An Open-Label, Dose Escalation Study of the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of a Single Subcutaneous Dose of BCD-089 in Healthy Volunteers
Phase: PHASE1
Conditions: Healthy
Sponsor: Biocad

Cover page 
• Official study title: 
An Open-label, Dose Escalation Study of the 
Pharmacokinetics, Pharmacodynamics, Tolerability and 
Safety of Single Subcutaneous Doses of BCD-089 in Healthy 
Volunteers 
• NCT number: 
NCT03103438 
• Document date 
June 1, 2016 
 
 

Clinical Study Protocol 
Study code: BCD-089-1 
Translated from Russian to English, dated 06-Jul-2020 
 
 
 
CONFIDENTIAL 
Version: 1.0 of June 1, 2016. 
Page 1 of 128 
 
 
 
CLINICAL STUDY PROTOCOL 
 
Protocol title: 
 
An 
Open-label, 
Dose 
Escalation 
Study 
of 
the 
Pharmacokinetics, Pharmacodynamics, Tolerability and 
Safety of Single Subcutaneous Doses of BCD-089 in 
Healthy Volunteers 
Protocol identification 
number: 
BCD-089-1 
Drafted on: 
June 1, 2016 
Protocol amendment 
number: 
Not applicable 
 
Protocol amendment 
approval date: 
 
 
Not applicable 
Protocol version: 
v. 1.0 
 
 
Name and address of the 
clinical study sponsor 
(monitor): 
 
JSC BIOCAD, Russia   
Registered Office: 34A Svyazi Street, Strelna, 
Petrodvortsovy District, St. Petersburg 198515, Russia. 
Mailing address: Petrovo-Dalnee, Krasnogorsk District, 
Moscow Region 143422  
Phone: +7 (495) 992-66-28, Fax: +7 (495) 992-82-98 
Names and positions of 
persons authorized by the 
sponsor to sign the protocol 
and protocol amendments: 
Roman Alekseevich Ivanov, Vice President, Research and 
Development 
Address: 34-A, Ulitsa Svyazi, Strelna, Petrodvortsovy 
District, St. Petersburg 198515, Russia.  
e-mail: ivanov@biocad.ru 
Tel.: +7 (812) 380 49 33, ext. 950 
 
Full name, position, address 
and telephone number of the 
sponsor’s designated 
medical expert for this 
study: 
 
Yulia Valentinovna Usacheva, Medical Expert, Category II 
Address: 34-A, Ulitsa Svyazi, Strelna, Petrodvortsovy 
District, St. Petersburg 198515, Russia. 
e-mail: usacheva@biocad.ru  
Tel.: +7 (812) 380 49 33 
The information in this document is confidential and intended for investigators, members of ethics committees, 
and health authorities. This information may not be disclosed to third parties without prior permission from JSC 
BIOCAD, except for the cases when this is necessary to obtain the volunteer’s consent for participation in the 
study. 
These requirements become effective as of the date of signing this Protocol. 

Clinical Study Protocol 
Study code: BCD-089-1 
Translated from Russian to English, dated 06-Jul-2020 
 
 
 
CONFIDENTIAL 
Version: 1.0 of June 1, 2016. 
Page 2 of 128 
 
TABLE OF CONTENTS 
TABLE OF CONTENTS .............................................................................................................. 2 
SIGNATURE PAGE ..................................................................................................................... 7 
LIST OF ABBREVIATIONS ....................................................................................................... 8 
Information about Investigators responsible for the clinical study conduction and the 
medical organizations where the clinical studies are to be conducted.................................... 11 
Other organizations involved in the study (clinical laboratories and other medical and/or 
technical services) ........................................................................................................................ 11 
SYNOPSIS .................................................................................................................................... 13 
1. Study rationale ......................................................................................................................... 23 
1.1. Introduction ....................................................................................................................... 23 
1.2. Name and description (characteristics) of the test drug ............................................... 29 
1.3. Summary of potentially clinically relevant results of preclinical studies, as well as 
results of clinical studies that are relevant for this study ..................................................... 34 
1.3.1. Non-clinical studies of the test drug ............................................................................. 34 
1.3.1.1. Summary of physicochemical studies ....................................................................... 34 
1.3.1.2. Preclinical studies in laboratory animals .................................................................. 35 
1.3.1.2.1. A study of the potency of BCD-089 in a model of collagen-induced arthritis .... 35 
1.3.1.2.2. BCD-089 pharmacokinetic study following a single-dose administration to 
monkeys .................................................................................................................................... 38 
1.3.1.2.4. Study of BCD-089 immunogenicity following repeated-dose administration .... 40 
1.3.1.2.5. Acute toxicity study of BCD-089 ............................................................................ 41 
1.3.1.2.6. BCD-089 repeated-dose toxicity study ................................................................... 41 
1.3.1.2.7. Evaluation of local tolerance of BCD-089 in a toxicity study with repeated-dose 
administration of the drug ...................................................................................................... 42 
1.3.1.2.8. BCD-089 cross-reactivity evaluation ...................................................................... 43 
1.3.2. Clinical studies of the test drug .................................................................................... 44 
1.4. Summary of known and potential risks and benefits for clinical trial subjects 
(risk/benefit ratio) .................................................................................................................... 44 
1.5. Description and justification of the study design, the method of administration of the 
test drug, dose, dosing regimen and the course of treatment .............................................. 47 
1.6. Clinical study compliance with standard regulatory requirements ............................. 52 
1.7. Study population ............................................................................................................... 52 
1.8. References .......................................................................................................................... 52 

Clinical Study Protocol 
Study code: BCD-089-1 
Translated from Russian to English, dated 06-Jul-2020 
 
 
 
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2. Study goals and objectives .................................................................................................. 53 
2.1. Study aims ......................................................................................................................... 53 
3. Hypotheses tested ..................................................................................................................... 54 
4. Study design ............................................................................................................................. 54 
4.1 Primary and secondary parameters that will be assessed in the study ......................... 54 
4.1.1. Pharmacokinetic endpoints ........................................................................................... 54 
4.1.2. Pharmacodynamic endpoints ........................................................................................ 54 
4.1.3. Subcutaneous injection-associated pain assessment endpoint ................................... 55 
4.1.4. Safety endpoints: ............................................................................................................ 56 
4.1.5. Immunogenicity endpoint ............................................................................................. 56 
4.2 Design .................................................................................................................................. 56 
4.3. Description of measures intended to minimize/exclude bias ........................................ 66 
4.3.1. The assignment of serial numbers to study sites ......................................................... 66 
4.3.2. Assignment of a screening number .............................................................................. 66 
4.3.3. The inclusion of volunteers in the study, assignment of study numbers .................. 66 
4.4. Description of doses and dosing regimens of the study drugs Description of the 
dosage form and labeling of the study drugs ......................................................................... 67 
4.4.1. Description of doses and dosing regimens of the study drugs ................................... 67 
4.4.2. Description of the dosage form and labeling of the study drugs ............................... 68 
4.5. Expected duration of study and subject participation in the study ............................. 71 
4.6. Description of sequence and duration of all study periods ........................................... 71 
4.6.1 Schedule of study visits and procedures ....................................................................... 71 
4.6.2. Description of individual study visits ........................................................................... 78 
4.6.3. Description of individual clinical, laboratory, and imaging assessments ................. 82 
4.6.3.1. Physical examination .................................................................................................. 82 
4.6.3.2. Clinical and demographic data collection, history of drug therapy ....................... 83 
4.6.3.3. Assessment of vital signs ............................................................................................. 83 
4.6.3.4. Complete blood count, blood chemistry, and urinalysis ......................................... 83 
4.6.3.5. Blood test for infection markers ................................................................................ 84 
4.6.3.6. Determination of BCD-089, IL-6 receptor, C-reactive protein, IL-6 
concentrations .......................................................................................................................... 85 
4.6.3.6.1 Determination of BCD-089 concentrations ............................................................ 85 
4.6.3.6.2 Determination of Interleukin-6 concentrations...................................................... 86 

Clinical Study Protocol 
Study code: BCD-089-1 
Translated from Russian to English, dated 06-Jul-2020 
 
 
 
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4.6.3.6.3 C-Reactive protein concentration determination .................................................. 88 
4.6.3.6.4 Determination of soluble IL-6 receptor concentration .......................................... 89 
4.6.3.7. Immunogenicity study ................................................................................................ 90 
4.6.3.8. Receptor occupancy assay .......................................................................................... 91 
4.6.3.9. Chest photofluorography ........................................................................................... 92 
4.6.3.10. Electrocardiography ................................................................................................. 93 
4.6.3.11. Assessment of injection-related pain by a volunteer ............................................. 93 
4.6.3.12. Assessment of injection site reactions ..................................................................... 93 
4.6.3.13. Technique of performing BCD-089 injections ....................................................... 93 
4.6.3.13. Urine drug test (psychotropic drugs, psychoactive medications) ......................... 94 
4.6.3.14. Alcohol breath test (quantitative) ............................................................................ 95 
4.6.3.15. Unscheduled visits ..................................................................................................... 95 
4.7. Description of Interruption Rules or Early Withdrawal Criteria for individual 
subjects, study parts, or the study in general ........................................................................ 95 
4.8. Drug accountability procedures used in the study ........................................................ 96 
4.8.1.  Handling of products used in the study ...................................................................... 97 
4.9. Study numbers storage and unblinding procedure ....................................................... 97 
4.10. List of all data recorded directly in the CRF (i.e., without prior written or electronic 
entry) and regarded as source data ........................................................................................ 97 
5. Selection and exclusion of study participants ....................................................................... 97 
5.1. Inclusion criteria ............................................................................................................... 97 
1.2. 
Exclusion criteria .......................................................................................................... 99 
5.3. Exclusion criteria ............................................................................................................ 100 
5.3.1. Substitution of volunteers who withdrew from the study ........................................ 101 
5.4. Follow-up of subjects who withdrew from the study ................................................... 101 
6. Use of the test drug ................................................................................................................ 101 
6.1.  Dosing regimen tested .................................................................................................... 101 
6.2. Investigational product dose correction ....................................................................... 102 
6.3. Overdose .......................................................................................................................... 103 
6.4. Concomitant therapy, allowed and prohibited medications ....................................... 103 
6.5. Methods of monitoring adherence to study procedures .............................................. 103 
6.6. Compliance assessment .................................................................................................. 103 
7. Pharmacokinetics and pharmacodynamics assessment ..................................................... 104 

Clinical Study Protocol 
Study code: BCD-089-1 
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7.1 List of pharmacokinetic variables .................................................................................. 104 
7.2 List of pharmacodynamical parameters ........................................................................ 105 
8. Safety assessment ................................................................................................................... 106 
List of safety parameters ....................................................................................................... 106 
8.2 Definitions ......................................................................................................................... 107 
8.2.1 Adverse Events .............................................................................................................. 107 
8.2.2 Serious adverse events .................................................................................................. 107 
8.3 Methods and timeframes for the assessment, recording, and analysis of safety 
parameters .............................................................................................................................. 108 
8.3.1 Timeframes for the assessment of safety parameters ................................................ 108 
8.3.2 Methods and timeframes for the assessment and registration of safety parameters
 ................................................................................................................................................. 109 
8.4 Requirements for reports, AE registration and reporting procedures, and AE 
Reporting Form completion .................................................................................................. 110 
8.4.1 AE/SAE registration ..................................................................................................... 110 
8.4.2 AE/SAE Reporting Form completion ......................................................................... 110 
9. Statistical methods ................................................................................................................. 113 
9.1 Calculation of the parameters of pharmacokinetics and pharmacodynamics .............. 113 
9.1.1. ................................................................................................ Pharmacokinetic parameters
 ..................................................................................................................................................... 113 
9.1.2. .......................................................................................... Pharmacodynamical parameters
 ..................................................................................................................................................... 115 
9.2 Statistical analysis methods ............................................................................................. 115 
9.2. Rationale for the study sample size, including reasoning or calculations to support 
the statistical power and clinical validity of the study ........................................................ 117 
9.3. Statistical analysis stages and timeline for reports ...................................................... 118 
9.4. Criteria for study termination ....................................................................................... 118 
9.5. Management of missing, non-evaluable, and uncertain data ..................................... 118 
9.6. Procedures for reporting any deviations from the initial statistical plan .................. 119 
9.7 Patient selection for analysis ........................................................................................... 119 
10. Direct access to source data/documents............................................................................. 119 
11. Quality control and quality assurance of the study conduct ........................................... 120 
11.1. Quality guarantees ........................................................................................................ 120 
11.2. Investigator’s adherence to protocol ........................................................................... 120 

Clinical Study Protocol 
Study code: BCD-089-1 
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11.3. The Investigator’s responsibility for Protocol adherence ......................................... 121 
11.4. Study monitoring .......................................................................................................... 122 
11.5. Study termination ......................................................................................................... 122 
12. Ethics .................................................................................................................................... 123 
12.1. Ethical aspects of the study .......................................................................................... 123 
12.2. Confidentiality of study subjects ................................................................................. 123 
13. Data management and record keeping .............................................................................. 124 
14. Funding and insurance ........................................................................................................ 124 
15. Publications .......................................................................................................................... 126 
APPENDIX 1. Injection site reaction reporting form ........................................................ 127 
 

Clinical Study Protocol 
Study code: BCD-089-1 
Translated from Russian to English, dated 06-Jul-2020 
 
 
 
CONFIDENTIAL 
Version: 1.0 of June 1, 2016. 
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SIGNATURE PAGE 
to version 1.0 of June 1, 2016 of Protocol “An Open-label, Dose Escalation Study of the Pharmacokinetics, 
Pharmacodynamics, Tolerability and Safety of Single Subcutaneous Doses of BCD-089 in Healthy Volunteers” 
 
I, the undersigned, agree with the following: 
1. I have fully read the provisions of this Protocol, accept them, and undertake to conduct the study in 
accordance with this Protocol and in compliance with ICH GCP, National Standard of the RF GOST R 
52379-2005 “Good Clinical Practice” and the requirements of state regulatory authorities.  
2. I will not deviate from Protocol without a prior written permission from the Sponsor, approved by the 
Ministry of Health of the Russian Federation and local ethics committees, except when necessary to prevent 
any immediate danger to a study subject. 
3. I have qualified staff, required equipment, and sufficient time to conduct the study in accordance with this 
Protocol. 
4. I will take all the necessary measures to ensure that the staff members involved in the study are adequately 
familiar with this Protocol and will appropriately fulfill their responsibilities during the study.  
5. I agree to audit and inspection procedures according to the rules set by the Sponsor and state regulatory 
organs. 
6. I understand that the text of this Protocol and all other materials and study results are confidential and are the 
Sponsor’s property. I undertake not to disclose them to third parties, except in cases provided for by the 
current legislation of the Russian Federation. 
Principal Investigator:  
 
______________________________ 
Signature 
______________________________   
 
Full name 
______________________________   
 
Date 
Vice President, Research and Development, JSC 
BIOCAD R.A. Ivanov: 
______________________________ 
Signature 
______________________________   
 
Date 
 
 
 

Clinical Study Protocol 
Study code: BCD-089-1 
Translated from Russian to English, dated 06-Jul-2020 
 
 
 
CONFIDENTIAL 
Version: 1.0 of June 1, 2016. 
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LIST OF ABBREVIATIONS 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase  
AST 
Aspartate aminotransferase 
AUC 
Area under the curve 
AUMC 
The total area under the curve of the product of time by the drug 
concentration 
BAb 
Binding antibody 
BCD-089 
Anti-interleukin 6 receptor monoclonal antibody developed by JSC 
BIOCAD 
BP 
Blood pressure 
CD 
Cluster of differentiation 
CDR 
Hypervariable part of the immunoglobulin responsible for binding to 
epitopes (complementary determining regions) 
CG 
Control group 
CHF 
Chronic heart failure 
Cmax 
Maximum concentration 
CNS 
Central nervous system 
CRF 
Case report form 
CRP 
C-reactive protein 
CTCAE 
Common Toxicity Criteria for Adverse Events 
DLT 
Dose limiting toxicity 
DMARDS 
Disease-modifying antirheumatic drugs 
DMARDS 
Disease-modifying anti-rheumatic drugs 
DMOBE 
Dose with minimal observable biological effects 
DNA 
Deoxyribonucleic acid 
ELISA 
Enzyme-linked immunosorbent assay 
ESR 
Erythrocyte sedimentation rate 
Fc-fragment 
Fragment crystallizable region 
GCP 
Good clinical practice 
GCs 
Glucocorticoids 

Clinical Study Protocol 
Study code: BCD-089-1 
Translated from Russian to English, dated 06-Jul-2020 
 
 
 
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GMP 
Good Manufacturing Practice 
HBsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HED 
Human equivalent dose 
HIV 
Human immunodeficiency virus 
HR 
Heart rate 
IAP 
Inflammation Area Percentage 
ICН 
International Conference on Harmonization 
Ig 
Immunoglobulin 
IL-6 
Interleukin 6  
INN 
International nonproprietary name 
JSC 
Joint-stock company 
LDH 
Lactate dehydrogenase  
LLN 
Lower limit of normal range 
MG 
Main group 
MIBDs 
Medical immunobiological drugs 
MP 
Medicinal product 
MRSD 
Minimum recommended starting dose 
MTD 
Maximum tolerated dose 
Nab 
Neutralizing antibody 
NFĸB 
Nuclear factor kappa-B 
NO 
Nitrogen monoxide 
NOAEL 
No observed adverse events level 
PD 
Pharmacodynamics 
PIL 
Patient Information Leaflet 
PK 
Pharmacokinetics 
RA 
Rheumatoid arthritis 
RAMS 
Russian Academy of Medical Sciences 
RANKL 
Receptor activator of nuclear factor kappa-B ligand 
RI 
Research institute 

Clinical Study Protocol 
Study code: BCD-089-1 
Translated from Russian to English, dated 06-Jul-2020 
 
 
 
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SAE 
Serious adverse event 
SC 
subcutaneous 
SD 
Standard deviation 
sIL6R 
Soluble interleukin-6 receptor 
SOP 
Standard operating procedure 
t½   
Half-life 
TD 
Test drug 
Th 
T-helpers 
TNF-α 
Tumor necrosis factor-alpha 
TO 
Thoracic organs 
ULN 
Upper limit of normal 
VAS 
Visual Analogue Scale 
WHO 
World Health Organization 
 
 
 

Clinical Study Protocol 
Study code: BCD-089-1 
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Information about Investigators responsible for the clinical study conduction and the 
medical organizations where the clinical studies are to be conducted 
No
. 
п.п. 
Name 
of the (clinical) 
study site 
Address of the 
(clinical)study 
site 
Telephon
e 
Full name of 
the Principal 
Investigator  
Position of the 
Principal 
Investigator  
1. 
Limited 
Liability 
Company BioEq  
23-Zh. 
Krasnogvargeyski
y per., Saint 
Petersburg 
197342 Ж 
+7 (812) 
913-04-
23; +7 
(931) 371-
77-07           
Polina 
Mikhailovna 
Khlyabova 
Chief physician, 
Limited 
Liability 
Company BioEc 
                    
Other organizations involved in the study (clinical laboratories and other medical and/or 
technical services) 
No. 
п.п. 
Name and 
role in the 
study 
 
Address 
Full name 
of the person 
carrying out 
the study 
Position 
of the person 
carrying out 
the study 
Telephone 
1. 
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Clinical Study Protocol 
Study code: BCD-089-1 
Translated from Russian to English, dated 06-Jul-2020 
 
 
 
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No. 
п.п. 
Name and 
role in the 
study 
 
Address 
Full name 
of the person 
carrying out 
the study 
Position 
of the person 
carrying out 
the study 
Telephone 
%%%%%%%%
%%%%%%% 
%%%%%%%%
%%%%%%% 

Clinical Study Protocol 
Study code: BCD-089-1 
Translated from Russian to English, dated 06-Jul-2020 
 
 
 
