surrogate cytokine storm markers .......................................................................... 63 
9.5. Determination of oxygenation parameters ..................................................................................... 63 
9.6. Assessment of ARDS severity ....................................................................................................... 63 
10. SAFETY ASSESSMENT .............................................................................................................. 64 
10.1. Adverse events ............................................................................................................................... 64 
10.2. Serious adverse events (SAEs) ....................................................................................................... 64 
10.3. AE recording .................................................................................................................................. 64 
10.4. SAE reporting ................................................................................................................................. 66 
10.5. Independent Data Monitoring Committee ...................................................................................... 67 
10.6. Pregnancies ..................................................................................................................................... 67 
10.7. Actions in emergency situations ..................................................................................................... 68 
11. STATISTICAL ANALYSIS .......................................................................................................... 68 
11.1. Justification of the planned sample size  ........................................................................................ 68 
11.2. Analytical methods ......................................................................................................................... 69 
11.3. Analysis sets ................................................................................................................................... 69 
11.4. Demographic and other baseline characteristics ............................................................................ 70 
11.5. Efficacy analysis............................................................................................................................. 70 
11.6. Safety analysis ................................................................................................................................ 71 
11.7. Early analysis of the pilot phase ..................................................................................................... 71 
11.8. Interim analysis .............................................................................................................................. 71 
12. DATA MANAGEMENT AND RECORD KEEPING .................................................................. 71 
12.1. Study site documentation ............................................................................................................... 71 
12.2. Source documents........................................................................................................................... 71 
12.3. Data collection ................................................................................................................................ 72 
12.4. Data confidentiality ........................................................................................................................ 72 


Clinical Study Protocol 
Protocol Number: CL04041078 
Sponsor: R-Pharm International LLC, Russia  
 
CONFIDENTIAL 
Version 3.0 dated April 26, 2020 
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12.5. Document archiving ....................................................................................................................... 72 
13. QUALITY CONTROL AND QUALITY ASSURANCE ............................................................. 73 
13.1. Overall quality assurance information ............................................................................................ 73 
13.2. Quality guarantees .......................................................................................................................... 73 
13.3. Investigator's adherence to the protocol ......................................................................................... 73 
13.4. Protocol deviations ......................................................................................................................... 73 
13.5. Liability for non-compliance with the study requirements ............................................................ 73 
13.6. Study monitoring ............................................................................................................................ 74 
13.7. Sponsor’s audit ............................................................................................................................... 75 
13.8. Database management and quality control ..................................................................................... 75 
14. STUDY STOPPING RULES ......................................................................................................... 75 
15. ETHICAL ASPECTS ..................................................................................................................... 76 
16. CONFIDENTIALITY .................................................................................................................... 76 
17. FUNDING AND INSURANCE..................................................................................................... 76 
18. PUBLICATIONS ........................................................................................................................... 77 
19. REFERENCES ............................................................................................................................... 77 
 
 
LIST OF TABLES  
 
Table 1. Overview of adverse event profile: Number of patients with adverse events (study 
RPH104FIH01/CL04018045) ..................................................................................................................... 25 
Table 2. Schedule of study visits and procedures. ...................................................................................... 48 
Table 3. The list of parameters determined by individual laboratory tests, their specifics and frequency . 59 
Table 4. Planned sample size for final analysis ........................................................................................... 68 
 
 
LIST OF FIGURES 
 
Figure 1. Reduction in CRP levels after a SC injection of RPH-104: 20 mg (blue line), 40 (green line), 
80 mg (red line), 160 mg (yellow line) ....................................................................................................... 29 
Figure 2. Study flow chart ........................................................................................................................... 37 
Figure 3. The abdominal areas where the study drugs may be injected. ..................................................... 41 
Figure 4. Study enrollment scheme ............................................................................................................. 69 


Clinical Study Protocol 
Protocol Number: CL04041078 
Sponsor: R-Pharm International LLC, Russia  
 
CONFIDENTIAL 
Version 3.0 dated April 26, 2020 
Page 6 of 78 
 
SIGNATURE PAGE 1 (PRINCIPAL INVESTIGATOR) 
to version No. 3.0 of April 26, 2020 of the protocol “An International Multicenter Randomized 
Double-blind Adaptive Placebo-controlled Study of the Efficacy and Safety  of a Single 
Administration of Olokizumab and RPH-104 with Standard Therapy in Patients with Severe 
SARS-CoV-2 Virus Infection (COVID-19)” (protocol number: CL04041078) 
I, the undersigned, agree to the following: 
1.  I have completely reviewed the provisions of this protocol, accept them and undertake to 
conduct the study in accordance with this protocol, as well as in accordance with the 
requirements of the ICH GCP, the Helsinki Declaration, and the requirements of the 
national regulatory authorities of the participating countries.   
2. I will not depart from the protocol without the prior written permission of the Sponsor, 
approved by the regulatory authorities and local ethics committees/IRBs of the 
participating countries unless it is necessary to prevent any immediate harm to the subject 
of the study. 
3. I work with a team of qualified personnel, have the necessary equipment and enough time 
to conduct a study in accordance with this protocol. 
4. I will make all my efforts to ensure that all personnel involved in the study are adequately 
familiar with this protocol and correctly fulfill their responsibilities during the study.  
5. I agree with the audit and inspection procedures in accordance with the rules set by the 
Sponsor and state regulatory authorities. 
6.  I understand that the text of this protocol, as well as all other materials and the study results 
are confidential and are the property of the Sponsor. I undertake not to disclose them to 
third parties, except as otherwise provided by applicable laws of the participating countries.  
7. I agree to comply with all other requirements regarding the responsibilities of clinical 
Investigators, as well as all other important requirements of Good Clinical Practice. 
 
 
Principal Investigator: 
 
______________________________ 
Signature 
______________________________ 
 
Full name  
______________________________   
Date 
 
 
 


Clinical Study Protocol 
Protocol Number: CL04041078 
Sponsor: R-Pharm International LLC, Russia  
 
CONFIDENTIAL 
Version 3.0 dated April 26, 2020 
Page 7 of 78 
 
SIGNATURE PAGE 2 (SPONSOR) 
to version No. 3.0 of April 26, 2020 of the protocol “An International Multicenter Randomized 
Double-blind Adaptive Placebo-controlled Study of the Efficacy and Safety of a Single 
Administration of Olokizumab and RPH-104 with Standard  Therapy in Patients with Severe 
SARS-CoV-2 Virus Infection (COVID-19)” (protocol number: CL04041078) 
I, the undersigned, approve the study protocol and undertake to conduct the study in accordance 
with all protocol requirements.  
I hereby confirm that the protocol has been developed in accordance with the following standards: 
 
Ethical principles defined in the Helsinki Declaration. 
 
The International Council for Harmonisation (ICH) Guideline for Good Clinical Practice 
(GCP; document E6), current edition. 
 
All the applicable laws and regulatory documents, including (but not limited to) laws on 
data confidentiality, laws on disclosure of clinical study data, etc. 
 
 
Authorized Sponsor Representative: 
(  according to the Power of Attorney No. 25 dated 
May 14, 2018 issued by R-Pharm International 
LLC)  
 
 
______________________________ 
Signature 
Mikhail Samsonov, MD PhD  
 
                                                  
______________________________   
Date 
 


Clinical Study Protocol 
Protocol Number: CL04041078 
Sponsor: R-Pharm International LLC, Russia  
 
CONFIDENTIAL 
Version 3.0 dated April 26, 2020 
Page 8 of 78 
 
LIST OF ABBREVIATIONS 
AE 
Adverse event 
AESI 
Adverse events of special interest 
ALT 
Alanine aminotransferase  
AP 
Alkaline phosphatase  
ARDS 
Acute respiratory distress syndrome 
ARVI 
Acute respiratory viral infection 
AST 
Aspartate aminotransferase  
CI 
Confidence interval  
CoV 
Coronavirus 
COVID 
CPAP 
Coronavirus disease 
Constant positive airway pressure 
CRF 
Case report form  
CRP 
C-reactive protein 
CT 
Computed tomography  
EAEU 
Eurasian Economic Union 
ECG 
Electrocardiogram 
ECMO 
Extracorporeal membrane oxygenation 
ESR 
Erythrocyte sedimentation rate  
EU 
European Union  
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transferase 
GIT 
Gastrointestinal tract  
HCG 
Human chorionic gonadotropin 
HR 
Heart rate  
IC 
Informed consent  
ICH 
International Council for Harmonization of Technical Requirements for 
Pharmaceuticals for Human Use 
ICU 
Intensive Care Unit 
IDMC 
Independent Data Monitoring Committee 
Ig 
Immunoglobulin 
IL 
Interleukin  
INN 
International nonproprietary name  
ITT 
Intent-to-treat population 
mITT 
Modified ITT 
IWRS 
Interactive Web Response System 
LDL 
Low-density lipoprotein  
LFT 
Liver function tests 
LHD 
Last day of hospitalization 
MedDRA 
Medical Dictionary for Regulatory Activities 
MERS 
Middle East Respiratory Syndrome  
MoH 
Ministry of Health  
MV 
Mechanical ventilation 
NEWS 
National Early Warning Score 
OKZ 
Olokizumab 
OR 
Odds ratio 
PCR 
Polymerase chain reaction 
PE 
Primary endpoint 
PEEP 
Positive end expiratory pressure 
PI 
Principal Investigator  


Clinical Study Protocol 
Protocol Number: CL04041078 
Sponsor: R-Pharm International LLC, Russia  
 
CONFIDENTIAL 
Version 3.0 dated April 26, 2020 
Page 9 of 78 
 
RF 
Russian Federation 
RNA 
Ribonucleic acid  
RR 
Relative risk; respiratory rate 
SAE 
Serious adverse event 
SARS 
Serious acute respiratory syndrome 
SOP 
Standard Operating Procedure  
SUSAR 
Suspected unexpected serious adverse reaction 
TNF 
Tumour necrosis factor  
ULN 
Upper limit of normal 
USA 
United States of America 
WHO 
World Health Organization 
 
 


Clinical Study Protocol 
Protocol Number: CL04041078 
Sponsor: R-Pharm International LLC, Russia  
 
CONFIDENTIAL 
Version 3.0 dated April 26, 2020 
Page 10 of 78 
 
DOCUMENT HISTORY 
Rationale for Version 1.1: 
 clarification of inclusion criterion No. 4; addition of information about the procedure for 
conducting a council of physicians; addition of information on effective methods and terms 
of contraception for patients; the description of the procedures for individual visits has 
been adjusted in accordance with the visit schedule table; addition of information on the 
assessment of available safety data by an Independent data monitoring committee. 
The remaining changes/corrections were made to ensure the consistency of the protocol text, 
technical errors were corrected. 
Rationale for Version 2.0, with Amendment 1 incorporated: 
 based on the recommendations of the Ministry of Health of the Russian Federation, Version 
2.0 was withdrawn and is not used; only the changes specified in Version 3.0 should be 
considered.  
 
Rationale for Version 3.0 with Amendment 2 incorporated (all changes from Version 1.1 are 
indicated): 
 Section 2. Study rationale was adjusted and updated;  
 the study flow chart (Figure 2), the table with the schedule of study visits and procedures 
(Table 2) and the table of the specifics of laboratory tests (Table 3) were adjusted; 
 the duration of the screening period and the treatment period of the study was clarified, the 
term “calendar day” used in the study was defined;  
 it was allowed for the screening period to take into account results of laboratory tests, 
anthropometric data, and the patient’s medical history obtained outside the protocol before 
the screening period; the laboratory tests (complete blood count and blood chemistry tests) 
should be performed no earlier than 48 hours before randomization; 
 the procedures for Visit 15 were specified depending on ongoing hospitalization or 
discharge on the Visit 15 day; 
 the procedures for the end-of- study visit on Day 29 were specified; 
 the procedures for a withdrawal visit were described; 
 the inclusion criteria were clarified: criteria No. 3 and No. 5 were combined and adjusted 
as options for confirming the diagnosis of COVID-19; non-inclusion criterion No. 7 was 
added regarding the administration of plasma from COVID-19 convalescent donors; non-
inclusion criteria No. 1, No. 8, No. 9 and No. 12 were adjusted;  
 inaccuracies in the introductory information on the study therapy were corrected;  
 the maximum dose of OKZ used in previous studies was clarified (regarding overdose of 
the drug);  
 sections regarding the labeling of the primary and secondary packages of the study drugs 
were added;  
 information was added about the possibility of subcutaneous injections of the study drugs 
into additional areas of the patient’s body used for subcutaneous injection;  


Clinical Study Protocol 
Protocol Number: CL04041078 
Sponsor: R-Pharm International LLC, Russia  
 
CONFIDENTIAL 
Version 3.0 dated April 26, 2020 
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 it was clarified that concomitant standard therapy of COVID-19 adopted at the institution 
may include drugs other than those indicated in the list of drugs prohibited during the study; 
examples of INNs from classes of prohibited drugs were provided;  
 the administration of plasma from COVID-19 convalescent donors was added to the list of 
drugs prohibited during the study; 
 tocilizumab and sarilumab were excluded from the list of prohibited drugs; instructions 
were given on the possible use of tocilizumab or sarilumab in the absence of improvement 
in the patient's condition by Investigator's discretion within 24 hours after the 
administration of one of the study drugs;  
 information on the procedure for assigning numbers to study centers and screening 
numbers for patients was updated;  
 Section 8.2.2. Medical Consilium was adjusted; 
 the information that should be obtained when collecting the history of allergies and 
information about bad habits, medical history, previous and concomitant diseases, as well 
as data on previous and concomitant therapy, was described in detail;  
 clarification was added that the physical examination procedures are optional and depend 
on the specifics of the organization of work with patients with the new coronavirus 
infection (for example, personal protective equipment, patient's position in the ICU, etc.);  
 the assessment of the results of PCR analysis and their recording were described in detail; 
 the procedure for evaluating chest CT results was described in detail; 
 a definition of “response to treatment” was given for this protocol; 
 the procedure for evaluating and recording the clinical status of a patient in intensive care 
was clarified; 
 the correct current version of the NEWS2 scale was added;  
 the contact details of the medical expert appointed by the Sponsor for this study, as well as 
of the responsible project manager, were corrected; 
 the list of countries expected to take part in the study was updated; 
 the statistical section was updated; the calculated newly planned sample size was indicated 
(the expected number of patients randomized in the pilot phase of the study and in total), 
the analytical methods were described; the mITT analysis population was introduced; 
information about the planned early analysis of the pilot phase of the study was updated. 
The remaining changes/corrections were made to ensure the consistency of the protocol text, and 
technical errors were corrected. 
 


Clinical Study Protocol 
Protocol Number: CL04041078 
Sponsor: R-Pharm International LLC, Russia  
 
CONFIDENTIAL 
Version 3.0 dated April 26, 2020 
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CONTACT INFORMATION 
Study Sponsor: R-PHARM INTERNATIONAL LLC  
The study is conducted by: R-Farm JSC, 119421, Russia, Moscow, Leninsky Prospekt 111/1; 
+7 (495) 956-79-37 
 
NAME 
Function 
Contact 
Mikhail  
Samsonov 
Chief Medical Officer, R-
Pharm JSC 
Phone:  +7 (985) 997-39-02 
e-mail:  
samsonov@rpharm.ru 
Sergey Grishin 
Head of Scientific Affairs 
Group, Head of Drug Safety 
and Pharmacovigilance, R-
Pharm JSC 
Phone:  
+7 (963) 683-05-71 
e-mail:  
sa.grishin@rpharm.ru 
Boris 
Berezhanskiy 
 
Chief Medical Advisor, 
Medical Support Group, 
R-Farm JSC 
Phone:  +7 (968) 776-81-37 
e-mail:  
berezhanskiy@rpharm.ru 
Anastasia 
Alexandrova 
Head of Quality 
Assurance and Control, 
Medical Department, 
MD, MRQA, R-Pharm 
JSC 
Phone: +7 (926) 098 26 10 
e-mail: av.aleksandrova@rpharm.ru 
Ilya Khimunin 
Project manager, 
R-Pharm JSC  
Phone: +7 (915) 090-20-07 
e-mail:  
khimunin@rpharm.ru 
 
EMERGENCY COMMUNICATION CONTACT 
For medical advice in an emergency, please, contact Boris Berezhanskiy, the on-duty expert on 
medical issues: 
 
 
When reporting serious adverse events, the procedures described in Section 10.4 SAE reporting 
should be followed. Investigators should inform the Sponsor about the development of serious 
adverse events within 24 hours of first becoming aware of the event. The completed SAE 
notification form should be sent to the following number/ email address:  
 
Emergency contact number 
+7 (968) 776-81-37 
Contact information for SAE reporting (24-hour) 
Fax: +7 (495) 956-79-38 
Safety@Rpharm.ru 


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CONFIDENTIAL 
Version 3.0 dated April 26, 2020 
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Full name and positions of Investigators responsible for conducting the study with addresses 
and phone numbers of the clinical (study) sites 
The list of study sites involved in this clinical study (name, address and telephone number of each 
study site) is presented in a separate List of Study Sites and Principal Investigators. 
Names and addresses of clinical and other medical and/or technical services and/or 
organizations involved in the study 
 
No. 
Name of the institution  
Study role: 
Address of the 
institution 
Phone, fax, email  
1. 
K-Research LLC 
Applicable to the 
study in the Russian 
Federation: 
preparation of 
clinical study 
documents and 
biostatistics; clinical 
study monitoring 
214019, Russia, 
Smolensk region, 
Smolensk, Marshal 
Konev passage, 29, 
building 43 
Contact person: 
Julia Kramanovich,  
Phone: +7 (4812) 
67-00-94; 
e-mail: 
julia.kramanovich
@cromospharma.c
om 
 
2.  Data Management 365 
LLC 
Applicable to the 
study in the Russian 
Federation: 
data management 
(access to the 
database, its 
configuration, 
adaptation, 
modification, 
validation, testing, 
maintenance; 
development of 
eCRF, randomization 
and drug 
management (IWRS) 
197022, Russia, St. 
Petersburg, 
str. Vsevolod 
Vishnevsky, bldg. 12, 
letter A 
 
Contact Person: 
Anna Polikarova 
Phone: +7 (812) 
426-73-07 
e-mail: 
anna.polikarova@d
atamanagement365.
com 


Clinical Study Protocol 
Protocol Number: CL04041078 
Sponsor: R-Pharm International LLC, Russia  
 
CONFIDENTIAL 
Version 3.0 dated April 26, 2020 
Page 14 of 78 
 
1. SYNOPSIS OF THE STUDY PROTOCOL CL04041078 
Protocol ID: 
CL04041078 
Study title: 
An International Multicenter Randomized Double-blind Adaptive 
Placebo-controlled Study of the Efficacy and Safety of a Single 
Administration of Olokizumab and RPH-104 with Standard Therapy in 
Patients with Severe SARS-CoV-2 Virus Infection (COVID-19) 
Clinical study phase: 
II/III phase 
Type of study: 
interventional 
Study Sponsor: 
R-Pharm International LLC, Russia 
Legal address and actual address: 123154, Russian Federation, 
Moscow, 19 Berzarina str., bldg. 1, floor 1, office V, room 9 
Phone: +7 (495) 956-79-37 
Investigational 
drugs: 
RPH-104, solution for subcutaneous injection, 40 mg/ml 
Olokizumab (OKZ), solution for subcutaneous injection, 160 mg/ml 
Reference product: 
Placebo 
Study sites: 
The study will be conducted in approximately 20 clinical sites of the 
Russian Federation. Study sites in the Republic of Belarus, Republic of 
Armenia, Georgia, Turkey, and EU countries are expected to open later. 
The list of study sites involved in this clinical study (name, address and 
telephone number of each study site) is presented in a separate List of 
Study Sites and Principal Investigators. 
Study rationale 
In December 2019, an outbreak of viral pneumonia of unknown etiology 
was detected by the public health authorities in Wuhan City, Hubei 
Province (China). Soon, coronavirus RNA was isolated from the cells 
of some patients. This newly discovered virus was named SARS-CoV-
2, and the disease caused by this virus was named COVID-19. Severe 
COVID-19 may be complicated by the development of the life-
threatening syndrome of a cytokine storm, with IL-1 and IL-6 playing a 
key role in the pathogenesis. There are currently no approved drugs for 
the treatment of COVID-19. 
Study goal: 
Evaluation of the efficacy and safety of RPH-104 (at a dose of 80 mg) 
or OKZ (at a dose of 64 mg) after a single administration compared with 
placebo in patients with severe SARS-CoV-2 virus infection (COVID-
19) 
Study objectives: 
Primary objective:  
1. To assess the efficacy of a single administration of RPH-104 
(80 mg) or OKZ (64 mg) compared with placebo in patients 
with severe SARS-CoV-2 virus infection (COVID-19) on Day 
15 of the study. 
Secondary objectives: 
1. To evaluate the effect of a single administration of RPH-104 
(80 mg) or OKZ (64 mg) compared with placebo on clinical 
status changes in patients with severe SARS-CoV-2 virus 
infection (COVID-19) during the study. 
2. To compare mortality rates in the groups of single 
administration of RPH-104 (80 mg), OKZ (64 mg) or placebo 
in patients with severe SARS-CoV-2 virus infection (COVID-


