A Double-blind, Randomized Clinical Study to Compare the Pharmacokinetics, Pharmacodynamics, Safety, and Immunogenicity of Single Intravenous Doses of BCD-148 (JSC BIOCAD, Russia) and Soliris® in Healthy Volunteers
Phase: PHASE1
Conditions: Healthy Subjects
Sponsor: Biocad

Clinical Study Protocol 
Protocol ID: BCD-148-3 
NCT04027803 
 
 
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Version 1.0 of 13-Jun-2018 
Page 1 of 64 
 
 
CLINICAL STUDY PROTOCOL 
 
Protocol Title: 
 
A Double-blind, Randomized Clinical Study to Compare 
the Pharmacokinetics, Pharmacodynamics, Safety, and 
Immunogenicity of Single Intravenous Doses of BCD-148 
(JSC BIOCAD, Russia) and Soliris® in Healthy Volunteers 
Protocol ID: 
BCD-148-3, NCT04027803 
Protocol Date: 
13-Jun-2018 
Protocol Amendment: 
N/A 
Date of Protocol Amendment: 
N/A 
Protocol Version: 
1.0 
Study Sponsor: 
 
JSC BIOCAD, Russia   
Legal address: 34-A, Ul. Svyazi, Strelna, 
Petrodvortsoviy District, St. Petersburg, 
Russian Federation, 198515 
Mailing address: Petrovo-Dalneye, 
Krasnogorskiy District, Moscow Region, 
Russian Federation, 143422 
Tel.: +7(495) 992-66-28; Fax: +7 (495) 992-82-98 
Sponsor’s Contact Person 
Responsible for Signing the 
Protocol and Protocol 
Amendments: 
 
Roman Alekseevich Ivanov, 
Vice President Research & Development 
Address: Petrovo Dalneye, Krasnogorskiy District, 
Moscow Region, Russian  Federation, 143422 
E-mail: ivanov@biocad.ru 
Tel.: + 7 (495) 992-66-28 (ext. 154) 
 
Sponsor’s Responsible Medical 
Officer: 
Arina Valerievna Zinkina-Orikhan, Medical Expert, 
Category III 
34-A, Ul. Svyazi, Strelna, Petrodvortsoviy District, 
St. Petersburg, Russian Federation, 198515 
E-mail: zinkina@biocad.ru 
Tel.: +7 (812) 380-49-33 (ext. 744)  
The information presented in this document is confidential and intended to be used solely by investigators, ethics 
committee members, and health care authorities. This information may not be transferred to any third party 
without prior written permission from JSC BIOCAD, except when necessary for obtaining subject’s consent to 
participate in the study. These requirements come into effect upon signature of the Protocol. 

Clinical Study Protocol 
Protocol ID: BCD-148-3 
NCT04027803 
 
 
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Version 1.0 of 13-Jun-2018 
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TABLE OF CONTENTS 
SIGNATURE PAGE ........................................................... Ошибка! Закладка не определена. 
ABBREVIATIONS ......................................................................................................................... 8 
TERMS AND DEFINITIONS ...................................................................................................... 10 
DOCUMENT HISTORY .............................................................................................................. 12 
SYNOPSIS .................................................................................................................................... 14 
1. STUDY RATIONALE .............................................................................................................. 19 
1.1. Introduction ............................................................................................................................ 19 
1.1.1. Complement system ......................................................................................................... 19 
1.1.2. Paroxysmal nocturnal hemoglobinuria ............................................................................ 20 
1.1.3. Atypical hemolytic uremic syndrome .............................................................................. 22 
1.1.4 Current treatment options for aHUS and PNH ................................................................. 23 
1.1.5. Brief overview of the study product and its advantages .................................................. 23 
1.2. Name and description of the investigational product ............................................................. 24 
1.2.1. Test drug .......................................................................................................................... 24 
1.2.2. Reference drug: ................................................................................................................ 24 
1.2.3. Labeling of the study and reference products in this study ............................................. 25 
1.2.4. Posology and route of administration .............................................................................. 26 
1.3. Relevant non-clinical and clinical aspects .............................................................................. 27 
1.3.1. Non-clinical studies ......................................................................................................... 27 
1.3.1.1. Physicochemical properties and potency ............. Ошибка! Закладка не определена. 
1.3.1.2. Cytokine release by peripheral blood mononuclear cells in response to BCD-148
 ........................................................................................... Ошибка! Закладка не определена. 
1.3.1.3. Potency of BCD-148 in murine intravascular hemolysis model Ошибка! Закладка не 
определена. 
1.3.1.4. Single-dose IV toxicity and PK study of BCD-148 in cynomolgus monkeys .. Ошибка! 
Закладка не определена. 
1.3.1.5. In vitro activity of BCD-148 ................................ Ошибка! Закладка не определена. 
1.3.1.6. Cross-reactivity study ........................................... Ошибка! Закладка не определена. 
1.3.1.7. Cross-reactivity study ........................................... Ошибка! Закладка не определена. 
1.3.2. Clinical studies ....................................................... Ошибка! Закладка не определена. 