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SYNOPSIS 
Study ID: 
BCD-089-1  
Study Title: 
An Open-label, Dose Escalation Study of the Pharmacokinetics, 
Pharmacodynamics, Tolerability and Safety of Single Subcutaneous 
Doses of BCD-089 in Healthy Volunteers 
Investigational 
Product (test 
drug): 
BCD-089 
- 
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
n 
Population:  
Healthy male volunteers aged 18 to 45 years. 
Study Sponsor: 
JSC BIOCAD, Russia.  
Mailing address: Petrovo-Dalnee, Krasnogorsk District, Moscow Region, 
Russian Federation, 143422. Tel.: +7 (495) 992 66 28, Fax: +7 (495) 992 
82 98  
Legal address: 34-A, Ulitsa Svyazi, Strelna, Petrodvortsovy District, St. 
Petersburg 198515, Russia   
Study goals and 
objectives 
Study goal: to evaluate tolerability, safety, and major pharmacokinetic 
and pharmacodynamic parameters of BCD-089 following single 
subcutaneous administration in increasing doses to healthy volunteers.   
Study Objectives 
1. To determine the safe dose range of BCD-089, which will 
subsequently be used in the phase II clinical study; 
2. To determine the proportion of study participants in whom a single 
subcutaneous administration of BCD-089 was accompanied by the 
development of adverse events, including the proportion of volunteers 
with neutropenia of varying severity; 
3. To determine the main pharmacokinetic parameters (AUC0-1680, 
AUC0-∞, Cmax, Тmax, Т½, Кel and CL) of BCD-089 after a single 
subcutaneous injection in increasing doses to healthy volunteers; 
4. To determine the main pharmacodynamic parameters (Cmax, Tmax, 
Cmin, Tmin, AUC0-1680) for C-reactive protein, IL-6 and soluble receptor 
IL-6;  
5. To determine the proportion of volunteers, in whom binding and/or 
neutralizing antibodies to BCD-089 were determined following its 
single administration. 
Study design: 
Clinical study No. BCD-089-1 is a classic open-label, single-center, non-
randomized 
cohort 
clinical 
study 
of 
the 
pharmacokinetics, 
pharmacodynamics, tolerability and safety of a novel drug in healthy 

Clinical Study Protocol 
Study code: BCD-089-1 
Translated from Russian to English, dated 06-Jul-2020 
 
 
 
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volunteers at increasing doses (phase 1, 3+3 design, with the first cohort 
consisting of one volunteer (“sentinel patient”) who will receive the 
product at a dose with an additional safety factor relative to the calculated 
minimum starting safe dose). 
Before being included in the study, healthy volunteers have to sign a 
written informed consent after having read it, after which they will 
undergo a 14-day screening examination to confirm compliance with the 
eligibility criteria for the study. No additional requirements regarding a 
certain diet or restriction of physical activity, both during the screening 
period and throughout the study, are specified in this protocol. 
Study No. BCD-089-1 includes seven cohorts: 
1. 
Cohort 01 (sentinel patient) - 1 volunteer to whom a single 
subcutaneous injection of BCD-089 at a dose of 0.06 mg/kg will be 
administered. 
2. 
Cohort 02 - a maximum of 6 volunteers to whom a single 
subcutaneous injection of BCD-089 at a dose of 0.3 mg/kg will be 
administered.  
3. 
Cohort 03 - a maximum of 6 volunteers to whom a single 
subcutaneous injection of BCD-089 at a dose of 0.625 mg/kg will 
be administered. 
4. 
Cohort 04 - a maximum of 6 volunteers to whom a single 
subcutaneous injection of BCD-089 at a dose of 1.0 mg/kg will be 
administered. 
5. 
Cohort 05 - a maximum of 6 volunteers to whom a single 
subcutaneous injection of BCD-089 at a dose of 1.6 mg/kg will be 
administered. 
6. 
Cohort 06 - a maximum of 6 volunteers to whom a single 
subcutaneous injection of BCD-089 at a dose of 2.2 mg/kg will be 
administered. 
7. 
Cohort 07 - a maximum of 6 volunteers to whom a single 
subcutaneous injection of BCD-089 at a dose of 2.9 mg/kg will be 
administered. 
The inclusion of volunteers in the study is sequential. The first to 
participate in the study is one volunteer, representing the cohort “01” 
(sentinel patient), who is administered a single subcutaneous injection of 
BCD-089 0.06 mg/kg. The injection is performed subcutaneously in the 
left or right front surface of the thigh (at a central point on the line between 
the iliac crest and the upper border of the patella). In the absence of grade 
3-4 adverse events related to the test product, developing within the first 
7 days after the injection, three volunteers are included in cohort 02. 

Clinical Study Protocol 
Study code: BCD-089-1 
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Further, the volunteer inclusion algorithm corresponds to the following 
general principle: 
In the absence of any grade 3-4 AEs (DLT) associated with the test 
product within 7 days after the injection, the next cohort of three 
volunteers with dose escalation will be included in the study - Cohort 03 
(cohort 04, cohort 05, cohort 06, cohort 07).  
If grade 3-4 AEs (DLT) associated with the test product were recorded in 
only one volunteer in a cohort of three volunteers, three more healthy 
volunteers will be additionally included in this cohort. 
With the development of grade 3-4 AEs (DLT) associated with the test 
product in two of six volunteers, the dose at which this event was recorded 
will be taken as the maximum tolerated dose, further dose escalation will 
be ceased. 
Thus, dose limiting toxicity will be assessed close to the time of 
administration, during the first seven days after the injection. However, it 
is not the end of the volunteers follow-up - monitoring of their condition, 
as well as blood sampling for the study of pharmacokinetics, 
pharmacodynamics, immunogenicity and safety, will be carried out up to 
71 days from the moment of injection. 
A 14-day screening examination and 13 subsequent visits are planned to 
be conducted during the study. The duration of the active phase of the 
study (from the moment of the drug injection to the final visit) is 71 days. 
Due to the need for multiple blood sampling, the volunteer has to stay at 
the study site for the first day after the injection. 
Test drug 
administration 
BCD-089 is administered according to the developed design: 
1. 
Cohort 01 (sentinel patient) - 1 volunteer to whom a single 
subcutaneous injection of BCD-089 at a dose of 0.06 mg/kg will be 
administered. 
2. 
Cohort 02 - a maximum of 6 volunteers to whom a single 
subcutaneous injection of BCD-089 at a dose of 0.3 mg/kg will be 
administered. 
3. 
Cohort 03 - a maximum of 6 volunteers to whom a single 
subcutaneous injection of BCD-089 at a dose of 0.625 mg/kg will 
be administered. 
4. 
Cohort 04 - a maximum of 6 volunteers to whom a single 
subcutaneous injection of BCD-089 at a dose of 1.0 mg/kg will be 
administered. 

Clinical Study Protocol 
Study code: BCD-089-1 
Translated from Russian to English, dated 06-Jul-2020 
 
 
 
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5. 
Cohort 05 - a maximum of 6 volunteers to whom a single 
subcutaneous injection of BCD-089 at a dose of 1.6 mg/kg will be 
administered. 
6. 
Cohort 06 - a maximum of 6 volunteers to whom a single 
subcutaneous injection of BCD-089 at a dose of 2.2 mg/kg will be 
administered. 
7. 
Cohort 07 - a maximum of 6 volunteers to whom a single 
subcutaneous injection of BCD-089 at a dose of 2.9 mg/kg will be 
administered. 
Time points for 
PK blood 
sampling  
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2. %%%%%%%%%%%%%%%%%%%%%%%%%% 
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for CRP, IL-6 and 
soluble IL-6 
receptor testing 
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Clinical Study Protocol 
Study code: BCD-089-1 
Translated from Russian to English, dated 06-Jul-2020 
 
 
 
CONFIDENTIAL 
Version: 1.0 of June 1, 2016. 
Page 17 of 128 
 
Time points for 
blood sampling 
for membrane 
receptor 
occupancy assay 
for BCD-089 
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Planned sample 
size: 
Up to 37 healthy volunteers. 
Inclusion criteria: 
1. Signed informed consent; 
2. Male; 
3. Age 18 - 45 years inclusive; 
4. Body mass index (BMI) within normal limits (18.5 - 30.0 kg/m2); 
5. A verified diagnosis of "healthy", established according to the 
medical history, physical examination and laboratory data:  
• absence in the history and at the time of the screening 
examination of clinically obvious impaired function of the 
cardiovascular, 
respiratory, 
nervous, 
hematopoietic, 
endocrine, gastrointestinal systems, liver and kidneys; 
• absence of history of cardiovascular diseases; 
• complete blood count, blood chemistry, and urinalysis results 
are within reference ranges adopted at the study site; 
• hemodynamic parameters within normal limits: SBP - within 
100 - 120 mm Hg., DBP - within 60 - 80 mm Hg. Art., heart 
rate - 50 - 90 bpm; 
• absence of chronic infections (tuberculosis) or history of 
chronic inflammatory diseases; 
• absence of laboratory markers of hepatitis B, C, HIV and 
syphilis; 
• absence of acute infectious diseases within 4 weeks before 
inclusion in the study; 
• absence of mental disorders and any other conditions that can 
affect the ability of the participant to follow the requirements 
of the protocol, including depression; 
• satisfactory well-being (in the opinion of the volunteer) within 
30 days before signing of the informed consent form; 
6. Absence of evidence of alcohol abuse or drug addiction at the time of 
inclusion in the study or in medical history, as well as negative results 
at the screening alcohol breath test, together with a negative result of 
the urine drug test; 
7. The ability of the volunteer to follow the Protocol procedures, in the 
Investigator’s opinion; 

Clinical Study Protocol 
Study code: BCD-089-1 
Translated from Russian to English, dated 06-Jul-2020 
 
 
 
CONFIDENTIAL 
Version: 1.0 of June 1, 2016. 
Page 18 of 128 
 
8. The willingness of volunteers and their sexual partners of childbearing 
potential to use reliable methods of contraception, starting 2 weeks 
before inclusion in the study and throughout the study (day of 
injection and 70 days from the date of its administration). This 
requirement does not apply to participants who underwent surgical 
sterilization. Reliable methods of contraception involve the use of 1 
barrier method in combination with one of the following: spermicides, 
intrauterine device/oral contraceptives for the sexual partner; 
9. Willingness not to drink alcohol within 24 hours before the 
administration of the test product and for 8 days after. 
Non-inclusion 
criteria: 
1. A history of use of monoclonal antibody products against interleukin-
6 or its receptor; 
2. Allergy history (anaphylactic shock or multidrug allergy); 
3. Known allergy or intolerance to monoclonal antibody drugs (murine, 
chimeric, humanized, or human) or any other components of the study 
drug. 
4. Extensive surgery less than within 30 days prior to signing the 
informed consent; 
5. Severe infections (including those that required hospitalization or 
parenteral 
antimicrobial/antimycotic/antiviral/antiprotozoal 
treatment) within 6 months before signing the ICF; 
6. Systemic 
antimicrobial/antimycotic/antiviral/antiprotozoal 
treatments within 2 months before signing the ICF; 
7. More than 4 episodes of respiratory infections within 6 months before 
signing the informed consent form; 
8. Impossibility to insert a venous catheter for blood sampling (for 
example, due to skin diseases at venipuncture sites);  
9. Diseases or other conditions that can affect the pharmacokinetics of 
the test product (e.g., chronic liver, kidney, blood, cardiovascular, 
bronchopulmonary and neuroendocrine systems disorders (including 
diabetes mellitus) etc.); 
10. A history of body temperature increase above 40°С; 
11. A history of episodes of elevated hepatic transaminases above 2.5 x 
ULN; 
12. Epileptic seizures, a history of seizures; 
13. Current 
depression 
or 
a 
history 
of 
depression, 
suicidal 
thoughts/attempts at the time of the screening examination or a history 
of such behavior; 
14. Regular use of any oral or parenteral medications, including over-the-
counter drugs, vitamins, and dietary supplements within less than 2 
weeks before signing the informed consent;  
15. Use of medications, including OTC drugs that have a pronounced 
effect on hemodynamics, liver function, etc. (barbiturates, 

Clinical Study Protocol 
Study code: BCD-089-1 
Translated from Russian to English, dated 06-Jul-2020 
 
 
 
CONFIDENTIAL 
Version: 1.0 of June 1, 2016. 
Page 19 of 128 
 
omeprazole, cimetidine, etc.) within less than 30 days before signing 
the informed consent form; 
16. Use of medicinal products that affect the immune status (cytokines 
and their inducers, glucocorticoid hormones, etc.) within less than 2 
months prior to signing the informed consent form; 
17. Vaccination within 4 weeks prior to signing of informed consent 
form; 
18. Values of standard laboratory tests and investigations results that are 
beyond the reference ranges; 
19. Smoking more than 10 cigarettes per day;  
20. Consumption of more than 10 units of alcohol per week (1 unit of 
alcohol is equivalent to ½ liter of beer, 200 mL of wine or 50 mL of 
liquor) or a history of alcoholism, drug addiction or drug abuse; 
21. Donation of 450 mL or more of blood or plasma within 2 months prior 
to signing of the informed consent form; 
22. Participation in other clinical studies within less than 2 months before 
signing the informed consent form or simultaneous participation in 
other clinical studies; 
23. Prior participation in this clinical study. 
Total duration of 
the study:  
 
The estimated duration of the study is 7 months, including volunteers 
recruitment (up to 2 months), period of administration of the study drugs 
and follow-up of study participants, data collection and statistical analysis 
of the results. The expected duration of participation of each subject in 
the study is up to 85 weeks, including the screening period (up to 2 weeks) 
and the active phase of the study (71 days). 
Pharmacokinetic 
endpoints  
Primary: 
 AUC0-1680 (area under the concentration-time curve from the 
administration of the drug to 1680 h (71 days after administration) 
and AUC0-∞ (to infinity). 
Secondary: 
 Cmax (maximum serum concentration of anti-IL-6 receptor 
antibody), 
 Tmax (time to maximum concentration); 
 Т½ (half-life), 
 Kel (elimination rate constant), 
 CL (total clearance). 
Pharmacodynami
c endpoints  
1. Determination of C-reactive protein concentration: 
Primary: 

Clinical Study Protocol 
Study code: BCD-089-1 
Translated from Russian to English, dated 06-Jul-2020 
 
 
 
CONFIDENTIAL 
Version: 1.0 of June 1, 2016. 
Page 20 of 128 
 
 
1 Given parameter is not an endpoint in the study. 
 AUC0-1680 (area under the concentration-time curve from the 
administration of the drug to 1680 h (71 days after administration) 
and AUC0-∞ (to infinity). 
Secondary: 
 Cmin (minimum detectable concentration in blood serum), 
 Тmin (time to minimum serum concentration). 
 
2. Determination of IL-6 concentration:  
Primary: 
 AUC0-1680 (area under the concentration-time curve from the 
administration of the drug to 1680 h (71 days after administration) 
and AUC0-∞ (to infinity). 
Secondary: 
 Cmax (maximum concentration in serum), 
 Tmax (time to maximum serum concentration). 
 
3. Determination 
of 
soluble 
IL-6 
receptor 
concentration: 
 
Primary: 
 AUC0-1680 (area under the concentration-time curve from the 
administration of the drug to 1680 h (71 days after administration) 
and AUC0-∞ (to infinity). 
Secondary: 
 Cmax (maximum concentration in serum), 
 Tmax (time to maximum serum concentration). 
 
It will be additionally calculated within the study of pharmacodynamics 
based on the results of flow cytometry: 
 Percentage of occupancy of membrane IL-6 receptors with BCD-
089 2 hours after drug administration, 168, 336 and 504 hours 
after single injection1 
 
Pain assessment 
endpoint 
 The mean pain score during the injection on the visual analogue 
scale. 
Safety endpoints: 
 Proportion of subjects who developed SAEs in each cohort. 
 Proportion of subjects who developed AEs in each cohort.  

Clinical Study Protocol 
Study code: BCD-089-1 
Translated from Russian to English, dated 06-Jul-2020 
 
 
 
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Version: 1.0 of June 1, 2016. 
Page 21 of 128 
 
 Proportion of subjects who developed local reactions in each 
cohort. 
 Proportion of subjects who developed grade 3-4 AEs and SAE in 
each cohort. 
 Proportion of subjects who developed any grade neutropenia in 
each cohort. 
 Proportion of subjects who discontinued the study due to AEs and 
SAEs in each cohort. 
Immunogenicity 
endpoints 
 The proportion of volunteers in which binding and/or neutralizing 
antibodies to BCD-089 were detected on day 71 from the moment 
of a single subcutaneous injection. 
Statistical analysis Calculation of Sample Size 
The calculation of the study sample size was based on the "3 + 3” design 
and dose levels used in the study. 
Volunteers cohort 
Dose, 
mg/kg 
 Number 
of 
mandatory 
included 
volunteers 
 Number 
of 
volunteers that 
can be included 
in case of DLT 
development 
01 
0.06 
1 
0 
02 
0.3 
3 
3 
03 
0.625 
3 
3 
04 
1.0 
3 
3 
05 
1.6 
3 
3 
06 
2.2 
3 
3 
07 
2.9 
3 
3 
 
Analysis methods 
The statistical analysis of the obtained data will be conducted using SAS 
10.0 software and the R programming language for statistical data 
processing.  Mann-Whitney, Wilcoxon, Kruskal-Wallis, and Friedman 
tests will be used to compare quantitative and scaled data.  The categorical 
data will be processed using the Fisher’s exact test and the χ2 Pearson test. 
Safety analysis 
Safety analysis will include all volunteers who received the test drug. 
Pharmacokinetic analysis 

Clinical Study Protocol 
Study code: BCD-089-1 
Translated from Russian to English, dated 06-Jul-2020 
 
 
 
CONFIDENTIAL 
Version: 1.0 of June 1, 2016. 
Page 22 of 128 
 
 
Pharmacokinetics analysis will include data from volunteers who have 
received BCD-089 and have had no more than two missing/lost/damaged 
blood serum samples for pharmacokinetics and had no more than two 
consecutive missing/lost/damaged samples and for whom a serum sample 
obtained before the test drug administration is available for the analysis.  
Pharmacodynamic analysis 
Pharmacodynamics analysis will include data from volunteers who have 
received BCD-089 and have had no more than two missing/lost/damaged 
of whole blood and/or blood serum for pharmacodynamics studies, and 
for whom a serum sample obtained before the test drug administration is 
available for the analysis. 
Immunogenicity analysis 
Immunogenicity analysis will include data from volunteers who have 
received BCD-089 and have not had missing/lost/damaged serum 
samples taken on Days 1 and 71 of the study. 
Report preparation 
Preparation of the final study report will be performed after the end of the 
procedures for examination of the last participant. 