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1. SYNOPSIS OF THE STUDY PROTOCOL CL04041078 
19). 
3. To compare the length of stay in the ICU, the duration of 
oxygen support and clinical parameters between the groups of 
single administration of RPH-104 (80 mg), OKZ (64 mg) or 
placebo in patients with severe SARS-CoV-2 virus infection 
(COVID -19) receiving the standard therapy. 
4. To assess the safety of a single administration of RPH-104 (80 
mg) or OKZ (64 mg) in patients with severe SARS-CoV-2 virus 
infection (COVID-19) 
Study design: 
This study is a multicenter randomized double-blind adaptive placebo-
controlled clinical trial of phase II/III, evaluating the efficacy and safety 
of a single administration of RPH-104 80 mg or OKZ 64 mg compared 
with placebo (1: 1: 1) in patients with severe SARS-CoV-2 virus 
infection (COVID-19) receiving standard care. 
The study will consist of two phases: 
• 
the pilot phase: inclusion and randomization of the first 189 
patients (63 patients in each group of OKZ, RPH-104, 
placebo), followed by an early analysis of efficacy and 
safety data, based on which the sample size will be finally 
defined; 
• 
the main phase is the further recruitment of patients and the 
conduct of all procedures prespecified in  the protocol.  
After inclusion of a patient in the study (signing the Informed Consent 
Form or the decision of the Principal Investigator to enroll the patient 
following a recommendation of the medical consilium), the Investigator 
will assess the patient's condition to check whether the patient meets the 
eligibility criteria. Eligible patients will be randomized to one of three 
treatment groups for a single subcutaneous injection of RPH-104 80 mg 
or OKZ 64 mg or placebo. Next, a follow-up will be performed during 
the hospitalization period (Day 1 - Day 15 or the last day of 
hospitalization (LHD), whichever comes first). This is followed by a 
follow-up period from the LHD or Day 15 (whichever is earlier) until 
Day 29. Throughout the study, standard COVID-19 therapy accepted at 
the institution is allowed, except for drugs that are not allowed by this 
protocol throughout the study, as well as tocilizumab and sarilumab 
during the first 24 hours after administration of the study drugs. In the 
absence of improvement in the patient's condition, as judged by the 
Investigator, a single administration of tocilizumab or sarilumab is 
allowed 24 hours after the administration of one of the study drugs, in 
accordance with current recommendations. On Day 15, the primary 
endpoint of the study, response to treatment, is assessed. A response to 
treatment means an improvement in the clinical status of the patient by 
at least 1 point on the 6-point COVID-19 scale with no use of 
tocilizumab or sarilumab. The last study visit is the visit on Day 29. If 
the patient is discharged from the hospital before Day 15 or Day 29, the 
visit procedures will be performed via a telephone call. 
Study schedule: 
The study will include the following periods: 


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Sponsor: R-Pharm International LLC, Russia  
 
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1. SYNOPSIS OF THE STUDY PROTOCOL CL04041078 
 screening period for no more than 48 hours before the sturt 
of  the day of randomization (Day 1). During the screening 
period, an assessment is performed to determine whether the 
patient meets the eligibility criteria; 
 treatment period lasting from the end of screening (which 
is the start of Day 1) to 23:59 Day 1, including randomizing 
patients into treatment groups and then a single 
administration of the study drug; 
 follow-up period , lasting from 00:00 Day 2 - to 23:59 Day 
29, including an assessment of the efficacy and safety after 
administration of a study drug. 
The total duration of 
the study:  
The total expected duration of the study for each patient will be not more 
than 31 days, including 48 hours of screening, 1 day of study drug 
administration and 28 days of observation. 
Planned sample size: 
Preliminary sample size: 372 randomized patients.  
The first phase of the study will include 189 patients (63 patients in each 
group of OKZ, RPH-104 or placebo). After analyzing the data of 189 
patients, a decision will be made about the final sample size. 
Population: 
Male and female patients over the age of 18 years (inclusive) diagnosed 
with COVID-19 and hospitalized with a severe illness  in the sites of the 
Russian Federation, Republic of Belarus, Republic of Armenia, 
Georgia, Turkey, and EU member states. 
Inclusion criteria: 
1. Male or female patient aged 18 years (inclusive) or older (at the 
beginning of the screening period). 
2. The presence of a voluntarily signed and dated Patient Informed 
Consent Form for participation in this study, or a record of an 
Medical Consilium decision justifying patient’s participation in case 
of patient is unable to state his/her will. 
3. Having either of the following COVID-associated respiratory 
syndromes: 
• 
Pneumonia with oxygen saturation SpO2 ≤ 93% (on room air) 
or RR greater than 30/min; 
• 
ARDS (PaO2/FiO2 ≤ 300 mmHg or SpO2/FiO2 ≤ 315 if PaO2 
is not available). 
4. A diagnosis of COVID-19 based on:  
• 
Laboratory confirmed f SARS-CoV-2 infection as determined 
by PCR  
OR 
• 
Bilateral changes in the lungs characteristic of COVID-19 on 
chest CT. 
Non-inclusion 
criteria 
1. A history of hypersensitivity to the study drugs (RPH-104 and/or 
OKZ), and/or their components.  
2. The presence of any of the following laboratory deviations: 
- absolute neutrophil count <0.5 x 109/l, 
- white blood cell count <2 x 109/l, 
- platelet count <50 x 109/l, 
- ALT and/or AST ≥ 3.0 x ULN. 


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Protocol Number: CL04041078 
Sponsor: R-Pharm International LLC, Russia  
 
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1. SYNOPSIS OF THE STUDY PROTOCOL CL04041078 
3. Severe renal failure: creatinine clearance <30 ml/min.  
4. Septic shock (vasopressors are required to maintain mean arterial 
pressure ≥65 mm Hg and lactate ≥ 2 mmol/L in the absence of 
hypovolemia). 
5. The disease progresses to death over the next 24 hours, regardless of 
treatment, according to Investigator. 
6. Perforation of the gastrointestinal tract, a history of diverticulitis 
7. Administration of plasma from COVID-19 convalescent donors 
within 4 weeks before study enrollment and/or planned 
administration during the study. 
8. Recent (less than 5 elimination half-lives) use of tocilizumab or 
sarilumab. 
9. Recent (less than 5 elimination half-lives) or planned use during the 
study of: 
- biologics 
(except 
RPH-104 
or 
OKZ) 
with 
immunosuppressive effect, including, but not limited to: 
IL-1 inhibitors (anakinra, rilonacept, canakinumab), IL-
6 inhibitors (except tocilizumab and sarilumab), IL-17A 
inhibitors (secukinumab), tumor necrosis factor α 
(TNFα) inhibitors (infliximab, adalimumab, etanercept, 
etc.), anti-B-cell drugs, etc.; 
- other immunosuppressive drugs (with the exception of 
methotrexate in a dose of up to 25 mg/week), including, 
but not limited to:  
 high doses of glucocorticoids (equivalent to 
prednisolone > 1 mg/kg) orally or parenterally; 
 JAK kinase inhibitors; cyclophosphamide, etc.  
10. Concurrent participation in another clinical trial. 
11. Pregnancy, breastfeeding.  
12. A history of active tuberculosis, or active tuberculosis suspected 
by the Investigator.  
Concomitant 
therapy drugs: 
Throughout the study, it is allowed to use standard COVID-19 therapy 
accepted at the institution, with the exception of drugs that are not 
allowed by this protocol throughout the study, as well as tocilizumab 
and sarilumab during the first 24 hours after administration of the study 
drugs. Tocilizumab or sarilumab at the doses recommended for the 
treatment of this disease may be added to concomitant therapy in the 
absence, in the Investigator's opinion, of improvement in the patient's 
condition within 24 hours after the administration of one of the study 
drugs. 
Prohibited or not 
planned drugs: 
The following medications are prohibited throughout the study: 
 immunosuppressive biologics (with the exception of 
RPH-104 or OKZ), including, but not limited to: IL-1 
inhibitors (anakinra, rilonacept, canakinumab), IL-6 
inhibitors (except tocilizumab and sarilumab), IL-17A 
inhibitors (secukinumab), tumor necrosis factor α 


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Protocol Number: CL04041078 
Sponsor: R-Pharm International LLC, Russia  
 
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Version 3.0 dated April 26, 2020 
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1. SYNOPSIS OF THE STUDY PROTOCOL CL04041078 
(TNFα) inhibitors (infliximab, adalimumab, etanercept, 
etc.), anti-B-cell drugs, etc.; 
 other immunosuppressors (with the exception of 
methotrexate in a dose of up to 25 mg/week), including, 
but not limited to:  
- high-dose glucocorticoids (> 1 mg / kg of prednisolone 
equivalent) orally or parenterally;  
- JAK inhibitors; cyclophosphamide and others; 
 administration of plasma from COVID-19 convalescent 
donors;  
 during the first 24 hours after the administration of the 
study drugs, the use of tocilizumab and sarilumab is 
prohibited. 
Efficacy assessment 
Primary endpoint: 
1. Proportion of responders in each treatment group   
A responder is a patient who has not received tocilizumab or 
sarilumab and who has a clinical status improvement of ≥1 point 
on the 6-point COVID-19 scale (where 1 is the most favorable 
outcome and 6 is the most undesirable outcome) 15 days after 
the administration of the study drug. 
Secondary Endpoints: 
1. Change over time in the clinical status of patients using a 6-point 
ordinal scale  
2. The proportion of patients with an improvement in clinical status 
by 2 or more points on the 6-point ordinal scale during the study 
with no use of tocilizumab or sarilumab 
3. The proportion of patients who received tocilizumab or 
sarilumab for COVID-19 during the follow-up period 
4. Mortality during the follow-up period 
Exploratory Endpoints: 
1. The proportion of patients with a score of ≤ 4 using the National 
Early Warning Score 2 (NEWS2) for 2 consecutive days; 
2. The proportion of patients with a score of ≤ 2 using the National 
Early Warning Score 2 (NEWS2) for 2 consecutive days; 
3. Time to reaching a NEWS2 score ≤ 4 for 2 consecutive days; 
4. Time to reaching a NEWS2 score ≤ 2 for 2 consecutive days; 
5. Change from baseline in the level of surrogate markers of the 
cytokine storm: leukocytes, lymphocytes, neutrophils, CRP, 
ferritin (if applicable), D-dimer (if applicable); 
6. Mortality during an ICU stay, at study days 7, 15, 29; 
7. Time to reaching SpO2≥94% without oxygen support, for 2 
consecutive days; 
8. Change from baseline in the oxygenation index of PaO2/FiO2 
(if applicable) during hospitalization; 
9. Duration of stay in ICU, in days;   
10. Change from baseline in ARDS severity defined according to 
WHO criteria (if applicable); 


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Protocol Number: CL04041078 
Sponsor: R-Pharm International LLC, Russia  
 
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1. SYNOPSIS OF THE STUDY PROTOCOL CL04041078 
11. Time to ARDS improvement according to the WHO criteria by 
one category compared to baseline (if applicable);  
12. Duration of mechanical ventilation and/or ECMO (if 
applicable), in days; 
13. Duration of oxygen support (if applicable), in days; 
14. Time until resolution of fever, i. e. axillary body temperature 
<38 °C without the use of antipyretics for 2 consecutive days (if 
applicable); 
15. Time to clinical status improvement by 1 point on the 6-point 
COVID-19 scale; 
16. Time to clinical status improvement by 2 points on the 6-point 
COVID-19 scale; 
17. The proportion of patients with a clinical status worsening by 1 
point on the 6-point COVID-19 scale during the study (if 
applicable); 
18. The proportion of patients with a clinical status worsening by 1 
point on the 6-point COVID-19 scale during the study, 
excluding patients moving to category 6 (if applicable); 
19. Time to a clinical status worsening by 1 point on the 6-point 
COVID-19 scale (if applicable). 
Safety assessment: 
Endpoints for safety assessment: 
1. Incidence, severity, nature and outcomes of AEs (grades 4 and 5 
according to CTCAE v.5.0) and SAEs during the study; 
2. The proportion of patients with AEs (grades 4 and 5 according to 
CTCAE v.5.0) and SAEs; 
3. Changes in physical examination findings, vital signs, and laboratory 
safety parameters during the study 
Ethical and 
regulatory aspects: 
The study will be conducted in full compliance with this protocol, the 
requirements of ICH GCP E6 R2, the principles of Good Clinical 
Practice of the EAEU, Russian National Standard P52379-2005 “Good 
Clinical Practice”, Order 200н “On Approval of the Principles of Good 
Clinical Practice”, ethical principles of the Helsinki Declaration, the 
latest revision, as well as current legislation and regulatory requirements 
of the participating countries 
Statistical 
Methodology and 
Analysis Steps 
Justification of the planned sample size: there are no reliable data on 
the course of COVID-19 disease and the distribution of hospitalized 
patients by the severity of the disease after receiving standard therapy 
and the study drugs. The study will include a pilot phase recruiting 63 
patients in each treatment group. The final sample size will be 
determined based on analysis of the results of the pilot phase.  
If about 60% of patients enrolled in the study fall into category 4 
on the clinical status scale (“Hospitalized, supplemental oxygen with 
independent breathing”) and about 40% fall into category 5 
(“Hospitalized, mechanical ventilation (invasive/non-invasive) or 
ECMO”), the estimated proportion of patients responding to treatment 
will be 40% in the placebo group and 60% in the active therapy groups. 
To demonstrate the superiority of any of the study drugs over placebo 


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1. SYNOPSIS OF THE STUDY PROTOCOL CL04041078 
with a statistical power of 80% and a general critical level of α = 2.5%, 
372 patients will have to be randomized (taking into account 20% drop-
out). 
Efficacy analysis: in this study, the proportion of patients responding 
to treatment in each of the therapy groups is the primary endpoint. A 
responder is a patient who has not received tocilizumab or sarilumab 
and who has a clinical status improvement of ≥1 point on the 6-point 
COVID-19 scale (where 1 is the most favorable outcome and 6 is the 
most undesirable outcome) 15 days after the administration of the study 
drug. 
To compare each of the active therapy groups with placebo relative risks 
[RR] with a bilateral 97.5% CI (the ratio of the probability of response 
in each of the active treatment groups to the probability of response in 
the placebo group) will be calculated by mathematical modeling 
methods. To test a superiority hypothesis for each of the active drugs 
compared with placebo, the null hypothesis RR ≤ 1 will be tested with 
a statistical power of 80% at a general critical level of α = 2.5% for each 
of the comparisons. 
Safety analysis: safety analysis will be performed by descriptive 
statistics methods in the safety population and the population of patients 
who received the study treatment and who did not receive tocilizumab 
or sarilumab; additionally, data from the subgroup of patients who 
received tocilizumab or sarilumab as part of standard therapy will be 
separately summarized and presented. The safety assessment will 
include the following parameters: 
• The frequency, severity, nature and outcome of AEs (grades 4 
and 5 according to CTCAE v.5.0) and SAEs during the study; 
• The frequency of AEs and/or SAEs related to the study drugs 
in the treatment groups; 
• Key vital signs (blood pressure, pulse rate, respiratory rate, 
body temperature); 
• Results of laboratory and instrumental investigations; 
• Changes in physical examination findings, vital signs and 
laboratory safety indicators during the study. 
 


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Sponsor: R-Pharm International LLC, Russia  
 
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2. STUDY RATIONALE 
2.1. Overview of data on pathogenesis, epidemiology and current treatment options 
for the disease 
At the end of 2019, an outbreak of a new coronavirus infection occurred in the People's 
Republic of China with an epicenter in Wuhan (Hubei Province), causing by pathogen 
provisionally named 2019-nCoV. 
On February 11, 2020, the World Health Organization assigned the official name to the 
infection caused by the new coronavirus, COVID-19 ("Coronavirus disease 2019"). The 
International Committee on Taxonomy of Viruses on February 11, 2020 officially named the 
infectious agent as SARS-CoV-2. 
Coronaviridae is a large family of RNA viruses that can infect humans and some animal 
species. In humans, coronaviruses can cause a range of diseases, from mild forms of acute 
respiratory infection to severe acute respiratory syndrome (SARS). Currently, it is known that four 
coronaviruses (HCoV-229E, -OC43, -NL63, and -HKU1) circulate in the population and occur 
year-round in the pattern of acute respiratory viral infections being the cause of mostly mild and 
moderate damage to the upper respiratory tract. 
Until 2002, coronaviruses were considered as agents causing mild diseases of the upper 
respiratory tract (with extremely rare fatal outcomes). At the end of 2002, emerged the new 
coronavirus SARS-CoV being the causative agent of atypical pneumonia and SARS in humans. 
In total, over the period of the epidemic in 37 countries, more than 8,000 cases were recorded, of 
which 774 were fatal. Since 2004, no new cases of atypical pneumonia caused by SARS-CoV have 
been reported. 
In 2012, the world faced the new MERS coronavirus (MERS-CoV), the causative agent of 
the Middle East respiratory syndrome. Since the emergence of the new virus strain until January 
31, 2020, 2519 cases of coronavirus infection caused by the MERS-CoV virus were reported with 
866 fatal cases. Currently, MERS-CoV continues to circulate and cause new cases of the disease. 
The new SARS-CoV-2 coronavirus (name assigned by the International Committee on 
Taxonomy of Viruses on February 11, 2020) is a single-stranded RNA-containing virus that 
belongs to the Coronaviridae family, Beta-CoV B lineage. The virus is assigned to pathogenicity 
group II, like some other members of this family (SARS-CoV virus, MERS-CoV virus). 
SARS-CoV-2 coronavirus is thought to be a recombinant virus containing sequences of bat 
coronavirus and a coronavirus of unknown origin. The genetic sequence of SARS-CoV-2 is similar 
to the sequence of SARS-CoV by at least 79%. 
Initially, the virus was widely spread in the territory of the People's Republic of China 
(PRC), where confirmed cases of the disease were reported in all administrative entities. The 
largest number of cases was detected in the southeastern part of China with an epicenter in Hubei 
province (more than 80% of cases). 
Imported cases of COVID-19 have been reported in more than 190 countries, some of them 
have been associated with trips to China, and since late February 2020, with trips to Italy, South 
Korea, and Iran. In many countries, cases were not associated with visiting China. Since March 
11, 2020, WHO has announced the COVID-19 pandemic. 
The initial source of infection has not been identified. The first cases of the disease could 
be associated with a visit to the seafood market in Wuhan (Hubei Province), where poultry, snakes, 
bats and other animals were sold. 
Currently, the main source of infection is a sick person, including those in the incubation 
period of the disease. 
The infection is transmitted through airborne droplets (with coughing, sneezing, talking), 
airborne dust and contact routes. Transmission factors are air, food and household items 
contaminated with SARS-CoV-2. 