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NCT04027803 
 
 
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1.3.2.1. Overview of clinical methodology ....................... Ошибка! Закладка не определена. 
1.3.2.2. Discussion of pharmacokinetic results ................. Ошибка! Закладка не определена. 
1.3.2.3. Discussion of pharmacodynamic results .............. Ошибка! Закладка не определена. 
1.3.2.4. Discussion of the safety results ............................ Ошибка! Закладка не определена. 
1.3.2.5. Discussion of the Phase I study results ................ Ошибка! Закладка не определена. 
1.4. Summary of the known and potential risks and benefits to human subjects, if any 
(risk/benefit balance) ................................................................................................................. 28 
1.4.1. Benefit assessment ................................................. Ошибка! Закладка не определена. 
1.4.2. Risk assessment ..................................................... Ошибка! Закладка не определена. 
1.5. Description and justification of route of administration, doses, and dosing regimen......... 28 
1.5.1 Description and justification of the study design ............................................................... 28 
1.5.2. Description and justification of the route of administration, doses, and dosage regimen. 30 
1.6. Clinical study compliance with regulatory requirements ................................................... 31 
1.7. Study population ................................................................................................................. 31 
1.8. References ........................................................................................................................... 31 
2. STUDY PURPOSE AND OBJECTIVES ............................................................................. 33 
2.1 Study purpose ...................................................................................................................... 33 
2.2 Study objectives ................................................................................................................... 33 
3. STUDY HYPOTHESIS ......................................................................................................... 33 
4. STUDY DESIGN .................................................................................................................. 33 
4.1. Primary and secondary outcome measures to be assessed in the study .............................. 33 
4.1.1 PK endpoints ...................................................................................................................... 33 
4.1.2 PD endpoints ...................................................................................................................... 34 
4.1.3. Safety endpoints: ............................................................................................................. 36 
4.1.4. Immunogenicity endpoints ................................................................................................ 36 
4.2. Study Design ....................................................................................................................... 36 
4.3. Measures to minimize/eliminate bias.................................................................................. 38 
4.3.1. Inclusion of subjects in the study and assigning the screening and study IDs .................. 38 
4.3.2. Stratification procedure ..................................................................................................... 38 
4.3.3. Randomization procedure ................................................................................................. 39 

Clinical Study Protocol 
Protocol ID: BCD-148-3 
NCT04027803 
 
 
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4.3.4. Blinding ............................................................................................................................. 39 
4.4. Description of the study treatment, dose and dosing regimen for the investigational 
product(s). Pharmaceutical form, packaging, and labeling of investigational products ............ 39 
4.1.4. Description of the study treatment, dose, and dosing regimen for the investigational 
product(s) .................................................................................................................................... 39 
4.4.2. Pharmaceutical form, packaging, and labeling of investigational products ...................... 39 
4.4.2.1. Test drug ......................................................................................................................... 39 
4.4.2.2. Reference drug ............................................................................................................... 39 
4.4.2.3. Meningococcal vaccine .................................................................................................. 40 
4.5. Expected duration of the study and subjects’ participation in the study ............................ 41 
4.6. Study periods ...................................................................................................................... 41 
4.6.1 Study visits and procedures ................................................................................................ 41 
4.6.2. Procedures by visits ................................................. Ошибка! Закладка не определена. 
4.6.3. Description of individual clinical, laboratory, and instrumental tests Ошибка! Закладка 
не определена. 
4.6.3.1. Physical examination ........................................... Ошибка! Закладка не определена. 
4.6.3.2. Clinical data, demographics, and medication history ................ Ошибка! Закладка не 
определена. 
4.6.3.3. Vital signs ............................................................. Ошибка! Закладка не определена. 
4.6.3.4. Hematology, chemistry, coagulation test, and urinalysis ........... Ошибка! Закладка не 
определена. 
4.6.3.5. Blood tests for infection markers ......................... Ошибка! Закладка не определена. 
4.6.3.6. Eculizumab assay, hemolytic complement activity assay, and immunogenicity 
assessment ......................................................................... Ошибка! Закладка не определена. 
4.6.3.6.1. Eculizumab assay in the serum ......................... Ошибка! Закладка не определена. 
4.6.3.7. Chest X-ray and fluorography .............................. Ошибка! Закладка не определена. 
4.6.3.8. ECG ...................................................................... Ошибка! Закладка не определена. 
4.6.3.9. Urine test for psychotropic and recreational drugs, psychoactive medications Ошибка! 
Закладка не определена. 
4.6.3.10. Saliva alcohol test .............................................. Ошибка! Закладка не определена. 
4.6.3.11. Unscheduled visits ............................................. Ошибка! Закладка не определена. 
4.7. Stop rules and criteria for premature withdrawal for study subjects, study periods, and 
study as a whole ............................................................... Ошибка! Закладка не определена. 