Clinical Study Protocol 
Study code: BCD-089-1 
Translated from Russian to English, dated 06-Jul-2020 
 
 
 
CONFIDENTIAL 
Version: 1.0 of June 1, 2016. 
Page 23 of 128 
 
1. STUDY RATIONALE 
1.1. Introduction 
Interleukin 6 (IL-6) is a pro-inflammatory cytokine with a wide biological activity, 
including an immunoregulatory component, affecting hematopoiesis, the development of 
inflammation, as well as carcinogenesis. Originally, IL-6 was identified as an antigen-non-specific 
factor for differentiation of B cells (Muragichi & all., 1981) (Yoshizaki & all., 1982) in 
mitogen/antigen-stimulated cultures of peripheral blood mononuclear cells.  The cytokine is 
produced by various types of lymphoid and non-lymphoid cells such as T-lymphocytes, B-
lymphocytes, monocytes, fibroblasts, keratinocytes, endothelial cells and some tumor cells 
(Kishimoto & all., 1995). IL-6 induces T-cell proliferation and differentiation of cytotoxic T-
lymphocytes by increasing the expression of the IL-2 receptor (Noma & all., 1987) and the 
production of IL-2 itself (Garman & all., 1987). When evaluating the effect on the hematopoietic 
system, it was shown that IL-6 has similar activity to IL-3 in maintaining multipotent 
hematopoietic cells (Koike & all., 1988). The effect of IL-6 on the differentiation of macrophages 
(Nicola & all., 1983), megakaryocytes (Koike & all., 1990), and osteoclasts (Tamura, Udagava, & 
all., 1993) was also demonstrated. In the acute phase of inflammation, IL-6 induces the production 
of acute phase proteins, including C-reactive protein (Castell, Gomez-Lechon, & all., 1988). IL-6 
is the main effector of joint inflammation and destructive changes associated with rheumatoid 
arthritis.  
IL-6 triggers the transmission of the intracellular signal in two ways: by binding to the 
membrane IL-6 receptor (mIL-6R) and trans-signaling. The intracellular part of mIL-6R is not 
involved in signal transmission. For this, another protein is required—gp130 (IL-6R β chain, 
CD130), which is present in cells that do not express mIL-6R. Along with MIL-6R, there is a 
soluble form of the IL-6 receptor (sIL-6R), which, by forming a complex with IL-6, has the ability 
to bind to gp130 and induce the transmission of an activation signal without involvement of the 
membrane form (trans-signaling). While the classical effects of IL-6 are limited to the effect on 
mIL-6R-expressing cells (hepatocytes, monocytes, macrophages and some subpopulations of 
lymphocytes), trans-signaling allows IL-6 to activate cells lacking mIL-6R but expressing gp130, 
including synovial cells. This underlies a wide range of pathological effects of IL-6 in RA: fever, 

Clinical Study Protocol 
Study code: BCD-089-1 
Translated from Russian to English, dated 06-Jul-2020 
 
 
 
CONFIDENTIAL 
Version: 1.0 of June 1, 2016. 
Page 24 of 128 
 
increased concentrations of acute phase proteins, anemia, synthesis of autoantibodies, pannus 
formation and joint destruction, activation of Th17 cells, etc. 
Figure 1. IL-6 classical signaling and IL-6 trans-signaling Classical IL-6 receptor signaling 
requires binding to mIL-6R and is limited to hepatocytes, some epithelial cells and some 
leukocytes. IL-6 trans-signaling requires sIL-6R and is possible on all cells of the body, since all 
cells express gp130 protein on their surface. 
 
 
Classical IL-6 signaling via IL-6 membrane receptor 
Membrane IL-6 and IL-6Rα receptors are found only on hepatocytes and some leukocytes 
(neutrophils, monocytes, T and B lymphocytes). Normally, IL-6Rα cannot transfer the signal 
inside the cell; to activate it, after binding to IL-6, it is necessary to form a complex with the 
homodimeric transducing protein gp130, which leads to the activation of the JAK1 kinase and 
transcription factor STAT3, which initiates differentiation and cell growth, prevents apoptosis and 
triggers the synthesis of Bcl2, Bcl-xL, TIMP proteins, LPS-binding protein, etc. The IL6-IL-6Rα-
Classical IL-6 signaling 
IL-6 trans-signaling 
IL-6 
Signaling 
Soluble IL6 receptor 
IL-6 
Signaling 

Clinical Study Protocol 
Study code: BCD-089-1 
Translated from Russian to English, dated 06-Jul-2020 
 
 
 
CONFIDENTIAL 
Version: 1.0 of June 1, 2016. 
Page 25 of 128 
 
gp130 signal leads to the activation of MAPK and ERK kinases activating the RAS proto-oncogen 
(GTPase, which mutates in various types of solid tumors). 
Alternative signaling (trans-signaling) via soluble IL-6 receptor 
The IL-6 receptor exists in soluble form in all bodily fluids (as a free receptor or as bound 
to IL-6). Such a receptor is capable of signaling in any cell that has gp130 on its surface (and such 
cells include the absolute majority of cells). IL-6 trans-signaling is apparently responsible for all 
pathological effects of this cytokine in inflammatory diseases of the connective tissue 
inflammatory bowel diseases and malignancies. sIL-6R plays a dual role. The formation of the 
IL6-sIL-6R complex not only protects IL-6 and extends its half-life, but also acts as an agonist that 
can directly activate cells through binding to gp130 (that is, unlike most soluble receptors, sIL-6R 
does not block, but rather promotes the IL-6 activity). This trans-signaling allows IL-6 to activate 
cells that have lost the alpha subunit of IL-6R, which normally would not respond to the action of 
this cytokine. 
Blockade of both forms of the receptor will prevent the development of IL-6-associated 
pro-inflammatory cascade, including the prevention of activation of antigen-presenting cells, B 
and T lymphocytes, monocytes and macrophages, endothelial cells and fibroblasts (Kishimoto et 
al., 1989), as well as excess production of other pro-inflammatory cytokines, including IL-2 
production by T cells. This cytokine stimulates T-cell proliferation and hematopoietic reactions 
(Kita et al., 1992). An imbalance between the pro- and anti-inflammatory effects of IL-6 has been 
demonstrated to cause various autoimmune diseases (e.g., rheumatoid arthritis), chronic 
inflammation and osteoporosis (Roodman et al., 1992), and psoriasis, while its excess production 
is 
associated 
with 
various 
forms 
of 
cancer. 
As 
a 
result, 
inhibition  
of the IL-6 action is an attractive target for research and treatment of these diseases. 
Block of the soluble form of the IL-6 receptor, which is impossible when using antibodies 
to the ligand itself, allows to disrupt the alternative trans-signaling process. 
Thus, the use of antagonistic anti-IL-6R antibodies will inhibit the main effects of this 
cytokine responsible for the development and maintenance of chronic inflammation in 
autoimmune diseases, and their use will allow: 
• Impairing the differentiation of naive T-lymphocytes into Th17-lymphocytes—a 
population of autoimmune inflammatory cells that initiates the recruitment of immunocytes 
to inflammation sites. 

Clinical Study Protocol 
Study code: BCD-089-1 
Translated from Russian to English, dated 06-Jul-2020 
 
 
 
CONFIDENTIAL 
Version: 1.0 of June 1, 2016. 
Page 26 of 128 
 
• Interfering with IL-6-dependent inhibition of regulatory T cell proliferation. 
• Interfering with IL-6-promoted differentiation of CD4 lymphocytes into type 2 T-helpers, 
activation of mature T-lymphocytes and natural killers. 
• Interfering with accumulation of autoreactive T cells by activating their apoptosis, as well 
as 
preventing 
the 
substitution 
of 
autoreactive 
T-cell 
binding  
to CD40 enabled by the IL-6/soluble IL-6 receptor complex. 
• Interfering with the presentation of autoantigens by blocking IL-6-dependent inhibition by 
Na2+/K+-ATPase, which regulates the internalization of the antigen and its presentation to 
T cells by dendritic cells. 
• Interfering with excessive activation, differentiation and proliferation of B-lymphocytes 
and antibody formation. 
• Interfering with IL-6-dependent proliferation of osteoclasts and destruction of bone tissue. 
• Neutralizing the oncogenic function of IL-6 due to its ability to activate intracellular 
signaling pathways aimed at stimulating proliferation and increasing the survival of most 
types of cells (via trans-signaling), and to normalize apoptosis. 
• For 
malignancies 
characterized 
by 
elevated  
IL-6 levels (e.g. multiple myeloma, hepatocellular carcinoma, colorectal cancer, cardiac 
myxoma, Castleman disease) - preventing continuous IL-6-dependent autocrine 
stimulation. 
Thus, an isolated blockade of signal transmission, carried out using an anti-IL-6R 
monoclonal antibody, is characterized by a wide range of anti-inflammatory and 
immunomodulatory effects, which determines the feasibility of further development and 
subsequent clinical use of this drug in patients with various autoimmune diseases, as well as 
determines the perspectives of studying its effects in the treatment of certain malignancies. 
To date, the origin of rheumatoid arthritis remains unclear, however, it is known that a 
large number of cytokines, including IL-6, are detected in RA patients' serum and joint fluid. Since 
activated T cells are present in the synovial fluid of patients with rheumatoid arthritis, it has long 
been believed that the disease is Th1 type. However, this paradigm was revised after the presence 
of Th17 in the synovial fluid and the significant role of IL-17 in the development of RA were 
demonstrated (Chabaud & all., 1999). In this regard, it can be assumed that the role of IL-6 in the 
development of RA can be determined by two main functions, the recruitment of T cells and 

Clinical Study Protocol 
Study code: BCD-089-1 
Translated from Russian to English, dated 06-Jul-2020 
 
 
 
CONFIDENTIAL 
Version: 1.0 of June 1, 2016. 
Page 27 of 128 
 
induction of CD4+ development towards Th17 (Naugler & Karin, 2007). A schematic 
representation of the mechanism of action of IL-6 is shown in Figure 2. 
Figure 2. IL-6 as a link in inflammation, B-cell proliferation and hematopoiesis. 
 
It has been shown that in inflammation, ‘shedding’ of soluble receptors from the surface of 
neutrophils leads, via trans-signaling, to the activation of endotheliocytes that do not express IL-6 
receptors on their surfaces and are, therefore, not sensitive to the cytokine. Stimulation of 
endothelial cells by IL-6/sIL-6R complex causes the secretion of the cytokine MCP-1, leading to 
the migration of mononuclear cells to the site of inflammation. Thus, ‘shedding’ of the soluble IL-
6 receptor determines damage, as measured by the number of neutrophils recruited to the 
inflammation site (DeLeo FR., 2007).  
Therefore, shedding of IL-6 receptor and inhibition of their interaction between should 
have a pronounced effect on the development of inflammatory and destructive changes, which has 
been confirmed on an in vivo model of collagen-induced arthritis using cynomolgus monkeys 
(Mihara, Kotoh, & all, 2001) and demonstrated during the clinical use of tocilizumab.  
The therapeutic mechanism of soluble IL-6 receptor blockade is shown in Figure 3. 
Endothelial 
cells 
Joint 
destruction 
Platelet count 
increased 
Red blood cell 
count decreased 
Acute phase protein production 
Chronic 
inflammation 
Antibodies and autoAb production, 
hypergammaglobulinemia 
Pannus formation 
Synovial 
membrane 
Hepatocytes 
Neutrophil 
Macrophage 
T cell 
Osteoclast activation and 
bone resorption 
Bone 
marrow 
B-cells 
Adhesion 
molecules 
induction 
Interleukin 6 

Clinical Study Protocol 
Study code: BCD-089-1 
Translated from Russian to English, dated 06-Jul-2020 
 
 
 
CONFIDENTIAL 
Version: 1.0 of June 1, 2016. 
Page 28 of 128 
 
Figure 3. Therapeutic mechanism of soluble IL-6 receptor block 
 
 
 
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Interleukin 6 
Soluble IL-6 
receptor 
Antibodies to soluble 
IL-6 receptor 
antibodies 
Signaling 
Membrane IL-6 
receptor 

Clinical Study Protocol 
Study code: BCD-089-1 
Translated from Russian to English, dated 06-Jul-2020 
 
 
 
CONFIDENTIAL 
Version: 1.0 of June 1, 2016. 
Page 29 of 128 
 
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn  
1.2. Name and description (characteristics) of the test drug 
1.2.1. Test drug 
Trade name: not applicable. Product code: BCD-089. 
National nonproprietary name: Anti-interleukin-6 receptor monoclonal antibody 
Pharmaceutical form: solution for injection. 
Composition per 1 mL:  
Active substance: nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn. 
Excipients: 
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnn. 
Manufacturer: JSC BIOCAD, Russia 
Shelf life: 2 years. 
Storage and transportation conditions: 
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnn. 
Packaging: 
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnn. 
nnnnnnnnnnnnnnnnnnnnn. 
Labeling:  
In accordance with Article 46 of Federal Law “On the Circulation of Medicinal Products” No. 61-
ФЗ of April 12, 2010, the primary packaging of the test drug contains the following Russian text 
in easily readable font: 

Clinical Study Protocol 
Study code: BCD-089-1 
Translated from Russian to English, dated 06-Jul-2020 
 
 
 
CONFIDENTIAL 
Version: 1.0 of June 1, 2016. 
Page 30 of 128 
 
- name of the medicinal product: “BCD-089”, 
- batch number, 
- release date, 
- expiry date, 
- strength. 
The secondary packaging contains the following information in Russian in easily readable font: 
- name of the medicinal product: “BCD-089”, 
- name of the medicinal product manufacturer: JSC BIOCAD, Russia,  
- batch number, 
- release date, 
- expiry date, 
- method of administration, 
- strength; 
- formulation, 
- general classification for supply, 
- storage conditions, 
- cautionary information. 
Primary and secondary packaging of the test drug will be additionally labeled with: “For clinical 
studies only”. 
 
1.2.2 Diluent 
The diluent in the study is needed to dilute the dosage form for administration to volunteers 
in the cohorts with less concentration 
 Composition of the diluent per 1 mL: 
nnnnnnnnnnnnnnnnnnnnnnnnnnnn 
nnnnnnnn 
nnnnnnnnnnnnnnnnn 
nnnnnnnnnnnnnnn 
nnnnnnnn 
nnnnnnnn 
nnnnnnnnnn 
nnnnnnn 

Clinical Study Protocol 
Study code: BCD-089-1 
Translated from Russian to English, dated 06-Jul-2020 
 
 
 
CONFIDENTIAL 
Version: 1.0 of June 1, 2016. 
Page 31 of 128 
 
nnnnnnnnnnnnnnnnnnnnnn 
nnnnnnnnnnnnnn 
 
Manufacturer: JSC BIOCAD, Russia 
Shelf life: 2 years. 
 
Storage and transportation conditions: 
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnn. 
Packaging: 
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnn 
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn. 
Labeling: 
In accordance with Article 46 of Federal Law “On the Circulation of Medicinal Products” 
No. 61-ФЗ of April 12, 2010, the primary packaging of the test drug contains the following Russian 
text in easily readable font: 
- “Diluent”, 
- batch number, 
- release date, 
- expiry date, 
- volume. 
The secondary packaging contains the following information in Russian in easily readable 
font: 
- name: “Diluent”, 
- manufacturer name: JSC BIOCAD, Russia,  
- batch number, 
- release date, 
- expiry date, 
- method of administration, 
- volume, 
- storage conditions, 

Clinical Study Protocol 
Study code: BCD-089-1 
Translated from Russian to English, dated 06-Jul-2020 
 
 
 
CONFIDENTIAL 
Version: 1.0 of June 1, 2016. 
Page 32 of 128 
 
- cautionary information. 
Primary and secondary packaging of the test drug will be additionally labeled with: “For clinical 
studies only”. 
Method of administration and dosing regimen:  
In this study, the drug will be administered as a single-dose subcutaneously. The administered 
dose of BCD-089 depends on the cohort into which the volunteer was assigned: 
1. 
Cohort 01 - 1 volunteer to whom a single subcutaneous injection of BCD-089 at a dose of 
0.06 mg/kg will be administered. 
2. 
Cohort 02 - a maximum of 6 volunteers to whom a single subcutaneous injection of BCD-
089 at a dose of 0.3 mg/kg will be administered. 
3. 
Cohort 03 - a maximum of 6 volunteers to whom a single subcutaneous injection of BCD-
089 at a dose of 0.625 mg/kg will be administered. 
4. 
Cohort 04 - a maximum of 6 volunteers to whom a single subcutaneous injection of BCD-
089 at a dose of 1.0 mg/kg will be administered. 
5. 
Cohort 05 - a maximum of 6 volunteers to whom a single subcutaneous injection of BCD-
089 at a dose of 1.6 mg/kg will be administered. 
6. 
Cohort 06 - a maximum of 6 volunteers to whom a single subcutaneous injection of BCD-
089 at a dose of 2.2 mg/kg will be administered. 
7. 
Cohort 07 - a maximum of 6 volunteers to whom a single subcutaneous injection of BCD-
089 at a dose of 2.9 mg/kg will be administered. 
Method of administration:  
Dose calculation: 
The dose is calculated in mg/kg of the volunteer's body weight. Based on the dose assigned 
according to the study design, the dose is calculated per 1 administration of the drug. 
The total dose per 1 administration (mg) is equal to the weight of the volunteer (kg) 
multiplied by the dose specified for the cohort, which the volunteer is assigned to (mg/kg). A 
detailed table with the calculation of drug doses based on the volunteer body weight is provided 
to the Investigator. 
 
Instructions for preparing the solutions for cohorts 
Preparation of the solution for injection should be prepared using aseptic technique. 

Clinical Study Protocol 
Study code: BCD-089-1 
Translated from Russian to English, dated 06-Jul-2020 
 
 
 
CONFIDENTIAL 
Version: 1.0 of June 1, 2016. 
Page 33 of 128 
 
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nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

Clinical Study Protocol 
Study code: BCD-089-1 
Translated from Russian to English, dated 06-Jul-2020 
 
 
 
CONFIDENTIAL 
Version: 1.0 of June 1, 2016. 
Page 34 of 128 
 
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnn.nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
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nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn 
  
1.3. Summary of potentially clinically relevant results of preclinical studies, as well as results 
of clinical studies that are relevant for this study  
1.3.1. Non-clinical studies of the test drug 
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn. 
1.3.1.1. Summary of physicochemical studies 
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

Clinical Study Protocol 
Study code: BCD-089-1 
Translated from Russian to English, dated 06-Jul-2020 
 
 
 
CONFIDENTIAL 
Version: 1.0 of June 1, 2016. 
Page 35 of 128 
 
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1.3.1.2. Preclinical studies in laboratory animals 
1.3.1.2.1. A study of the potency of BCD-089 in a model of collagen-induced arthritis 
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
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nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnn. 

Clinical Study Protocol 
Study code: BCD-089-1 
Translated from Russian to English, dated 06-Jul-2020 
 
 
 
CONFIDENTIAL 
Version: 1.0 of June 1, 2016. 
Page 36 of 128 
 
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nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn 

Clinical Study Protocol 
Study code: BCD-089-1 
Translated from Russian to English, dated 06-Jul-2020 
 
 
 
CONFIDENTIAL 
Version: 1.0 of June 1, 2016. 
Page 37 of 128 
 
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nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn 

Clinical Study Protocol 
Study code: BCD-089-1 
Translated from Russian to English, dated 06-Jul-2020 
 
 
 
CONFIDENTIAL 
Version: 1.0 of June 1, 2016. 
Page 38 of 128 
 
1.3.1.2.2. BCD-089 pharmacokinetic study following a single-dose administration to 
monkeys 
Nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnNnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
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nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnn 

Clinical Study Protocol 
Study code: BCD-089-1 
Translated from Russian to English, dated 06-Jul-2020 
 
 
 
CONFIDENTIAL 
Version: 1.0 of June 1, 2016. 
Page 39 of 128 
 
Nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
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nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn 
1.3.1.2.3. BCD-089 pharmacokinetic study following repeated-dose administration to 
monkeys 
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn 
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn 
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nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
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nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
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nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn 

Clinical Study Protocol 
Study code: BCD-089-1 
Translated from Russian to English, dated 06-Jul-2020 
 
 
 
CONFIDENTIAL 
Version: 1.0 of June 1, 2016. 
Page 40 of 128 
 
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
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nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn 
1.3.1.2.4. Study of BCD-089 immunogenicity following repeated-dose administration 
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn 

Clinical Study Protocol 
Study code: BCD-089-1 
Translated from Russian to English, dated 06-Jul-2020 
 
 
 
CONFIDENTIAL 
Version: 1.0 of June 1, 2016. 
Page 41 of 128 
 
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
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nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn 
1.3.1.2.5. Acute toxicity study of BCD-089 
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn 
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
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nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn 
1.3.1.2.6. BCD-089 repeated-dose toxicity study 
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

Clinical Study Protocol 
Study code: BCD-089-1 
Translated from Russian to English, dated 06-Jul-2020 
 
 
 
CONFIDENTIAL 
Version: 1.0 of June 1, 2016. 
Page 42 of 128 
 
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
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nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnn 
1.3.1.2.7. Evaluation of local tolerance of BCD-089 in a toxicity study with repeated-dose 
administration of the drug   
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

Clinical Study Protocol 
Study code: BCD-089-1 
Translated from Russian to English, dated 06-Jul-2020 
 
 
 
CONFIDENTIAL 
Version: 1.0 of June 1, 2016. 
Page 43 of 128 
 
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
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nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn 
1.3.1.2.8. BCD-089 cross-reactivity evaluation 
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn 
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
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nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn 

Clinical Study Protocol 
Study code: BCD-089-1 
Translated from Russian to English, dated 06-Jul-2020 
 
 
 
CONFIDENTIAL 
Version: 1.0 of June 1, 2016. 
Page 44 of 128 
 
1.3.1.2.9. Preclinical study of cytokine storm 
Nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnn.  
 
1.3.2. Clinical studies of the test drug 
Not performed. 
1.4. Summary of known and potential risks and benefits for clinical trial subjects 
(risk/benefit ratio) 
Benefit evaluation 
BCD-089 is an innovative drug, which has never been used in humans. The first stage of 
BCD-089 clinical development will be to evaluate its effects in healthy volunteers, which means 
that participants in such a study will not derive subjective (personal) benefits from their 
participation in it, except for a detailed medical examination; however, data obtained after the 
completion of this study will have high scientific value and may help introduce into clinical 
practice a new highly effective product for the treatment of severe autoimmune disorders. 
 