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The emergence of COVID-19 posed challenges for healthcare professionals due to the need 
in rapid diagnosis and the provision of medical care to patients. Currently, information on the 
epidemiology, clinical features, prevention and treatment of this disease is limited. Immunity to 
the infections caused by other members of the coronavirus family is not persistent and re-infection 
is possible [1]. 
The most common symptoms of COVID-19 are fever (83-98%), cough (46-82%), myalgia 
and weakness (11-44%), shortness of breath (31%) [2, 3]. According to preliminary estimates, 
about 80% of patients with COVID-19 have mild or asymptomatic disease, 13.8% of cases are 
moderate and severe, and 6.1% of cases develop respiratory/multiple organ failure and septic 
shock. According to various estimates, mortality is up to 4%, which is less than mortality due to 
pneumonia (12-15%), but higher than mortality due to influenza (about 0.1-0.5%, depending on 
the strain). Acute respiratory distress syndrome (ARDS) is observed in 17-29% of cases in the 
Chinese cohort of patients [2], and kidney damage is reported in 2.5% [4]. The basis of ARDS 
pathogenesis is hyperactivation of innate immunity, while IL-1 levels correlate with lung damage 
[5]. 
High levels of cytokines and chemokines in the blood were observed in patients with 
COVID-19 infection: IL1-β, IL-1RA, etc. [6]. However, only elevated levels of IL-6 and the 
receptor for IL-2 were predictors of severe disease [7]. The risk of death increases in patients older 
than 60 years with comorbid diseases. In such patients, the acquired immune response can be 
weakened and more compensated by the innate immune response, which not only leads to the 
elimination of the virus, but also causes extensive tissue damage as the patient develops a cytokine 
storm that accompanies ARDS. 
Currently a vaccine to prevent SARS-CoV-2 infection and the development of COVID-19, 
as well as approved drugs for the etiotropic treatment of Coronavirus infection are not available. 
As of today the treatment of coronavirus infection is based on symptomatic therapy and 
minimizing disease complications [1]. 
At the same time, mathematical epidemiological models predict a further spread of the 
disease and an increase in the number of cases. Thus, the development of new drugs for the 
treatment of coronavirus infection is currently an acute challenge health systems are facing 
worldwide.   
Scientists around the world are making efforts to assess and study the new antiviral drugs 
for the treatment of COVID-19, as well as drugs for the treatment of the cytokine storm, a 
formidable complication of COVID-19 and the cause of a high mortality rate.  
It is expected that the most effective drugs for the treatment of cytokine storms will be drugs 
from the group of IL-6 and IL-1 blockers. Many researchers consider the use of glucocorticoids to 
be dangerous because of the increased risk of infections and prothrombotic effects [8]. There is 
evidence of the successful use of IL-1 inhibitors in the treatment of patients with a cytokine storm 
during sepsis [9-11]. Tocilizumab has successfully passed clinical trials and was approved for the 
treatment of a cytokine storm during the CAR-T immunotherapy [12]. In an open-label, 
retrospective, non-comparative study, the efficacy of the IL-6 receptor blocker tocilizumab was 
demonstrated in 21 patients with severe COVID-19 [13]. A randomized controlled phase IV trial 
(ChiCTR2000029765) of tocilizumab was initiated in China (188 patients are expected to be 
enrolled by May 10, 2020). In addition, a double-blind, randomized, placebo-controlled phase 
II/III trial (NCT04315298) of sarilumab, another IL-6 receptor blocker (400 patients planned), was 
initiated in the United States. In addition, numerous studies have been initiated in China and Italy 
to assess the efficacy of IL-6 inhibitors in the treatment of patients with severe COVID-19 
(NCT04315480, NCT04306705, NCT04310228, NCT04317092). 
An open, non-comparative study conducted in February 2020 in China in patients with 
severe COVID-19 showed the efficacy of tocilizumab used together with the standard care. After 
the drug administration, a reduction of fever and a significant improvement in other symptoms 
were observed. The need for additional oxygen therapy decreased in 75% of patients (15 out of 20 


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patients), oxygen therapy was completely canceled in one patient due to a condition improvement. 
The relative number of lymphocytes that was increased in 85% of patients before treatment (mean 
15.52 ± 8.89%) after the administration of tocilizumab returned to normal in 52.6% of patients. 
Positive changes were also observed in CT scans of the lungs. Initially elevated CRP decreased 
significantly in 84.2% of patients. At the same time there were no adverse events clearly associated 
with the drug. 90.5% of patients were discharged on average 13.5 days after the use of tocilizumab, 
the health status of the remaining patients also improved over time [13]. Considering that this study 
had an open label design without comparison groups, the results obtained require further 
evaluation and study. 
2.2. Background information on the study therapy 
Currently R-Pharm is developing two biological products: RPH-104 (a fusion protein that 
selectively binds IL-1β) and olokizumab (a humanized monoclonal antibody that binds IL-6). Both 
IL-1 and IL-6 are the key cytokines involved in the inflammation, and blocking effect of the 
biological agents is currently successfully used in the treatment of a wide range of auto-
inflammatory diseases, rheumatoid arthritis, giant cell arteritis, cytokine storm, and etc. Both R-
Pharm drugs are administered subcutaneously. 
Detailed information on the physicochemical and pharmacological properties, as well as 
the results of preclinical and clinical studies of the formulations is contained in the current versions 
of the RPH-104 and OKZ Investigator Brochures. 
2.2.1.  RPH-104 
The RPH-104 molecule is a fusion protein that selectively binds and inactivates IL-1β. 2 
active parts of this molecule are responsible for the binding of RPH-104 to IL-1β: the extracellular 
part of the human type 1 IL-1 receptor and part of the human IL-1 receptor accessory protein (IL-
1RAcP), which is the co-receptor of IL-1.  
The RPH-104 has passed the full range of preclinical studies in vitro and in vivo and 
entered the clinical development phase. In vivo studies have shown good tolerability of the drug 
in animals. 
The RPH-104 formulation has linear pharmacokinetics and a two-phase excretion profile 
in animals and humans, indicating the presence of a distribution phase and an excretion phase. 
Following subcutaneous administration in preclinical animal studies, the bioavailability of the drug 
was 52-85%.  
In 2018, the first clinical study RPH104FIH01 was completed to evaluate the tolerability, 
safety, pharmacokinetics, pharmacodynamics and immunogenicity of RPH-104 in healthy male 
and female volunteers in Turkey.  
During the use of RPH-104 in healthy volunteers, there were no reported cases of serious 
adverse events (SAE), as well as adverse events (AE) that led to the withdrawal from the study. 
Only 70 AEs were reported during the entire period of the study. All reported AEs in all dose 
groups were mild and resolved completely without sequelae. Thus, a study in healthy male and 
female volunteers demonstrated the safety and good tolerability of single subcutaneous injection 
of RPH-104 at doses from 4 mg to 160 mg [14].  
To date, RPH-104 is undergoing clinical trials phase II/III in patients with gout 
(CL04018054) and idiopathic recurrent pericarditis (CL04018068) in the Russian Federation, the 
study of RPH-104 in Schnitzler syndrome was approved in the USA (CL04018066) and the study 
in colchicine-resistant Mediterranean fever was approved in the Russian Federation and Armenia 
(CL04018065; C04018071). The decision of the Ministry of Health of the Russian Federation on 
a clinical study of RPH-104 in patients with acute myocardial infarction with ST-segment 
elevation (CL04018075) is expected.  


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2.2.2. Olokizumab 
Olokizumab is a humanized ([CDR]-grafted variable region) immunoglobulin G4/kappa 
isotype monoclonal antibody (mAB), developed as an IL-6 antagonist with expected activity in a 
broad spectrum of autoimmune/inflammatory processes. 
The inhibition of IL-6 signaling was shown in nonclinical studies to have no life-threatening 
effects both in animal models and in formal toxicology studies [15].  
OKZ has successfully passed phase IIa and IIb clinical studies, which included a total of 
380 patients with rheumatoid arthritis, The results of these studies were published in two articles 
[16, 17]. The Phase III research program in patients with rheumatoid arthritis includes 2443 
patients and comprises the following international projects: CREDO 1 (CL04041022) 
(successfully completed: a total of 428 patients with RA were included, of which 381 in the 
Russian Federation, the efficacy and safety of OKZ 64 mg every 2 or 4 weeks were demonstrated), 
the results of which were presented in 2019 at ACR and published [20], CREDO 2 (CL04041023) 
and CREDO 3 (CL04041025), the results of which will become available in May-June 2020, as 
well as the open-label study CREDO 4 (CL04041024) including patients who have completed the 
first three studies. 
In phase I and II studies, the pharmacokinetic bioavailability of subcutaneous olokizumab 
was 63% [15]. 
Currently available results of the clinical development program suggest that olokizumab is 
effective in improving symptoms of rheumatoid arthritis patients and is well tolerated. The safety 
profile of olokizumab is consistent with known effects of IL-6 blockers.  
2.3. Summary of known and potential risks and benefits for clinical trial subjects 
(risk/benefit ratio) 
2.3.1. Benefit evaluation 
The benefit that patients can obtain from participating in the study is the chance to receive 
therapy, which may potentially help to improve the symptoms of the disease and the respiratory 
function as well as reduce the need for oxygen therapy in patients with severe COVID-19 caused 
by new SARS-CoV-2 virus, under the lack of an approved therapy. A significant decrease in 
mortality and reduced duration of stay in the ICU is expected in patients receiving OKZ and RPH-
104. Moreover, a shorter period when intensive therapy is required will help reduce the burden on 
ICUs in epidemic settings. 
These expectations are based on the pathogenetic mechanisms of ARDS and cytokine 
storm and the mechanisms of action of OKZ and RPH-104, as well an on preliminary results on 
the efficacy of IL-6 inhibitors in COVID-19 patients. Considering the IL-1-mediated mechanism 
of IL-6 inhibition, which was also demonstrated in nonclinical studies of RPH-104, and the data 
on the successful use of a product from the same class in patients with sepsis and cytokine storm, 
the use of both RPH-104 and OKZ is justified. 
2.3.2. Risk evaluation 
The risks for patients, associated with their participation in this study, include the risks 
associated directly with the use of the study drug, the risks associated with treatment inefficacy in 
the subjects randomized to the placebo group, the risks related to study procedures, as well as the 
risks determined by the experimental nature of the study. 
Since both RPH-104 and OKZ are protein preparations, anaphylactic and anaphylactoid 
reactions may occur with their use. These reactions can manifest as acute infusion reactions, 
allergic reactions or delayed-type hypersensitivity reactions. To minimize this risk, the study drugs 


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will be administered only at medical facilities and only if medications and equipment necessary 
for the treatment of anaphylactic or anaphylactoid reactions are available. 
 
Risks associated with RPH-104 
Based on data on the safety of drugs with a similar mechanism of action (canakinumab, 
rilonacept, anakinra), other risks of administering the study drug to study participants are 
associated primarily with AEs typical for drugs with a similar mechanism of action, i.e. 
interleukin-1 blockers [14]. 
These include an increased probability of infectious diseases, neutropenia, and 
thrombocytopenia.  
During a phase I study of RPH-104 in healthy volunteers, 70 AEs were reported. All AEs 
reported in all dose groups were mild and completely resolved. 
Table 1 shows a summary of AEs observed in healthy volunteers by administered dose. It 
should be noted that only 2 patients received placebo in each dose group. 
No serious adverse events (SAEs) were reported in this study.  
Table 1. Overview of adverse event profile: Number of patients with adverse events (study 
RPH104FIH01/CL04018045) 
 
Dose Group 
1 (4 mg) 
Dose Group 2 
(20 mg) 
Dose Group 3 (40 
mg) 
Dose Group 4 (80 
mg) 
Dose Group 5 
(160 mg) 
 
(N = 7) 
(N = 7) 
(N = 7) 
(N = 7) 
(N = 7) 
Subjects with any AEs (n) 
6 (85.7%) 
5 (71.4%) 
6 (85.7%) 
6 (85.7%) 
6 (85.7%) 
Receiving RPH104 
5 (71.4%) 
3 (42.9%) 
4 (57.1%) 
5 (71.4%) 
5 (71.4%) 
Receiving placebo 
1 (14.3%) 
2 (28.6%) 
2 (28.6%) 
1 (14.3%) 
1 (14.3%) 
Subjects with any SAEs (n) 
0 
0 
0 
0 
0 
Subjects with any AEs leading to death 
(n) 
0 
0 
0 
0 
0 
Subjects with any AEs leading to 
permanent treatment discontinuation 
(n) 
0 
0 
0 
0 
0 
AE = adverse event; SAE = serious adverse event; N = number of subjects receiving treatment in each group; n = 
number of subjects with at least one AE in each category. 
The most common adverse events in all dose groups were nervous system disorders (52% 
in the RPH-104 group vs. 40% in the placebo group), gastrointestinal disorders (32% in the RPH-
104 group vs. 40% in the placebo group), and infections and infestations (24% in the RPH-104 
group vs. 30% in the placebo group). 
In the 4 mg and 20 mg dose groups, 3 out of 5 subjects (60%) receiving RPH-104 in each 
group experienced gastrointestinal disorders. In the 20 mg dose group, nervous system disorders 
were reported with a similar frequency (60%). In the 40 mg dose group, the most commonly 
reported AEs were from the system organ class (SOC) Infections and Infestations (40%). AEs 
related to Nervous system were reported in all 5 subjects (100%) receiving RPH-104 80 mg, and 
in 3 subjects (60%) receiving RPH-104 160 mg. 
The data on SAEs and other RPH-104 safety profiles registered in ongoing clinical studies 
is presented in the current version of the Investigator's Brochure. 


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Risks associated with olokizumab 
Based on the currently available data on the safety of 24-week OKZ therapy in patients 
with rheumatoid arthritis who failed methotrexate treatment, obtained from a well-designed 
placebo-controlled, pivotal phase III study, the following AEs are expected:  
 Liver function test abnormalities (preferred terms according to Medical Dictionary 
for Regulatory Activities [MedDRA] included ALT increased, AST increased and 
abnormal LFTs); 
 Elevated total cholesterol, LDL cholesterol and triglyceride levels (MedDRA 
preferred terms cholesterol increased, blood triglycerides increased and 
hypertriglyceridemia); 
 Decreased leukocyte and neutrophil count (MedDRA preferred terms included 
neutropenia, neutrophil count decreased, leukopenia and leukocyte count 
decreased); 
 Increased rate of infections: in the phase III pivotal study, no increase in the rate of 
infections was reported for olokizumab versus placebo, both in patients receiving 
the cumulative dose of 64 mg/4 weeks and in those receiving 128 mg/4 weeks. The 
percent of patients with at least one AE attributed to the SOC Infection and 
infestations was 14.1%, 15.4%, and 16.2% for olokizumab 64 mg/4 weeks, 
olokizumab 128 mg/4 weeks and placebo, respectively. However, a higher number 
of serious infections were reported in patients receiving olokizumab at the 
cumulative dose of 128 mg/4 weeks compared to placebo. 
In addition, following side effects beingcharacteristic to other IL-6 inhibitors are 
considered expected AEs for olokizumab as well: 
Gastrointestinal disorders: diverticular perforation.  
Injection site reactions: injection site erythema, injection site hematoma, injection 
site pruritus.  
Other important potential risks identified for other IL-6 inhibitors and observed in 
nonclinical studies include: 
Immune system disorders: anaphylactic reaction, hypersensitivity, hypersensitivity 
to administered product. 
Skin and subcutaneous tissue disorders: pruritus, rash, dermatitis, ecchymosis, 
pruritic rash, sweat discoloration. 
Developmental disorders: reproductive toxicity was demonstrated in nonclinical 
studies. IL-6 presumably plays an important role in cervical dilation and, possibly, in the placental 
expulsion. Thus, olokizumab therapy can impair labor and delivery. 
Drug-drug interactions: olokizumab was reported to reverse the inhibitory effects 
of IL-6 on CYP1A1/2, 2B6, 2C9, 3A4/5, 2C19, and NTCP activity in in vitro studies on 
cryopreserved human hepatocytes. For other inhibitors of IL-6 signaling pathway, this effect was 
observed in vivo at 1 week after a single administration of the drug. Consequently, the potential 
need for dose adjustments of drugs metabolized by these CYP isotypes after the administration of 
olokizumab should be taken in consideration. 
 
Risks associated with placebo  
Since this clinical trial is placebo-controlled, there is also a risk of treatment failure in 
patients randomized to the placebo group. Nevertheless, regardless of the therapy group assigned 
at randomization, patients will receive standard therapy for the treatment of COVID-19 accepted 
at the institution, which will help reduce this risk. In addition, in the absence of improvement in 
the patient's condition 24 hours after the administration of one of the study drugs, the protocol 
allows a single administration of tocilizumab or sarilumab recommended for the treatment of this 
disease in order to minimize risks. 


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Risks associated with diagnostic study procedures 
The risks associated with diagnostic study procedures do not exceed the risks that normally 
occur in routine medical practice. 
 
Other risks to which subjects may be exposed in association with their participation in this 
clinical study are determined by the experimental nature of the study, since its exact outcomes 
are not known: the efficacy of the study drug may be insufficient. 
2.3.3. Conclusions 
Since there is limited data on potential adverse reactions to RPH-104 and OKZ in humans, 
safety and tolerability of the drugs will be closely monitored. All adverse events reported in 
patients will be recorded and appropriate medical care will be promptly given within this clinical 
study. The Investigator must be vigilant towards any changes in clinical and laboratory data raising 
concerns regarding patient safety. The Investigator must be prepared to implement all necessary 
measures to resolve such events. 
The protocol provides for additional safety precautions at the enrollment stage precluding 
the enrollment of subjects in whom the use of the study drug may be associated with additional 
health risks.  
If the patient is unable to provide informed consent and sign the Informed Consent Form, 
e.g., in case of patients in severe condition or unconscious patients, in the absence of his/her legal 
representative, he/she may be enrolled in the study based on the decision of a council of physicians; 
in these cases, it is mandatory to obtain the patient’s informed consent as soon as it becomes 
possible. 
To reduce the risk of adverse reactions, the protocol provides for regular safety monitoring 
of the patients, including periodic assessment of the general condition, vital signs, laboratory 
parameters, as well as adverse events monitoring.  
The study also provides for an Independent Data Monitoring Committee (IDMC), that will 
review the available efficacy and safety data, and based on this review the Sponsor will receive 
recommendations on further conduct of the study. 
Thus, it may be concluded that the risks associated with potential adverse reactions are 
generally known and characterized. At the same time, the benefit that the patients may obtain in 
this study is quite high: improved symptoms, improved respiratory function and reduced need for 
oxygen therapy, as well as a shorter length of stay in the ICU and reduced mortality. 
Consequently, the overall risk-benefit ratio for RPH-104 and OKZ in patients appears to 
be favorable.  
2.4. Rationale for study design 
A randomized, double-blind, adaptive, placebo-controlled design was chosen for this 
clinical study.  
Randomized controlled double-blind studies are currently the gold standard design for 
clinical trials.  
In this study, the randomized blinded administration of therapy will allow to obtain 
placebo-controlled data on the efficacy and safety of the study drugs, while excluding the potential 
for subjective assessments.  
The adaptive design implies an early data analysis by the Independent Data Monitoring 
Committee (IDMC) after the first 189 patients has been randomized and evaluated on Day 15 or 
complete participation in the study, whichever comes first. Based on the analysis of the efficacy 
and safety data obtained from these subjects, the final sample size will be determined (which will 


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help to avoid the inclusion of an excessive number of patients that may be exposed to the risk 
associated with their participation in the study). 
Thus, the adaptive design of this study involves the inclusion of a small number of patients 
in the pilot phase for an early risk assessment and preliminary assessment of the course of the 
disease. This approach is widely used in the treatment of patients with serious illnesses, including 
ARDS [19]. 
The use of standardized methods and timeframes for data collection in the study will allow 
a detailed evaluation of the specific characteristics and consequences of the disease in the adult 
population hospitalized for severe COVID-19.   
In addition, retrospective data of patients with severe COVID-19 who did not receive 
subcutaneous OKZ and RPH-104 may be used in comparative analysis in the future. 
2.5. Justification for the route of administration, dose, dosage regimen, and treatment 
course 
RPH-104 will be administered once at a dose of 80 mg (2 mL) by subcutaneous injection. 
OKZ will be administered once at a dose of 64 mg (0.4 mL) by subcutaneous injection. 
The selected route of administration (subcutaneous) is standard for drugs of this class. 
Data on RPH-104 use in healthy subjects suggests a good tolerability of a single 
administration of the drug in doses ranging from 4 to 160 mg, inclusive. Single doses of 4 mg, 20 
mg, 40 mg, 80 mg and 160 mg were selected for phase II studies. A single dose of RPH-104 80 mg 
will be administered in this study. 
CRP is one of the most well-established inflammation markers. This marker is also elevated 
in COVID-19 patients with ARDS and cytokine storm [20]. Preliminary results of an open-label 
phase IIa study in patients with gout show a clear trend of CRP reduction in the RPH-104 80 mg 
and 160 mg groups (Figure 1) compared with RPH-104 20 mg and 40 mg groups. Data is presented 
as mean reduction in CRP (mg/L). In patients with acute gouty arthritis receiving the drug at doses 
of 20 mg and 40 mg, an increase in CRP is observed at 24 hours after the administration with a 
subsequent reduction in CRP, whereas in patients receiving 80 mg and 160 mg, a reduction in CRP 
is observed as early as 24 hours after the injection. Thus, using a dose of 80 mg is justified for this 
study. 


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Figure 1. Reduction in CRP levels after a SC injection of RPH-104: 20 mg (blue line), 40 (green 
line), 80 mg (red line), 160 mg (yellow line) 
 
Dose levels for phase III studies of OKZ (64 mg subcutaneously every 2 weeks or 64 mg 
subcutaneously every 4 weeks) were chosen based on primary efficacy endpoint data obtained in 
individual phase II studies, and the results of an additional dose-dependency analysis conducted 
using a pooled database of these studies. The same dose will be administered once in this study. A 
phase II study in patients with rheumatoid arthritis showed that a single dose of OKZ 1 mg/kg s.c., 
approximately the dosage to be used in this study, caused a rapid decrease in CRP compared to 
placebo as soon as within the first 24 hours (Figure 2). 
 