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4.8. Drug accountability ................................................... Ошибка! Закладка не определена. 
4.1.8. Handling of investigational products ...................... Ошибка! Закладка не определена. 
4.9. Procedure for code keeping and unblinding ............. Ошибка! Закладка не определена. 
4.10. Data entered directly into the CRF (i.e. no prior written or electronic record of data) and 
considered as source data ................................................. Ошибка! Закладка не определена. 
5. ELIGIBILITY AND EXCLUSION OF STUDY SUBJECTS .................................................. 44 
5.1. Inclusion criteria ................................................................................................................. 44 
5.2 Exclusion criteria ................................................................................................................. 44 
5.3. Withdrawal criteria ............................................................................................................. 45 
5.3.1. Replacing drop-outs .......................................................................................................... 46 
5.4 Follow-up of subjects withdrawn from the study or subjects who discontinued the study 
treatment but remain in the study for follow-up ........................................................................ 46 
5.4.1. Follow-up of subjects who received at least one dose of BCD-148/Soliris® .................... 46 
6. Administration of the investigational product ........................................................................... 46 
6.1 Route of administration used in the study ............................................................................... 46 
6.2. Dose modification for the study drug ................................................................................. 46 
6.3. Overdose ............................................................................................................................. 47 
6.4. Concomitant therapy, medications allowed and prohibited by the Protocol ...................... 47 
6.5. 
Compliance with study procedures ................................................................................. 48 
6.6. Compliance ......................................................................................................................... 48 
7. PK AND PD ASSESSMENT .................................................................................................... 48 
7.1. List of pharmacokinetic parameters .................................................................................... 48 
7.2. 
List of pharmacodynamics parameters ........................................................................... 49 
8. SAFETY ASSESSMENT ......................................................................................................... 49 
8.1 List of safety endpoints ........................................................................................................ 49 
8.2 Definitions ................................................................. Ошибка! Закладка не определена. 
8.2.1 Adverse events ........................................................ Ошибка! Закладка не определена. 
8.2.2 Serious adverse events ............................................ Ошибка! Закладка не определена. 
8.2.3. Unexpected adverse drug reaction ......................... Ошибка! Закладка не определена. 

Clinical Study Protocol 
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NCT04027803 
 
 
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8.3 Methods and time of assessment, recording and analysis of safety parameters ..... Ошибка! 
Закладка не определена. 
8.3.1 Time windows for analysis of safety parameters .... Ошибка! Закладка не определена. 
8.3.2 Methods and timeframes for assessment and recording of safety parameters ..... Ошибка! 
Закладка не определена. 
8.4 Requirements for reports. Documenting and reporting AEs and completing AE Report 
Forms ............................................................................... Ошибка! Закладка не определена. 
8.4.1 Documenting AEs/SAEs ......................................... Ошибка! Закладка не определена. 
8.4.2 AE/SAE reporting ................................................... Ошибка! Закладка не определена. 
8.5 Information concerning the method and duration of follow-up for study subjects after the 
onset of AE/SAE .............................................................. Ошибка! Закладка не определена. 
9. STATISTICAL METHODOLOGY .......................................................................................... 50 
9.1 
Calculation of PK and PD parameters ............................................................................ 50 
9.1.1. PK parameters ................................................................................................................... 50 
9.1.2. PD parameters ................................................................................................................. 51 
9.2. 
Statistical methods .......................................................................................................... 52 
9.3. 
Justification of sample size, including reasoning or calculations to justify statistical 
power and clinical justification of the study .............................................................................. 53 
9.4. Statistical analysis steps and timelines for reports .............................................................. 55 
9.5. Study termination criteria ................................................................................................... 56 
9.6. Handling of missing, unevaluable or uncertain data ........................................................... 56 
9.7. Reporting any deviations from the initial statistical plan ................................................... 56 
9.8 Selection of subjects for analysis ......................................................................................... 56 
10. DIRECT ACCESS TO SOURCE DATA/DOCUMENTS ..................................................... 57 
11. QUALITY CONTROL AND QUALITY ASSURANCE ...................................................... 57 
11.1. Data quality assurance ...................................................................................................... 57 
11.2. Investigator adherence to the Protocol .............................................................................. 57 
11.3. Investigator responsibility to comply with the Protocol ................................................... 58 
11.4. Study monitoring .............................................................................................................. 58 

Clinical Study Protocol 
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NCT04027803 
 
 
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11.5. 
Data management and quality control ......................................................................... 59 
11.6. Study termination .............................................................................................................. 60 
12. ETHICS ................................................................................................................................... 60 
12.1. Ethical aspects of the study ............................................................................................... 60 
12.2. Confidentiality of study subjects ...................................................................................... 61 
13. DATA HANDLING AND RECORD KEEPING ................................................................... 61 
13.1. Record keeping at the study site ....................................................................................... 61 
13.2. Confidentiality of data ...................................................................................................... 62 
13.3. Collection of data .............................................................................................................. 62 
14. FINANCE AND INSURANCE .............................................................................................. 63 

Clinical Study Protocol 
Protocol ID: BCD-148-3 
NCT04027803 
 
 
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ABBREVIATIONS 
ABEC 
The area between the baseline and effect curves for hemolytic activity 
of serum complement from 0 to 1392 h. 
AE 
Adverse event 
aHUS 
Atypical hemolytic uremic syndrome 
AlkPh 
Alkaline phosphatase 
ALT 
Alanine transaminase  
AST 
Aspartate transaminase 
AUC 
Area under the Concentration vs. Time curve 
AUMC 
Area under the first moment curve 
BAbs 
Binding antibodies 
BCD-148 
A monoclonal antibody developed by JSC BIOCAD to target the 
complement component C5. 
BP 
Blood pressure 
Cmax 
Maximum drug concentration in the serum 
CRF 
Case Report Form 
CTCAE 
Common Toxicity Criteria for Adverse Events 
DLT 
Dose-limiting toxicity 
DNA 
Deoxyribonucleic acid 
ELISA 
Enzyme-linked immunosorbent assay 
ESR 
Erythrocyte sedimentation rate 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transferase 
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 
ICН 
International Conference on Harmonization 
IDMC 
Independent Data Monitoring Committee  