Risk evaluation  
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

Clinical Study Protocol 
Study code: BCD-089-1 
Translated from Russian to English, dated 06-Jul-2020 
 
 
 
CONFIDENTIAL 
Version: 1.0 of June 1, 2016. 
Page 45 of 128 
 
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
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nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
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nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

Clinical Study Protocol 
Study code: BCD-089-1 
Translated from Russian to English, dated 06-Jul-2020 
 
 
 
CONFIDENTIAL 
Version: 1.0 of June 1, 2016. 
Page 46 of 128 
 
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Clinical Study Protocol 
Study code: BCD-089-1 
Translated from Russian to English, dated 06-Jul-2020 
 
 
 
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Version: 1.0 of June 1, 2016. 
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1.5. Description and justification of the study design, the method of administration of the test 
drug, dose, dosing regimen and the course of treatment 
1.5.1. Description and justification of the study design 
 
Clinical study No. BCD-089-1 is a classic open-label, single-center, non-randomized 
cohort clinical study of the pharmacokinetics, pharmacodynamics, tolerability and safety of a 
novel drug in healthy volunteers at increasing doses (phase 1, 3+3 design). 
Study No. BCD-089-1 includes seven cohorts: 
1. 
Cohort 01 - 1 volunteer to whom a single subcutaneous injection of BCD-089 at a dose of 
0.06 mg/kg will be administered. 
2. 
Cohort 02 - a maximum of 6 volunteers to whom a single subcutaneous injection of BCD-
089 at a dose of 0.3 mg/kg will be administered. 
3. 
Cohort 03 - a maximum of 6 volunteers to whom a single subcutaneous injection of BCD-
089 at a dose of 0.625 mg/kg will be administered. 
4. 
Cohort 04 - a maximum of 6 volunteers to whom a single subcutaneous injection of BCD-
089 at a dose of 1.0 mg/kg will be administered. 
5. 
Cohort 05 - a maximum of 6 volunteers to whom a single subcutaneous injection of BCD-
089 at a dose of 1.6 mg/kg will be administered. 
6. 
Cohort 06 - a maximum of 6 volunteers to whom a single subcutaneous injection of BCD-
089 at a dose of 2.2 mg/kg will be administered. 
7. 
Cohort 07 - a maximum of 6 volunteers to whom a single subcutaneous injection of BCD-
089 at a dose of 2.9 mg/kg will be administered. 
The inclusion of volunteers in the study is sequential. The first to participate in the study 
is one volunteer, representing the cohort “01”, who is administered a single subcutaneous injection 
of BCD-089 0.06 mg/kg. In the absence of grade 3-4 adverse events related to the test product, 
developing within the first 7 days after the injection, three volunteers are included in cohort 02, 
who will receive the estimated minimum single starting dose.  
The doses for each cohort were calculated using a modified Fibonacci sequence. 
According to the “3+3” principle, enrollment to the study is sequential. First, one volunteer 
is included in the first cohort. In the absence of grade 3-4 adverse events related to the test product, 

Clinical Study Protocol 
Study code: BCD-089-1 
Translated from Russian to English, dated 06-Jul-2020 
 
 
 
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Version: 1.0 of June 1, 2016. 
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developing within the first 7 days after the injection, three volunteers are included in cohort 02. 
Further, the volunteer inclusion algorithm corresponds to the following general principle: 
a) In the absence of any grade 3-4 AEs (DLT) associated with the test product within 7 
days after the injection, the next cohort of three volunteers with dose escalation is 
included in the study - cohort 02 (cohort 03, cohort 04, etc.).  
b) If grade 3-4 AEs (DLT) associated with the test product are recorded in only one 
volunteer in a cohort of three volunteers, three more healthy volunteers are 
additionally included in this cohort. 
c) With the development of grade 3-4 AEs (DLT) associated with the test product in 
two of six volunteers, the dose at which this event was recorded will be taken as the 
maximum tolerated dose, further dose escalation will be ceased. 
Thus, dose limiting toxicity will be assessed close to the time of administration, during the 
first seven days after the injection. However, it is not the end of the volunteers follow-up - 
monitoring of their condition, as well as blood sampling for the study of pharmacokinetics, 
pharmacodynamics, and safety, will be carried out up to 71 days from the moment of injection - 
the selected duration of the study is sufficient for a full study of pharmacokinetics, 
pharmacodynamics and safety following a single-dose administration. 
1.5.2. Justification of for the starting and maximum doses of BCD-089 
1.5.2.1. Starting dose of BCD-089 
According to the Guidelines for Conducting Preclinical Studies of Medicinal Products (part 
one)” (M.: FSBI “SCEEMP” of the Ministry of Health of Russia. - 2013, p. 854-864) for 
calculation of the maximum single starting dose (MSSD) for the first use of a novel drug in 
humans, it is necessary to determine the no-observed-adverse-effect level (NOAEL) in animals. 
The definition of NOAEL in the above guidelines says: “no-observed-adverse-effect level is the 
largest dose studied in animals, which does not cause a significant increase in negative effects 
compared to the control group. Negative effects that are biologically significant should be 
considered when determining NOAEL” (p. 855). 
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1.5.2.2. Maximum BCD-089 dose in the study 
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1.5.3. Rationale for the route of administration and dosing frequency 
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1.6. Clinical study compliance with standard regulatory requirements 
 This clinical study will be conducted in compliance with this Protocol, which is fully 
compliant with the legislation of the Russian Federation, National Standard of the Russian 
Federation, GOST R 52379-2005 “Good Clinical Practice”, as well as GCP standard. 
1.7. Study population 
Male healthy volunteers aged 18 to 45 years, inclusive who are eligible to participate in the 
study according to the Protocol eligibility criteria. 
1.8. References 
Castell, J., Gomez-Lechon, M., & all., a. (1988). Recombinant human interleukin-6 (IL-6/BSF-2/HSF) 
regulates the synthesis of acute phase proteins in human hepatocytes. Blood, pp. 347-350. 
Chabaud, M., & all., a. (1999). Human interleukin-17: a T cell-derived proinflammatory cytokine 
produced by the rheumatoid synovium. Arthritis Rheum, pp. 963-970. 
Dendorfer, U., & all., a. (1994). Multiple regulatory elements in the interleukin-6 gene mediate induction 
by prostaglandins, cyclic AMP, and lipopolysaccharide. Mol. Cell. Biol, pp. 4443-4454. 
Garman, R., & all., a. (1987). B cell-stimulatory factor 2 (β2 interferon) functions as a second signal for 
interleukin 2 production by mature murine T cells. Proc Natl Acad Sci USA, pp. 7629-7633. 
Heinrich, P., Behrmann, I., & all., a. (2003). Principles of interleukin (IL)-6-type cytokine signalling and its 
regulation. pp. 1-20. 
Horai, N., Nagaoka, T., & all., a. (2013). Muscle wasting associated with pathologic change is a risk factor 
for the exacerbation of join swelling in collagen-induced arthritis in cynomolgus monkeys. 
Musculoskeletal Disorders, pp. 1-10. 
Kishimoto, T., & all., a. (1995). Interleukin-6 family of cytokines and gp130. Blood, pp. 1243-1254. 
Koike, K., & all., a. (1988). Synergism of BSF2/interleukin-6 and interleukin-3 on development of 
multipotential hemopoietic progenitors. pp. 879-890. 
Koike, K., Nakahata, T., Kubo, T., & all., a. (1990). Interleukin-6 enhances murine megakariocytopoiesis in 
serum-free culture. Blood, pp. 2286-2291. 
Leech, M. D., Barr, T., Turner, D. G., & all., e. (2013, February). IL-6-dependent autoimmune disease: 
dendritic cells as a sufficient, but transient, source1. J Immunol., pp. 881-885. 
Mihara, M., Kotoh, M., & all, e. (2001). Humanized antibody to human interleukin-6 receptor inhibits the 
development of collagen arthritis in cynomolgus monkeys. Clin Immunol, pp. 319-326. 
Muragichi, A., & all., a. (1981). T cell-replacing factor (TRF)-induced IgG secretion in human B blastoid 
cell line and demonstration of acceptors for TRF. J Immunol, pp. 412-416. 

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Naugler, W., & Karin, M. (2007). The wolf in sheep’s clothing: the role of interleukin-6 in immunity, 
inflammation and cancer. Elsevier, pp. 1-11. 
Nicola, N., & all., a. (1983). Purification of a factor inducing differentiation in murine myelomonocytic 
leukemia cells. Identification as granulocyte colony-stimulating factor. J Biol Chem, pp. 9017-
9023. 
Noma, T., & all., a. (1987). Enhancement of the interleukin-2 receptor expression on T-cells by multiple 
B-lymphotropic lymphokines. Immunol Lett, pp. 249-253. 
Pritzker, K., & Gay, S. (2006). Osteoarthritis cartilage histopathology: grading and staging. Osteoarthritis 
and cartilage , pp. 13-29. 
Tamura, T., Udagava, N., & all., a. (1993). Soluble interleukin-6 receptor triggers osteoclast formation by 
interleukin 6. Proc Natl Acad Sci USA, pp. 11924-11928. 
Uchiyama, Y., Yorozu, K., Hashizime, M., Moriya, Y., & Mihara, M. (2008). Tocilizumab, a Humanized 
Anti-interleukin-6 receptor antibody, ameliorates joint swelling in established monkey collagen-
Induced arhtritis. Biol. Pharm. Bull., 1159-1163. 
Vierboom, M., & all., a. (2010). Collagen-induced arhtritis in common marmosets: a new non-human 
primate model for chronic arthritis. Arthritis Research & Therapy, pp. 1-16. 
Yoshizaki, K., & all., a. (1982). Induction of proliferation and Ig production in human B leukemic cells by 
anti-immunoglobulins and T cell factors. J Immunol, pp. 1296-1301. 
 
 2. STUDY GOALS AND OBJECTIVES 
2.1. Study aims 
To evaluate tolerability, safety, and major pharmacokinetic and pharmacodynamic 
parameters of BCD-089 following single subcutaneous administration in increasing doses to 
healthy volunteers.   
2.2. Study Objectives 
 
1. To determine the safe dose range of BCD-089, which will subsequently be used in the 
phase II clinical study; 
2. To determine the proportion of study participants in whom a single subcutaneous 
administration of BCD-089 was accompanied by the development of adverse events, 
including the proportion of volunteers with neutropenia of varying severity; 

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3. To determine the main pharmacokinetic parameters (AUC0-1680, AUC0-∞, Cmax, Тmax, Т½, 
Кel and CL) of BCD-089 after a single subcutaneous injection in increasing doses to 
healthy volunteers; 
4. To determine the main pharmacodynamic parameters (Cmax, Tmax, Cmin, Tmin, AUC0-1680) 
for C-reactive protein, IL-6 and soluble receptor IL-6; 
5. To determine the proportion of volunteers, in whom binding and/or neutralizing 
antibodies to BCD-089 were determined following its single administration. 
3. HYPOTHESES TESTED 
The study is based on the hypothesis that the maximum tolerated dose of BCD-089 with a single-
dose subcutaneous injection to healthy volunteers is 2.9 mg/kg of body weight. 
 
 
4. STUDY DESIGN 
4.1 Primary and secondary parameters that will be assessed in the study 
4.1.1. Pharmacokinetic endpoints 
• 
AUC0-1680 (area under the concentration-time curve from the administration of the drug to 
1680 h (71 days after administration) and AUC0-∞ (to infinity), 
• 
Cmax (maximum serum concentration of anti-IL-6 receptor antibody), 
• 
Tmax (time to maximum concentration); 
• 
Т½ (half-life), 
• 
Kel (elimination rate constant), 
• 
CL (total clearance). 
4.1.2. Pharmacodynamic endpoints 
1. 
C-reactive protein concentration determination: 

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Primary: 
• AUC0-1680 (area under the concentration-time curve from the administration of the drug to 
1680 h (71 days after administration) and AUC0-∞ (to infinity). 
Secondary: 
• Cmin (minimum detectable concentration in blood serum), 
• Тmin (time to minimum serum concentration). 
 
 
2. 
Determination of IL-6 concentration, soluble IL-6 receptor concentration: 
Primary: 
• AUC0-1680 (area under the concentration-time curve from the administration of the drug to 
1680 h (71 days after administration) and AUC0-∞ (to infinity). 
Secondary: 
• Cmax (maximum concentration in serum), 
• Tmax (time to maximum serum concentration). 
 
Additionally, the percentage of occupancy of membrane IL-6 receptors with BCD-089 2 hours 
after drug administration, 168, 336 and 504 hours after single injection will be determined in the 
study (however, it is not specified in the mandatory analyzed endpoints as it is a pilot study). 
4.1.3. Subcutaneous injection-associated pain assessment endpoint 
• 
The mean pain score during the injection on the visual analogue scale. 

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4.1.4. Safety endpoints: 
• Proportion of subjects who discontinued the study due to AEs and SAEs in each cohort. 
4.1.5. Immunogenicity endpoint 
• The frequency of development of binding and/or neutralizing antibodies to BCD-089 on 
Day 71 from the moment of a single-dose subcutaneous injection. 
4.2 Design 
Clinical study No. BCD-089-1 is a classic open-label, single-center, non-randomized 
cohort clinical study of the pharmacokinetics, pharmacodynamics, tolerability and safety of a 
novel drug in healthy volunteers at increasing doses (phase 1, 3+3 design). 
Before being included in the study, healthy volunteers have to sign a written informed 
consent after having read it, after which they will undergo a 14-day screening examination to 
confirm compliance with the eligibility criteria for the study. No additional requirements regarding 
a certain diet or restriction of physical activity, both during the screening period and throughout 
the study, are specified in this protocol. 
Study No. BCD-089-1 includes seven cohorts: 
1. 
Cohort 01 - 1 volunteer to whom a single subcutaneous injection of BCD-089 at a dose of 
0.06 mg/kg will be administered. 
2. 
Cohort 02 - a maximum of 6 volunteers to whom a single subcutaneous injection of BCD-
089 at a dose of 0.3 mg/kg will be administered. 
3. 
Cohort 03 - a maximum of 6 volunteers to whom a single subcutaneous injection of BCD-
089 at a dose of 0.625 mg/kg will be administered. 
• Proportion of subjects who developed SAEs in each cohort. 
• Proportion of subjects who developed AEs in each cohort.  
• Proportion of subjects who developed local reactions in each cohort. 
• Proportion of subjects who developed grade 3-4 AEs in each cohort. 
• Proportion of subjects who developed any grade neutropenia in each cohort. 

Clinical Study Protocol 
Study code: BCD-089-1 
Translated from Russian to English, dated 06-Jul-2020 
 
 
 
CONFIDENTIAL 
Version: 1.0 of June 1, 2016. 
Page 57 of 128 
 
4. 
Cohort 04 - a maximum of 6 volunteers to whom a single subcutaneous injection of BCD-
089 at a dose of 1.0 mg/kg will be administered. 
5. 
Cohort 05 - a maximum of 6 volunteers to whom a single subcutaneous injection of BCD-
089 at a dose of 1.6 mg/kg will be administered. 
6. 
Cohort 06 - a maximum of 6 volunteers to whom a single subcutaneous injection of BCD-
089 at a dose of 2.2 mg/kg will be administered. 
7. 
Cohort 07 - a maximum of 6 volunteers to whom a single subcutaneous injection of BCD-
089 at a dose of 2.9 mg/kg will be administered. 
*Note. If a volunteer is administered 1 mL of the solution and, therefore, it is necessary to 
perform two injections to administer the calculated dose, it is preferable to administer the drug to 
the same anatomical region, provided that the site of the subsequent injection is no closer than 5 
cm from the previous one. The duration of administering several injections should not exceed 10 
minutes; calculation of time for PK sampling starts from the “last” drug injection. 
The inclusion of volunteers in the study is sequential. The first to participate in the study 
is one volunteer, representing the cohort “01”, who was administered a single subcutaneous 
injection of BCD-089 at a dose calculated with an additional safety factor relative to the safe 
starting dose - 0.06 mg/kg. In the absence of grade 3-4 adverse events related to the test product, 
developing within the first 7 days after the injection, three volunteers are included in cohort 02. 
Further, the volunteer inclusion algorithm corresponds to the following general principle: 
In the absence of any grade 3-4 AEs (DLT) associated with the test product within 7 days 
after the injection, the next cohort of three volunteers with dose escalation is included in the study 
- cohort 02 (cohort 03, cohort 04, etc.).  
If grade 3-4 AEs (DLT) associated with the test product are recorded in only one volunteer 
in a cohort of three volunteers, three more healthy volunteers are additionally included in this 
cohort. 
With the development of grade 3-4 AEs (DLT) associated with the test product in two of 
six volunteers, the dose at which this event was recorded will be taken as the maximum tolerated 
dose, further dose escalation will be ceased. 
Thus, dose limiting toxicity will be assessed close to the time of administration, during the 
first seven days after the injection. However, it is not the end of the volunteers follow-up - 

Clinical Study Protocol 
Study code: BCD-089-1 
Translated from Russian to English, dated 06-Jul-2020 
 
 
 
CONFIDENTIAL 
Version: 1.0 of June 1, 2016. 
Page 58 of 128 
 
monitoring of their condition, as well as blood sampling for the study of pharmacokinetics, 
pharmacodynamics, and safety, will be carried out up to 71 days from the moment of injection. 
A 14-day screening examination and 13 subsequent visits are planned to be conducted 
during the study. The duration of the active phase of the study (from the moment of the drug 
injection to the final visit) is 71 days.  
The volunteer will need to be in a hospital for the entire duration of the first visit procedures 
(during which the test drug will be administered), since at this visit multiple blood sampling for 
PK studies will be performed. The volunteer will be able to leave the study site 24 hours after the 
administration of the test drug, provided he/she feels well and all prescribed blood sampling is 
completed.  Starting from the "Day 3" visit, the volunteer must come to the study site 
approximately 1 hour before the PK blood sampling. 
Due to the need for multiple blood sampling, the volunteer has to stay at the study site for 
the first day after the injection. 
Safety and tolerability assessment 
Safety and tolerability will be assessed by monitoring vital signs (blood pressure, heart 
rate, and body temperature), conducting periodic physical examinations, assessing the frequency 
and severity of local reactions, and evaluating the results of complete blood count and blood 
biochemistry tests, urinalysis, and electrocardiography. These parameters will be assessed over a 
period of 71 days after a single-dose administration of the test drug. Additionally, information 
about the tenderness of subcutaneous injection, evaluated by a volunteer using a 10-point visual 
analog scale, will be analyzed. 
Pharmacokinetic assessment 
 
Pharmacokinetic assessment will be carried out based on data on the BCD-089 
concentration in the serum of healthy volunteers. Volunteers included in the study arrive at the 
study site on the morning of the drug administration day. A venous catheter is installed 
immediately before the first blood sampling (the time from the catheter placement to the first blood 
sampling from it should not exceed one hour). Since multiple blood sampling is carried out only 
during the first day after the test drug administration, the time of placement a venous catheter will 
be 24 hours, after which the blood is taken by venipuncture. Detailed description of blood sampling 
points is presented in Table 3 below. 

Clinical Study Protocol 
Study code: BCD-089-1 
Translated from Russian to English, dated 06-Jul-2020 
 
 
 
CONFIDENTIAL 
Version: 1.0 of June 1, 2016. 
Page 59 of 128 
 
 
Table 3. Detailed description of blood sampling for PK assessment. 
 