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Figure 2. CRP reduction after a subcutaneous injection of OKZ 1 mg/kg (blue line) and placebo 
(orange line) 
 
 
2.6. Justification for placebo use 
As shown above, the placebo-controlled design is the “gold standard” for randomized 
clinical studies. All subjects of this study, including those in the placebo group, will receive 
standard therapy for COVID-19 as per routine practice of participating facility.  
The inclusion of the standard therapy + placebo group in this study is necessary due to the 
following considerations: 
1. The absence of a well-studies reference drug for the treatment of cytokine storm in 
patients with severe coronavirus infection.  
2. Rapid changes in the standard therapy for COVID-19 as new data becoming 
available. The latest standards of care as they are updated are planned to be used in 
this study to avoid the exposure of patients to an additional risk and ensure most 
favorable treatment outcomes. Therefore, it will not be possible to interpret the 
efficacy and safety data for the study drugs without comparing them with placebo. 
3. The need for a reliable assessment of the risk/benefit ratio of immunosuppressive 
drugs in patients with viral infection. The main risks associated with the use of IL-
6 antagonists are the increased rate of serious infections, neutropenia, leukopenia, 
increased level of liver enzymes, GI perforation and hypersensitivity reactions. The 
main risks associated with the use of IL-1 antagonists are the increased rate of 
serious infections, neutropenia and hypersensitivity reactions.  Such an assessment 
requires to exclude as much as possible potential bias, which cannot be attained 
using a non-comparative design.  
4. Low reliability of non-comparative data. For example, the combination drug 
lopinavir/ritonavir, which was included in the standard therapy based on promising 
observation data on its off-label use, was shown in a randomized controlled study 
0
1
2
3
4
5
6
7
8
9
10
0
24
48
72
96
120
144
168
Плацебо
ОКЗ
Time after administration, h 
Placebo
OKZ


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to be ineffective in reducing the duration of COVID-19, in lowering the rate of 
deaths and in improving disease outcomes compared with supportive therapy [21].  
5. High variability of clinical parameters and disease outcome statistics. Demographic 
characteristics of patients, rate of complications, and mortality values may vary 
dramatically in different countries [22]. This excludes the use of designs based on 
historical control data. 
2.7. Rationale for the choice of study population 
Patients with COVID-19 caused by the SARS-CoV-2 virus discovered for the first time in 
December 2019 are planned to be included in this study. No etiotropic or pathogenesis-based 
therapy is currently approved for this disease with a mortality rate of 3.4% in the general 
population and up to 14.8% in elderly patients (older than 80 years). In March 2020, the WHO 
declared a global pandemic, and 2,171,031 cases of the disease and 146,201 deaths had already 
been reported worldwide by April 17 [23]. In view of the above, COVID-19 patients were selected 
to participate in this study.  
The rationale for including in the study patients with severe disease and ARDS is, firstly, 
the high mortality in this population, and secondly, the potential benefit of drugs from the same 
group as the study therapy (IL-6 and IL-1 blockers) in such patients being suggested by preliminary 
data. At the base of the ARDS pathogenesis and multiple organ failure in COVID-19 patients lies 
the cytokine storm, i.e. an uncontrolled hyperactivation of innate immunity in response to viral 
infection [9, 24, 25]. High levels of IL-6 cytokine were observed as predictors of severe and critical 
course of COVID-19 [8, 24, 25]. There is evidence of successful use of IL-1 and IL-6 inhibitors 
in the treatment of patients with cytokine storm during sepsis [9-11]. Tocilizumab has successfully 
passed clinical trials and was approved for the treatment of cytokine storm associated with CAR-
T immunotherapy [12]. The results of a recent Chinese study which included COVID-19 patients 
with severe or critical disease demonstrated the clinical efficacy of a single administration of 
tocilizumab [13]. COVID-19 is a life-threatening disease which leads to death in a significant 
number of cases, especially in elderly patients with such comorbidities as hypertension, COPD, 
malignancies and diabetes mellitus. No medicinal products were shown to be effective in the 
treatment of this disease. 
2.8. Clinical study compliance with standard regulatory requirements 
 The study will be conducted in full compliance with this protocol, as well as the following 
regulatory requirements: 
 ICH GCP E6 (R2) (2016); 
 ethical principles set out in the latest revision of the Declaration of Helsinki (2013), 
 Principles of Good Clinical Practice of the Eurasian Economic Union, approved by 
Decision No. 79 of the Council of the Eurasian Economic Commission “On approval of 
the Principles of Good Clinical Practice of the Eurasian Economic Union”, dated 
November 03, 2016; 
 Current legislation and regulatory requirements; Current legislation and regulatory 
requirements of the member-states. 
 


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3. STUDY OBJECTIVES AND ENDPOINTS 
3.1. Study goal 
 To evaluate the efficacy and safety of a single administration of RPH-104 (80 mg) or 
OKZ (64 mg) compared with placebo in patients with severe SARS-CoV-2 virus infection 
(COVID-19). 
3.2. Study objectives and their corresponding endpoints 
OBJECTIVES 
ENDPOINTS  
[assessment timeframes] 
Primary objective 
Primary endpoint 
1. To assess the efficacy of a single 
administration of RPH-104 (80 mg) or 
OKZ (64 mg) compared with placebo 
in patients with severe SARS-CoV-2 
virus infection (COVID-19) on Day 15 
of the study. 
1. Proportion of responders in each 
treatment group. 
A responder is a patient who has not received 
tocilizumab or sarilumab and who has a 
clinical status improvement of ≥1 point on the 
6-point COVID-19 scale (where 1 is the most 
favorable outcome and 6 is the most 
undesirable outcome) 15 days after the 
administration of the study drug [Day 15]:  
 
1). Not hospitalized; no activity limitations; 
2). Not hospitalized; limited activity; 
3). Hospitalized, not requiring supplemental 
oxygen; 
4). Hospitalized, supplemental oxygen with 
independent breathing; 
5). Hospitalized; mechanical ventilation 
(invasive/non-invasive) or ECMO; 
6). Death. 
 
 
Secondary objectives 
Secondary endpoints 
1. To evaluate the effect of a single 
administration of RPH-104 (80 mg) or 
OKZ (64 mg) compared with placebo 
on clinical status changes in patients 
with 
severe 
SARS-CoV-2 
virus 
infection (COVID-19) during the study  
. 
1. Change over time in the clinical status 
of patients on a 6-point ordinal scale 
[Day 2 – Day 15, Day 29]; 
2. The proportion of patients with an 
improvement in clinical status by 2 or 
more points on the 6-point ordinal scale 
during the study with no use of 
tocilizumab or sarilumab [from Day 2 
to Day 15, Day 29]; 
3. The proportion of patients who 
received tocilizumab or sarilumab for 
COVID-19 during the follow-up period 
[from Day 2 to Day 29]; 
2. To compare mortality rates in the 
groups of single administration of 
RPH-104 (80 mg), OKZ (64 mg) or 
4. Mortality during the follow-up period 
[Day 1 – Day 29]. 


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placebo in patients with severe SARS-
CoV-2 virus infection (COVID-19). 
Secondary objectives 
Exploratory endpoints 
3. To compare the length of stay in the 
ICU, the duration of oxygen support 
and clinical parameters between the 
groups of single administration of 
RPH-104 (80 mg), OKZ (64 mg) or 
placebo in patients with severe SARS-
CoV-2 virus infection (COVID-19) 
receiving the standard therapy. 
1. The proportion of patients with 
National Early Warning Score 2 
(NEWS2) ≤ 4 for 2 consecutive days 
[Day 3 – Day 15];  
2. The proportion of patients with a score 
of ≤ 2 using the National Early 
Warning Score 2 (NEWS2) for 2 
consecutive days [Day 3 – Day 15]; 
3. Time to reaching a NEWS2 score ≤ 4 
for 2 consecutive days [Day 1 – Day 
15]; 
4. Time to reaching a NEWS2 score ≤ 2 
for 2 consecutive days [Day 1 – Day 
15]; 
5. Change from baseline in the level of 
surrogate markers of the cytokine 
storm: 
leukocytes, 
lymphocytes, 
neutrophils, 
CRP, 
ferritin 
(if 
applicable), D-dimer (if applicable) 
[Day 2, Day 3, Day 5, Day 7, Day 15]; 
6. Mortality during an ICU stay, at study 
days 7, 15, 29 [Day 7, Day 15, Day 29]; 
7. Time to reaching SpO2≥94% without 
oxygen support, for 2 consecutive days 
[Day 2 – Day 15]; 
8. Change 
from 
baseline 
in 
the 
oxygenation index of PaO2/FiO2 (if 
applicable) during hospitalization [Day 
2 – Day 15]; 
9. Duration of stay in ICU, in days [Day 
2 – Day 15];   
10. Change from baseline in ARDS 
severity defined according to WHO 
criteria (if applicable) [Day 1 – Day 
15]; 
11. Time to ARDS improvement according 
to the WHO criteria by one category 
compared to baseline (if applicable) 
[Day 1 – Day 15];  
12. Duration of mechanical ventilation 
and/or ECMO (if applicable), in days 
[Day 2 – Day 15]; 
13. Duration 
of 
oxygen 
support 
(if 
applicable), in days [Day 1 – Day 15]; 
14. Time until resolution of fever, i. e. 
axillary body temperature <38 °C 
without the use of antipyretics for 2 


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consecutive days (if applicable) [Day 1 
– Day 15]; 
15. Time to clinical status improvement by 
1 point on the 6-point COVID-19 scale 
[Day 1 – Day 29]; 
16. Time to clinical status improvement by 
2 points on the 6-point COVID-19 
scale [Day 1 – Day 29]; 
17. The proportion of patients with a 
clinical status worsening by 1 point on 
the 6-point COVID-19 scale during the 
study (if applicable) [Day 2 – Day 15, 
Day 29]; 
18. The proportion of patients with a 
clinical status worsening by 1 point on 
the 6-point COVID-19 scale during the 
study, excluding patients moving to 
category 6 (if applicable) [Day 2 – Day 
15, Day 29];  
19. Time to a clinical status worsening by 
1 point on the 6-point COVID-19 scale 
(if applicable) [Day 2 – Day 15, Day 
29]. 
 
Secondary objectives 
Safety endpoints 
4. To assess the safety of a single 
administration of RPH-104 (80 mg) or 
OKZ (64 mg) in patients with severe 
SARS-CoV-2 virus infection (COVID-
19) 
1. Incidence, 
severity, 
nature 
and 
outcomes of AEs (grades 4 and 5 
according to CTCAE v.5.0) and SAEs 
during the study; 
2. The proportion of patients with AEs 
(grades 4 and 5 according to CTCAE 
v.5.0) and SAEs; 
3. Changes in physical examination 
findings, vital signs, and laboratory 
safety parameters during the study. 
LHD = last day of hospitalization 
4. STUDY DESIGN  
4.1. Description of the study design 
This study is a multicenter randomized double-blind adaptive placebo-controlled phase 
II/III clinical trial to evaluate the efficacy and safety of a single administration of RPH-104 80 mg 
or OKZ 64 mg compared with placebo in hospitalized patients with a confirmed diagnosis of 
COVID-19 in severe condition.  
 
The study will consist of two phases: 
• 
pilot phase: inclusion and randomization of the first 189 patients (63 patients in each 
group of OKZ, RPH-104, placebo), followed by an early analysis of efficacy and safety 
data, based on which the sample size will be finally defined; 
• 
pivotal phase: subsequent subject enrollment and the conduct of all procedures 
specified in the protocol.  


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The preliminary sample size is 372 randomized patients hospitalized with severe or critical 
COVID-19. The final sample size will be determined by the results of the pilot phase of the study. 
A patient is considered enrolled in the study after signing the Informed Consent Form or by 
decision of a medical consilium (see Section 8.2. Description of individual study procedures). 
For each patient, the study will consist of 3 periods with a total duration of up to 31 days: 
• 
screening period for up to 48 hours before the start of  the day of randomization (Day 
1). During the screening period, subject eligibility is assessed; 
• 
treatment period lasting from the end of screening (which is the start of Day 1) to 23:59 
of Day 1, including randomization of patients into the treatment groups, followed by 
a single administration of the study drug; 
• 
follow-up period, lasting from 00:00 on Day 2 to 23:59 on Day 29, which includes the 
assessment of the efficacy and safety after the administration of one of the study drugs. 
After enrollment into the study (signing of the Informed Consent Form or, if the patient is 
unable to express his/her will, a documented decision of a medical consilium on the need to include 
the patient in this clinical study), subjects will be screened for compliance with eligibility criteria. 
Eligible patients will be randomized 1:1:1 to one of three treatment groups to receive a single 
subcutaneous injection: RPH-104 80 mg or OKZ 64 mg or placebo. Regardless of the treatment 
group to which a patient is randomized, they will receive standard COVID-19 therapy accepted at 
the institution, with the exception of the drugs specified in section 6.5.2 Prohibited concomitant 
therapies, as well as tocilizumab and sarilumab during the first 24 hours after the administration of 
the study drugs. In the absence of improvement in the patient's condition, by Investigator’s 
discretion, within 24 hours after the administration of one of the study drugs, a single 
administration of tocilizumab or sarilumab is allowed, in accordance with current 
recommendations. Evaluations of efficacy and safety, including laboratory and instrumental 
investigations, will be performed in study subjects on a daily basis during the hospitalization period 
until Day 15 or the LHD (whichever comes first). Blood samples for complete blood count, blood 
chemistry tests, determination of the cytokine storm markers, as well as urine samples will be 
taken on Days 1, 3, 5, 7, and 15 of the study. Additionally, blood samples for the cytokine storm 
markers will be taken on Day 2 of the study, as well as before the administration of tocilizumab or 
sarilumab (if applicable). On Day 15, the primary endpoint of the study, response to treatment, 
will be assessed. A response to treatment is an improvement in the clinical status of the patient by 
at least 1 point on the 6-point COVID-19 scale with no use of tocilizumab or sarilumab. The last 
study visit is on Day 29. If a patient is discharged earlier than Day 15 and/or Day 29 of the study, 
the clinical status, concomitant therapy, and AE assessments on this/these day(s) will be evaluated 
via a telephone call. The adaptive design of this study entails the inclusion of a small number of 
patient in the pilot phase to ensure an early assessment of the risk and a preliminary assessment of 
the course of the disease. This approach is used in the treatment of patients with severe disease, 
including ARDS [19]. 
The inclusion of the standard therapy + placebo group in this study is necessary due to the 
following: 
1. The absence of a well-studied reference drug for the treatment of cytokine storm in 
patients with severe coronavirus infection.  
2. Rapid changes in the standard therapy for COVID-19 as new data becomes 
available. The latest standards of care as they are updated are planned to be used in 
this study to avoid the exposure of patients to an additional risk and ensure most 
favorable treatment outcomes. Therefore, it will not be possible to interpret the 
efficacy and safety data for the study drugs without comparing them with placebo. 
3. The need for a reliable assessment of the risk/benefit ratio of immunosuppressive 
drugs in patients with viral infection. The main risks associated with the use of IL-


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6 antagonists are the increased rate of serious infections, neutropenia, leukopenia, 
increased level of liver enzymes, GI perforation and hypersensitivity reactions. The 
main risks associated with the use of IL-1 antagonists are the increased rate of 
serious infections, neutropenia and hypersensitivity reactions. Such an assessment 
requires to exclude as much as possible potential bias drugs, which cannot be 
attained using a non-comparative design.  
4. Low reliability of non-comparative data. For example, the combination drug 
lopinavir/ritonavir, which was included in the standard therapy based on promising 
observation data on its off-label use, was shown in a randomized controlled study 
to be ineffective in reducing the duration of COVID-19, in lowering the rate of 
deaths and in improving disease outcomes compared with supportive therapy [21]. 
5. High variability of clinical parameters and disease outcome statistics. Demographic 
characteristics of patients, rate of complications, and mortality values may vary 
dramatically in different countries [22]. This excludes the use of designs based on 
historical control data. 
4.2. Study flow chart 
The study flow chart is shown in Figure 3. 


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Figure 3. Study flow chart 
 
PE = primary endpoint; OKZ = olokizumab; IMP = investigational medicinal product; R = randomization; 
Day = calendar days from 00:00 to 23:29 beginning from Day 2.
Enrollment 
R 
OKZ 
RPH-104 
Placeb
o 
SARS-CoV-2 
diagnosis 
Day -2 
Day 1 
Day 15 
Day 29 
Screening 
Observation period 
Administration 
of IMP 
All patients receive standard therapy for COVID-19 and required critical 
care 
PE assessment 
End-of-Study Visit (in person or 
by telephone) 
Administration of tocilizumab or sarilumab is allowed (24 
hours after the administration of the study drug)   


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5. STUDY POPULATION 
The preliminary sample size is 372 randomized male and female patients aged 18 years 
(inclusive) or older, admitted to healthcare institutions with COVID-19 in severe or critical 
condition; of them, 189 patients will be included in the pilot phase of the study. The final sample 
size will be determined by the results of the pilot phase of the study..  
5.1. Inclusion criteria 
Patients meeting all of the criteria below may be included in the study: 
1. Male or female patients aged 18 years (inclusive) or older (at the beginning of the screening 
period). 
2. Voluntarily signed and dated Patient Informed Consent Form for participation in this study, 
or record of a Medical Consilium decision justifying patient’s participation in case of 
patient is  unable to express his or her will. 
3. Having either of the following COVID-associated respiratory syndromes:: 
• 
Pneumonia with oxygen saturation SpO2 ≤93% (on room air) or RR greater than 30 
breaths/min; 
• 
ARDS (PaO2/FiO2 ≤300 mmHg or SpO2/FiO2 ≤315 if PaO2 is not available). 
4. A diagnosis of COVID-19 based on:  
• 
Laboratory confirmed SARS-CoV-2 infection as determined by PCR  
OR 
• 
Bilateral changes in the lungs characteristic of COVID-19 on chest CT 
5.2. Non-inclusion criteria 
To be eligible for the study, patients must not meet any of the following criteria: 
1. A history of hypersensitivity to the study drugs (RPH-104 and/or OKZ), and/or its 
components. 
2. Any of the following laboratory abnormalities: 
- absolute neutrophil count <0.5 x 109/L, 
- white blood cell count <2 x 109/L, 
- platelet count <50 x 109/L, 
- ALT and/or AST ≥3.0 x ULN. 
3. Severe renal failure: creatinine clearance <30 mL/min.  
4. Septic shock (vasopressors are required to maintain mean blood pressure ≥65 mmHg and 
lactate ≥2 mmol/L in the absence of hypovolemia). 
5. Disease progression to death within the next 24 hours, regardless of therapy, in the 
physician’s opinion. 
6. History of gastrointestinal perforation or diverticulitis. 
7. Administration of plasma from COVID-19 convalescent donors within 4 weeks before 
study enrollment and/or planned administration during the study. 
8. Recent (less than 5 elimination half-lives) use of tocilizumab or sarilumab. 
9. Recent (less than 5 elimination half-lives) or planned use during the study of: 
- biologics (except RPH-104 or OKZ) with immunosuppressive effect, including, but 
not limited to: IL-1 inhibitors (anakinra, rilonacept, canakinumab), IL-6 inhibitors 
(except tocilizumab and sarilumab), IL-17A inhibitors (secukinumab), tumor 
necrosis factor α (TNFα) inhibitors (infliximab, adalimumab, etanercept, etc.), anti-
B-cell drugs, etc.; 
- other immunosuppressive drugs (except methotrexate at doses of up to 25 
mg/week), including but not limited to:  


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 high doses of glucocorticoids (equivalent to prednisolone >1 mg/kg) orally or 
parenterally; 
 JAK kinase inhibitors; cyclophosphamide, etc.  
10. Concurrent participation in another clinical trial. 
11. Pregnancy, breastfeeding.  
12. A history of active tuberculosis, or active tuberculosis suspected by the Investigator. 
5.3. Restrictions for patients during the study 
The Investigator will explain to the patient that during his/her participation in the study, 
certain restrictions must be followed: 
• 
treatment regimen: during hospitalization, patients should comply with  applicable 
study center policies and follow Investigator’s instructions; after discharge, subjects 
should also follow all the Investigator’s recommendations regarding treatment and 
lifestyle and contact the Investigator on Day 15 and/or Day 29 of the study (whichever 
is applicable); 
• 
contraception: female subjects should use effective contraception methods from the 
time of inclusion in the study to 3 months after the administration of the study drugs. 
Male subjects must inform their female partners of the need for effective contraception 
methods and use them from the time of the inclusion of the male subject in the study 
to 3 months after he receives the study drugs. These methods include: 
- Sterilization: surgical bilateral oophorectomy (with or without hysterectomy), or 
tubal ligation at least 6 weeks before the beginning of the study. In case of 
oophorectomy alone, the woman’s reproductive status should be confirmed by a 
subsequent assessment of hormone levels. 
- Male partner sterilization (with appropriate documentation of the absence of sperm 
in the ejaculate after vasectomy) at least 6 months before the start of the study. In 
this case, the vasectomized male must be the sole partner of the female subject.   
- A combination of any two (i.e., a+b or a+c or b+c) of the methods below: 
a) Oral, injectable, or implantable hormonal contraceptive drugs. If an oral 
contraceptive drug is used, it must not be changed for at least 3 months prior to 
study therapy. 
b) Intrauterine device or intrauterine system. 
c) Barrier contraception methods: condom or occlusive cap (diaphragm or 
cervical cap/vault cap) with spermicidal foam/gel/film/cream/vaginal 
suppository. 
These restrictions are also detailed in the Patient Information Leaflet with the Informed 
Consent Form. 
5.4. Exclusion criteria (early study termination) 
Subject will be completely withdrawn from all assessments in the following cases:  
 The subject chooses to withdraw from the study, i.e. withdraws informed 
consent. 
 The subject is lost to follow-up. 
 Death of the subject. 
The study is terminated early by the decision of the Investigator, Sponsor, or at the request 
of the regulatory authorities of the country where the study is conducted, ethics committees or 
other authorities (see Section 14. STUDY STOPPING RULES).  


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The subjects may decide to withdraw from the study at any time without giving a reason. 
However, the Investigator should make a reasonable effort to find out the reasons for the subject’s 
withdrawal.  
Subjects lost to follow-up should be indicated accordingly in the eCRF. If a subject is lost 
to follow-up, the Investigator should appropriately attempt to contact him/her and record in the 
primary documents the steps taken in this respect, for example, the dates of telephone calls, 
registered letters, etc.  
The Investigator should inform the Sponsor about early patient withdrawal within 24 
hours, specifying the reasons for withdrawal.  
In case of early discontinuation of a patient from the study, the Study Completion Form in 
eCRF should be filled out. 
If a patient discontinues the study and withdraws his/her consent to the disclosure of future 
information, any further evaluations should be performed and no additional data should be 
collected. The Sponsor may retain and continue to use the data obtained prior to withdrawal of 
consent. 
If a subject decides to withdraw from the study or does not complete the study for any 
reason, his/her individual screening number should not be reused.  
Patients who are prematurely discontinued from the study for any reason should not be 
replaced. 
6. STUDY THERAPY 
Detailed information on the labeling, receipt, storage, accountability, preparation, 
dispensation, administration to the patients, and disposal of study drugs is provided in the 
Pharmacy Manual.  
6.1. Doses and dosing schedules of the study drugs 
 
In this study, patients will receive a single injection of one of the study drugs below, 
according to the treatment group to which they are randomized: 
• 
OKZ 64 mg, one injection 0.4 mL, OR 
• 
RPH-104 80 mg, one injection 2 mL, OR 
• 
Placebo, one injection of a corresponding volume of 2 mL. 
No dose adjustments are planned in this study. 
6.2. Preparation of the study drugs for administration and the administration 
procedures 
An independent pharmacist or a designee who is unblinded to the treatment assignements 
will prepare OKZ, RPH-104 or placebo in 2 mL syringes for subcutaneous injections. To maintain 
the blinded design of the study, the syringes for subcutaneous injections will be blinded prior to 
the administration of the drug as specified in the Pharmacy Manual so that all three products being 
identical in appearance. Appropriate measures should be taken at the study site to prepare the 
syringes for subcutaneous injections so that the specified time of stability of the prepared product 
is not exceeded. The study drug solution may remain in the syringe for up to 4 hours prior to use. 
The syringes prepared for subcutaneous injection should be warmed to room temperature for at 
least 30 minutes prior to administration to the patient.  
The study drugs should be prepared in a secure place, not accessible to the blinded members 
of the study team (including the blinded study stuff from the Sponsor). 
The unblinded qualified personnel of the study will administer single subcutaneous 
injections (0.4 mL olokizumab or 2 mL RPH-104 or 2 mL placebo) to each subject.  