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Ig 
Immunoglobulin 
IMU 
Instruction for Medical Use 
INN: 
International non-proprietary name 
JSC 
Joint Stock Company 
LDH 
Lactate dehydrogenase  
LLN 
Lower limit of normal 
MABEL 
Minimal Anticipated Biological Effect Level 
MBEDL 
Minimal Biological Effect Dose Level 
MP 
Medicinal product 
MTD 
Maximum tolerated dose 
NAb 
Neutralizing antibodies 
NBEDL 
No Biological Effect Dose Level 
NOAEL 
The No Observed Adverse Effect Level 
PD 
Pharmacodynamics 
PK 
Pharmacokinetics 
PNH 
Paroxysmal nocturnal hemoglobinuria 
RAMS 
Russian Academy of Medical Sciences 
SAE 
Serious adverse event 
SD 
Standard deviation 
SOP 
Standard Operating Procedure 
T½   
Elimination half-life 
TD 
Test drug 
Th 
T-helper cells 
ULN 
Upper limit of normal 
WHO 
World Healthcare Organization 
ТМА 
Thrombotic microangiopathy 
 

Clinical Study Protocol 
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TERMS AND DEFINITIONS 
Term 
Definition 
Investigational 
product 
This term includes the test drug, comparator, or placebo. A 
pharmaceutical form of an active ingredient or placebo being tested or 
used as a reference in a clinical trial, including a product with a 
marketing authorization when used or assembled (formulated or 
packaged) in a way different from the approved form, or when used 
for an unapproved indication, or when used to gain further information 
about an approved use 
Study/test 
product/drug 
A pharmaceutical forms the properties of which are investigated in this 
clinical trial. 
Comparator/reference 
product/drug 
An active control being tested as a control in the clinical study to 
reduce the bias of assessments, keep the study therapy blind, and assess 
the internal validity of the study and/or comparative effects of the 
study product. 
Case 
Report 
Form 
(CRF) 
A printed or electronic document designed to record all the protocol-
required information to be reported to the Sponsor on each study 
subject. 
Investigator's 
Brochure 
A compilation of the clinical and non-clinical information on the 
investigational product(s) that is relevant to the study of the 
investigational product(s) in human subjects. 
Subject identification 
code / subject ID 
|__|__|-|__|__|__| 
A unique identifier assigned by the investigator to each trial subject to 
protect the subject's identity and used in lieu of the subject's name 
when the investigator reports adverse events and/or other trial-related 
data. 
Usually, the subject ID is a five-digit code where the first two digits 
are the site number and the last three digits are assigned sequentially 
to each participant as he/she enters the study. 
Screening ID  
|__|__|-|__|__| 
A unique code assigned to each study subject who have signed the 
informed consent. The first two digits are the site number, and the last 
two digits are assigned sequentially to each subject as he/she gets 
enrolled at this particular study site. 
Assessment 
The procedure of obtaining the data that have to be gathered in this 
trial. 
Enrollment 
in 
the 
study 
A time point when the subject signs the informed consent. 
Other therapy used in 
the study 
Any medications other than the investigational product that are used to 
perform the study procedures. This includes, for example, the drugs 
used as part of the combination therapy. 
Premature withdrawal  The time point when the subject stops participation in the study before 
the planned investigational treatment is completed and/or assessments 

Clinical Study Protocol 
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NCT04027803 
 
 
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Term 
Definition 
are performed. No further assessments are performed beyond this point 
except for monitoring of the survival and/or disease progression in 
certain trials. If the subject discontinues the study due to an event 
planned by the Protocol (for example, a complete response), he/she is 
considered a dropout anyway. 
End-of-study 
The time point when the subject attends his/her last study visit. 
Study therapy 
Any medication or a combination of medications used in any arm as 
part of study procedures, including concomitant medications and 
introductory therapy before the active medication. 
Concomitant therapy 
Therapy with any drugs included in the study therapy, except for the 
test drug and reference drug. For example, drugs used for combination 
therapy, pre-medication etc. 
Discontinuation 
of 
study therapy 
The time point when the investigational therapy is terminated 
regardless of what caused the termination. It does not necessarily 
coincide with subject’s withdrawal from the study. 
Variable 
An identifier used for the data analysis and derived directly or 
indirectly from the protocol-specified assessments at pre-determined 
time points. 

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DOCUMENT HISTORY 
N/A. 
 
 

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Names/positions of investigators responsible for the study conduct. Contacnt information of 
the study sites 
# 
Title 
of the study site 
(center) 
Address 
Phone  
Full name of 
the PI  
Job Title of 
the PI  
1. 
Limited Liability 
Company Research 
Center Eco-
Bezopasnost  
(OOO Research 
Center Eco-
Bezopasnost) 
65, Pr. Yurija Gagarina,  
St. Peterburg, Russian 
Federation, 196143 
+7 812-
500-52-03, 
+7 812-
325-03-05, 
+7 812-
500-52-03 
Konstantin 
Anatolievich 
Zakharov 
Deputy Director 
Name, job title, address and telephone number of the qualified physician responsible for 
taking medical decisions 
N/A. 
 