Visit 
Sample labeling 
number 
Blood sampling 
time 
Acceptable window 
for blood sampling 
Blood volume (for 
2 aliquots) 
nnnnnnnn 
nnnnnnnn 
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Clinical Study Protocol 
Study code: BCD-089-1 
Translated from Russian to English, dated 06-Jul-2020 
 
 
 
CONFIDENTIAL 
Version: 1.0 of June 1, 2016. 
Page 60 of 128 
 
Pharmacodynamics and immunogenicity assessment 
 
Pharmacodynamics assessment will be carried out based on data on the concentrations of 
C-reactive protein, soluble IL-6 receptor, human IL-6 in the serum of healthy volunteers.  
Table 4. Detailed description of blood sampling for CRP, sIL-6R, IL-6 testing 
Visit 
Sample labeling 
number 
Blood sampling 
time 
Acceptable 
window for blood 
sampling 
Blood volume (for 
3 types of analyzed 
substances) 
nnnnnnnn 
Nnnnnnnnnnn 
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Clinical Study Protocol 
Study code: BCD-089-1 
Translated from Russian to English, dated 06-Jul-2020 
 
 
 
CONFIDENTIAL 
Version: 1.0 of June 1, 2016. 
Page 61 of 128 
 
Visit 
Sample labeling 
number 
Blood sampling 
time 
Acceptable 
window for blood 
sampling 
Blood volume (for 
3 types of analyzed 
substances) 
nnnnnnnn 
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Clinical Study Protocol 
Study code: BCD-089-1 
Translated from Russian to English, dated 06-Jul-2020 
 
 
 
CONFIDENTIAL 
Version: 1.0 of June 1, 2016. 
Page 62 of 128 
 
Visit 
Sample labeling 
number 
Blood sampling 
time 
Acceptable 
window for blood 
sampling 
Blood volume (for 
3 types of analyzed 
substances) 
Nnnnnnnnnnnnn 
Nnnnnnnnnnnnn 
Nnnnnnnnnnnnnn 
nnnnnnnnnnnnnn 
 

Clinical Study Protocol 
Study code: BCD-089-1 
Translated from Russian to English, dated 06-Jul-2020 
 
 
 
CONFIDENTIAL 
Version: 1.0 of June 1, 2016. 
Page 63 of 128 
 
Additionally, the percentage of occupancy of IL-6 membrane receptors with BCD-089 will 
be determined. Detailed description of blood sampling points is presented in Table 5 below. 
Table 5. Detailed description of blood sampling for IL-6 receptor occupancy assay 
Visit 
Sample labeling 
number 
Blood sampling 
time 
Acceptable 
window for blood 
sampling 
Blood volume  
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Table 6. Detailed description of blood sampling for immunogenicity assessment. 
 
Visit 
Sample labeling 
number 
Blood sampling 
time 
Acceptable 
window for blood 
sampling 
Blood volume (for 
3 aliquots) 
nnnnnnnn 
nnnnnnnn 
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Clinical Study Protocol 
Study code: BCD-089-1 
Translated from Russian to English, dated 06-Jul-2020 
 
 
 
CONFIDENTIAL 
Version: 1.0 of June 1, 2016. 
Page 64 of 128 
 
Reporting: 
The study report will be prepared after receiving data on the results of follow-up of the last 
volunteer included in the study. 
Figure 7. Dose escalation scheme (starting from the cohort “02”). 
 
 
 
 
 
 
 
 
 
 
 
 
3 volunteers - dose 
X group 
DLT in 0 of 3 
DLT in 1 of 3 
DLT in 2–3 of 3 
+ 3 volunteers - 
dose X group 
Stop escalation 
 
Dose escalation 
DLT in ≥2 of 6 
DLT in 1 of 6 
Stop escalation 

Clinical Study Protocol 
Study code: BCD-089-1 
Translated from Russian to English, dated 06-Jul-2020 
 
 
 
CONFIDENTIAL 
Version: 1.0 of June 1, 2016. 
Page 65 of 128 
 
Figure 8. Study flowchart 
 
 
 
 
Day 
Injection of the product 
Group inclusion in 
the study  
End of 
participation 
in the study 
Administration of 
the product 
Per protocol 
examination 
Cohort 04 
BCD-089 – 1.0 mg/kg 
Cohort 05 
BCD-089 – 1.6 
mg/kg 
1                                                                                                                
Cohort 06 
BCD-089 – 2.2 
mg/kg 
Cohort 07 
BCD-089 – 2.9 mg/kg 
Cohort 02 
BCD-089 – 0.3 mg/kg 
Cohort 01 
BCD-089 – 0.06 
/k
Cohort 03 
BCD-089 – 0.625 mg/kg 

Clinical Study Protocol 
Study code: BCD-089-1 
Translated from Russian to English, dated 06-Jul-2020 
 
 
 
CONFIDENTIAL 
Version: 1.0 of June 1, 2016. 
Page 66 of 128 
 
4.3. Description of measures intended to minimize/exclude bias 
4.3.1. The assignment of serial numbers to study sites 
One study site is planned to be involved, and its number will consist of any two digits. 
4.3.2. Assignment of a screening number 
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4.3.3. The inclusion of volunteers in the study, assignment of study numbers 
Randomization is not used in this study.  
Volunteers will be enrolled in the study sequentially according to the cohort principle, 
when the inclusion in each subsequent cohort is made after confirming the safety of the dose of 
BCD-089 used in the previous cohort (a detailed description is presented in Section “Design”). 
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The investigator records the screening number and study site number in the source 
documentation and CRF. 
JSC BIOCAD maintains lists of screening and identification numbers of all volunteers 
enrolled in the study. 

Clinical Study Protocol 
Study code: BCD-089-1 
Translated from Russian to English, dated 06-Jul-2020 
 
 
 
CONFIDENTIAL 
Version: 1.0 of June 1, 2016. 
Page 67 of 128 
 
4.4. Description of doses and dosing regimens of the study drugs Description of the dosage 
form and labeling of the study drugs 
4.4.1. Description of doses and dosing regimens of the study drugs 
Study No. BCD-089-1 includes seven cohorts: 
 
1. 
Cohort 01 - 1 volunteer to whom a single subcutaneous injection of BCD-089 at a dose of 
0.06 mg/kg will be administered. 
2. 
Cohort 02 - a maximum of 6 volunteers to whom a single subcutaneous injection of BCD-
089 at a dose of 0.3 mg/kg will be administered. 
3. 
Cohort 03 - a maximum of 6 volunteers to whom a single subcutaneous injection of BCD-
089 at a dose of 0.625 mg/kg will be administered. 
4. 
Cohort 04 - a maximum of 6 volunteers to whom a single subcutaneous injection of BCD-
089 at a dose of 1.0 mg/kg will be administered. 
5. 
Cohort 05 - a maximum of 6 volunteers to whom a single subcutaneous injection of BCD-
089 at a dose of 1.6 mg/kg will be administered. 
6. 
Cohort 06 - a maximum of 6 volunteers to whom a single subcutaneous injection of BCD-
089 at a dose of 2.2 mg/kg will be administered. 
7. 
Cohort 07 - a maximum of 6 volunteers to whom a single subcutaneous injection of BCD-
089 at a dose of 2.9 mg/kg will be administered. 
A guidance for preparation of the solution for injection and the table of dose calculations 
and administration volumes depending on the volunteer’s body weight are presented in a separate 
manual for performing BCD-089 injections. 
The inclusion of volunteers in the study is sequential. The first to participate in the study 
is one volunteer, representing the cohort “01”, who was administered a single subcutaneous 
injection of BCD-089 at a dose calculated with an additional safety factor relative to the safe 
starting dose - 0.06 mg/kg. In the absence of grade 3-4 adverse events related to the test product, 
developing within the first 7 days after the injection, three volunteers are included in cohort 02. 
Further, the volunteer inclusion algorithm corresponds to the following general principle: 
In the absence of any grade 3-4 AEs (DLT) associated with the test product within 7 days 
after the injection, the next cohort of three volunteers with dose escalation is included in the study 
- cohort 02 (cohort 03, cohort 04, etc.).  

Clinical Study Protocol 
Study code: BCD-089-1 
Translated from Russian to English, dated 06-Jul-2020 
 
 
 
CONFIDENTIAL 
Version: 1.0 of June 1, 2016. 
Page 68 of 128 
 
If grade 3-4 AEs (DLT) associated with the test product are recorded in only one volunteer 
in a cohort of three volunteers, three more healthy volunteers are additionally included in this 
cohort. 
With the development of grade 3-4 AEs (DLT) associated with the test product in two of 
six volunteers, the dose at which this event was recorded will be taken as the maximum tolerated 
dose, further dose escalation will be ceased. 
4.4.2. Description of the dosage form and labeling of the study drugs 
Test drug: BCD-089 (JSC BIOCAD, Russia) 
Pharmaceutical form: solution for injection. 
Composition per mL: 
Active substance: nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn 
Excipients: 
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Manufacturer: JSC BIOCAD, Russia 
 
Packaging: 
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Labeling:  
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Clinical Study Protocol 
Study code: BCD-089-1 
Translated from Russian to English, dated 06-Jul-2020 
 
 
 
CONFIDENTIAL 
Version: 1.0 of June 1, 2016. 
Page 69 of 128 
 
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Composition per mL: 
nnnnnnnnnnnnnnnnnnnnnnnnnn                                    
 
nnnnnnnnn 
nnnnnnnnnnnnnnnnnnnn 
nnnnnnnnnnnnnnnn 
nnnnnnnnnn 
nnnnnnnn 
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nnnnnnnnnnnnnnnnnnnnnnn 
nnnnnnnnnnnnnn 
 
Manufacturer: JSC BIOCAD, Russia 
Shelf life: 2 years. 
Storage 
and 
transportation 
conditions: 
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn. 

Clinical Study Protocol 
Study code: BCD-089-1 
Translated from Russian to English, dated 06-Jul-2020 
 
 
 
CONFIDENTIAL 
Version: 1.0 of June 1, 2016. 
Page 70 of 128 
 
Packaging: 
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnn 
Labeling:  
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
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nnnnnnnnnnnnnnnnnnnnnnnnnnnn 
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnn 
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnn 
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn 

Clinical Study Protocol 
Study code: BCD-089-1 
Translated from Russian to English, dated 06-Jul-2020 
 
 
 
CONFIDENTIAL 
Version: 1.0 of June 1, 2016. 
Page 71 of 128 
 
4.5. Expected duration of study and subject participation in the study 
The estimated duration of the study is 7 months, including volunteers recruitment (up to 2 
months), period of administration of the study drugs and follow-up of study participants, data 
collection and statistical analysis of the results. The expected duration of participation of each 
subject in the study is up to 85 weeks, including the screening period (up to 2 weeks) and the 
active phase of the study (71 days). 
4.6. Description of sequence and duration of all study periods 
4.6.1 Schedule of study visits and procedures 
The schedule of visits and their conduct are similar for the volunteers in all cohorts. A 
14-day screening examination and 13 subsequent visits are planned to be conducted during the 
study. The first day of the study is the day of the first administered of BCD-089. The subsequent 
visits are calculated relative to the first BCD-089 administration. The frequency and timing of the 
study procedures are shown in Table 7. 
Table 7. Listing and frequency of investigations and clinical examinations. 
Study type 
Control parameters 
Frequency 
nnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnn
nnnnnnnnnnn 
• Nnnnnnnnnnnnnnnnnnnnnnnn 
• Nnnnnnnnnnnnnnnnnnnnnnnn 
• nnnnnnnnnnnnnnnnnnnnnnnn 
nnnnnnnnnnnnnnnnnnnn 
nnnnnnnnnnnnnnnnnnn  
• nnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnn 
nnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnn 
nnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnn 
• 
nnnnnnnnnnnnn 
nnnnnnnnnnnnnnn 
nnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnt 
• 
nnnnnnnnnnnnnnn 
nnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnn 

Clinical Study Protocol 
Study code: BCD-089-1 
Translated from Russian to English, dated 06-Jul-2020 
 
 
 
CONFIDENTIAL 
Version: 1.0 of June 1, 2016. 
Page 72 of 128 
 
Study type 
Control parameters 
Frequency 
nnnnnnnnnnnnnnnnnnn
nnnn 
• 
nnnnnnnnnnnnnnnnnnnnnnn 
• 
nnnnnnnnnnnnnnnnnnnnnnnn 
• 
nnnnnnnnnnnnnnnnnnnnnnnn 
• 
nnnnnnnnnnnnnnnnnnnnnnnn 
nnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnn 
nnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnn 
• 
nnnnnnnnnnnnnnnnnnnnn  
nnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnn 
nnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnn 
• 
nnnnnnnnnnnnnnnnnnnnnnnnnn 
nnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnn 
nnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnn 
• 
nnnnnnnnnnnnnnnnnnnnnnnn 
nnnnnnnnnnnnnnnnnnnnn 
nnnnnnnnnnnnnnnnnnn 
• 
nnnnnnnnnnnnnnnnnn 
• 
nnnnnnnnnnnnnnnnnnnnn 
• 
nnnnnnnnnnnnnnnnnnnnnn 
• 
nnnnnnnnnnnnnnnnnnnn 
nnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnn 
nnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnn 
• 
nnnnnnnnnnnnnnnnnnnnnn 
nnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnn 

Clinical Study Protocol 
Study code: BCD-089-1 
Translated from Russian to English, dated 06-Jul-2020 
 
 
 
CONFIDENTIAL 
Version: 1.0 of June 1, 2016. 
Page 73 of 128 
 
Table 8. Listing and frequency of laboratory tests 
Study type 
Control parameters 
Frequency 
Location 
nnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnn
nnnnnnnnnnn 
nnnnnnn: 
• nnnnnnnnnnnnnnn
nnnnnnnnnnnnn 
• nnnnnnnnnnnnnnn
nnnnnnnnnnnnn 
nnnnnnnnnnnn: 
• nnnnnnnn 
nnnnnnnnnnnn: 
• nnnnnnnnnnnnnnn
nnnnnnnnnn: 
nnnnnnnnnnnnnnnnnnnnn 
• nnnnnnnnnnnnnnn
nnnnnnnnnnn 
nnnnnnnnnnnnnnnnn
nnnnnnnnnnnn 
nnnnnnnnnnnnnnn
nnnnnnnnnnnnnnn
nnnnnnnnnnnnnnn 
nnnnnnnnnnnnnnnn
nnnnnnnnnnnnnn 
• nnnnnnnnnnnnnnn
nnnnnnnnnnn 
• nnnnnnnnnnnnnn 
• nnnnnnnnnnnnnnn 
• nnnnnnnnnnnnnnn 
• nnnnnnnnnnnnnnn 
• nnnnnnnnnnnnnnn 
nnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnn 
nnnnnnnnnnnnnnn
nnnnnnnnnnn 
nnnnnnnnnnnnnnnn
nnnnnnnnnnnnnn 
• nnnnnnnnnnnnnnn
nnnnnnnnnnnnnnn 
• nnnnnnnnnnnnnnn
nnnnnnnnnnn 
• nnnnnnnnnnnnnnn
nnnnnnnnnnnnnn 
• nnnnnnnnnnnnnnn
nnnnnnnnn 
• nnnnnnnnnnnnnnn
nnnnnnnnnnnn 
• nnnnnnnnnnnnnnn
nnnnnnnnnnnnnnn 
• nnnnnnnnnnnnnnn
nnnnnnnnnn 
nnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnn 
nnnnnnnnnnnnnnn
nnnnnnnnnnn 
nnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnn 
• nnnnnnnnnnnnnnn
nnnnnnnnnnnn  
nnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnn
nnnnnnnnnn 

Clinical Study Protocol 
Study code: BCD-089-1 
Translated from Russian to English, dated 06-Jul-2020 
 
 
 
CONFIDENTIAL 
Version: 1.0 of June 1, 2016. 
Page 74 of 128 
 
Study type 
Control parameters 
Frequency 
Location 
nnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnn 
nnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnn 
• nnnnnnnnnnnnnnn
nnnnnnnnnnnnnnn
nnnnnnnnnnnnnnn
nnnnnnnnnnnnnn 
nnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnn 
nnnnnnnnnnnnnnn
nnnnnnnnnn 
nnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnn 
• nnnnnnnnnnnnnnn
nnnnnnnnnnnnnnn
nnnnnnnnnnnnnnn 
nnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnn 
nnnnnnnnnnnnnnn
nnnnnnnnnn 
nnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnn 
• nnnnnnnnnnnnnnn
nnnnnnnnnnnnnnn
nnnnnnnnnnnnnn 
nnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnn 
nnnnnnnnnnnnnnn
nnnnnnnnnn 
nnnnnnnnnnnnnnnn 
• nnnnnnnnnnnnnnn 
• nnnnnnnnnnnnnnn
nnnnnnnn 
nnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnn 
nnnnnnnnnnnnnnn
nnnnnnnnnn 
nnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnn
nnnnnnnnnnnnn 
nnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnn
nn 
nnnnnnnnnnnnnnn 
nnnnnnnnnnnnnnn
nnnnnnnnnn 

Clinical Study Protocol 
Study code: BCD-089-1 
Translated from Russian to English, dated 06-Jul-2020 
 
 
 
CONFIDENTIAL 
Version: 1.0 of June 1, 2016. 
Page 75 of 128 
 
Table 9. Study flowchart. 
Visit number 
scre
enin
g 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
Visit 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 8 
Day 
11 
Day 15 
Day 
22 
Day 
29 
Day 
50 
Day 
71 
Day from the first 
injection 
-14 
0 
1 
2 
3 
4 
5 
7 
10 
14 
21 
28 
49 
70 
Signing the Informed 
Consent Form 
+ 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical and 
demographic data 
collection 
+ 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assessment of vital signs 
+ 
+2 
 
 
 
 
 
+ 
 
+ 
+ 
+ 
+ 
+ 
Height measurement 
+ 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body weight 
measurement 
+ 
+ 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
+ 
+ 
 
 
 
 
 
+ 
 
+ 
+ 
+ 
+ 
+ 
Chest photofluorography 
+ 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pain assessment using 
VAS 
 
+ 
+ 
 
 
 
 
 
 
 
 
 
 
 
Complete blood count 
+ 
 
 
 
 
 
 
+ 
 
+ 
 
+ 
 
+ 
NNNNNNNNNNNNNN
NNNNNNNNNNNNNN
NNNNNNNNNNNNN 
N 
N 
N 
N 
N 
N 
N 
N 
N 
N 
N 
N 
N 
N 
nnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnn 
N 
N 
N 
N 
N 
N 
N 
N 
N 
N 
N 
N 
N 
N 
 
2 On day 1, the assessment of vital signs is performed prior to administration of the drug and 1 hour after it. 

Clinical Study Protocol 
Study code: BCD-089-1 
Translated from Russian to English, dated 06-Jul-2020 
 
 
 
CONFIDENTIAL 
Version: 1.0 of June 1, 2016. 
Page 76 of 128 
 
Visit number 
scre
enin
g 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
Visit 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 8 
Day 
11 
Day 15 
Day 
22 
Day 
29 
Day 
50 
Day 
71 
Day from the first 
injection 
-14 
0 
1 
2 
3 
4 
5 
7 
10 
14 
21 
28 
49 
70 
nnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnn 
N 
N 
N 
N 
N 
N 
N 
N 
N 
N 
N 
N 
N 
N 
nnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnn 
N 
N 
N 
N 
N 
N 
N 
N 
N 
N 
N 
N 
N 
N 
Blood chemistry test 
+ 
 
 
 
 
 
 
+ 
 
+ 
 
+ 
 
+ 
Blood tests for infection 
markers 
+ 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
+ 
 
 
 
 
 
 
+ 
 
 
 
 
 
+ 
Alcohol breath test 
+ 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine drug test 
(psychotropic drugs, 
psychoactive 
medications) 
+ 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG 
+ 
 
 
 
 
 
 
+ 
 
 
 
 
 
+ 
Study drug injection 
 
+ 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant therapy 
data collection 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
 
+ 
Recording of injection 
site reactions 
 
+3 
+ 
 
+ 
 
 
+ 
 
+ 
 
+ 
 
+ 
 
3 On Day 1, an assessment of injection site reactions is performed prior to administration of the drug and 8 hour after it. 