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The date, time, and place of subcutaneous injection should be documented and entered into 
the eCRF. The Investigator should also document in the eCRF if the full dose of the drug was 
administered.  
The blinded study drug (OKZ or RPH-104) will be injected subcutaneously, preferably in 
one of the abdominal areas shown on Figure 4. Alternatively, if the indicated areas are inaccessible, 
another area acceptable for subcutaneous injection may be used: the outer surface of the shoulder, 
the front surface of the thigh. If subcutaneous injection in these areas is technically impossible due 
to the patient’s body position, a subcutaneous injection may be performed in another area with a 
sufficiently developed subcutaneous fat layer.  
 
 
Figure 4. The abdominal areas where the study drugs may be injected. 
6.3. Overdose 
6.3.1. Olokizumab overdose 
No cases of OKZ overdose have been reported yet from clinical experience. The maximum 
dose administered in the phase I studies was 3 mg/kg for a single subcutaneous administration and 
10 mg/kg for a single intravenous administration. In this group, the rate of AEs was not different 
from other dose groups and no SAEs were reported (see Section 2.2.2. Olokizumab (OKZ)).  
The antidote to OKZ is not known. Overdose signs and symptoms should be treated in 
accordance with the local standards of care. 
6.3.2. RPH-104 overdose 
No cases of RPH-104 overdose were reported. The maximum amount of the drug that can 
be safely administered has not been determined. In a phase I study, the maximum single dose was 
160 mg. This dose was safe and well tolerated (see Section 2.2.1. RPH-104).  
The antidote to RPH-104 is not known. In case of an overdose, symptomatic therapy is 
recommended. 
 
6.4. Treatment compliance  
 
The assigned dose, regimen, and method of administration should not be changed. The date 
and time of administration of all doses of the drug and any deviation from the specified treatment 
regimen should be documented in the relevant eCRF section.  
An unblinded monitor who is aware of the therapy receiving by individual patients will 
review the pharmacy records at each clinic, including the dispensing log, where the pharmacist or 
a designated person should record all the study drugs dispensed to patients. This monitor shall 
compare the dispensing records with the vials labeled with individual subject IDs and the visit 
schedule to confirm that the patients have received the appropriate treatment and dose and have 
followed the treatment schedule. The site personnel will be informed of the identified errors to 


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prevent such errors in the future. The study stuff knowing about the treatment administered to 
individual patients will receive the unblinded information, b, whereas the other study stuff will 
receive blinded data.. The monitor’s report will include detailed information on any missed doses, 
dose errors, treatment errors, or scheduling errors and relevant explanations. All the supplies and 
pharmacy documents should be made available to the monitor for review throughout the study. 
The study sites will not be required to keep used syringes. Any patient with deviations from 
the treatment regimen should be immediately reported to the Sponsor or its representative to decide 
on subsequent actions.  
6.5. Concomitant therapies 
6.5.1. Allowed concomitant therapies 
The administration of standard COVID-19 therapy approved at the healthcare institution is 
allowed during the study, with the exception of drugs specified in section 6.5.2 Prohibited 
concomitant therapies, throughout the study, as well as tocilizumab and sarilumab during the first 
24 hours after the administration of the study drugs. 
Patients should inform the study site personnel about any new drugs they use after they 
start receiving the study therapy. All drugs (except the study drugs) and significant non-drug 
therapies used during the study should be recorded in the eCRF section “Concomitant therapy” 
(including medicinal products, herbal/natural products, etc.) or “Concomitant procedures” 
(including MV, blood transfusions, etc.).  
If a concomitant disease is not a criterion for excluding the patient from the study, it should 
be treated according to the accepted standard of care under this protocol. In this case, concomitant 
therapy drugs should not be included in the list of those prohibited by the protocol.  
 
Tocilizumab and sarilumab 
If, in the opinion of the Investigator, there is no improvement in the patient’s condition 24 
hours after the administration of one of the study drugs, tocilizumab or sarilumab at the doses 
recommended for the treatment of this disease may be added to concomitant therapy. The 
administration of tocilizumab or sarilumab before this time is impractical in view of the 
pharmacokinetic/pharmacodynamic properties of the study drugs. The Sponsor will not provide 
the study centers with tocilizumab and sarilumab for use as standard therapy for the disease 
investigated in the study. 
 
Allowed concomitant therapies requiring special precautions and/or any actions  
Both OKZ (directly) and RPH-104 (by inhibiting IL-1) are expected to reduce IL-6-
mediated inhibition of CYP or transmembrane transporters, as CYP1A1/2, 2B6, 2C9, 3A4/5 and 
2C19, as well as of the sodium/taurocholate co-transporting polypeptide (NTCP). A reduced 
inhibition of CYP or transporters may lead to reduced levels of the drugs metabolized via these 
enzymes. This decrease in drug levels may be clinically relevant for CYP450 substrates with a 
narrow therapeutic index where the dose is adjusted individually (for example, warfarin). In 
patients receiving these types of drugs, therapeutic monitoring by the attending physician is 
recommended (without entering additional information into the eCRF).  
6.5.2. Prohibited concomitant therapies  
The following medications are prohibited during the study: 
 Immunosuppressive biologics (with the exception of RPH-104 or OKZ), including, 
but not limited to: IL-1 inhibitors (anakinra, rilonacept, canakinumab), IL-6 inhibitors 
(except tocilizumab and sarilumab), IL-17A inhibitors (secukinumab), tumor necrosis 


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factor α (TNFα) inhibitors (infliximab, adalimumab, etanercept, etc.), anti-B-cell 
drugs, etc.;  
 other immunosuppressants (with the exception of methotrexate in a dose of up to 25 
mg/week), including, but not limited to:  
- high doses of glucocorticoids (equivalent to prednisolone >1 mg/kg) orally or 
parenterally;  
- JAK kinase inhibitors; 
- cyclophosphamide etc.;  
 administration of plasma from COVID-19 convalescent donors;  
 during the first 24 hours after the administration of the study drugs, the use of 
tocilizumab and sarilumab is prohibited.   
 
6.6. Dosage form, packaging and labeling of the study drugs 
6.6.1. Olokizumab  
Trade name: Not assigned. 
Product Internal Code: CDP6038, L04041. 
International non-proprietary name: Olokizumab. 
Pharmaceutical form: Solution for subcutaneous injection. 
Strength: 160 mg/mL. 
Composition:  
Component 
Content per 1 mL 
Relative content 
Active substance 
Olokizumab 
160.000 mg 
- 
Excipients 
Sodium chloride 
3.51 mg 
60 mМ 
Polysorbate 80 
0.3 mg 
0.03% 
L-Histidine hydrochloride 
6.29 mg 
30 mМ 
Sorbitol 
36.434 mg 
200 mМ 
Water for injection 
QS to 1.0 mL 
- 
QS = quantity sufficient 
Storage and shipping conditions: Store and ship at +2 to +8С. 
Primary and secondary packaging: 
Primary packaging: 2 mL type I clear glass vial with a target volume of 0.4 mL. The vials are 
sealed with a chlorobutyl rubber stopper and an aluminium and polypropylene crimp.  
Secondary packaging: 1 vial is packed in a labeled carton. 
 
6.6.2. RPH-104 
Trade name: Not assigned. 
Product Internal Code: RPH-104, L04018 
International nonproprietary name: Not assigned. 
Pharmaceutical form: Solution for subcutaneous injection. 
Strength: 40 mg/mL. 
Composition:  
Component 
Content per 1 mL 
Relative content 
Active substance 
RPH-104 
40 (± 4) mg 
- 


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Excipients 
Sucrose 
60 mg 
6% 
Polyethylene glycol (PEG) 3350 
30 mg 
3% 
Sodium chloride 
2.92 mg 
50 mМ 
L-Histidine 
3.1 mg 
20 mМ 
Storage and shipping conditions: Store and ship at +2 to +8С.  
Primary and secondary packaging: 
Primary packaging: 4 mL transparent glass vial sealed with a rubber stopper with an aluminum 
crimp and covered with a red cap. 1 vial contains 2 mL of 40 mg/mL drug product solution. 
Secondary packaging: 1 vial is packed in a labeled carton. 
6.6.3. Placebo 
Trade name: Not applicable. 
International nonproprietary name: Not applicable. 
Pharmaceutical form: Solution for subcutaneous injection.  
Composition:  
Component 
Content per 1 mL 
Relative content 
Sodium chloride  
9 mg 
0.9% 
Water for injection 
To 1 mL 
99.1% 
Storage and shipping conditions: Store and ship below +25С.  
Primary and secondary packaging: According to the commercial packaging. 
6.6.4. Labeling 
According to the regulatory requirements of the member states, the following information 
will be presented on the primary and secondary packaging of the study drugs: 
 
 name and dosage of the corresponding study drug, 
 Sponsor's company name, address and contact information (secondary packaging only), 
 name of the study drug manufacturer, address and contact information (secondary 
packaging only),  
 batch number, 
 release date, 
 expiration date, 
 method of administration, 
 dosage form, 
 storage conditions, 
 individual primary package number, 
 protocol number, 
 warning statements. 
 
The primary and secondary packaging of the study drugs will additionally be labeled with: 
“For clinical studies only.” 
The primary and secondary packaging will also have space for information to be entered 
by the designated unblinded member of the study team: 
- number of the study site, full name of the Principal Investigator, 
- visit date, 
- patient ID. 


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6.7.   Handling of study drugs 
The Investigator is responsible for the appropriate administration, accountability and 
storage of the study drugs at the study site. The study drugs may be stored only at the official study 
site involved in this study. The access to the study drugs shall be restricted to authorized study site 
employees only. The Investigator should ensure drug storage under secure conditions that prevent 
loss, theft and deviations from the environmental conditions (temperature) specified in the 
Pharmacy Manual and indicated the Investigator's Brochure for the respective drug (RPH-104 or 
OKZ), and also proper maintaining of records of study product receipt, accountability, storage, 
and dispensation of study drugs. At the study site, OKZ and RPH-104 must be stored in the 
refrigerator at +2 to +8°С; placebo must be stored below +25°С. The Investigator must keep a 
storage temperature log for the study drugs. 
The study drugs should always be prepared and administered to the patients at the study 
site, by a designated unblinded member of the study team (see Section 6.2. Preparation of the study 
drugs for administration and the administration procedures). 
 
7. SUBJECTIVITY MINIMIZATION/EXCLUSION MEASURES 
7.1. Patient disposition by study site 
Enrollment at the study sites will be competitive. Recruitment will be terminated after the 
inclusion of the number of patients determined by the analysis of the pilot phase of the study. The 
preliminary plan is to include 372 patients.   
7.2. Assignment of screening numbers 
Assignment of screening numbers will be carried out in accordance with internal 
instructions of the Sponsor. 
Each study center will be assigned a three-digit identification number starting with "101", 
with the last two digits indicating the center's number in the MoH permit. If a clinical center under 
a single Principal Investigator has more than one actual study address, each actual address of such 
a clinical center will be assigned a three-digit number, for example, "101", "201", "301", etc. (the 
number of each of the actual addresses of the clinical center will be encoded by the first digit of 
the three-digit number, and the last two digits will indicate the number of the clinical center in the 
MoH permit common to all actual addresses) for correct display in the IWRS system.After a 
patient has signed the Informed Consent Form or is included in the study based on a Medical 
Consilium decision, the patient is assigned an individual eight-digit screening number recorded in 
the source documentation, where 78 at the beginning is the last two digits of the clinical study 
protocol number, the next three digits are the center number, starting with 101, and the last three 
digits represent the patient's number in the center, starting with 001; thus, the full individual 
screening number will be shown, for example, as 78101001. During randomization, the patient 
retains this individual eight-digit number. 
The Investigator must maintain a separate log containing information about patients’ 
screening numbers, which must be stored in compliance with the rules applicable to confidential 
documents. 
If a patient completes the study prematurely (is withdrawn from the study for any reason), 
their screening number will not be reused. 
 


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7.3. Randomization  
If the Investigator decides that a patient is eligible for the study after performing all 
screening procedures, the patient is randomized. Randomization is necessary to minimize 
subjectivity in the allocation of patients to treatment groups. Randomization is carried out in 
accordance with internal instructions of the Sponsor. 
Randomization of patients in this study will be centralized and performed using the 
Interactive Web Response System (IWRS). Patients will be randomized into 3 groups in a ratio of 
1:1:1.  
Before the study, each Investigator will be trained to use the system and receive unique 
access codes and IWRS Manual. 
A confirmation of randomization will be available for print. A notification of 
randomization will be sent by e-mail to the addresses of the authorized members of the project 
team. 
The number of the drug assigned at the randomization must be registered in the source 
documentation and in the patient's eCRF. 
The randomization codes are also kept by the Sponsor in strict confidence.  
7.4. Blinding 
This study is designed as a double-blind trial, which means that neither the Investigator nor 
other members of the study site team nor Sponsor representatives nor the patient will be aware of 
which drug is being used (as well as which group the patient was allocated to).  
Since the study drugs differ in appearance, they will be prepared and administered by an 
openly acting, designated member of the study team who is not involved in the management of 
patients and the study assessments and who has no access to the patient’s medical records.  
All drugs to be administered will be drawn into identical 2 mL syringes. 
Preparation and administration of drugs for a patient should be carried out separately from 
other study participants so that it is impossible to see the differences between OKZ, RPH-104, and 
placebo. Additional conditions will be in place during the administration of the test drug to limit 
visibility to the patient (see section 6.2. Preparation of the study drugs for administration and the 
administration procedures).  
Monitoring procedures for the study drugs will be carried out by an unblinded clinical 
research associate.  
Unblinding will only be possible in the event of a safety emergency. Unblinding of the 
treatment group is performed by IWRS at the request of the Investigator. The Investigator sends a 
request to IWRS stating the reasons for unblinding, after which, with the permission of the 
Sponsor, receives the treatment group information (in the system). 
Unblinding will also be done for the final analysis. 
7.5. Compliance with study therapy 
The administration of the study drugs will be carried out only by qualified members of the 
study team. The date, time, and place of drug administration will be recorded in the patient's eCRF.  
8. STUDY PROCEDURES 
The visit schedule with all study procedures are presented in Table 2. 
A deviation is allowed only for Day 29 (± 1 day).  
The day of randomization (Visit 1, Day 1) continues from the end of screening until 23:59 
of the same calendar day; the drug administration should be performed on Day 1 after 


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randomization of the patient. Starting from Day 2, the study days are the calendar days from 00:00 
to 23:59.


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Table 2. Schedule of study visits and procedures. 
Procedures 
Schedule** 
Unscheduled visit 
(safety) 
Visit number 
screening 
1* 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15*** 
EoS 
During the study  
Study day 
-48 h to 
Day 1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
159 
299 
 
Obtaining IC/  
Enrollment based on a medical 
consilium recommendation  
+ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Preparation of the Patient's Card  
and insurance policy 
+ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
+1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Allergy history, bad habits  
+1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
History of the present illness  
+1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Information about previous and 
concomitant diseases  
+1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Evaluation of the results of SARS-
CoV-2 PCR analysis 
+1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assessment of chest CT findings  
+1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior therapy review 
+1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Anthropometry 2 
+1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs 3 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
 
+ 
Physical examination 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
 
+ 
Hematology 4 
+1 
+ 
+ 
+ 
 
+ 
 
+ 
 
 
 
 
 
 
 
+ 
 
+ 
Blood chemistry panel 5 
+1 
+ 
 
+ 
 
+ 
 
+ 
 
 
 
 
 
 
 
+ 
 
+ 
CRP 12 
+ 
+ 
+ 
+ 
 
+ 
 
+ 
 
 
 
 
 
 
 
+ 
 
+ 
Ferritin 12 (if applicable) 
+ 
+ 
+ 
+ 
 
+ 
 
+ 
 
 
 
 
 
 
 
+ 
 
+ 
D-dimer (if applicable) 12 
+ 
+ 
+ 
+ 
 
+ 
 
+ 
 
 
 
 
 
 
 
+ 
 
+ 
Urinalysis 6 
 
+ 
 
+ 
 
+ 
 
+ 
 
 
 
 
 
 
 
+ 
 
+ 
Pregnancy test (urine) 7 
+ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Evaluation of the inclusion/non-
inclusion criteria 
 
+ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
+ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blinded administration of OKZ/RPH-
104/placebo  
 
+ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assessment of the clinical status   
using a 6-point ordinal scale 
 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+9 
+9 
 
NEWS2 score 
 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
 
 
SpO2 assessment 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
 
 
PaO2/FiO2 assessment (if applicable) 
+10 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
 
 


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Procedures 
Schedule** 
Unscheduled visit 
(safety) 
Visit number 
screening 
1* 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15*** 
EoS 
During the study  
Study day 
-48 h to 
Day 1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
159 
299 
 
ECG  
 
+ 
 
 
 
 
 
+ 
 
 
 
 
 
 
 
+ 
 
+ 
Concomitant medication review  
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+9 
+9 
+ 
AE/SAE recording  
+8 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+9 
+9 
+ 
Collection of retrospective data 11 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
+ 
 
Notes: LDH – last day of hospitalization; EoS – end-of-study visit. Day 1, Visit 1, (randomization day) continues from the end of screening until 23:59 of the same calendar day. Starting from 
Day 2 of the study Study Day corresponds to calendar day defined as a continuous period from 00:00 to 23:59. 
* If the screening procedures period coincides with the calendar day of Visit 1, laboratory tests and other duplicate procedures are not performed on Day 1; the data obtained at the screening visit 
and entered into the eCRF screening record are also transferred to the eCRF Day 1 record. 
** For the efficacy and safety follow-up period: daily during the hospitalization until Visit 15 (Day 15) inclusive or the last day of hospitalization (LHD), whichever comes first. 
*** Visit 15 procedures can be carried out on any other LDH day (before discharge of the patient); no procedures or evaluations are carried out from the LHD to Day 29 except those specified in 
Footnote 9. 
 
1. Results of SARS-CoV-2 PCR tests, chest CT, laboratory tests, anthropometric data, and the patient's medical history data obtained outside the Protocol may be taken into account. Laboratory 
tests (complete blood count, blood chemistry tests) should be performed within 48 hours prior to randomization. 
2. Includes height and weight measurements, BMI. Body weight and height are measured once at the screening. If the anthropometric parameters cannot be evaluated during the screening period, it 
is allowed to use the data closest to the screening period or to make a measurement during the hospitalization, where applicable. BMI is calculated in the eCRF automatically. 
3. Measurements include: blood pressure, pulse rate, respiratory rate, body temperature. 
4. The analysis includes: hemoglobin, red blood cells, platelets, white blood cells, neutrophils, lymphocytes, basophils, monocytes, eosinophils (% and absolute values), ESR. 
5. The analysis includes: total protein, albumin, glucose, total bilirubin, indirect bilirubin, direct bilirubin, ALT, AST, alkaline phosphatase, GGT, LDH, creatinine, sodium, potassium, calcium, 
chlorides, blood urea nitrogen. 
6. The analysis includes: color, clarity, specific gravity, pH, glucose, protein, bilirubin, ketones, nitrites, white blood cells and red blood cells, sediment microscopy. 
7. The urine pregnancy test is performed using test strips in all female participants of the study.  
8. Only SAEs are registered. 
9. If a patient is discharged before the specified study day, the indicated procedures are carried out by telephone; retrospective data are also collected (if applicable); no other procedures are 
conducted. 
10. If the PaO2 cannot be determined, the SpO2/FiO2 is determined.  
11. The following should be included: the date of the last day of hospitalization, the date of switching from MV, the end date of oxygen therapy, the date of transfer from the ICU, the results of the 
PCR tests (primary and confirmatory). 
12. Performed in accordance with the schedule of procedures, as well as before the administration of tocilizumab or sarilumab (if applicable). 
 