Names and addresses of clinical or other medical and/or technical services and/or 
organizations involved in the study 
# 
Institution, role in 
the study 
Address  
Phone 
Full name  
of responsible 
person 
Job Title 
of responsible 
person 
1. 
Bioanalytical 
Laboratory, Analytical 
Development 
Department, 
JSC 
BIOCAD 
PK, PD, and IG study 
34-A, 
Ul. 
Svyazi, 
Strelna, 
Petrodvortsoviy  
District, 
St. Petersburg, 
Russian Federation, 
1985155 
+7(812) 
380-49-33 
Aleksander 
Valerievich 
Novikov 
PhD, Analytical 
Development 
Director at JSC 
BIOCAD 
 

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SYNOPSIS 
SYNOPSIS 
Protocol ID: 
BCD-148-3 
Study Title 
A Double-blind, Randomized Clinical Study to Compare the 
Pharmacokinetics, Pharmacodynamics, Safety, and Immunogenicity 
of Single Intravenous Doses of BCD-148 (JSC BIOCAD, Russia) and 
Soliris® in Healthy Volunteers 
Study Phase: 
Phase I 
Study Sponsor: 
JSC BIOCAD  
Mailing 
address: 
Petrovo-Dalneye, 
Krasnogorskiy 
District, 
Moscow Region, Russian Federation, 143422  
Tel.: (495) 992 66 28 (ext.193), fax: +7 (495) 992 82 98.  
Legal address: 34-A, Ul. Svyazi, Strelna, Petrodvortsoviy District, 
St. Petersburg, Russian Federation, 198515 
Test Drug: 
BCD-148 (INN: eculizumab), concentrate for solution for infusion 
Reference Drug: 
Soliris® (INN: eculizumab), concentrate for solution for infusion 
Study Purpose and 
Objectives: 
Purpose:  
To perform a comparative assessment of the pharmacokinetics, 
pharmacodynamics, safety, and immunogenicity of a single 
intravenous infusion of BCD-148 and Soliris® in healthy volunteers. 
Study objectives: 
1. To determine and compare the PK parameters of BCD-148 and 
Soliris®, each given as a single intravenous infusion 
2. To determine and compare the PD parameters of BCD-148 and 
Soliris®, each given as a single intravenous infusion 
3. To determine and compare the adverse event profile with a single 
infusion of BCD-148 and Soliris® 
4. To evaluate and compare the proportion subjects positive for 
binding and neutralizing anti-drug antibodies in the BCD-148 and 
Soliris® arms after a single drug infusion 
Study Population 
Healthy male volunteers aged from 18 to 45 years (inclusive) 
Planned Sample Size 
78 healthy volunteers (39 in each trial arm) 

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Protocol ID: BCD-148-3 
NCT04027803 
 
 
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SYNOPSIS 
Study Design 
This is a double-blind, randomized clinical study to compare 
the 
pharmacokinetics, 
pharmacodynamics, 
safety, 
and 
immunogenicity of single intravenous doses of BCD-148 (JSC 
BIOCAD, Russia) and Soliris® in healthy volunteers. 
The suggested double-blind randomized parallel-group design 
that utilizes a drug with demonstrated efficacy (reference drug) as an 
active control is aimed at proving pharmacokinetic equivalence of a 
biosimilar BCD-148 (test drug) and Solaris® (reference drug) in terms 
of the key PK parameters. This is a common approach in the 
development of biosimilars, which complies with the Russian1 and 
international2 regulations. 
The EMA3,4 guidelines state that for long half-life products 
(such as eculizumab) a parallel-group study design is preferred to 
crossover. 
Randomization 
It is planned to randomize 78 adult healthy volunteers who 
then will be assigned at a 1:1 ratio to one of the two treatment arms: 
39 subjects in the BCD-148 arm and 39 subjects in the Soliris® arm.  
During the study, each volunteer will receive a single IV 
infusion of 900 mg BCD-148 (test drug) or 900 mg Soliris® (reference 
drug). 
Before enrollment, all volunteers will be given all the 
information about this clinical study, its purpose, and the risks 
associated with study participation. After signing the informed consent 
form (ICF), each subject will undergo a screening examination (no 
longer than 20 days), which is to find out whether the subject meets 
the eligibility criteria. 
Study periods 
1. Screening period will include 2 visits and 1 phone call. 
• 
Screening Visit 1/ Days -20 to -18  
ICF signing and eligibility assessment (interview, history taking, 
physical examination, and laboratory and instrumental investigations). 
• 
Visit 2/ Day -17  
It has been shown that patients treated with eculizumab may 
have increased susceptibility to infections caused by encapsulated 
 
1 A.N. Mironov, V.G. Kukes, V.I. Petrov, A.L. Kuznetsov, D.V. Goryachev, R.R. Niyazov, A.B. Prokofyeva, S.V. 
Nedogoda, M.Yu.Frolov, A.Shnayder. Bioequivalence evaluation for generic medicinal products // Guidance on 
evaluation of medicinal products Vol. I – M.: Grif and K, 2013. 
2Rules for investigation of biologics (Eurasian Economic Commission)  
https://docs.eaeunion.org/docs/ru-ru/01411969/cncd_21112016_78 
3Guideline on similar biological medicinal products containing monoclonal antibodies – non-clinical and clinical 
issues. EMA/CHMP/BMWP/403543/2010, 2012. 
4Guideline on the clinical investigation of the pharmacokinetics of therapeutic proteins (CHMP/EWP/89249/2004) 