Clinical Study Protocol 
Study code: BCD-089-1 
Translated from Russian to English, dated 06-Jul-2020 
 
 
 
CONFIDENTIAL 
Version: 1.0 of June 1, 2016. 
Page 77 of 128 
 
Visit number 
scre
enin
g 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
Visit 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 8 
Day 
11 
Day 15 
Day 
22 
Day 
29 
Day 
50 
Day 
71 
Day from the first 
injection 
-14 
0 
1 
2 
3 
4 
5 
7 
10 
14 
21 
28 
49 
70 
AE/SAE recording 
+4 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
 
4 Only SAEs should be registered at the screening. 

Clinical Study Protocol 
Study code: BCD-089-1 
Translated from Russian to English, dated 06-Jul-2020 
 
 
 
CONFIDENTIAL 
Version: 1.0 of June 1, 2016. 
Page 78 of 128 
 
4.6.2. Description of individual study visits 
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn 
• nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn 
• nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn 
• Nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn  
• Nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn 
• Nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn  
• nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn. 
• nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn 
• nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn 
• Nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn  
• Nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn 
• Nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn  
• nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn. 
• nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn 
• nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn 
• Nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn  
• Nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn 
• Nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn  
• nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn. 
Nnnnnnnnnnnnnnnn 
• nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn 
• nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn 
• Nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn  
• Nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn 
• Nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn  
• nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn. 
• nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn 

Clinical Study Protocol 
Study code: BCD-089-1 
Translated from Russian to English, dated 06-Jul-2020 
 
 
 
CONFIDENTIAL 
Version: 1.0 of June 1, 2016. 
Page 79 of 128 
 
• nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn 
• Nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn  
• Nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn 
• Nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn  
• nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn. 
• nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn 
• nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn 
• Nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn  
• Nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn 
• Nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn 
Nnnnnnnnnnnnnnnnnn 
• nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn. 
• nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn 
• nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn 
• Nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn  
• Nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn 
Nnnnnnnnnnnnnnnnn 
• nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn. 
• nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn 
• nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn 
• Nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn  
Nnnnnnnnnnnnnnnn 
• nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn. 
• nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn 
• nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn 
• Nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn  
• Nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn 

Clinical Study Protocol 
Study code: BCD-089-1 
Translated from Russian to English, dated 06-Jul-2020 
 
 
 
CONFIDENTIAL 
Version: 1.0 of June 1, 2016. 
Page 80 of 128 
 
Nnnnnnnnnnnnnnnnn 
• nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn. 
• nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn 
• nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn 
• Nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn  
nnnnnnnnnnnnnn 
• nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn. 
• nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn 
• nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn 
• Nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn  
Nnnnnnnnnnnnnnnn 
• nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn 
• nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn 
• Nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn  
• Nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn 
• Nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn  
• nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn. 
• nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn 
• nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn 
• Nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn  
• Nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn 
• Nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn  
Nnnnnnnnnnnn 
• nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn. 
• nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn 
• nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn 

Clinical Study Protocol 
Study code: BCD-089-1 
Translated from Russian to English, dated 06-Jul-2020 
 
 
 
CONFIDENTIAL 
Version: 1.0 of June 1, 2016. 
Page 81 of 128 
 
• Nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn  
Nnnnnnnnnnn 
• nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn 
• nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn 
• Nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn  
• Nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn 
• Nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn  
• nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn. 
• nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn 
• nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn 
• Nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn  
Nnnnnnnnnnn 
• nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn 
• nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn 
• Nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn  
• Nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn 
• Nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn 
• nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn 
nnnnnnnnnnnn 
• nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn 
• nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn 
• Nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn  
• Nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn 
• Nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn  
• nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn. 
• nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn 

Clinical Study Protocol 
Study code: BCD-089-1 
Translated from Russian to English, dated 06-Jul-2020 
 
 
 
CONFIDENTIAL 
Version: 1.0 of June 1, 2016. 
Page 82 of 128 
 
nnnnnnnnnnnnnn 
• nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn 
• nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn 
• Nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn  
• Nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn 
• Nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn 
• nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn 
nnnnnnnnnnnnn 
• nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn 
• nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn 
• Nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn  
• Nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn 
• Nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn 
• Nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn 
• nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn 
• nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn 
• Nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn  
• Nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn 
• Nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn 
• Nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn 
• nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn 
4.6.3. Description of individual clinical, laboratory, and imaging assessments 
4.6.3.1. Physical examination 
Physical examination must include the assessment of the following organs and systems:  
− Skin and visible mucous membranes (visual inspection) 
− Lymph nodes (visual inspection, palpation) 
− ENT organs, respiratory system (visual inspection, lung auscultation) 

Clinical Study Protocol 
Study code: BCD-089-1 
Translated from Russian to English, dated 06-Jul-2020 
 
 
 
CONFIDENTIAL 
Version: 1.0 of June 1, 2016. 
Page 83 of 128 
 
− Cardiovascular system (heart auscultation, examination of the area of the major vessels) 
− GI tract assessment (visual inspection, abdomen palpation) 
− Assessment of the liver size (palpation, percussion) 
− Assessment of the spleen size (palpation, percussion) 
− Genitourinary tract assessment (percussion over the area of the kidneys, urinary bladder) 
− Nervous system (meningeal signs, focal neurologic deficits) 
− Mental status examination (signs of depression, suicidal tendencies, acute psychotic 
disorder) 
4.6.3.2. Clinical and demographic data collection, history of drug therapy 
The following data on the volunteer should be recorded at the screening: 
− Date of birth 
− Sex 
− Age 
− Assessment of child-bearing potential (birth control methods use, data on sterilization if 
applicable) 
− Collection of past medical history (infectious diseases, general disorders, surgery etc.) 
− Collection of history of drug therapy: medicinal products that the volunteer had been taking 
within 30 days before the screening specifying the dose, dosing frequency, duration of 
treatment, reasons for discontinuation (if applicable)  
4.6.3.3. Assessment of vital signs 
Vital sign assessment includes measurement of axillary body temperature (in degrees 
Celsius), measurement of blood pressure (on one arm, in mmHg), pulse rate at the wrist. 
4.6.3.4. Complete blood count, blood chemistry, and urinalysis 
Standard complete blood count testing methods shall be used under fasting conditions (8 
hours without food). Test material – venous blood, volume drawn – at least 2 mL. This test includes 
the measurement of the following hematologic parameters: 
− Hemoglobin, g/L 

Clinical Study Protocol 
Study code: BCD-089-1 
Translated from Russian to English, dated 06-Jul-2020 
 
 
 
CONFIDENTIAL 
Version: 1.0 of June 1, 2016. 
Page 84 of 128 
 
− Red blood cells (cells ×1012/L) 
− Platelets (cells ×109/L) 
− White blood cells (cells ×109/L) 
− Neutrophils (cells ×109/L) 
− Lymphocytes (cells ×109/L) 
− Erythrocyte sedimentation rate (mm/h)  
Standard blood chemistry testing methods are used under fasting conditions (8 hours 
without food, including sweet or alcoholic beverages). Test material – venous blood, volume 
drawn – at least 4 mL. The test includes determination of the following parameters: 
− Total protein (g/L) 
− Glucose (mmol/L) 
− ALT (U/L) 
− AST (U/L) 
− Total bilirubin, μmol/L 
− Creatinine, μmol/L 
Standard urinalysis shall be performed with assessment of physical, chemical properties 
and sediment microscopy. 
4.6.3.5. Blood test for infection markers 
HIV tests include the qualitative assessment of type 1 and 2 anti-HIV antibodies (HIV 
Ag/Ab Combo) in blood serum or plasma. 
Screening syphilis tests include an anti-cardiolipin test (RPR-test) in blood serum. 
The presence of hepatitis B infection is assessed based on the results of blood serum or 
plasma HBsAg testing. The presence of hepatitis C infection is assessed based on total anti-HCV 
antibody test results. 
All the investigations above are conducted in accordance with the standard procedure used 
at the study site laboratory or central laboratory. Blood volume needed is 6 mL. 

Clinical Study Protocol 
Study code: BCD-089-1 
Translated from Russian to English, dated 06-Jul-2020 
 
 
 
CONFIDENTIAL 
Version: 1.0 of June 1, 2016. 
Page 85 of 128 
 
4.6.3.6. Determination of BCD-089, IL-6 receptor, C-reactive protein, IL-6 concentrations 
4.6.3.6.1 Determination of BCD-089 concentrations 
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn 
Table 10. Example of a serum sample label for PK studies 
nnnnnnnnnnnnnnnnnn 
nnnnnnn 
nnnnnnnnnnnnnnnnnn 
nnnnnnn 
nnnnnnnnnnnnnnnnnn 
nnnnnnn 
nnnnnnnnnnnnnnnnnn 
nnnnnnn 
nnnnnnnnnnnnnnnnnn 
nnnnnnn 
 
Nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

Clinical Study Protocol 
Study code: BCD-089-1 
Translated from Russian to English, dated 06-Jul-2020 
 
 
 
CONFIDENTIAL 
Version: 1.0 of June 1, 2016. 
Page 86 of 128 
 
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnn  
4.6.3.6.2 Determination of Interleukin-6 concentrations 
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn 

Clinical Study Protocol 
Study code: BCD-089-1 
Translated from Russian to English, dated 06-Jul-2020 
 
 
 
CONFIDENTIAL 
Version: 1.0 of June 1, 2016. 
Page 87 of 128 
 
Table 11. Example of a serum sample label for IL-6 level determination 
nnnnnnnnnnnnnnnnnnnnnn 
nnnn 
nnnnnnnnnnnnnnnnnnnnnn 
nnnn 
nnnnnnnnnnnnnnnnnnnnnn 
nnnn 
nnnnnnnnnnnnnnnnnnnnnn 
nnnn 
nnnnnnnnnnnnnnnnnnnnnn 
nnnn 
Nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnn  

Clinical Study Protocol 
Study code: BCD-089-1 
Translated from Russian to English, dated 06-Jul-2020 
 
 
 
CONFIDENTIAL 
Version: 1.0 of June 1, 2016. 
Page 88 of 128 
 
4.6.3.6.3 C-Reactive protein concentration determination 
Nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn 
Table 12. Example of a serum sample label for PD studies 
nnnnnnnnnnnnnnnnnnn 
nnnnnnnnnnnnnn 
nnnnnnnnnnnnnnnnnnn 
nnnnnnnnnnnnnn 
nnnnnnnnnnnnnnnnnnn 
nnnnnnnnnnnnnn 
nnnnnnnnnnnnnnnnnnn 
nnnnnnnnnnnnnn 
nnnnnnnnnnnnnnnnnnn 
nnnnnnnnnnnnnn 
 
Nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

Clinical Study Protocol 
Study code: BCD-089-1 
Translated from Russian to English, dated 06-Jul-2020 
 
 
 
CONFIDENTIAL 
Version: 1.0 of June 1, 2016. 
Page 89 of 128 
 
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnn  
4.6.3.6.4 Determination of soluble IL-6 receptor concentration 
Nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn 
Table 13. Example of a serum sample label for PD studies 
nnnnnnnnnnnnnnnnnnn 
nnnnnnnnnnnnnn 

Clinical Study Protocol 
Study code: BCD-089-1 
Translated from Russian to English, dated 06-Jul-2020 
 
 
 
CONFIDENTIAL 
Version: 1.0 of June 1, 2016. 
Page 90 of 128 
 
nnnnnnnnnnnnnnnnnnn 
nnnnnnnnnnnnnn 
nnnnnnnnnnnnnnnnnnn 
nnnnnnnnnnnnnn 
nnnnnnnnnnnnnnnnnnn 
nnnnnnnnnnnnnn 
nnnnnnnnnnnnnnnnnnn 
nnnnnnnnnnnnnn 
 
Nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnn  
4.6.3.7. Immunogenicity study 
Nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

Clinical Study Protocol 
Study code: BCD-089-1 
Translated from Russian to English, dated 06-Jul-2020 
 
 
 
CONFIDENTIAL 
Version: 1.0 of June 1, 2016. 
Page 91 of 128 
 
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn 
 
4.6.3.8. Receptor occupancy assay 
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Figure 9. Test tube preparation after blood sampling 
 
 
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4.6.3.9. Chest photofluorography 
Chest photofluorography is performed to exclude lung disorders using the method adopted 
at the study site. If necessary, the Sponsor’s representative may request the scans (if active 
tuberculosis develops during participation in the study). 

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4.6.3.10. Electrocardiography 
Standard 12-lead ECG is performed.  
4.6.3.11. Assessment of injection-related pain by a volunteer  
The tenderness assessment is performed immediately after the injection or on Day 2 and is 
performed by a volunteer independently by filling in a special 10-point visual scale (see below) 
For each injection site (if there were several injections), a separate scale should be filled in to 
assess the pain. 
Figure 10. Point Scale for Pain Assessment 
Instruction: this scale reflects how much pain you have experienced during the drug injection. 
"0" means no pain, "10" - the maximum possible, almost unbearable pain. 
 
4.6.3.12. Assessment of injection site reactions  
Injection site reactions are recorded in a separate Injection Site Reaction Registration Form 
(see Appendix 1). If several injections have been performed, each injection site should be 
evaluated separately. 
 
4.6.3.13. Technique of performing BCD-089 injections 
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Pain description using 
words 
Wong Baker Face 
Scale 

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4.6.3.13. Urine drug test (psychotropic drugs, psychoactive medications) 
It is performed once during screening by immunochromatography (using test strips) and is 
aimed at searching for traces of the use of amphetamine, marijuana, morphine, cocaine (and its 
metabolites), and methamphetamine. If the test results are positive or doubtful for any of the listed 
substances, the volunteer must not be included in the study. 

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4.6.3.14. Alcohol breath test (quantitative) 
The study is performed once at a screening using a certified breathalyzer mentioned in the 
State register of measuring instruments, with a sensitivity range of 0.00-2.50 mg/mL. If the test 
results are positive for any of the listed substances, the volunteer must not be included in the study. 
4.6.3.15. Unscheduled visits 
If adverse events occur, the volunteer may come for an unscheduled visit to conduct 
additional safety tests which should mandatorily include data collection on concomitant 
medication, physical examination, BP, body temperature measurements, complete blood count, 
blood biochemistry, urinalysis, and/or other tests deemed necessary by the Investigator. 
 
4.7. Description of Interruption Rules or Early Withdrawal Criteria for individual subjects, 
study parts, or the study in general 
Volunteers will be excluded from further participation in the study in the following cases: 
1. 
Identification, after the volunteer's inclusion in the study, of gross violations of 
inclusion/non-inclusion criteria (as decided by JSC BIOCAD)5; 
2. 
Patient’s withdrawal of the consent to participate in the study; 
3. 
AEs and SAEs, laboratory abnormalities or concomitant diseases, when, in the 
opinion of the investigator or Sponsor, the continuation of the study treatment is impossible or 
dangerous for the volunteer, or is not in the best interests of the volunteer, or is unsafe; 
4. 
The volunteer misses more than 1 doses of BCD-089 (in this case, the withdrawal 
of such a patient will have to be agreed with representatives of JSC BIOCAD); 
5. 
The patient has a major depressive disorder or suicidal ideation or makes suicidal 
attempts;  
6. 
If the study is terminated by the decision of JSC BIOCAD, local Ethics Committee, 
or regulatory bodies; 
7. 
In case of the use of drugs prohibited by the Protocol; 
 
5Deviations from the eligibility criteria, which are justified by the Investigator and agreed by the Sponsor, are not a 
reason to exclude the patient from the study. 

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8. 
In case of the volunteer’s death. 
The Investigator has to inform JSC BIOCAD about the volunteer’s premature withdrawal 
and the reasons of premature withdrawal within 24 hours. 
If a volunteer is withdrawn from the study, the Study Completion Form in the CRF must 
be completed. Follow-up procedures of prematurely withdrawn patients are described in Section 
5.4. 
See Section 11.5 “Study Termination” below for further details. 
4.8. Drug accountability procedures used in the study  
The Investigator is responsible for study drug accountability. The Investigator must keep 
accurate records of the drugs throughout the study, in compliance with regulatory requirements. 
The Investigator must document the supply of drugs from JSC BIOCAD.  
When the Investigator or a pharmacist receives the drugs, he/she must check the received lot, sign 
and date the form of drug supply and the documentation provided by JSC BIOCAD, and then 
return it to JSC BIOCAD. Copies of these documents must be stored in the Investigator's File. 
The amount of supplied drugs must be recorded in the Drug Accountability Form provided 
by JSC BIOCAD, which then may be used as a balance sheet for the investigational product. 
Accurate accountability records must be made available to the monitor for verification at 
each monitoring visit. Drug accountability records must include: 
• Confirmation of supply to the study site; 
• Inventory at the study site; 
• Use of drugs by each study subject;  
• Return to JSC BIOCAD of unused products. 
Records must also include the date, amount, batch number, lot number and expiry date (if 
applicable). The Investigator must keep records to ensure that: 
• The study participants must be provided with the doses established by the 
Protocol/amendment; 
• All the investigational products supplied by JSC BIOCAD was fully checked, delivered in 
full and undamaged. 
Any unused investigational product must be restricted from use for any other purposes outside this 
study.  

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Study code: BCD-089-1 
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A monitor of JSC BIOCAD will collect drug accountability reports on a regular basis. 
4.8.1.  Handling of products used in the study 
At study sites, the test drug must be stored in a refrigerator at 2 to 8°C in a place that may 
only be accessed by the Principal Investigator, co-investigators and an authorized administrative 
representative of the healthcare facility, who is provided with access according to local rules.  
The product may be stored only at the official study site involved in this study. The 
Investigator must ensure safe product storage, preventing its loss, theft or inappropriate storage 
conditions (temperature) required by the Sponsor and specified in the Investigator’s Brochure. The 
Investigator is required to keep a temperature log. 
4.9. Study numbers storage and unblinding procedure 
The drug will be used in an open-label mode so the unblinding procedure is not envisaged. 
4.10. List of all data recorded directly in the CRF (i.e., without prior written or electronic 
entry) and regarded as source data 
All data that must be recorded in the CRF must be present in the source documents of the 
study site. 
Data that is not subject to registration in the source documents should not be included in 
the CRF. 
5. SELECTION AND EXCLUSION OF STUDY PARTICIPANTS 
5.1. Inclusion criteria 
1. Signed informed consent; 
2. Male; 
3. Age 18 - 45 years inclusive; 
4. Body mass index (BMI) within normal limits (18.5 - 30.0 kg/m2); 
5. A verified diagnosis of "healthy", established according to the medical history, physical 
examination and laboratory data:  

Clinical Study Protocol 
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• absence in the history and at the time of the screening examination of clinically obvious 
impaired function of the cardiovascular, respiratory, nervous, hematopoietic, 
endocrine, gastrointestinal systems, liver and kidneys; 
• absence of history of cardiovascular diseases;  
• complete blood count, blood chemistry, and urinalysis results are within reference 
ranges adopted at the study site; 
• hemodynamic parameters within normal limits: SBP - within 100 - 120 mm Hg., DBP 
- within 60 - 80 mm Hg. Art., heart rate - 50 - 90 bpm; 
• absence of chronic infections (tuberculosis) or history of chronic inflammatory 
diseases; 
• absence of laboratory markers of hepatitis B, C, HIV and syphilis; 
• absence of acute infectious diseases within 4 weeks before inclusion in the study; 
• absence of mental disorders and any other conditions that can affect the ability of the 
participant to follow the requirements of the protocol, including depression; 
• satisfactory well-being (in the opinion of the volunteer) within 30 days before signing 
of the informed consent form; 
6. Absence of evidence of alcohol abuse or drug addiction at the time of inclusion in the study or 
in medical history, as well as negative results at the screening alcohol breath test, together with 
a negative result of the urine drug test; 
7. The ability of the volunteer to follow the Protocol procedures, in the Investigator’s opinion; 
8. The willingness of volunteers and their sexual partners of childbearing potential to use reliable 
methods of contraception, starting 2 weeks before inclusion in the study and throughout the 
study (day of injection and 70 days from the date of its administration). This requirement does 
not apply to participants who underwent surgical sterilization. Reliable methods of 
contraception involve the use of 1 barrier method in combination with one of the following: 
spermicides, intrauterine device/oral contraceptives for the sexual partner; 
9. Willingness not to drink alcohol within 24 hours before the administration of the test product 
and for 8 days after. 
 