 


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8.1. Procedures of individual visits 
Prior to the start of any study procedures, including other screening procedures, the 
Investigator provides the patient with all the necessary information about the study and the 
conditions for participation, as well as sufficient time to decide whether to participate in the clinical 
study or refuse to participate (see section 8.2.1. Obtaining written informed consent for 
participation in the clinical study). The patient is guaranteed that he/she will be provided with 
qualified medical care both in the course of the study and after the study and that the data related 
to the patient, which is obtained during the study, will be kept confidential. After receiving all the 
necessary information and making a decision on participation, the patient should personally sign 
and date the Informed Consent Form for participation in the clinical study in 2 hard copies. One 
hard copy of the Informed Consent Form is given to the patient. Together with the Informed 
Consent Form, the patient is given a life and health insurance policy for a patient participating in 
a clinical study of a medicinal product and a Patient’s Card.  
If the patient's condition is severe, when neither the patient personally nor their legal 
representative are able to read and sign the Patient Information Sheet and the Informed Consent 
Form, the patient may be enrolled in the study by the Principal Investigator’s decision based on a 
Medical Consilium’s recommendation (see section 8.2.2. Medical Consilium). 
The moment when the patient signs the Informed Consent Form or the PI’s decision to 
include the patient based on a Medical Consilium’s recommendation on the advisability of the 
patient’s participation in this study is taken, is considered the time of enrollment of the patient in 
the study and the start of the screening period.  
8.1.1. Screening period 
The screening period involves a complex of patient examinations aimed to assess the 
patient's compliance with all the inclusion/non-inclusion criteria (see sections 5.1. Inclusion 
criteria and 5.2. Non-inclusion criteria) for participation in the study.  
The maximum duration of the screening period is 48 hours, before the start of the day of 
randomization (Day 1).   
If lab test results for a patient do not meet the inclusion/non-inclusion criteria, the patient 
may be retested during the screening, after receiving the original test results. 
If lab test results for a patient do not meet the inclusion/non-inclusion criteria on the basis 
of laboratory tests during the entire screening period, the patient may be rescreened after obtaining 
a confirmation from the medical monitor of the study. 
Results of SARS-CoV-2 PCR tests, chest CT, laboratory tests, anthropometric data, and 
the patient's medical history data obtained outside the Protocol, prior to the start of the screening 
period, may be accepted. Laboratory tests (complete blood count, blood chemistry tests) should be 
performed within 48 hours prior to randomization.  
If the anthropometric parameters cannot be evaluated during the screening period, it is 
allowed to use the data closest to the screening period or to evaluate them later during the 
hospitalization, when this becomes possible. If there is no body weight data available at the time 
of screening, creatinine clearance values are calculated using any other applicable formula that 
does not include body weight, rather than the Cockcroft-Gault formula.  
The screening period includes the following procedures:  
 Obtaining IC / PI’s decision to include the patient based on a Medical Consilium’s 
recommendation  
 Preparation of the Patient’s Card and insurance policy 
 Collection of demographic data 
 Allergy history, bad habits  
 History of the present illness 


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 Information about previous and concomitant diseases 
 Evaluation of the results of SARS-CoV-2 PCR analysis  
 Assessment of chest CT findings  
 Prior and concomitant therapy review 
 Anthropometry 
 Vital signs 
 Physical examination 
 Hematology 
 Blood chemistry panel 
 CRP  
 Ferritin  (if applicable) 
 D-dimer  (if applicable) 
 Pregnancy test (hCG urine test using a test strip); if the test is positive, the patient 
is withdrawn from the study  
 SpO2 assessment 
 PaO2/FiO2 assessment (if applicable); if the PaO2 cannot be determined, determine 
the SpO2/FiO2; 
 Serious adverse event recording. 
 
Patients with a confirmed diagnosis of COVID-19 who meet the inclusion/non-inclusion 
criteria based on the screening results may be transferred to the treatment period.  
8.1.2. Treatment period  
Visit 1 (Day 1, from the end of screening to 23:59 of Day 1):  
Patients transferred to the treatment period undergo the randomization procedure after 
completing all other Visit 1 procedures. The patient receives an injection of the study drug on this 
day. All subsequent events are timed from Day 1. The study drugs are administered no later than 
23:59 of Day 1. 
If the screening procedures period coincides with the calendar day of Visit 1, laboratory 
tests and other duplicate procedures are not performed on Day 1; the data obtained at the screening 
visit and entered into the eCRF screening record are also transferred to the eCRF Day 1 record  
The visit procedures are listed below: 
 Vital signs 
 Physical examination 
 Blood sampling for: 
- Complete blood count; 
- Blood chemistry tests; 
- CRP determination; 
- Ferritin determination (if applicable); 
- D-dimer determination (if applicable); 
 Urine sampling for urinalysis; 
 ECG 
 Clinical status assessment using a 6-point ordinal scale 
 SpO2 assessment 
 PaO2/FiO2 assessment (if applicable) 
 NEWS2 score 
 Concomitant medication review 
 Study eligibility check 


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 Randomization 
 Blinded administration of OKZ/RPH-104/placebo 
 
Recording of AEs/SAEs (after drug administration). 
 
Patients are transferred to the follow-up period after the study drug injection and other 
procedures of this visit. All procedures of this visit, except for the recording of AEs/SAEs, are 
performed before the administration of the study drug.  
8.1.3. Follow-up period  
During the follow-up period (from 00:00 on Day 2 to 23:59 on Day 29), the efficacy and 
safety assessments are performed daily during the hospitalization until Visit 15 (Day 15) inclusive 
or the last day of hospitalization (LHD), whichever comes first. If the patient is discharged earlier 
than Day 15, no procedures are performed between the LHD and Day 15. If a scheduled session 
before Day 15 coincides with the LHD, the LHD procedures are performed. Further, the efficacy 
and safety assessments are performed on Day 15 and Day 29. If the patient continues to be 
hospitalized until Day 29, no scheduled procedures are carried out between Day 15 and Day 29.  
The following procedures are performed at Visits 2 (Day 2) through 14 (Day 14) or the 
LHD (whichever comes first): 
 Vital signs 
 Physical examination 
 SpO2 assessment 
 PaO2/FiO2 assessment (if applicable) 
 Clinical status assessment using a 6-point ordinal scale 
 NEWS2 score 
 Concomitant medication review 
 AE/SAE recording. 
   
The following procedures are performed only at Visit 2 (Day 2), Visit 3 (Day 3), Visit 5 
(Day 5), Visit 7 (Day 7), and the LHD Visit:  
 Blood sampling for: 
- Complete blood count; 
- Blood chemistry tests (except Visit 2); 
- CRP determination; 
- Ferritin determination (if applicable); 
- D-dimer determination (if applicable); 
 Urine sampling for urinalysis (except Visit 2). 
 
Additional procedure for Visit 7 (Day 7) and the LHD Visit: 
 ECG. 
 
If the patient is discharged earlier than Day 14, no procedures are performed from the LDH to Day 
15. 
 
Visit 15 (Day 15):  
If the patient is discharged earlier than Day 15, the following procedures are performed via 
telephone contact (if applicable):  
 Assessment of the clinical status using a 6-point ordinal scale; 


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 Concomitant medication review; 
 AE/SAE recording. 
If the patient could not be contacted via telephone in person, the Investigator should make 
reasonable efforts to find out the necessary information (by interviewing relatives, studying 
available medical documents or officially published data). 
 
If the hospitalization is ongoing at Day 15 or the LHD coincides with Day 15, these 
procedures are performed during face-to-face contact with the patient. In addition, the following 
procedures are carried out:  
 Assessment of vital signs; 
 Physical examination; 
 SpO2 assessment; 
 PaO2/FiO2 assessment (if applicable); 
 NEWS2 score; 
 Blood sampling for: 
- Complete blood count; 
- Blood chemistry tests; 
- CRP determination; 
- D-dimer determination (if applicable); 
- Ferritin determination (if applicable); 
 Urine sampling for urinalysis; 
 ECG. 
 
Afterwards, from Day 15 to Day 29 of the study, no procedures are carried out regardless of 
whether the patient is still hospitalized or has been discharged.  
 
8.1.4. End-of-study visit 
The end-of study visit (EoS) will be performed on Day 29 as telephone contact with the 
patient and/or retrospective analysis of the patient’s medical records (if the patient is discharged 
before Day 29).  
The following information should be collected during the telephone contact (if applicable): 
 Clinical status assessment using a 6-point ordinal scale 
 Concomitant medication review 
 AE/SAE recording. 
If personal telephone contact with the patient cannot be established, the Investigator should 
make reasonable efforts to collect the necessary information (by interviewing relatives, studying 
available medical records or officially published data). 
Based on the patient’s medical records, the following information is retrospectively 
obtained and recorded (if applicable): 
 The date of the last day of hospitalization 
 The date of switching from mechanical ventilation 
 The end date of oxygen therapy 
 The date of transfer from the ICU 
 The results of the PCR tests (primary and confirmatory). 
 
If the hospitalization is ongoing at Day 29, these procedures are performed during contact 
in person.  
 


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A patient is considered having completed the study per protocol after finishing all the 
procedures scheduled for Day 29.   
After finishing all the procedures scheduled for this visit, a Study Completion Form in the 
eCRF is filled out. 
 
8.1.5. Study withdrawal visit  
A patient is considered withdrawn from the study if they meet the criteria specified in 
Section 5.4. Exclusion criteria (early study termination). 
If a patient is withdrawn from the study, the Study Completion Form in the eCRF is filled 
out, where the following information must be recorded, depending on what is applicable at the 
time of completion of the patient's participation: 
 Assessment of the clinical status using a 6-point ordinal scale 
 Concomitant medication review 
 AE/SAE recording 
 The date of the last day of hospitalization 
 Results of physical examination findings, laboratory tests and other investigations 
applicable to the study and available at the time of the patient’s withdrawal from 
the study 
 The date of switching from mechanical ventilation 
 The end date of oxygen therapy 
 The date of transfer from the ICU 
 The date of and reason for the administration of tocilizumab or sarilumab, if 
tocilizumab or sarilumab was administered   
 The results of the PCR tests (primary and confirmatory). 
 
If a patient is withdrawn from the study and withdraws their consent to data disclosure in 
the future, it is prohibited to conduct any additional assessments or collect any additional data. The 
Sponsor may retain and continue to use the data received prior to revocation of consent.  
 
8.1.6. Additional unscheduled visits  
At the discretion of the Investigator, an unscheduled visit may be arranged to perform 
additional safety assessments (repeated laboratory tests, evaluation of AEs) or for other additional 
assessments during the study. 
At an unscheduled visit due to an AE, at least the following assessments may be performed 
at the discretion of the Investigator: 
 Body weight measurement 
 
Physical examination 
 
Vital signs 
 
Hematology 
 
Blood chemistry panel 
 
CRP determination  
 
Ferritin determination (if applicable)  
 
D-dimer determination (if applicable) 
 
Urinalysis 
 
ECG 
 
Concomitant medication review 
 
AE/SAE recording. 


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8.2. Description of individual study procedures 
8.2.1. Obtaining written informed consent for participation in the clinical study 
Prior to the start of any procedure scheduled for the screening, the Investigator should 
provide the patient or his/her legal representative with comprehensive information about the study 
and the conditions for participation, including the following information: 
 that the clinical study is experimental in nature, participation of the patient in the clinical 
study is voluntary, and he/she may refuse to participate in the clinical study at any time; 
 the objective of the clinical study, its duration, and the approximate number of participants; 
 the treatment options available within the clinical study and the likelihood of random 
allocation to the treatment groups; 
 about the clinical study procedures, including all invasive procedures; 
 about the responsibilities of a participant (patient) of the clinical study; 
 about the expected risks and/or benefits for a participant of the clinical study, as well as the 
risks of pregnancy in a female participant during the study; 
 about the procedures or treatment options (other than those stipulated by the protocol) that 
may be available to a participant of the clinical study, as well as their potential benefits and 
risks; 
 about the compensation and/or treatment available to a participant of the clinical study in 
case of harm to his/her health as a result of participation in the clinical study; 
 about the planned expenses for a participant of the clinical study, if any, expected to be 
associated with his/her participation in the clinical study; 
 that the clinical study participant, by signing the Patient Information Sheet with the Informed 
Consent Form, gives permission to access to his/her medical records: to the person 
designated for monitoring; auditors, members of independent ethical committees, employees 
of authorized bodies; 
 that the records identifying the participant of the clinical study will be kept confidential and 
that their disclosure is permitted only in accordance with the legislation of the participating 
countries; that the data of the clinical study participant will be kept confidential if results of 
the clinical study are published; 
 that the clinical study participant will be immediately notified of any new information that 
could affect his/her willingness to continue to participate in the clinical study; 
 about the persons who can be contacted for more information about the clinical study, and 
the rights of participants of the clinical study; 
 about the possible circumstances of and/or reasons for withdrawal of a participant from the 
clinical study. 
Before obtaining voluntary informed consent, the Investigator must give the patient 
sufficient time necessary for making a decision whether to participate in the clinical study or not. 
The patient has the right to receive comprehensive and reliable answers to all questions about the 
clinical study. 
After receiving all the necessary information, the patient should sign and date two copies 
of the Patient Information Sheet and the Informed Consent Form for participation in the study. The 
Investigator should also sign and date the Patient Information Sheet with the Informed Consent 
Form, thereby confirming that the Investigator has discussed them with the patient, the patient has 
had the possibility to ask questions and received comprehensive answers, and the patient’s consent 
has been obtained.  
The patient will receive one copy of the Patient Information Sheet with the Informed 
Consent Form, and the second copy will be kept by the Investigator at the study site along with 
other study documents. 


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After signing the Informed Consent Form, Investigator should also give the patient a copy 
of the insurance policy and the Patient's Card. 
8.2.2. Medical Consilium 
The Medical Consilium is a meeting of several doctors of one or several specialties to 
establish  patient’s health status, diagnosis, determine the prognosis and management, the 
advisability of referring a patient to specialized departments of the health care organization or 
other health care organizations, and to resolve other issues in cases stipulated by the legislation of 
participating countries. The Medical Consilium is conducted in accordance with the applicable 
regulatory requirements of the participating countries.  
The Principal Investigator must notify the Head of ICU of the study start and the patient 
inclusion/non-inclusion criteria. In view of the specificity and mode of operation of these units, 
notification (informing) may take any form: an oral conversation over the telephone, providing an 
electronic or printed version of the Protocol synopsis. The main task of the notification is to inform 
the Head of the ICU about the conduct of this clinical study at the health center and the possibility 
of patients’ participation in it. Documentation of the notification process is regulated by local 
regulations of the health center. 
When a patient is admitted at the intensive care unit, before he/she is included in the study, 
he/she receives standard COVID-19 therapy as per routine practice of participating facility.  If the 
Head of ICU establishes at daily rounds that the patient has no improvement or his/her condition 
worsens while on standard therapy, while neither the patient personally nor his legal representative 
have an opportunity to read and sign the Patient Information Leaflet and the Informed Consent 
Form, the Head of ICU shall make a decision to call a Medical Consilium to recommend including 
the patient in the clinical study.  
The Medical Consilium includes (but is not limited to) the attending critical care physician, 
the Head of ICU and the supervising Deputy Chief Physician. If any of these persons participates 
in the clinical study, independent physicians must be invited to the consilium, and at least one of 
the consilium participants must be an anesthesiologist-resuscitator. The Principal Investigator is 
invited to the council, he/she does not make decisions, but advises on questions related to the study, 
if the members of the Consilium have any. The Medical Consilium is aimed at establishing the 
patient's health status, diagnosis, and prognosis, working out a plan of medical examination and 
treatment, identifying any need to change therapy, including evaluation of the benefit-risk ratio 
(expediency) of the patient's participation in the clinical study in each case where obtaining the 
informed consent of the patient or their legal representative is impossible.  Based on the Consilium 
decision, the attending critical care physician prints minutes indicating the names of the doctors 
involved in the Consilium, information about the reasons for the Consilium, the course of the 
patient’s disease, the patient’s condition at the time of the council, including interpretation of 
clinical data, laboratory, instrumental and other investigations and the decision of the Medical 
Consilium. If there is a dissenting opinion of the member of Consilium, an appropriate entry is 
made in the minutes; the minutes should also indicate the date and time; the minutes are signed by 
all members of the Medical Consilium (attending physician, Head of ICU, Deputy Head Physician, 
etc., if applicable). The decision of the Medical Consilium does not imply inclusion 
(randomization) of the patient in the study, but gives the Principal Investigator a recommendation 
and a right (but not an obligation) to start the screening procedures according to the Protocol. The 
selection of patients who have medical indications for participation in a clinical study of a 
medicinal product for human use is a function of the Investigator. 
If the decision of the Medical Consilium is positive, the Investigator can include the patient 
in the study and start performing the screening procedures. 
 


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At the earliest opportunity, the patient or his/her legal representative should be informed 
as soon as possible about the study, and they should be asked for consent to continue participation 
in the study in accordance with section 8.2.1. Obtaining written informed consent for participation 
in the clinical study.  
8.2.3. Collection of demographic data, life history, medical history, and prior 
therapy 
Based on the patient’s medical records and the results of questioning the patient, the 
following parameters will be recorded (if applicable): 
 
Demographics: 
 date of birth (age); 
 sex; 
 race and ethnicity; 
 assessment of childbearing potential (use of contraception, presence of menopause, its 
duration, sterilization data) 
 
Bad habits: 
 information about bad habits (smoking and drinking). 
 
History of allergies: 
 information about any allergic reactions in the patient. 
 
History of the present illness:  
 medical history of the primary disease. 
 
Previous and concomitant diseases: 
 medical history of past/concurrent diseases (past oncological and infectious diseases, 
chronic infectious and inflammatory diseases, concomitant somatic diseases) with an 
indication of the known onset/end date. 
 
Prior and concomitant therapies: 
 collection of data on previous and concomitant therapy that the patient has received earlier 
and is receiving at the time of screening for the treatment of the primary disease, including 
the names of the drugs, doses, regimens; 
 collection of data on medicines that the patient received within 1 month (for drugs listed 
in the non-inclusion criteria: within 5 half-lives of the drug or 1 month, whichever is 
longer) prior to screening or is receiving at the time of screening for the treatment of 
concomitant diseases, indicating the doses, frequency of administration and duration of 
use. 
8.2.4. Evaluation of the results of SARS-CoV-2 PCR analysis  
Results of laboratory tests for 2019-nCoV RNA by polymerase chain reaction (PCR) 
obtained earlier during the patient's examination may be used to assess the compliance of the 
patient with the inclusion/non-inclusion criteria of the study if applicable. If no PCR results are 
available at the time of screening, the results of the primary and confirmatory tests (in accordance 
with the diagnostic standards for the disease) should be recorded in the patient’s eCRF 
retrospectively, after they become available. The test results, together with the reports of the 
relevant specialists, are stored as source documentation. 


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8.2.5. Anthropometric parameters 
Anthropometric parameters include the following: 
 body weight (kg) – measured once at a screening visit;  
 height (cm) – measured once at a screening visit; 
 body mass index (BMI) – the calculation is made in the eCRF automatically using the 
following formula: 
BMI = body weight (kg)/(height (m)2) 
 
If it is not possible to evaluate anthropometric data during the screening period, it is allowed 
to use the data closest to the screening period or to make measurements later during the 
hospitalization, when this becomes possible. 
 
8.2.6. Physical examination 
A physical examination will include examinations of the following systems: 
 skin, visible mucous membranes, hair, nails (examination), 
 lymph nodes (examination, palpation), 
 ENT organs, respiratory system (examination, auscultation of the lungs), 
 cardiovascular system (auscultation of the heart, examination of the area of large vessels), 
 gastrointestinal tract (examination, palpation of the abdomen), 
 assessment of the liver size (palpation, percussion). 
The sequence of assessments during the visit is not strictly defined. 
In view of the specific arrangements of work with patients with the new coronavirus 
infection, the mandatory use of personal protective equipment and the need to have the patient in 
the prone position may preclude a full physical examination. Therefore, physical examination 
procedures are optional, if applicable.  
8.2.7. Vital signs 
Assessment of vital signs includes the following: 
 body temperature (in Celsius degrees), 
 blood pressure (BP) (on one arm, in mmHg), 
 pulse (per minute),   
 respiratory rate (RR) (resp. per min.), except for mechanically ventilated patients. 
Blood pressure (systolic and diastolic blood pressure) will be determined using blood 
pressure cuff on the same arm. Body temperature is measured in the same way throughout the 
study.  
When a patient is in ICU, the pulse is measured using a cardiac monitor. After transferring 
patients to the specialized department, the pulse is measured by a health care professional. Pulse 
rate and RR measurements are performed for 1 minute.  
When the patient is outside the ICU, vital signs are measured after a 5-minute rest in a 
sitting position (if applicable).  
The sequence of assessments during the visit is not strictly defined. 


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8.2.8. Laboratory tests 
During the study, blood and urine samples will be taken from each patient for laboratory 
tests, efficacy and safety assessments. Laboratory tests include an assessment of the main 
parameters of hematology, blood chemistry, and urinalysis. The levels of cytokine storm markers: 
CRP, ferritin (if applicable) and D-dimer (if applicable) will also be determined. If necessary, 
additional laboratory tests may be carried out to assess changes in the analyzed parameters over 
time. 
To exclude pregnancy, all women participating in the screening study will have urine hCG 
levels measured. 
All analyses are performed at the local laboratory of the study site. 
If the screening procedures period coincides with the calendar day of Visit 1, then 
laboratory tests on Day 1 are not performed again; the data obtained at the screening visit and 
entered into the eCRF record for screening are also transferred to the eCRF record for Day 1. 
Laboratory test results obtained outside the Protocol, prior to the start of the screening 
period may be taken into account. In any case, a complete blood count and blood chemistry tests 
should be performed no earlier than 48 hours before randomization. 
The list of parameters determined by individual laboratory tests, their specifics and the 
frequency are presented in Table 3.  
 