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SYNOPSIS 
bacteria, especially to meningococcal infection. Therefore, all subjects 
who are considered eligible for the study will be preventively 
vaccinated against Neisseria meningitidis to ensure their safety. 
• 
Screening phone call / Day -15 
The study team member interviews the subject by phone to 
monitor for any post-vaccination complications. 
• 
Screening Visit 3/ Days -3 to -1  
This visit occurs at least 14 days post-vaccination. This time is 
enough for a subject to develop post-vaccination immunity. During 
this visit, each subject will be re-evaluated for eligibility based on their 
clinical and laboratory results. Hematology and chemistry tests will be 
performed, and the subjects will be assessed for any post-vaccination 
complications that may interfere with further participation in the study. 
2. Main study period 
The duration of the main study period is 59 days, including the 
day of the BCD-148/Soliris® infusion. During this period, multiple 
blood collections will be performed for assessment of PK/PD, safety, 
and immunogenicity of eculizumab. 
Because of multiple blood collections and the necessity of 
monitoring the safety and tolerability of eculizumab, each subject will 
stay in a hospital for the first 48 h post-infusion.   
Blood samples will be collected from study subjects for the PK 
study (assessment of eculizumab concentration in the serum) and PD 
study (hemolytic complement activity CH50).   
The immunogenicity assessment is a mandatory part of the 
drug safety monitoring and will be performed prior to the infusion of 
eculizumab, 29 days post-infusion, and upon completion of the main 
study period (Day 59). 
The study results will be used to test the hypothesis of 
pharmacokinetic equivalence (in terms of the primary endpoint AUC(0-
∞) of eculizumab following a single IV infusion) of the biosimilar 
BCD-148 and the reference drug Soliris® and to assess the PD, safety, 
and immunogenicity of the test drug versus the reference drug. 
Test Drug/ Reference 
Drug and Dosing 
Regimen 
In this clinical study, each healthy volunteer will get one infusion 
of either the test drug BCD-148 or the reference drug Soliris®, 
depending on the study arm to which the subject is randomized. Both 
eculizumab products (BCD-148/Soliris®) will be administered as a 
single 900 mg drip infusion given over 25-45 min. The drug will be 
infused at the study site.  
Main Inclusion 
1. Signed ICF for participation in the study 
2. Men from 18 to 45 years old (inclusive) at the time of signing 

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SYNOPSIS 
Criteria: 
the ICF 
3. BMI within the normal limits (18.0 to 30.0 kg/m2) 
4. The subject is able to follow the Protocol procedures (in the 
investigator’s opinion) 
5. The subject is verified as  “Healthy” according to the results of 
standard clinical, laboratory, and instrumental tests 
Main Exclusion 
Criteria: 
1. Psychiatric disorders or other conditions that can affect the 
ability of the subject to follow the study protocol 
2. Acute infections within 4 weeks before signing the ICF 
3. Results of laboratory and/or instrumental tests are outside the 
site’s normal range. 
PK Endpoints: 
The primary endpoint for PK assessment after a single 
infusion of BCD-148/Soliris®: 
• AUC0-∞ of eculizumab (the area under the Concentration vs. 
Time curve from 0 to infinity).  
The secondary endpoints for PK assessment after a single 
infusion of BCD-148/Soliris®: 
• Cmax of eculizumab (maximum drug concentration in the 
serum). 
• Тmax of eculizumab (time to Cmax) 
• AUC0-1392 of eculizumab (area under the Concentration vs. 
Time curve from 0 to 1392 h post-infusion) 
• Т1/2 of eculizumab (half-life) 
• Vd of eculizumab (steady-state volume of distribution) 
• Кel  of eculizumab (elimination constant) 
• Cl of eculizumab (clearance) 
PD Endpoints: 
The secondary endpoints for PD assessment after a single 
infusion of BCD-148/Soliris®: 
• ABEC(0-1392) CH50 (the area between the baseline and effect curves 
for hemolytic activity of serum complement from 0 to 1392 h). 
• AUEC(0-1392) CH50 ((area under the Time vs. Effect curve from 0 
to 1392 h) 
• Emin CH50 (minimum hemolytic complement activity from 0 to 
1392 h) 
• Tmin CH50 (time to minimum hemolytic complement activity 
within the period from 0 to 1392 h). 
Safety Endpoints: 
• 
The proportion of subjects who develop AEs/SAEs that, in the 
Investigator’s opinion, are related to eculizumab 

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SYNOPSIS 
• 
The proportion of subjects who develop СТСАЕ v. 4.03 grade 
3/4 AEs that, in the Investigator’s opinion, are related to 
eculizumab, by study arms. 
Immunogenicity 
Endpoints 
• 
The proportion of BAb- and NAb-positive subjects 
 

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1. STUDY RATIONALE 
 1.1. Introduction 
1.1.1. Complement system 
 