Clinical Study Protocol 
Study code: BCD-089-1 
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1.2. Exclusion criteria 
1. 
A history of use of monoclonal antibody products against interleukin-6 or its receptor; 
2. 
Allergy history (anaphylactic shock or multidrug allergy); 
3. 
Known allergy or intolerance to monoclonal antibody drugs (murine, chimeric, humanized, 
or human) or any other components of the study drug. 
4. 
Major surgery less than within 30 days prior to signing the informed consent form; 
5. 
Severe infections (including those that required hospitalization or parenteral 
antimicrobial/antimycotic/antiviral/antiprotozoal treatment) within 6 months before signing the 
ICF; 
6. 
Systemic antimicrobial/antimycotic/antiviral/antiprotozoal treatments within 2 months 
before signing the ICF; 
7. 
More than 4 episodes of respiratory infections within 6 months before signing the informed 
consent form; 
8. 
Impossibility to insert a venous catheter for blood sampling (for example, due to skin 
diseases at venipuncture sites);  
9. 
Diseases or other conditions that can affect the pharmacokinetics of the test product (e.g., 
chronic liver, kidney, blood, cardiovascular, bronchopulmonary and neuroendocrine systems 
disorders (including diabetes mellitus) etc.); 
10. 
A history of fever above 40°С; 
11. 
A history of episodes of elevated hepatic transaminases above 2.5 x ULN; 
12. 
Epileptic seizures, history of seizures; 
13. 
Current depression or a history of depression, suicidal thoughts/attempts at the time of the 
screening examination or a history of such behavior; 
14. 
Regular use of any oral or parenteral medications, including over-the-counter drugs, 
vitamins, and dietary supplements within less than 2 weeks before signing the informed consent;  
15. 
Use of medications, including OTC drugs that have a pronounced effect on hemodynamics, 
liver function, etc. (barbiturates, omeprazole, cimetidine, etc.) within less than 30 days before 
signing the informed consent form; 
16. 
Use of medicinal products that affect the immune status (cytokines and their inducers, 
glucocorticoid hormones, etc.) within less than 2 months prior to signing the informed consent 
form; 

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17. 
Vaccination within 4 weeks prior to signing of informed consent form; 
18. 
Values of standard laboratory tests and investigations results that are beyond the reference 
ranges; 
19. 
Smoking more than 10 cigarettes per day;  
20. 
Consumption of more than 10 units of alcohol per week (1 unit of alcohol is equivalent to 
½ liter of beer, 200 mL of wine or 50 mL of liquor) or a history of alcoholism, drug addiction or 
drug abuse; 
21. 
Donation of 450 mL or more of blood or plasma within 2 months prior to signing of the 
informed consent form; 
22. 
Participation in other clinical studies within less than 2 months before signing the informed 
consent form or simultaneous participation in other clinical studies; 
23. 
Prior participation in this clinical study. 
 
5.3. Exclusion criteria 
Volunteers will be excluded from further participation in the study in the following cases: 
1. Identification, after the volunteer's inclusion in the study, of gross violations of 
inclusion/non-inclusion criteria (as decided by JSC BIOCAD); 
2. Patient’s withdrawal of the consent to participate in the study; 
3. AEs and SAEs, laboratory abnormalities or concomitant diseases, when, in the opinion of 
the investigator or Sponsor, the continuation of the study treatment is impossible or 
dangerous for the volunteer, or is not in the best interests of the volunteer, or is unsafe; 
4. The volunteer misses more than 1 doses of BCD-089 (in this case, the withdrawal of such 
a patient will have to be agreed with representatives of JSC BIOCAD); 
5. The patient has a major depressive disorder or suicidal ideation or makes suicidal 
attempts;  
6. If the study is terminated by the decision of JSC BIOCAD, local Ethics Committee, or 
regulatory bodies; 
7. In case of the use of drugs prohibited by the Protocol; 
8. In case of the volunteer’s death. 

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Study code: BCD-089-1 
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The investigator had to inform JSC BIOCAD about his premature withdrawal and 
the reasons of premature withdrawal within 24 hours. 
 
5.3.1. Substitution of volunteers who withdrew from the study 
The volunteers can be substituted in the following cases: 
1. Volunteers who withdrew the study for reasons not related to administration of the 
study drug (missing visit, withdrawal of consent, systematic violation of visit 
windows, etc.). 
2. Non-compliant volunteers (see Section 6.6). 
Volunteers who withdrew from the study after administration of the study drug for safety 
reasons (AE that did not allow to come to a visit to perform the Protocol procedures) will not be 
replaced. 
5.4. Follow-up of subjects who withdrew from the study  
Follow-up of volunteers who received at least one dose of the drug 
In case of early withdrawal of a volunteer after administration of the study drug, it is 
required to conduct an “Early Withdrawal Visit” and fill out an “Early Withdrawal Form”.  
If a patient is discontinued from the study due to an AE/SAE, the Investigator should 
continue his/her management and follow-up after the “Early Withdrawal Visit” in accordance with 
the standard practices used at the study site for AE/SAE treatment. The volunteer will be followed 
up until full resolution of the AE or SAE.  
6. USE OF THE TEST DRUG  
6.1.  Dosing regimen tested  
Study No. BCD-089-1 includes seven cohorts: 
 
1. 
Cohort 01 - 1 volunteer to whom a single subcutaneous injection of BCD-089 at a dose of 
0.06 mg/kg will be administered. 

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2. 
Cohort 02 - a maximum of 6 volunteers to whom a single subcutaneous injection of BCD-
089 at a dose of 0.3 mg/kg will be administered. 
3. 
Cohort 03 - a maximum of 6 volunteers to whom a single subcutaneous injection of BCD-
089 at a dose of 0.625 mg/kg will be administered. 
4. 
Cohort 04 - a maximum of 6 volunteers to whom a single subcutaneous injection of BCD-
089 at a dose of 1.0 mg/kg will be administered. 
5. 
Cohort 05 - a maximum of 6 volunteers to whom a single subcutaneous injection of BCD-
089 at a dose of 1.6 mg/kg will be administered. 
6. 
Cohort 06 - a maximum of 6 volunteers to whom a single subcutaneous injection of BCD-
089 at a dose of 2.2 mg/kg will be administered. 
7. 
Cohort 07 - a maximum of 6 volunteers to whom a single subcutaneous injection of BCD-
089 at a dose of 2.9 mg/kg will be administered. 
 
The inclusion of volunteers in the study is sequential. The first to participate in the study is 
one volunteer, representing the cohort “01”, who is administered a single subcutaneous injection 
of the estimated maximum safe dose of BCD-089 - 0.06 mg/kg. In the absence of grade 3-4 adverse 
events related to the test product, developing within the first 7 days after the injection, three 
volunteers are included in cohort 02. Further, the volunteer inclusion algorithm corresponds to the 
following general principle: 
In the absence of any grade 3-4 AEs (DLT) associated with the test product within 7 days 
after the injection, the next cohort of three volunteers with dose escalation is included in the study 
- cohort 02 (cohort 03, cohort 04, etc.).  
If grade 3-4 AEs (DLT) associated with the test product were recorded in only one 
volunteer in a cohort of three volunteers, three more healthy volunteers will be additionally 
included in this cohort. 
With the development of grade 3-4 AEs (DLT) associated with the test product in two of 
six volunteers, the dose at which this event was recorded will be taken as the maximum tolerated 
dose, further dose escalation will be ceased. 
6.2. Investigational product dose correction 
Not planned.  

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6.3. Overdose 
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6.4. Concomitant therapy, allowed and prohibited medications 
In the course of the study, the volunteers must not use any additional medicinal products 
(besides those specified in the study design). 
In this study, there are no specific restrictions on medications for intercurrent diseases and 
conditions that a volunteer might have during the study period. In case of disorders that occur 
during the study, the volunteers can receive full supportive care in accordance with standard 
guidelines. 
6.5. Methods of monitoring adherence to study procedures 
Information about drug administration, doses, and between-visit intervals will be 
documented during the study.  
Clinical Studies Specialist will review the accountability documents during monitoring 
visits and at the end of the study. 
6.6. Compliance assessment 
In this clinical study, any volunteer is considered to be non-compliant if he: 
− Missed more than one visit; 
− Deviated from the scheduled window for more than one visit; 
− Missed sampling of more than 2 blood samples for evaluation of pharmacokinetics and 
pharmacodynamics; 
− Deviated from the scheduled window for pharmacokinetic and pharmacodynamic 
sampling by a time exceeding the acceptable deviation described in Tables 3 and 4. 

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7. PHARMACOKINETICS AND PHARMACODYNAMICS ASSESSMENT  
7.1 List of pharmacokinetic variables 
To evaluate PK parameters of the drugs based on the data obtained on the concentration of 
anti-IL-6 receptor monoclonal antibody in the blood of volunteers, the following pharmacokinetic 
parameters will be calculated: the area under the "concentration-time" curve (AUC from the 
moment of administration of the drug to 1680 h (71 days after administration) and AUC0 - ∞ (to 
infinity), the maximum concentration of anti-IL-6 receptor monoclonal antibody in human serum, 
Cmax, time to reach the maximum concentration, Tmax, half-life, T½, the elimination constant Kel 
and total clearance, CL, after a single-dose subcutaneous injection of the test drug. The values of 
the Cmax and Tmax will be calculated as the highest of the measured concentration values and the 
corresponding time of the observed maximum. The AUC (0-t) will be calculated using the 
logarithmic trapezoid method. The value of AUC(0 -∞) will be determined by the formula: AUC(0 -
∞) = AUCt+CT/kel, where AUCt is the area under the "concentration-time" curve from the moment 
of drug administration to the last measured BCD-089 concentration (in this study it is AUC (0-
1680h)), Ct and Kel are the calculated values of the drug concentration in the last sample (in this 
study – C1680h) and the elimination constants, respectively. To calculate Ct and Kel, the final 
(monoexponential) section of the pharmacokinetic curve is described using nonlinear regression 
analysis. 
Thus, the main PK parameters evaluated will include: 
Primary: 
 AUC0-1680 - area under the concentration-time curve from the administration of the drug to 
1680 h (71 days after administration) and AUC0-∞ (to infinity). 
Secondary: 
 Cmax (maximum serum concentration of anti-IL-6 receptor antibody); 
 Tmax (time to maximum concentration); 
 Т½ (half-life), 
 Kel (elimination rate constant), 
 CL (total clearance). 

Clinical Study Protocol 
Study code: BCD-089-1 
Translated from Russian to English, dated 06-Jul-2020 
 
 
 
CONFIDENTIAL 
Version: 1.0 of June 1, 2016. 
Page 105 of 128 
 
7.2 List of pharmacodynamical parameters 
To evaluate PD parameters of the drugs based on the data obtained on the concentration of 
soluble IL-6 receptor, as well as CRP level in the blood of volunteers, the following 
pharmacokinetic parameters will be calculated: the area under the "concentration-time" curve 
(AUC from the moment of administration of the drug to 1680 h (71 days after administration) and 
AUC0 - ∞ (to infinity), the maximum concentrations of the aforementioned markers in human 
serum, Cmax, time to achieve maximum concentration, Тmax (Cmin  and  Тmin for C-reactive protein) 
following a single-dose subcutaneous administration of the test drug. The values of the Cmax and 
Tmax will be calculated as the highest of the measured concentration values and the corresponding 
time of the observed maximum. The values of the Cmin and Тmin will be calculated as the lowest of 
the measured concentration values and the corresponding time of the observed minimum. The 
AUC (0-t) will be calculated using the logarithmic trapezoid method. The value of AUC(0 -∞) will be 
determined by the formula: AUC(0 -∞) = AUCt+CT/kel, where AUCt is the area under the 
"concentration-time" curve from the moment of drug administration to the last measured CRP, IL-
6 and sIL-6R concentrations (in this study it is AUC (0-1680h)), Ct and Kel are the calculated 
values of the drug concentration in the last sample (in this study – C1680h) and the elimination 
constants, respectively. To calculate Ct and Kel, the final (monoexponential) section of the 
pharmacokinetic curve is described using nonlinear regression analysis. 
Thus, the main PD parameters evaluated will include: 
1. 
C-reactive protein concentration determination: 
Primary: 
 AUC0-1680 (area under the concentration-time curve from the administration of the drug to 
1680 h (71 days after administration) and AUC0-∞ (to infinity). 
 
Secondary: 
 Cmin (minimum detectable concentration in blood serum), 
 Тmin (time to minimum serum concentration). 
 
2. 
Determination of IL-6 concentration, soluble IL-6 receptor concentration: 
Primary: 

Clinical Study Protocol 
Study code: BCD-089-1 
Translated from Russian to English, dated 06-Jul-2020 
 
 
 
CONFIDENTIAL 
Version: 1.0 of June 1, 2016. 
Page 106 of 128 
 
 AUC0-1680 (area under the concentration-time curve from the administration of the drug to 
1680 h (71 days after administration) and AUC0-∞ (to infinity). 
Secondary: 
 Cmax (maximum concentration in serum), 
 Tmax (time to maximum serum concentration). 
Based on the results of flow cytometry, the following parameters will be calculated (a pilot 
study, it is not the endpoint) 
 Percentage of occupancy of IL-6 receptors with BCD-089 2 hours after drug 
administration, as well as in 168, 336 and 504 hours. 
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8. SAFETY ASSESSMENT  
List of safety parameters  
To assess the safety of the study therapy, the following parameters (secondary endpoints) 
will be used: 
 Proportion of subjects who developed SAEs in each cohort.  
 Proportion of subjects who developed AEs in each cohort.  
 Proportion of subjects who developed injection site reactions in each cohort.  
 Proportion of subjects who developed grade 3-4 AEs in each cohort. 
 Proportion of subjects who developed any grade neutropenia in each cohort. 
 Proportion of subjects who discontinued the study due to AEs and SAEs in each cohort. 

Clinical Study Protocol 
Study code: BCD-089-1 
Translated from Russian to English, dated 06-Jul-2020 
 
 
 
CONFIDENTIAL 
Version: 1.0 of June 1, 2016. 
Page 107 of 128 
 
8.2 Definitions 
8.2.1 Adverse Events  
Adverse event (AE): Any untoward medical event occurring in a participant of a clinical 
study after the administration of a medicinal product, which can have no causal relationship with 
the administration of the drug. 
An AE is any untoward and unintended sign (including an abnormal laboratory finding), 
symptom, or disease, the time of occurrence of which does not exclude a causal relationship with 
the use of the drug, regardless of whether it is related or not, from the start of the study drug 
administration until day 28 inclusive after withdrawal of the volunteer from the clinical study. 
As part of this study, the Investigator had to register all AEs, starting from grade 1 
according to the classification, regardless of their clinical significance. 
8.2.2 Serious adverse events 
Serious adverse event (SAE) is any untoward medical event, regardless of the dose of the 
drug: 
• Results in death; 
• is life-threatening; 
• requires hospitalization or prolongation of existing hospitalization; 
• results in persistent or significant disability/incapacity; 
• is a congenital anomaly or birth defect. 
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Clinical Study Protocol 
Study code: BCD-089-1 
Translated from Russian to English, dated 06-Jul-2020 
 
 
 
CONFIDENTIAL 
Version: 1.0 of June 1, 2016. 
Page 108 of 128 
 
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8.3 Methods and timeframes for the assessment, recording, and analysis of safety parameters 
8.3.1 Timeframes for the assessment of safety parameters 
Information about serious adverse events will include data on SAEs occurring from the 
moment of signing the ICF and until the patient stops participating in the study (as planned or 
prematurely). Information about AEs not meeting the seriousness criteria will be registered from 
the first administration of the drug and until the volunteer stops participating in the study (as 
planned or prematurely). 
Information about all SAEs will be reviewed immediately starting from the submission of 
SAE report to the Drug Safety Division of JSC BIOCAD (provided timely notification of the 

Clinical Study Protocol 
Study code: BCD-089-1 
Translated from Russian to English, dated 06-Jul-2020 
 
 
 
CONFIDENTIAL 
Version: 1.0 of June 1, 2016. 
Page 109 of 128 
 
Investigator in case of SAEs). A pooled analysis of SAEs will be carried out during the preparation 
of the final study report.  
AEs not meeting the seriousness criteria will be analyzed routinely during the preparation 
of the final study report. 
8.3.2 Methods and timeframes for the assessment and registration of safety parameters 
Safety analysis will include all volunteers who received the test drug. Cases of SAEs that 
developed before the test drug administration should also be analyzed. 
Safety analysis will be based on: 
- data on reported AEs and SAEs; 
- physical examination data and vital signs assessment; 
- complete blood count, blood chemistry, and urinalysis results; 
- electrocardiography results; 
- data on cases of injection site reactions. 
The frequency of these procedures throughout the study is described in Section 4.6.1 “The 
schedule of study visits and procedures”. AE/SAE are registered according to the guidance 
provided by the Sponsor. 
The Investigator is responsible for registering the adverse events reported in clinical 
studies. 
AE are registered from the moment of signing the informed consent form and until the 
volunteer completes his participation in the study (as planned or prematurely). SAEs are registered 
from the moment of signing the informed consent and until the patient stops participating in the 
study (as planned or prematurely) as well as for a longer period after the last dosing, if the 
Investigator believes that this SAE is associated with the use of the drug or any study procedures.  
Adverse events (AEs) that do not meet the seriousness criteria are registered by the 
Investigator in source documents and in the CRF and the records are provided to the clinical study 
monitor at the next scheduled monitoring visit for evaluation. Serious adverse events (SAEs) must 
be 
promptly 
reported 
to 
the 
Sponsor, 
within 
24 
hours. 
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Clinical Study Protocol 
Study code: BCD-089-1 
Translated from Russian to English, dated 06-Jul-2020 
 
 
 
CONFIDENTIAL 
Version: 1.0 of June 1, 2016. 
Page 110 of 128 
 
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8.4 Requirements for reports, AE registration and reporting procedures, and AE Reporting 
Form completion 
8.4.1 AE/SAE registration 
Presence or absence of adverse events during the period from the last visit is evaluated at 
each visit. Any serious adverse event observed in a volunteer from signing the informed consent 
form should be registered in source documents and in the dedicated Adverse Event Reporting Form 
(in eCRF).  
Adverse events are registered and numbered consecutively, as they occur. Each AE is 
reported using the AE Reporting Form. The rules for AE/SAE reporting are described in detail in 
the Guidance provided by the Sponsor. 
Adverse events are registered regardless of seriousness or causal relationship with study 
therapy. All AEs are subject to recording in the study, including Grade 1 AEs (CTCAE 
v.4.03). If the same adverse event reoccurs (after the previous case resolved), it should be 
registered as a new adverse event, with a separate number. 
8.4.2 AE/SAE Reporting Form completion 
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Clinical Study Protocol 
Study code: BCD-089-1 
Translated from Russian to English, dated 06-Jul-2020 
 
 
 
CONFIDENTIAL 
Version: 1.0 of June 1, 2016. 
Page 111 of 128 
 
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Clinical Study Protocol 
Study code: BCD-089-1 
Translated from Russian to English, dated 06-Jul-2020 
 
 
 
CONFIDENTIAL 
Version: 1.0 of June 1, 2016. 
Page 112 of 128 
 
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Clinical Study Protocol 
Study code: BCD-089-1 
Translated from Russian to English, dated 06-Jul-2020 
 
 
 