Table 3. The list of parameters determined by individual laboratory tests, their specifics and 
frequency 
Procedure 
Parameters 
Specifics 
Dosing 
frequency 
Hematology 
 Hemoglobin (g/L) 
 Red blood cells (x1012/L) 
 Platelets (х109/L) 
 White blood cells (х109/L) 
 WBC differential: 
 Neutrophils (% and 
х109/L) 
 Lymphocytes (% and 
х109/L) 
 Basophils (% and х109/L) 
 Monocytes (% and х109/L) 
 Eosinophils (% and 
х109/L) 
 ESR (mm/h) 
 
Whole blood is sampled 
using standard methods. 
 
 
x 7: 
screening 
Visit, Visits 
1, 2, 3, 5, 7, 
15/LHD. 
Blood chemistry 
 
 Total protein (g/L) 
 Albumin (g/L) 
 Glucose (mmol/L) 
 Total bilirubin (µmol/L) 
 Indirect bilirubin (μmol/L) 
 Direct bilirubin (μmol/L) 
 ALT (U/L) 
 AST (U/L) 
 ALP (U/L) 
 GGT (U/L) 
 LDH (U/L) 
Whole blood is sampled 
using standard methods. 
 
 
x6: screening 
Visit, Visits 
1, 3, 5, 7, 
15/LHD. 


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Procedure 
Parameters 
Specifics 
Dosing 
frequency 
 Creatinine (μmol/L) 
 Sodium (mmol/L) 
 Potassium (mmol/L) 
 Total calcium (mmol/L) 
 Chloride (mmol/L) 
 Blood urea nitrogen 
(μmol/L) 
 
Determination of 
CRP levels 
 C-reactive protein (mg/L), 
the reference range is 
established by the local 
laboratory  
Whole blood is sampled 
using standard methods. 
 
x7: screening 
Visit, Visits 
1, 2, 3, 5, 7, 
15/HD. 
Determination of 
D-dimer level (if 
applicable) 
 D-dimer (ng/mL), the 
reference range is 
established by the local 
laboratory  
Whole blood is sampled 
using standard methods. 
 
x7: screening 
Visit, Visits 
1, 2, 3, 5, 7, 
15/LHD. 
Determination of 
ferritin level (if 
applicable) 
 Ferritin (µg/L), the 
reference range is 
established by the local 
laboratory 
Whole blood is sampled 
using standard methods. 
 
x7: screening 
Visit, Visits 
1, 2, 3, 5, 7, 
15/LHD. 
Urinalysis 
 Color 
 Clarity 
 Specific gravity 
 рН 
 Glucose 
 Protein 
 Bilirubin 
 Ketone bodies 
 Nitrites 
 White blood cells 
 Red blood cells 
  
Carried out according to 
the standard method 
x5: Visits 1, 
3, 5, 7, 
15/LHD. 
Pregnancy test 
 Urine hCG 
Test dip-sticks are used 
 
Tests are performed for 
all women participating 
in the study.  
 
The test drugs may be 
used only if the test 
result is negative 
 
An indecisive test result 
is regarded as positive. 
 
If the test result is 
positive or erroneous, the 
test drugs are not used, 
the patient is excluded 
х1: 
Screening 
Visit 


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Procedure 
Parameters 
Specifics 
Dosing 
frequency 
from the study and 
followed-up in 
accordance with 
generally accepted 
standards of care 
 
8.2.9. Electrocardiography 
An electrocardiogram (ECG) will be recorded after the patient rested lying down for at 
least 10 minutes (if applicable). 
ECG data will be entered into the patients’ eCRFs. The heart rate will be measured and a 
conclusion will be made on normal results or presence of clinically significant or clinically 
insignificant ECG abnormalities. Original electrocardiograms with expert opinions will be stored 
as source documentation.  
8.2.10. Assessment of chest CT findings 
Chest CT results obtained earlier during the patient's examination may be used to assess 
whether the patient meets the inclusion/non-inclusion criteria of the study. The results of 
investigations, together with the conclusions of the relevant specialists, are stored as source 
documentation.  
8.2.11. Determination of oxygenation parameters 
SpO2 is determined using a pulse oximeter. 
PaO2/FiO2 is a parameter used in anesthesiology, critical and intensive care to evaluate the 
oxygen exchange function in the lungs. The oxygenation index is calculated using the formula, 
such as the PaO2/FiO2 ratio (the ratio of partial pressure of oxygen in arterial blood to the fraction 
of inspired oxygen). It is determined in patients in ICU, including mechanically ventilated patients. 
If the PaO2 cannot be determined at the screening visit, the SpO2/FiO2 should be determined. 
  


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9. EFFICACY ASSESSMENT  
According to efficacy endpoints, the following should be evaluated at study visits from 
Day 1 to Day 15: 
1. Clinical status of the patient; 
2. The fact of administration of tocilizumab or sarilumab (not earlier than 24 hours after 
the administration of the study drugs); 
3. Changes in oxygenation parameters over time; 
4. The need for non-invasive ventilation; 
5. The need for invasive mechanical ventilation (IMV) and/or ECMO; 
6. Changes in cytokine storm biomarkers: blood sampling is performed on Days 1, 2, 3, 5, 
7 and Day 15.  
9.1. Assessment of treatment response 
A treatment response is an improvement of 1 point or more on the 6-point scale (section 9.2 
Assessment of the clinical status of the patient) after the administration of the study drugs, 
provided that tocilizumab or sarilumab was not administered to the patient before the assessment. 
9.2. Assessment of the clinical status of the patient 
The clinical status of the patient is evaluated on a 6-point ordinal scale daily during 
hospitalization (Day 1 to Day 15). If the patient is discharged before Day 15 or Day 29, the clinical 
status on these days is assessed by contacting the patient on the telephone. 
The 6-point ordinal scale includes the following categories: 
 
1. Not hospitalized; no activity limitations; 
2. Not hospitalized; limited activity; 
3. Hospitalized, not requiring supplemental oxygen; 
4. Hospitalized, supplemental oxygen; with independent breathing; 
5. Hospitalized, mechanical ventilation (invasive/non-invasive) or ECMO; 
6. Death. 
 
 
 
Activity limitations are defined as absent if the patient, at the time of assessment, is able to 
perform all the daily physical activity that he/she could perform before the disease. The clinical 
status is evaluated daily.   
The clinical status of patients in the intensive care unit is assessed at each visit for the day 
preceding the day of the visit (i.e., the status of Day 2 is recorded on Day 3 and is indicated as 
“status on Day 2”). The worst value of the estimated parameter obtained within 24 hours is 
recorded in the eCRF. 
 
The clinical status of patients undergoing treatment in specialized departments and those 
followed-up outpatiently is recorded at the day of assessment in accordance with the schedule of 
visits (Table 2).  
9.3. NEWS2 score 
The National Early Warning Score 2 (NEWS2) scale allows identifying patients with an 
increased risk of adverse outcome based on 7 clinical parameters: respiratory rate (RR), blood 
oxygen saturation (SpO2), use of oxygen therapy or room air breathing, body temperature, systolic 
blood pressure (SBP), pulse, level of consciousness. The scale has a special section (SpO2 2) for 
use in patients with hypercapnic respiratory failure. 


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Physiological 
parameter 
3 
2 
1 
0 
1 
2 
3 
respiration rate 
(per minute) 
≤ 8 
 
9-11 
12-20 
 
21-24 
≥ 25 
SpO2 Scale 1 (%) 
≤ 91 
92-93 
94-95 
≥ 96 
 
 
 
SpO2 Scale 2 (%) 
≤ 83 
84-85 
86-87 
88–92 
≥93 (air) 
93–94 
(oxygen) 
95-96 
(oxygen) 
≥97 
(oxygen) 
Air or oxygen? 
 
Oxygen 
 
Air 
 
 
 
Body temperature, 
°C 
 
≤ 35.0 
 
35,1-
36,0 
36,1-38,0 
38,1-39,0 
≥ 39.1 
 
SBP, mm Hg 
≤ 90 
91-100 
101-110 
111-219 
 
 
≥ 220 
Pulse, per minute 
≤ 40 
 
41-50 
51-90 
91-110 
111-130 
≥ 131 
Consciousness 
 
 
 
A 
 
 
C, V, P or 
U 
Levels of consciousness: A - alert, V (voice) - responds to voice, P (pain) - responds to pain, C - confusion, U 
(unresponsive) - unconscious, does not respond. 
 
The scores for each physiological parameter are summarized, the final score can be range 
from 0 to 20. A higher score means a more severe condition of the patient.  
The NEWS2 scale score is recorded directly on the day of assessment (i.e., Day 3 score is 
recorded on Day 3) from Day 1 to Day 15 (LHD) inclusive. The score is estimated as the sum of 
all the scale parameters. During the stay in the ICU, the maximum and minimum scale scores are 
recorded; when the patient is outside the ICU during hospitalization, the scale is evaluated once a 
day at the same time with an acceptable time window of ± 2 hours. 
9.4. Assessment of surrogate cytokine storm markers 
During the study, on Days 1, 2, 3, 5, 7, and Day 15 (LHD), blood samples will be collected 
to evaluate surrogate cytokine storm markers (blood CRP, ferritin (if applicable), D-dimer (if 
applicable), neutrophil count, white blood cell count, lymphocyte count) (see Tables 2, 3). 
Additionally, blood samples to determine cytokine storm markers will be collected before the 
administration of tocilizumab or sarilumab (if applicable). 
9.5. Determination of oxygenation parameters 
During the patient’s stay in the ICU, the following oxygenation parameters will be 
determined: SpO2, PaO2/FiO2.  
During the stay in the ICU, the maximum and minimum scale scores are recorded; when 
the patient is outside the ICU during hospitalization the scale is evaluated once a day at the same 
time with an acceptable time window of ± 2 hours. For a description of the procedure, see section 
8.2.11. Determination of oxygenation parameters. 
9.6. Assessment of ARDS severity 
ARDS severity is assessed (when applicable) based on PaO2/FiO2a and corresponds to the 
following categories: 
 
 Mild ARDS: 200 mm Hg <PaO2/FiO2a ≤ 300 mm Hg (with PEEP or CPAP ≥ 5 
cm H2O or without ventilation) 
 Moderate ARDS: 100 mm Hg <PaO2/FiO2 ≤ 200 mm Hg (with PEEP ≥ 5 cm 
H2O or without ventilation) 


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 Severe ARDS: PaO2/FiO2 ≤ 100 mm Hg (with PEEP ≥ 5 cm H2O or without 
ventilation) 
 If it is not possible to evaluate PaO2, ARDS is assumed in SpO2/FiO2 ≤ 315 
(including in non-ventilated patients). 
 
10. SAFETY ASSESSMENT  
10.1. Adverse events 
In this study, an adverse event (AE) means any untoward medical event in a patient 
receiving the study drugs that does not necessarily have a causal relationship with the study drug. 
Thus, an adverse event can be any unintended and adverse symptom (for example, a laboratory 
abnormality), a symptom or a disease with temporal relationship with the use of the drug, 
regardless of whether they are considered to be related to the drug.  
All AEs should be followed-up until resolution or stabilization (as assessed by the 
Investigator).  
10.2. Serious adverse events (SAEs) 
A serious adverse event (SAE) is any adverse event that meets one or more of the criteria 
listed below: 
 Resulted in the patient's death; 
 Is life-threatening; 
 Requires hospitalization or prolongation of existing hospitalization; 
 Resulted in persistent or significant disability or incapacity, or 
 Is a congenital anomaly or developmental defect occurring in children born to 
patients treated with the study drug. 
In addition, serious adverse events may include other important medical manifestations if 
the physician-Investigator believes, on the basis of his/her medical experience, that this 
manifestation may result in one of the outcomes described above if no medical intervention is 
undertaken. 
An adverse event is considered to be “life-threatening” if the patient was at an immediate 
risk of death at the time of the event. This category does not include adverse events, which 
hypothetically might have caused the patient's death if they were more severe. 
10.3. AE recording 
Adverse events are registered either on the basis of complaints spontaneously reported by 
the patient or by the Investigator interviewing the patient or using physical examination findings 
and results of laboratory and instrumental investigations. The Investigator should formulate his / 
her questions to the patient so that they do not prompt the patient to report unreliable information. 
Adverse events had to be registered in the respective sections of the eCRF, as well as in 
the patient's source medical documents.  
All adverse events, except serious ones, are recorded from the moment of the use of the 
investigational drugs. Adverse events recorded prior to the start of the study therapy, but after the 
patient is included in the study, are recorded in the eCRF as “Concomitant diseases”. Adverse 
events will be registered until the end of the follow-up period.  
The following information should be reported for registered AEs: 
- The patient's identification number; 


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- The diagnosis made in connection with the adverse event (making a diagnosis 
should be preferred to listing symptoms); 
- The start and resolution dates for the adverse event (and the times if applicable); 
- AE severity; 
- The relationship with the use of the investigational medicinal product; 
- The measures that have been taken due to the adverse manifestation; 
- Whether the adverse event fulfils the serious adverse event criteria; 
- The outcome of the adverse event. 
 
Assessment of the cause-and-effect relationship between the adverse event and the use 
of the investigational medicinal product 
The Investigator is responsible for the assessment of the relationship between the 
investigational drug and AE. The Investigator should use his/her knowledge about the patient, the 
circumstances of the event, and assessed any potential alternative causes to determine whether or 
not the AE is related to the study drug. The relationship between the AE and the study drug should 
be characterized as either “related” or “unrelated”. The following recommendations should be 
considered: 
• 
Temporal relationship between the onset of the adverse event and the beginning of 
the study drug use. 
• 
Evolution of the adverse event over time, discontinuation of the study drug. 
• 
Known association of the adverse event with the study drug or a similar ttreatment. 
• 
Risk factors in patients increasing the likelihood of an adverse event. 
• 
Factors not related to treatment, associated with the event frequency. 
The Investigator should report the relationship of each event to the study drug based on the 
most probable causality; the study staff is responsible for obtaining any missing information. 
If the assessed relationship changes over time as a result of new or changing information, 
it may be revised. 
 
Adverse event severity grade 
AE severity is graded according to the CTCAE classification V5.0. 
If certain adverse events were not listed in the CTCAE, the physician-Investigator will 
classify them according to the following grades and definitions: 
 
Grade 0: 
No AE (or within normal limits) 
Grade 1: 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated 
Grade 2: 
Moderate; non-significant, local or noninvasive intervention indicated (e.g. 
wrapping, application of cauterants); limiting age-appropriate instrumental 
activities of daily living 
Grade 3: 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self care activities of daily living 
Grade 4: 
Life-threatening complications; urgent intervention is indicated 
Grade 5: 
Death related to AE 
 
Severe AE may be not serious and, conversely, a serious AE is not necessarily severe.  
Given the nature of the disease under study, it is expected that patients will develop 
frequent laboratory and vital sign abnormalities. During the study, all AEs will be recorded, only 
grade 4 and 5 AEs according to CTCAE v.5.0 will be included in the analysis. 


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Specific requirements for registration of AEs: 
 Increasing severity of symptoms of the underlying disease (COVID-19) in this 
study will not be considered an AE. 
 In patients with clinical and laboratory abnormalities or those with any other 
pathology at the time of screening, a change in the severity or other clinically 
significant deterioration should be recorded as AE, at the discretion of the 
Investigator. 
 If hospitalization or its prolongation is a criterion for AE severity, the following 
hospitalizations are not considered as SAEs: 
o carrying out the procedures specified in the protocol, or administration of 
the study therapy; for example, hospitalization or prolongation of 
hospitalization are part of the routine practice at this study site; 
o treatment or examination due to a preexisting condition unrelated to the 
study therapy (administration of the study therapy) for the underlying 
disease, which did not worsen; 
o scheduled or unscheduled examination, rehabilitation for social reasons or 
surgical intervention not aimed at treatment of SAE;  
o social reasons, for example, additional supervision by a doctor or 
hospitalization in order to provide additional comfort in the winter season 
when there are multiple visits according to the Protocol, etc. 
10.4. SAE reporting 
SAEs are recorded after inclusion of the patient in the study (signing the Informed Consent 
Form or enrollment following the Principal Investigator’s decision based on a Medical 
Consilium’s recommendation). To ensure safety for study subjects in case of any SAE developing 
during the study, regardless of the suspected causes of the SAE or the relationship with the use of 
the investigational drug, the SAE should be reported to the study Sponsor within 24 hours after 
the Investigator becomes aware of the SAE. 
If a patient develop a serious adverse event assessed by the Investigator as related to the 
use of the investigational drug, it should be reported even if the study has already been completed. 
 
Filling out the serious adverse event reporting form. 
SAEs should be reported by sending a scanned copy of the filled serious adverse event 
reporting form in paper format by e-mail to:  
Safety@Rpharm.ru. 
or by fax to: 
+7 (495) 956-79-38 
The principal person to contact on any issues related to the safety of the study drugs is 
Sergey, MD PhD., Head of Drug Safety and Pharmacovigilance, R-Pharm JSC.  
Phone:+7 495 956-79-37, ext. 1506 
fax: +7 (495) 956-79-38.  
email: Safety@rpharm.ru  
The Investigator should notify LEC of SAEs in accordance with LEC’s standard operating 
procedures. 
 
Reporting suspected unexpected serious adverse reactions (SUSAR). 
The Study Sponsor should notify the regulatory authorities of all suspected unexpected 
serious adverse reactions within the time frame specified by the law.  In the context of notifying 
regulatory authorities and Investigators, suspected unexpected serious adverse reactions will be 


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deemed to be unexpected serious adverse events assessed by the Investigator and/or Sponsor to be 
related to the study drug. 
The sponsor will inform Investigators of all suspected unexpected serious adverse reactions 
recorded during the study. It is the Investigator’s responsibility to submit appropriate reports to 
the Local Ethics Committees of healthcare institution. 
 
Submission of other safety reports. 
The Investigators will report to the Local Ethics Committees of the healthcare institutions 
on other treatment safety-related aspects subject to expedited reporting if they affect the benefit-
risk ratio for the study therapy or can necessitate significant modification of the study therapy or 
study methods. 
In addition to submitting expedited reports, the Sponsor will annually prepare safety update 
reports for OKZ and RPH-104, containing all new relevant safety information received during the 
reporting period. These reports will be forwarded to the Investigator for submission to the Local 
Ethics Committees of healthcare institutions once a year. 
10.5. Independent Data Monitoring Committee 
The Independent Data Monitoring Committee (IDMC) will periodically review the 
available safety data on the investigational drugs from the study and provide the Sponsor with 
recommendations for further study based on these reviews. The frequency and procedure for 
conducting safety assessments of drugs will be determined in the IDMC procedures.  
In addition, the IDMC will conduct an early analysis of the data obtained in the pilot phase 
of the study and provide recommendations to the Sponsor on changing the endpoint and the final 
sample size. 
10.6. Pregnancies 
Pregnancy is not an adverse event as such, except where there is reason to believe that the 
use of the investigational drug resulted in decreased effectiveness of the contraceptives used. 
If there is a positive pregnancy test before the first use of the drug, the patient is excluded 
from the study before randomization.  
Information concerning pregnancies in female patients or partners of male patients 
participating in the study should be recorded from the first dose of the study drug. 
Male patients will receive instructions in the Patient Information Leaflet and Informed 
Consent Form to immediately inform the Investigator if the patient’s partner becomes pregnant 
during the study.  
If a female patient or a female partner of a male patient participating in the study becomes 
pregnant, the study Sponsor should be notified by filling out the “Pregnancy reporting”. A 
pregnancy report should be filled out by an authorized employee of the study site within 24 hours 
after the pregnancy information is received. Pregnancy cases should be reported by sending a 
scanned copy of the filled pregnancy reporting form in paper format by e-mail to: 
Safety@Rpharm.ru. 
Collection of pregnancy-related information should continue until the end of the 
pregnancy. After the end of the pregnancy, the study Sponsor should be informed about the 
outcome of the pregnancy (miscarriage, elective abortion, delivery of a healthy infant or infant 
with congenital anomalies or developmental defects). If possible, the newborn infant’s health 
should be monitored until 6 weeks, 6 months, and 12 months of age. 
Any complications of pregnancy should be recorded as adverse events or serious adverse 
events depending on the seriousness criteria. Congenital anomalies and developmental defects in 
subjects’ children are serious adverse events. Miscarriages should be recorded as serious adverse 


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events. Elective abortions carried out at the woman’s discretion, without medical indications for 
abortion and not associated with complications, are not adverse events. 
10.7. Actions in emergency situations 
The study site should have appropriate equipment and medications necessary for 
emergency care. Their use should be recorded in the e-CRF; 
11. STATISTICAL ANALYSIS 
11.1. Justification of the planned sample size  
Since there is no reliable data on the course of COVID-19 and the distribution of 
hospitalized patients by disease severity after the use of standard therapy and the study drugs, the 
study will include a pilot phase during which it is expected to enroll 63 patients in each treatment 
group. The final sample size will be determined based on the results of the pilot phase data analysis.  
Based on the literature data available as of April 15, 2020 [21, 27-29] and provided that 
approximately 60% of the patients enrolled in the study fall into category 4 on the clinical status 
scale ("Hospitalized, supplemental oxygen with independent breathing”) and approximately 40% 
fall into category 5 ("Hospitalized, mechanical ventilation (invasive/non-invasive) or ECMO"), 
the estimated proportion of treatment responders will be 40% in the placebo group and 60% in the 
active therapy groups. Table 4 shows the calculation of the total number of patients who should 
be included in the early and final analysis in order to demonstrate the superiority of any of the 
study drugs over placebo with a statistical power of 80% and an overall critical level of α = 2.5% 
[30]. The calculation was performed using the SAS procedure for planning sequential adaptive 
designs. Figure 5 shows the study enrollment scheme. 
 