The complement system is a system of serum proteins consisting of nine main and three 
inhibitory proteins. The complement system is a part of the innate immune system and activates 
through an enzyme cascade pathway, where the product from the previous reaction is a catalyst in 
the subsequent reaction. 
Complement triggers the following immune functions: promotes phagocytosis by releasing 
certain substances that cover pathogens or immune complexes; promotes inflammation by 
regulating the expression of biologically active substances by basophils; promotes cytotoxicity 
through the formation of the membrane attack complex (MAC) from terminal complement 
components [1].  
There are three pathways through which complement can be activated:  the classical, lectin, 
and alternative pathways. The classical and lectin pathways are triggered when antibodies 
(classical pathway) or pattern-recognition molecules (pentraxins and C1q in the classical pathway 
and lectins and ficolins in the lectin pathway) recognize pathogens or damage on the cell surface. 
Both classical and lectin pathways lead to the cleavage of C4 resulting in the formation of the 
C4bC2a C3 convertase complex on the target surface. The C4bC2a is an enzymatic complex that 
cleaves C3 into the anaphylatoxin C3a and C3b. The alternative pathway is activated as a result of 
the spontaneous generation of fluid-phase C3b (C3 tick-over). C3b accumulates on the surface of 
pathogens or self-cells and, together with the activated factors D and B, forms the C3-convertase 
enzyme complex of the alternative pathway (C3b/Bb), which triggers additional C3 cleavage, thus 
creating a positive feedback loop.  It is important that, after C3b is generated, the alternative C3-
convertase further promotes complement activation by triggering other activation pathways. C3b 
accumulates on the surface of a pathogen and binds to specific receptors on white blood cells, 
which induces phagocytosis of cells labeled by complement enzymes. Attachment of C3b to C3-
convertase converts this enzyme into C 5-convertase, an enzyme that cleaves C5 into C5a and C5b. 
C5a is a pro-inflammatory and pro-thrombotic protein, while C5b initiates the terminal 
complement pathway with the formation of the terminal complement complex C6-C9. Finally, the 
C5b-9 complex (MAC) is formed on the surface of the target cells. The MAC causes hemolysis, 
stimulates the production of pro-coagulant micro particles, and activates platelets [1].  

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The complement activation is regulated by certain complement control molecules - 
membrane receptors (MCP (membrane cofactor protein), CD55 (DAF), CD59 (MIRL), and THBD 
(thrombomodulin)) and soluble molecules (e.g., CFH (complement factor H)). These control 
molecules may cause C3b cleavage into inactive forms and dissociation of C3- and C5-convertases 
or may prevent MAC assembly.  
The complement system imbalance resulting from certain genetic disorders is one of the 
key components in the mechanism of the atypical hemolytic uremic syndrome (aHUS) and 
paroxysmal nocturnal hemoglobinuria (PNH). 
Figure 1. The complement system 
 
 
1.1.2. Paroxysmal nocturnal hemoglobinuria  
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare acquired, clonal disease of the blood. 
The disease is characterized by chronic intravascular hemolysis, impaired bone marrow function, 
high risk of blood clots, kidney disease, and pulmonary hypertension. A somatic mutation in the 
X-linked gene encoding phosphatidylinositol glycan A (PIG-A) leads to the deficiency of glycosyl 
phosphatidylinositols (GPI) anchors that attach a number of proteins to blood cell membranes (e.g. 
certain complement system control molecules such as CD55/DAF, HRF, and CD59). Normally, 

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these proteins interact with complement components, particularly with C3b and C4b, thus inducing 
dissociation of the convertase complexes and slowing down the accelerating activation of the 
complement. The lack of these proteins on the cell membrane in subjects with PNH results in cells 
(primarily erythrocytes) becoming hypersensitive to complement-induced lysis, intravascular 
hemolysis, and anemia. Released free hemoglobin partially binds to haptoglobin in the serum, but 
the concentration of plasma hemoglobin in PNH exceeds the capacity of haptoglobin. Thus, 
hemoglobin binds irreversibly to nitric oxide, which is a physiological vasodilator. Depletion of 
nitric oxide induces vasospasm, pulmonary hypertension, impaired renal blood flow, and GI 
smooth muscle spasm. Excretion of free hemoglobin into urine results in tubular necrosis and renal 
impairment. Moreover, PNH is frequently associated with thrombotic complications, which may 
be due to the higher platelet aggregation caused by the deficiency of the membrane CD59 and due 
to elevated plasma pro-coagulant activity. Typically, the clinical onset of PNH occurs in people 
from 20 to 40 years old; the median survival based on historical data is about 10 years. [2]. 
The worldwide prevalence of PNH is approximately 13 cases per 1 000 000 people [3] with 
the incidence of about 1 case per 1 000 000 people per year. Large-scaled epidemiological studies 
have shown that 35% of PNH patients lose their lives within 5 years from the date of diagnosis 
and their 10 years mortality reaches approximately 50% despite supporting therapy. Thrombotic 
events are responsible for 40-67% of deaths [2, 3, 4, 5, 6, 7, 8]. Other causes of morbidity and 
mortality can be listed as renal failure, pulmonary hypertension, erectile dysfunction and 
dysphagia [9]. 
Allogeneic bone marrow transplantation is the only potentially curative treatment for PNH, 
however, it is associated with high mortality. In one of the PNH studies, the 10-year survival rate 
was 42%. Regardless of the indication, the frequency of complications with allogenic bone marrow 
transplantation remains very high. The average incidence of graft versus host disease has been 
observed as 42-54%.   
Patients with complement-mediated hemolysis may be candidates for eculizumab therapy. 
According to literature, eculizumab therapy in PNH patients significantly reduces hemolysis, 
decreases the frequency of thrombosis and transfusion dependence, and alleviates the severity of 
symptoms such as dyspnea, fatigue, and pulmonary hypertension. Eculizumab also improves the 
renal function and quality of life. Long-term use of eculizumab increases survival up to the level 
of general population in the same age group. Eculizumab is not a curative treatment but long-term 
eculizumab treatment has a good safety profile and reduces complications and the risk of death 