CONFIDENTIAL 
Version: 1.0 of June 1, 2016. 
Page 113 of 128 
 
Information about the method and duration of subjects’ follow-up after an AE/SAE 
If a volunteer is discontinued from the study due to an AE/SAE, the Investigator should 
continue his/her management and follow-up in accordance with the standard practices used at the 
study site for AE/SAE treatment. The volunteer will be followed up until full resolution of the AE 
or SAE. See Section 5.4 for further details. 
9. STATISTICAL METHODS 
9.1 Calculation of the parameters of pharmacokinetics and pharmacodynamics 
9.1.1. Pharmacokinetic parameters 
Based on the calculated concentration values for the anti-IL-6 monoclonal antibody in the 
blood of each volunteer, the following pharmacokinetic variables will be estimated at time points 
specified in this protocol: 
1. Cmax - maximum serum concentration of anti-IL-6 receptor antibody over the 
observation period.  
2. tmax - time to achieve maximum serum concentration (Cmax) of anti-IL-6 
receptor antibody. 
3. AUC0-1680 –- the area under the concentration of anti-IL-6 receptor monoclonal 
antibody-time curve over the time interval from 0 to 1680 hours. AUC0-1680 will 
be calculated using the trapezoid method using the following formula, where 
Cp is the concentration of the drug BCD-089 in the blood at the time tp in hours: 
 
 𝑡𝑡𝑝𝑝∈{0; 2; 8; 12; 24; 48; 72; 96; 120; 168; 240; 336; 504; 672; 1176; 1680 }p=1,…,16 
4. AUMC0-1680 - total area under the curve of the concentration of anti-IL-6 
receptor monoclonal antibody multiplied by time over the time interval from 0 
to 1680 hours. AUMC0-1680 will be calculated using the following formula: 
𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴0−1680 = ෍൫𝐶𝐶𝑝𝑝∗𝑡𝑡𝑝𝑝+ 𝐶𝐶𝑝𝑝−1 ∗𝑡𝑡𝑝𝑝−1൯∗൫𝑡𝑡𝑝𝑝−𝑡𝑡𝑝𝑝−1൯
2
16
𝑝𝑝=2
, 
 𝑤𝑤ℎ𝑒𝑒𝑒𝑒𝑒𝑒 𝐶𝐶𝑝𝑝− 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐 of anti −IL −6
−receptor monoclonal antibody против рецептора ИЛ6  

Clinical Study Protocol 
Study code: BCD-089-1 
Translated from Russian to English, dated 06-Jul-2020 
 
 
 
CONFIDENTIAL 
Version: 1.0 of June 1, 2016. 
Page 114 of 128 
 
𝑖𝑖𝑖𝑖 𝑡𝑡ℎ𝑒𝑒 𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏 𝑎𝑎𝑎𝑎 𝑡𝑡𝑝𝑝 
 𝑡𝑡𝑝𝑝∈{0; 2; 8; 12; 24; 48; 72; 96; 120; 168; 240; 336; 504; 672; 1176; 1680 }p=1,…,16 
 
5. Total clearance (Cl) is a parameter that reflects the volume of test tissue, which 
is cleared from the anti-IL-6 receptor monoclonal antibody per unit of time and 
is determined by the ratio of the anti-IL-6 receptor monoclonal antibody dose 
(DOSE) to AUC(0-1680): 
𝐶𝐶𝐶𝐶=
𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷
𝐴𝐴𝐴𝐴𝐴𝐴0−1680  
6. Mean residence time (MRT) of the anti-IL-6 receptor monoclonal antibody 
molecule in the body will be calculated as the ratio of AUMC0-1680 to AUC0-1680: 
MRT = AUMC0−1680
AUC0−1680
 
7. Elimination constant of the anti-IL-6 receptor monoclonal antibody (kel) will 
be determined using the following formula: 
𝑘𝑘𝑒𝑒𝑒𝑒=
1
𝑀𝑀𝑀𝑀𝑀𝑀   
8. Half-life period of the anti-IL-6 receptor monoclonal antibody (T1/2) will be 
determined using the following formula: 
 𝑇𝑇1/2 = ln (2)
𝑘𝑘𝑒𝑒𝑒𝑒
= ln(2) ∗𝑀𝑀𝑀𝑀𝑀𝑀 
9. The area under the concentration-time curve for anti-IL-6 receptor 
monoclonal antibody over the time interval from 0 to ∞ (AUC0-∞). 
𝐴𝐴𝐴𝐴𝐴𝐴𝟎𝟎−∞= 𝐴𝐴𝐴𝐴𝐴𝐴0−1680 +
𝐶𝐶𝟏𝟏𝟏𝟏𝟏𝟏𝟏𝟏
𝑘𝑘𝒆𝒆𝒆𝒆, where 

Clinical Study Protocol 
Study code: BCD-089-1 
Translated from Russian to English, dated 06-Jul-2020 
 
 
 
CONFIDENTIAL 
Version: 1.0 of June 1, 2016. 
Page 115 of 128 
 
C1680 – concentration of anti-IL-6 receptor antibody over the period equal to 1680 hours after the 
drug administration. 
9.1.2. Pharmacodynamical parameters 
Based on the obtained concentrations of C-reactive protein, IL-6 and soluble IL-6 
receptor in the blood of each volunteer, the following pharmacodynamic parameters will be 
calculated at the Protocol-specified time intervals: 
1. 
Cmax – maximum blood concentration of C-reactive protein, IL-6 and soluble IL-6 
receptor over the observation period.  
2. 
tmax – time to maximum blood concentration (Cmax) of C-reactive protein, IL-6 and 
soluble IL-6 receptor. 
3. 
AUC0-1680 – the area under the concentration-time curve for C-reactive protein, IL-
6 and soluble IL-6 receptor over the time interval from 0 to 1680 hours. AUC0-1680 
is calculated using the trapezoidal method with the following formula: 
𝐴𝐴𝐴𝐴𝐴𝐴0−1680 = ෍൫𝐶𝐶𝑝𝑝+ 𝐶𝐶𝑝𝑝−1൯∗൫𝑡𝑡𝑝𝑝−𝑡𝑡𝑝𝑝−1൯
2
16
𝑝𝑝=2
, 
  
𝑤𝑤ℎ𝑒𝑒𝑒𝑒𝑒𝑒 𝐶𝐶𝑝𝑝 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐 of C −reactive protein, IL −6 and soluble IL
−6 receptor values  
ИЛ6 𝑖𝑖𝑖𝑖 𝑡𝑡ℎ𝑒𝑒 𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏 𝑎𝑎𝑎𝑎 𝑡𝑡 𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚 𝑜𝑜𝑜𝑜 𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡 𝑡𝑡𝑝𝑝 (ℎ𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜), 
 𝑡𝑡𝑝𝑝∈{0; 2; 8; 12; 24; 48; 72; 96; 120; 168;240; 336; 504;672; 1176; 1680 }p=1,…,16 
4. Cmin – minimum blood concentration of C-reactive protein, IL-6 and soluble IL-6 
receptor over the observation period.  
5. tmin – time to minimum blood concentration (Cmin) of C-reactive protein, IL-6 and 
soluble IL-6 receptor. 
9.2 Statistical analysis methods 
The study results will be analyzed using the two-sided statistical hypotheses with a 
significance level of 0.05. 

Clinical Study Protocol 
Study code: BCD-089-1 
Translated from Russian to English, dated 06-Jul-2020 
 
 
 
CONFIDENTIAL 
Version: 1.0 of June 1, 2016. 
Page 116 of 128 
 
Quantitative and scale data 
To describe quantitative and scale variables, it is planned to use the following 
characteristics: mean, median, standard deviation, quartiles, minimum and maximum, and 
coefficient of variance.  
The statistical analysis of the obtained data will be conducted using SAS 10.0 software 
and the R programming language for statistical data processing. Mann-Whitney, Wilcoxon, 
Kruskal-Wallis, and Friedman tests will be used to compare quantitative and scaled data.  The 
categorical data will be processed using the Fisher’s exact test and the χ2 Pearson test.   
Quantitative data include the following parameters: 
• 
Membrane receptor occupancy with BCD-089 
Pharmacokinetics: 
• 
Anti-human 
interleukin-6 
receptor 
monoclonal 
antibody 
concentration 
• 
Area under the curve 
• 
Time (including time to maximum concentration, half-life period) 
• 
Elimination characteristics (clearance, elimination constant) 
Pharmacodynamics: 
• 
Human 
IlL-6, 
C-Reactive 
Protein, 
soluble 
IL-6 
receptor 
concentrations 
• 
Area under the curve 
• 
Time (including time to maximum concentration, trough 
concentration, time to achieve trough concentration) 
Elimination characteristics (clearance, elimination constant) 
Tenderness: 
Value specified in Visual Analogue Scale (out of 10 points) 
Safety: 
• 
Complete blood count parameters 
• 
Blood biochemistry parameters 
• 
ECG parameters 
• 
Urinalysis parameters 

Clinical Study Protocol 
Study code: BCD-089-1 
Translated from Russian to English, dated 06-Jul-2020 
 
 
 
CONFIDENTIAL 
Version: 1.0 of June 1, 2016. 
Page 117 of 128 
 
• 
Blood pressure, wrist pulse rate and body temperature 
• 
Size of an abnormal lesion at the injection site reactions 
• 
Time of presence of the abnormal lesion at the injection site 
Categorical data include the following parameters: 
Pharmacodynamics: 
• Proportion of samples showing the maximum signal for membrane IL-6 receptor 
occupancy 
Safety: 
• 
Nature of an abnormal lesion at the injection site 
• 
Frequency of AEs and SAEs by severity grades  
• 
Frequency of grade 3/4 toxicity events 
• 
Frequency of injection-site reactions (total and depending on the 
type of the lesion) 
• 
Proportion of subjects who developed any grade neutropenia in each 
cohort. 
• 
Frequency of cases of premature discontinuation from the study due 
to an AE/SAE 
 During the analysis, the list of methods used may be extended, if necessary for a high-
quality data processing.   
9.2. Rationale for the study sample size, including reasoning or calculations to support the 
statistical power and clinical validity of the study 
The calculation of the study sample size was based on the "3 + 3” design and dose levels 
used in the study. 
Volunteers cohort 
Dose, mg/kg 
Number of 
mandatory included 
volunteers 
Number of volunteers that 
can be included in case of 
DLT development 
01 
0.06 
1 
0 
02 
0.3 
3 
3 
03 
0.625 
3 
3 

Clinical Study Protocol 
Study code: BCD-089-1 
Translated from Russian to English, dated 06-Jul-2020 
 
 
 
CONFIDENTIAL 
Version: 1.0 of June 1, 2016. 
Page 118 of 128 
 
Volunteers cohort 
Dose, mg/kg 
Number of 
mandatory included 
volunteers 
Number of volunteers that 
can be included in case of 
DLT development 
04 
1.0 
3 
3 
05 
1.6 
3 
3 
06 
2.2 
3 
3 
07 
2.9 
3 
3 
9.3. Statistical analysis stages and timeline for reports 
The analysis of the results in this clinical trial will be performed upon receipt of all the data 
planned by the Protocol of the last volunteer included in the study.  
9.4. Criteria for study termination 
JSC BIOCAD may temporary or permanently stop the study due to issues related to safety, 
ethics, adherence to protocol, or other reasons. If necessary, JSC BIOCAD will undertake the 
necessary measures to inform the study site in advance. If the study is temporary or permanently 
closed, JSC BIOCAD and the Investigator must inform the Ethics Committees and regulatory 
authorities. In such cases, all study-related data must be submitted to JSC BIOCAD and all unused 
study drugs must be returned. 
9.5. Management of missing, non-evaluable, and uncertain data  
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Clinical Study Protocol 
Study code: BCD-089-1 
Translated from Russian to English, dated 06-Jul-2020 
 
 
 
CONFIDENTIAL 
Version: 1.0 of June 1, 2016. 
Page 119 of 128 
 
9.6. Procedures for reporting any deviations from the initial statistical plan 
If the initial clinical study plan must be changed, modifications will be described and 
explained in the protocol amendment or Interim/Final clinical study report. 
9.7 Patient selection for analysis 
Demographic data and baseline clinical and laboratory characteristics will be evaluated in 
all volunteers included in the study.  
Safety analysis 
Safety analysis will include all volunteers who received the test drug. 
Pharmacokinetic analysis 
Pharmacokinetics analysis will include data from volunteers who have received BCD-
089 and have had no more than two missing/lost/damaged blood serum samples for 
pharmacokinetics and had no more than two consecutive missing/lost/damaged samples and for 
whom a serum sample obtained before the test drug administration is available for the analysis. 
Pharmacodynamic analysis 
Pharmacodynamics analysis will include data from volunteers who have received BCD-
089 and have had no more than two missing/lost/damaged of whole blood and/or blood serum for 
pharmacodynamics studies, and for whom a serum sample obtained before the test drug 
administration is available for the analysis. 
Immunogenicity analysis 
Immunogenicity analysis will include data from volunteers who have received BCD-089 
and have not had missing/lost/damaged serum samples taken on Days 1 and 71 of the study. 
10. DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
The Investigator or the organization involved in the study must allow direct access to the 
source data/documents for study-related monitoring, auditing, ethical expertise, and inspection 
carried out by authorized agencies. 

Clinical Study Protocol 
Study code: BCD-089-1 
Translated from Russian to English, dated 06-Jul-2020 
 
 
 
CONFIDENTIAL 
Version: 1.0 of June 1, 2016. 
Page 120 of 128 
 
11. QUALITY CONTROL AND QUALITY ASSURANCE OF THE STUDY CONDUCT 
11.1. Quality guarantees 
In accordance with ICH GCP and regulatory requirements, the Sponsor, third parties on its 
behalf, regulatory authorities or Ethics Committees can conduct audits (inspections) to ensure 
quality at any time during the study or after the end of the study. The Investigator must provide 
the auditors direct access to all study-related documents, including source documents, and allocate 
his/her time and time of his/her team to discuss with auditors the results of audits and inspections, 
as well as other issues. 
11.2. Investigator’s adherence to protocol 
No deviations from the Protocol are allowed during the study without prior written 
permission from JSC BIOCAD, except when necessary to prevent any immediate danger to the 
volunteer.  
Protocol deviation is any change, discrepancy, or deviation from the study design or 
procedures of the study Protocol. 
Any protocol deviation in the course of the clinical study must be registered and reflected in 
the study documents.  
All protocol deviations are classified as major or minor deviations. 
A minor deviation from the Protocol is an unforeseen and unintended event that occurred 
during the study and contradicts the requirements of the Protocol, which does not significantly 
affect the rights, safety and well-being of the volunteer or the consistency, accuracy and reliability 
of the study data. 
A major deviation from the Protocol (or a protocol violation) is a deviation that may affect 
the rights, safety of a volunteer or the consistency, accuracy, and reliability of the study data.  
Examples of probable major protocol deviations: 
− 
A volunteer met study exclusion criteria but was not excluded;  
− 
A volunteer received a prohibited concomitant medication; 
− 
A volunteer was included in the study without meeting the eligibility criteria; 
− 
Study procedures were conducted without obtaining a written informed consent 
from a volunteer; 

Clinical Study Protocol 
Study code: BCD-089-1 
Translated from Russian to English, dated 06-Jul-2020 
 
 
 
CONFIDENTIAL 
Version: 1.0 of June 1, 2016. 
Page 121 of 128 
 
− 
Volunteer’s indiscipline, non-compliance with restrictions during participation in 
the study (taking alcohol, drugs); 
− 
Errors in selection of doses/route of administration/drug storage; 
− 
Protocol violations that may be considered by the clinical trial monitor or study 
coordinator to have an impact on the safety of participants or the consistency and reliability 
of the study data; 
− 
Missing two or more of the scheduled blood samples for analysis of 
pharmacokinetics/pharmacodynamics; 
− 
Any violation of the confidentiality of information about study participants. 
Information about major deviations should be presented to the Sponsor and the local ethics 
committee. In case of any major protocol deviations, the volunteer must be excluded from the final 
PK/PD data analysis. 
The Investigator must have enough time to conduct the study correctly and complete the 
study within the timeline agreed with JSC BIOCAD, and also have a sufficient number of qualified 
team members and adequate equipment to perform the procedures specified in this Protocol. 
Each co-investigator involved in the study must be familiarized with the Protocol 
requirements and his/her responsibilities in the study. Delegation by the Principal Investigator of 
any of his/her responsibilities within this study must be documented in written form in the relevant 
section of the Investigator's File. 
 
11.3. The Investigator’s responsibility for Protocol adherence 
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Clinical Study Protocol 
Study code: BCD-089-1 
Translated from Russian to English, dated 06-Jul-2020 
 
 
 
CONFIDENTIAL 
Version: 1.0 of June 1, 2016. 
Page 122 of 128 
 
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11.4. Study monitoring 
The monitoring procedures for this study are established in accordance to Standard 
Operation Procedure of JSC BIOCAD.  
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11.5. Study termination  
JSC BIOCAD may temporary or permanently stop the study due to issues related to safety, 
ethics, adherence to protocol, or other reasons. If necessary, JSC BIOCAD will undertake the 
necessary measures to inform the study site in advance. If the study is temporary or permanently 
closed, JSC BIOCAD and the Investigator must inform the Ethics Committees and regulatory 

Clinical Study Protocol 
Study code: BCD-089-1 
Translated from Russian to English, dated 06-Jul-2020 
 
 
 
CONFIDENTIAL 
Version: 1.0 of June 1, 2016. 
Page 123 of 128 
 
authorities. In such cases, all study-related data must be submitted to JSC BIOCAD and all unused 
study drugs must be returned. 
12. ETHICS 
12.1. Ethical aspects of the study 
The study will be conducted in compliance with the ethical principles set forth in the World 
Medical Association’s Declaration of Helsinki "International Ethical Guidelines for Biomedical 
Research Involving Human Subjects"1964–2008 and ICH GCP rules.  
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12.2. Confidentiality of study subjects 
The Investigator undertakes to maintain confidentiality regarding the identity of 
volunteers, the text of this Protocol, as well as all other materials and study results. 
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Clinical Study Protocol 
Study code: BCD-089-1 
Translated from Russian to English, dated 06-Jul-2020 
 
 
 
CONFIDENTIAL 
Version: 1.0 of June 1, 2016. 
Page 124 of 128 
 
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nn 
13.0. DATA MANAGEMENT AND RECORD KEEPING 
All study-related documents must be archived at the study site or at the institution’s central 
archive. The list of all study subject identification data must be carefully drafted.  
According to ICH GCP definition, the required documents include: signed Protocol and all 
the amendments, copies of completed CRFs, signed Informed Consent Forms for all volunteers, 
medical records, diaries and other source documents, approved by ethics committees and 
regulatory authorities, as well as correspondence with them, including approved documents, drug 
accountability records, study-related correspondence and the list of volunteers names and 
addresses. This list is the essential document that should be kept by the Investigator. 
The Investigator must keep copies of the required documents for 5 years. 
At the end of this period, the Sponsor will inform the Investigator(s) about the date, after 
which this documents may be destroyed. 
The study participant’s documentation shall be archived in compliance with the study site 
rules. 
The Investigator must inform the Sponsor about the place of storage of required documents 
and contact JSC BIOCAD for approval before destroying any of them. The Investigator must 
prevent accidental or premature destruction of these documents. 
14. FUNDING AND INSURANCE 
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nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

Clinical Study Protocol 
Study code: BCD-089-1 
Translated from Russian to English, dated 06-Jul-2020 
 
 
 
CONFIDENTIAL 
Version: 1.0 of June 1, 2016. 
Page 125 of 128 
 
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nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

Clinical Study Protocol 
Study code: BCD-089-1 
Translated from Russian to English, dated 06-Jul-2020 
 
 
 
CONFIDENTIAL 
Version: 1.0 of June 1, 2016. 
Page 126 of 128 
 
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nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn 
15. PUBLICATIONS 
After the end of the study and statistical processing, its data will be published.  The 
Investigator must not publish the results of this study, including those obtained at his/her study 
site, without consent from JSC BIOCAD. The results obtained at an individual study site should 
not be published prior to the publication of overall study results. 

 
Clinical Study Protocol 
Study code: BCD-089-1 
Translated from Russian to English, dated 06-Jul-2020 
 
CONFIDENTIAL 
Version: 1.0 of June 1, 2016. 
Page 127 of 128 
 
APPENDIX 1. Injection site reaction reporting form 
 
INJECTION SITE REACTION REPORTING FORM 
 
Visit No. __ __  
Medicinal product: □ BCD-089     
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