Table 4. Planned sample size for final analysis  
 
Stage of 
analysis  
Randomization  Overall 
α level  
Power  
Number 
of 
patients 
in the 
group  
Total 
number 
of 
patients  
Randomized 
patients (20% 
dropout) 
Pilot  
1:1:1 
0.025 
80% 
50 
150 
189 
Final  
1:1:1 
0.025 
80% 
99 
297 
372 
 


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Figure 5. Study enrollment scheme 
 
OKZ = olokizumab; PE = primary endpoint; SE = secondary endpoints 
* 63 patients will be randomized to each group and have the evaluation on Day 15 or complete the study, whichever 
comes first. 
# Preliminary number of patients to be randomized. It can be revised based on the results of the pilot phase of the 
study. 
 
11.2. Analytical methods  
Statistical analysis will be performed using specialized software, which will be selected at 
the stage of preparing the statistical analysis plan.  
Continuous (quantitative) data to be presented include the number of observations, the 
arithmetic mean with standard deviation, the minimum and maximum. Presented qualitative data 
(ordinal, nominal) will include absolute frequencies (number of observations), relative frequencies 
(percentages) and 95% CIs. 
Medical history, concomitant diseases and adverse events will be encoded using the 
MedDRA terminology (the Russian version corresponding to the current Medical Dictionary of 
Regulatory Activities terminology). Concomitant and prior therapy will be encoded using the ATX 
classifier. 
This section briefly describes the planned analysis. The full analysis will be described in 
the statistical analysis plan. 
 
11.3. Analysis sets 
The intent-to-treat (ITT) population will include all randomized patients. Patients will be 
analyzed in accordance with the treatment group to which they are randomized. The ITT 
population will be the primary analysis population. 
Modified intent-to-treat (mITT) population: the mITT population will include all 
randomized patients who received the study drug and did not require tocilizumab or sarilumab as 
part of standard therapy. 
Safety population: The safety population will include all patients who have received at least 
one dose of the study drug. Patients will be analyzed based on the actually received treatment.  
Study start 
Early analysis of pilot phase 
Final analysis 
OKZ 
RPH-104 
Placebo 
Assessment of 
effect size and 
patient 
distribution by 
severity 
PEP revision if 
necessary 
Sample size 
revision 
A total up 
to 397 
A total up 
to 397 
A total up 
to 397 
Efficacy 
assessment based 
on final PEP 
SE assessment 
Safety assessment 
Enrollment of first 189 
patients* 
Continue recruiting until the sample size 
determined by the results of the pilot phase 
is reached 
63 
63 
63 
A total of up 
to 124# 
A total of up 
to 124# 
A total of up 
to 124# 


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11.4. Demographic and other baseline characteristics 
Demographic and other baseline characteristics will be presented using descriptive 
statistics tools by therapy group, as well as separately by therapy group for patients who received 
at least one dose of tocilizumab or sarilumab and for patients not receiving tocilizumab or 
sarilumab during the study. 
11.5. Efficacy analysis 
Analysis of the primary endpoint  
In this study, the primary endpoint is the proportion of responders in each treatment group. 
A responder is a patient who has not received tocilizumab or sarilumab as part of standard therapy 
and who has a clinical status improvement of ≥1 point on the 6-point COVID-19 scale (where 1 is 
the most favorable outcome and 6 is the most undesirable outcome) 15 days after the 
administration of the study drug. 
To compare each of the two active therapy groups with placebo, mathematical modeling 
of the response to treatment will be performed depending on prognostic factors (age and severity 
of the condition, gender, clinical center, and other significant factors). Relative risk [RR] with a 
two-way 97.5% CI (the ratio of the probability of response in each of the active treatment groups 
to the probability of response in the placebo group) will be calculated from the logistic model. To 
test the hypothesis of superiority of each of the active drugs over placebo, the null hypothesis RR 
≤ 1 will be tested with a statistical power of 80% at an overall critical level α = 2.5% for each of 
the comparisons. The overall alpha level for the early analysis will be controlled using the alpha 
spending function. 
Analysis of the secondary endpoints 
The distribution of patient outcomes on the 6-point ordinal COVID-19 clinical status scale 
will be presented using the absolute values (the number of patients in each category) and as a 
percentage for each assessment day, for each of the treatment groups. A detailed description of 
changes over time in the clinical status of patients using a 6-point ordinal scale will be presented 
in the statistical analysis plan. 
The percentage of patients with a clinical status improvement of 2 or more points on a 6-
point ordinal scale occurring during the study with no use of tocilizumab and sarilumab will be 
presented using the absolute values (number of patients) and as a percentage for each assessment 
day, for each of the treatment groups. The comparative analysis of the groups will be performed 
in the same way as the primary endpoint analysis. 
The percentage of patients who received tocilizumab or sarilumab during the assessment 
period and the mortality rate during the follow-up period will be presented using the absolute 
values (number of patients) and as a percentage for each assessment day, for each treatment group. 
The comparison of the groups will be performed using a regression logistic model, taking into 
account the prognostic factors (age and severity of the condition, gender, clinical center, and other 
significant factors). 
 
Handling missing values and subjects dropping out from the study  
Every effort will be made to reduce the proportion of missing data, however, it is expected 
that a certain amount of data will be missing due to patient drop out of the study. Patients who do 
not have PE data will be excluded from the primary efficacy analysis.  
A sensitivity analysis will be performed using data from the last available patient’s 
observation. 


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11.6. Safety analysis 
The safety analysis will be performed using descriptive statistics in the safety population 
and the mITT population, and data from the subgroup of patients who received tocilizumab or 
sarilumab will be separately summarized and presented. 
The safety assessment will include the following parameters: 
 Frequency, severity, nature and outcomes of AEs (grades 4 and 5 according to 
CTCAE v.5.0) and SAEs during the study; 
 Frequencies of AEs and/or SAEs related to the study drugs observed in the 
treatment groups; 
 Vital signs (BP, pulse rate, RR, body temperature); 
 Results of laboratory and other investigations;  
 Changes in physical examination findings, vital signs, and laboratory safety 
parameters during the study. 
; 
11.7. Early analysis of the pilot phase 
The early analysis will be performed after the procedures of Visit 15 (Day 15) or 
completion of the study, whichever comes first, for the first 63 patients in each of the 
randomization groups (a total of 189 patients). Descriptive statistics will be used to evaluate the 
distribution of patients on a 6-point ordinal scale on Day 15 after randomization, the proportion of 
patients responding to treatment, and the proportion of patients requiring tocilizumab or sarilumab 
24 hours after the administration of the study drugs. Mathematical modeling of the response to 
treatment will be carried out based on the prognostic factors (age, severity of the condition, clinical 
center, gender, and other significant factors). 
All applicable secondary and exploratory endpoints, as well as applicable safety endpoints, 
will be evaluated as well. 
Based on the results of the pilot phase, the final sample size will be calculated for the main 
phase of the study using the actual disease outcome data. 
11.8. Interim analysis 
There is no interim analysis in this study. 
12. DATA MANAGEMENT AND RECORD KEEPING 
12.1. Study site documentation 
As defined by ICH GCP E6 (R2), the primary study documents include: signed Protocol 
and all Amendments, signed Informed Consent Forms for all patients, Investigator's Brochure, 
medical records and other source documents, approvals issued by the ethics committees and 
regulatory authorities, study drug accountability records, study-related correspondence, and a list 
of patient last names and addresses. These documents should be kept by Investigator. 
12.2. Source documents 
Source documents include the original documents that are relevant to the examination, 
treatment, medical history and description of the patient's condition. For example, these documents 
include original medical records and discharge summaries with the laboratory test results. 
The responsibility to document the course of the study correctly and accurately lies with 
the InvestigatorInvestigator. Source documentation is kept according to regulatory requirements. 


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Records are introduced into the patient’s source documents during each examination. The required 
data are transferred to eCRFs within the period specified in the SOPs of the CRO/Sponsor/Study 
Site or in other documents.  
When there was a need to make corrections in the source documents, the corrector shall 
cross out the incorrect entry with a single horizontal line, enter the correct information, date of the 
correction and his/her initials. Do not use any means deleting the previous record or making it 
illegible.  
12.3. Data collection 
Electronic CRFs (eCRFs) will be used for this study. The Principal Investigator is 
responsible for the completeness and accuracy of all data introduced to the eCRF as well as for the 
proper timing of data entry and update. 
The Monitor is responsible for verification of eCRFs for completeness and accuracy of 
records, instructions for the study site personnel regarding the required corrections or updates  
To work in the eCRF system, the Principal Investigator and members of his/her team will 
receive logins and access passwords.  
The eCRF should be completed within a period not exceeding 5 working days from the 
date of the visit. Screening data should be entered into eIRCs simultaneously, upon completion of 
screening.  
If the screening procedures period coincides with the calendar day of Visit 1, laboratory 
tests and other duplicate procedures are not performed on Day 1, the data obtained at the screening 
visit and entered into the eCRF screening record are also transferred to the eCRF Day 1 record. 
All data that should be present in the eCRF have to be present in the site source documents. 
eCRFs used in this study does not envisage entry of any data that are not recorded in the 
source documents. 
12.4. Data confidentiality 
Information about the study subjects will be kept confidential. It will be processed in 
accordance with applicable laws and regulations.  
In order to prevent unauthorized access to confidential information about the study 
subjects, security elements have been built into the data collection system for this study to encrypt 
all data when it is transmitted in both directions. Access to the system will be controlled by a 
sequence of individually assigned user identification codes and passwords that will be provided 
only to authorized employees. 
12.5. Document archiving 
By signing this Protocol, the Investigator agrees to comply with the rules for storage and 
archiving of the study documents. Source documents and the study site file including the Patient 
Information Leaflet as well as study-related correspondence should be retained. Study subject 
documents shall be archived according to the regulations adopted at the study site.  
The Investigator shall inform the Sponsor about the place of storage of essential documents 
and contact the Sponsor to obtain his approval before destroying any of them. The Investigator 
shall take measures to prevent accidental or premature destruction of these documents. 
The Sponsor is responsible for archiving the Master File of the Clinical Study. 
If the Sponsor stops the clinical development of the study drug, the Investigator and 
regulatory authorities shall be informed of it.  


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13. QUALITY CONTROL AND QUALITY ASSURANCE 
13.1. Overall quality assurance information 
The Sponsor should ensure an appropriate quality assurance and quality control system for 
this clinical study in accordance with the study protocol, Good Clinical Practice, and applicable 
regulatory requirements. 
The study procedures specified in the protocol should be strictly followed by the 
Investigator and members of the study team.  
13.2. Quality guarantees 
In accordance with the ICH GCP E6 (R2) and regulatory requirements, the Sponsor, a third 
party on its behalf, regulatory authorities or Ethics Committees may conduct audits (inspections) 
to guarantee quality assurance at any time during the study or after completion of the study. The 
Investigator should provide the auditors with direct access to all study-related documentation, 
including source documents, and to ensure that he/she and his/her staff members dedicate time to 
discuss with the auditors the results of audits and inspections, as well as other issues. 
13.3. Investigator's adherence to the protocol 
Prior to the beginning of the study, the Investigator should fully review the provisions of 
this protocol, accept them, and conduct the study in accordance with this protocol, ICH GCP E6 
(R2),, and other applicable regulatory requirements of the participating countries.  
During the study, deviations from the protocol requirements are not allowed, unless they 
are necessary to prevent any immediate danger to the patient.  
The Investigator should have sufficient time to conduct the study correctly and complete 
the study within the period approved by the Sponsor, as well as have a sufficient number of 
qualified staff members and adequate equipment to conduct the study according to this protocol. 
Each co-Investigator involved in the study should be aware of the protocol requirements 
and his/her obligations within the study. The Principal Investigator shall document delegation of 
any of his/her functions in this study to co-Investigators in writing in the appropriate section of the 
Investigator's File. 
In case of repeated deviations from the protocol, temporary suspension or permanent 
termination of the study at this study site will be considered. 
13.4. Protocol deviations 
A protocol deviation is any change in, non-compliance with, or deviation from the study 
design or procedures described in the study protocol, as well as the guidelines and instructions 
provided for in the study. 
Any protocol deviation occurring during the course of the clinical study should be 
registered and recorded in the study documentation.  
13.5. Liability for non-compliance with the study requirements 
Failure to comply with the protocol, SOPs and/or applicable regulatory requirements by 
the Investigator / study site, CRO, or the Sponsor’s staff should prompt urgent actions by the 
Sponsor to ensure compliance.  
If monitoring or auditing identifies serious and/or recurring cases of non-compliance with 
applicable requirements by the Investigator / study site or CRO, the Sponsor should terminate the 
participation of the violating party in the study and notify regulatory authorities as appropriate. 


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13.6. Study monitoring 
Monitoring of the clinical study should be conducted by the Sponsor or the CRO authorized 
by the Sponsor for the following purposes: 
 assurance of protection of the rights and wellbeing of study subjects; 
 verification of the accuracy, completeness and reliability of the data recorded in the 
data collection system, and their compliance with the data of the source 
documentation;  
 verification of the adherence of the Investigator and members of the study team to the 
procedures of the approved study protocol, amendments to the protocol in the current 
version (if applicable), the rules of Good Clinical Practice, and current regulatory 
requirements. 
The clinical study is monitored according to the approved Monitoring plan described in a 
separate document. The clinical study monitor should ensure that the study is properly conducted 
and documented. The responsibilities of the clinical study monitor include the following functions:  
 checking that the Investigator has the necessary qualifications and sufficient resources, 
including laboratories, equipment, and personnel, throughout the study;  
 control of the use of the study drug (storage conditions and shelf life, availability of a 
sufficient amount of the drug in the study site, correctness of the administration of the 
study drug, drug accounting); 
 checking that the Investigator adheres to the approved plan and all approved protocol 
amendments (if applicable); 
 control of the timely (i.e., before the beginning of the patient's participation in the 
study) signing of the Patient Information Leaflet and Informed Consent Form or 
provision of an appropriately documented decision of the Principal Investigator based 
on a Medical Consilium’s recommendation to include the patient in the study; 
 ensuring that the Investigator holds the current versions of the documents related to 
the conduct of the clinical study (protocol, amendments to the protocol (if applicable), 
Investigator's Brochure, Patient Information Leaflet and Informed Consent Form); 
 ensuring that sufficient information about the study has been provided to the 
Investigator and members of the study team; 
 monitoring the fulfillment by the Investigator and members of the study team of the 
responsibilities related to the study in accordance with the protocol and other 
applicable agreements/contracts between the Sponsor and the Investigator / health care 
institution, as well as the independence of the fulfillment of their responsibilities 
(identifying any delegation of the Investigator’s functions to unauthorized persons); 
 control of the Investigator’s adherence to the eligibility criteria; 
 notifying the Sponsor about the subject recruitment rate; 
 control of the correctness and completeness of the data in the eCRFs, source 
documentation, and other study-related records by comparing them; 
 notifying the Investigator about any errors, omissions, and illegible records made in 
the eCRFs; 
 verification of the adherence to the adverse event reporting time frames laid down in 
this protocol; 
 control of the maintenance of the essential documents by the Investigator; 
 notifying the Investigator about any deviations from the protocol, SOPs, regulatory 
requirements; taking necessary actions to prevent the recurrence of such deviations. 
The Investigator should provide the Monitor with direct access to all source documents of 
the patient.  


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Monitoring procedures related to the preparation, administration and recording of the drug 
in accordance with patient randomization groups are carried out by an unblinded monitor. A 
blinded monitor shall not have access to this data. 
13.7. Sponsor’s audit 
Sponsor’s audit is conducted separately and independently of routine clinical study 
monitoring and quality control functions. The objective of this audit is to evaluate the compliance 
of the conducted study with the protocol, SOPs, and applicable regulatory requirements. 
For this audit, the Sponsor appoints persons independent of the conduct of this clinical 
study.  
The Sponsor should make sure that the auditors have sufficient qualifications to conduct 
the audit properly. The auditor’ qualifications should be documented.  
The Sponsor or authorized organization develops an audit plan and audit procedures for 
this study, which should be followed during the audits. 
13.8. Database management and quality control 
In studies using eCRFs, the Sponsor’s (or assigned CRO’s) employees will analyze the 
data introduced by the study site personnel for accuracy and completeness. If inconsistencies or 
missing data are detected, data queries will be submitted to the study site specifying the nature of 
the problem and the required details. These queries will be sent to the study site. Designated study 
staff members shall promptly answer the queries and modify the data accordingly. 
At the end of the study, protocol deviations will be identified. After these activities are 
completed and database accuracy and completeness are confirmed, it will be locked and prepared 
for data analysis.  
After the database lock, the Investigator shall receive a CD-based or a hardcopy containing 
the patients’ data for archiving at the study site. 
14. STUDY STOPPING RULES  
The study may be terminated for the following reasons: 
1. By the decision of local Ethics Committees or regulatory authorities; 
2. By decision of the Investigator / study site (in a specific study site). 
3. By the decision of the Study Sponsor for the reasons related to safety, ethical 
principles, compliance with the Protocol or other reasons. 
The Sponsor has the right to suspend the study at any time for the reasons related (but not 
limited to) to safety, ethical aspects or administrative issues. The sponsor has the right to terminate 
the study at any time if the goals and objectives of the study are not met. In this case, the Sponsor 
shall inform the Investigator or the management of the study site of suspension or termination of 
the study in writing.  
If the Investigator / management of the study site prematurely terminates the study at a 
specific study site without the prior consent of the Sponsor, he/she should inform the management 
of the study site (if applicable) and inform the Sponsor and the local ethics committee (LEC), as 
well as provide the Sponsor and LEC with a detailed explanation of the reason for the suspension 
or termination of the study in writing. 
If the study is suspended or terminated for safety reasons, the Sponsor shall immediately 
inform the Investigator as well as the regulatory authorities or ethics committees.  
If, for any reason, the study is prematurely terminated or suspended, the Investigator 
(medical institution) shall immediately inform the patients, provide them with appropriate 
treatment and supervision and, if required by applicable requirements, inform the regulatory 
authorities.  


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15. ETHICAL ASPECTS 
This study will be conducted in accordance with ethical concepts stated in the World 
Medical Association’s Declaration of Helsinki and ICH GCP regulations.  
The final Protocol version (including the Patient Information Leaflet and Informed Consent 
Form) shall be submitted for approval to the regulatory authorities of the member states, as well 
as to the local ethics committees of the study sites prior to the study beginning 
All subsequent amendments to the Protocol, including purely administrative, will be 
approved in accordance with the procedure established in the respective country participating in 
the study. The procedure of obtaining the Informed Consent Form will be conducted prior to the 
beginning of any study procedures. The Patient Information Leaflet will contain all information 
about this clinical study that is needed to make a sensible and voluntary decision. If the patient’s 
condition does not allow to express his/her will, the patient can be included in the study by decision 
of the Principal Investigator based on a Medical Consilium’s recommendation in accordance with 
the applicable regulations of the country in which the study is conducted. The decision of the 
Medical Consilium is drawn up in minutes, signed by the participants of the Medical Consilium 
and entered into the patient’s medical records. In this case, the procedure for obtaining informed 
consent from the patient shall be carried out as soon as the patient's condition permits. If the patient 
decides not to continue to participate in this clinical trial, he/she will be excluded from the study 
due to withdrawal of informed consent. 
In the course of the study, all SAEs will be reported to the Sponsor (that may make a 
decision to suspend the study based on the analysis of submitted data) within 24 hours. Ethics 
Committee also shall be informed of SAEs, including unexpected and related, as believed by the 
Investigators to the study drug administration. 
Information identifying the patients is confidential and may be disclosed only in cases 
provided for by law and upon decisions of the judicial bodies.  
All study subjects will be insured as required by local regulatory requirements. 
16. CONFIDENTIALITY  
The Investigator undertakes to maintain confidentiality regarding the identity of patients, 
the text of this Protocol, as well as all other materials and study results.  
The Investigator should ensure the anonymity of the volunteers. Electronic Case Report 
Forms and other documents submitted to the Sponsor shall not contain volunteers’ names or last 
names and should use only assigned identification numbers and/or initials.  
The Investigator should keep a special log to register identification numbers, last names, 
addresses, phone numbers and medical record numbers (if any). The Investigator shall keep the 
data intended for the Sponsor strictly confidential. 
Any study materials that belong to the Sponsor should not be handed over to any third 
parties except as required by the applicable laws. 
17. FUNDING AND INSURANCE 
The patients will not receive any payment for participation in this study.  
During the study, the patients will be insured as study subjects according to the legislation 
of the member state.  
If the patient's health is damaged due to the use of the study drugs or medical procedures 
specified in the Study Protocol, he/she will be provided with free qualified medical care to the 
extent necessary, paid for by the Insurance company.  


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18. PUBLICATIONS 
After the completion of the study and statistical data analysis, it data will be published. The 
Investigator should not publish the results of this study (including those obtained at the study site) 
without the Sponsor’s consent. The results obtained in a specific study site should not be published 
prior to publication of general study results. 
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