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significantly. Eculizumab should be prescribed based on clinical and laboratory signs. For patients 
diagnosed with PNH, Eculizumab treatment indications are available in the following cases: 
– Presence of thrombotic event 
– Presence of organ damage due to chronic hemolysis 
– Transfusion dependence 
– If PNH patient is pregnant. 
For patients who had thrombotic complications in the past, eculizumab is indicated to 
prevent further thrombosis. For patients with high LDH activity (>1.5 of the normal limit), PNH 
complications including life-threatening cases increased significantly.  For this reason, eculizumab 
should be used in the treatment of patients having LDH activity > 1.5 of the normal, which is 
associated with chronic hemolysis – for example, thrombosis, anemia, acute and chronic renal 
failure, pulmonary hypertension, smooth muscle dystonia (e.g., abdominal pain, dysphagia, 
erectile dysfunction etc.). Eculizumab treatment is also indicated to transfusion-dependent patients 
with chronic hemolysis. Eculizumab blocks hemolysis and significantly decreases the number of 
transfusions [2]  
1.1.3. Atypical hemolytic uremic syndrome  
Atypical hemolytic uremic syndrome (aHUS) is a chronic systemic genetic disease caused 
by uncontrolled activation of the alternative pathway in the complement system. The disease is 
characterized by generalized thrombotic microangiopathy (complement-mediated TMA). This is 
an orphan disease with the prevalence of 2 to 7 subjects per 1 000 000 people. 
 
  The atypical hemolytic uremic syndrome can manifest at any age; however, children and young 
adults are affected more often than other categories.  Approximately 60% of aHUS cases are 
diagnosed in children versus 40% in adults. The disease affects males and females in equal 
numbers. In adulthood, females are affected more often than males. 
Atypical HUS is caused by genetic defects in the regulation of the alternative pathway of 
the complement system, which results in its uncontrolled activation. It is believed that aHUS 
patients have mutations in the genes encoding certain regulatory proteins (CFH, CFI, MCP, 
THBD). By causing the deficiency or, more often, dysfunction of these proteins, such mutations 
deteriorate the defense mechanism against complement-induced endothelial cell activation. This 
results in increased liberation of MAC at the endothelial surface, causing additional endothelial 
cell damage with exposure of the subendothelial matrix, conversion of athrombotic phenotype into 
prothrombotic, and subsequent thrombus formation. The complement activation on the platelet 

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surface, which triggers the platelet functional activity, is an additional factor contributing to the 
thrombus formation in aHUS patients with factor H mutations.  
Besides improving survival in aHUS patients, aHUS therapy aims at inhibiting the 
uncontrolled complement activation, alleviating clinical and laboratory signs/symptoms of TMA, 
preserving and improving damaged organ functions (e.g. preventing terminal renal failure, taking 
patients off from dialysis, preventing damage of visceral organs other than kidneys) and providing 
better quality of life. 
The aHUS therapy includes fresh frozen plasma infusions, plasma exchange, and heparin 
therapy if indicated. According to the national guidelines, eculizumab therapy is indicated to adult 
aHUS patients who do not respond to plasma therapy, have adverse events, have recurrent disease, 
or have a family history of aHUS.    
1.1.4 Current treatment options for aHUS and PNH 
Treatment options for aHUS and PNH include eculizumab (Soliris®), a humanized 
monoclonal antibody binding to the complement protein C5. This inhibits C5 cleavage to C5a and 
C5b and thereby prevents the generation of pro-inflammatory cytokines (via C5a) and MAC (via 
C5b).  
Clinical studies and further clinical practice have shown that eculizumab therapy in PNH 
patients significantly reduces hemolysis, decreases the frequency of thrombosis and transfusion 
dependence, and alleviates the severity of symptoms such as dyspnea, fatigue, and pulmonary 
hypertension. Eculizumab also improves the renal function and quality of life. Long-term use of 
eculizumab increases survival up to the level of general population in the same age group. Thus, 
eculizumab therapy significantly reduces the mortality and incidence of complications, although 
it is not a curative treatment [2]. 
In aHUS patients, eculizumab reverses the TMA effect and/or prevents further kidney 
damage. Although eculizumab suppresses the terminal complement system, the proximal 
complement system, responsible for opsonization of microorganisms and clearance of immune 
complexes, remains intact [10]. 
1.1.5. Brief overview of the study product and its advantages 
JSC BIOCAD (Russia) develops BCD-148 as a biosimilar to Soliris®. This is a drug to treat 
PNH and aHUS.   

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Eculizumab is a humanized monoclonal antibody that specifically binds to the complement 
protein C5.  Binding C5, eculizumab prevents its cleavage to C5a and C5b and, therefore, inhibits 
the generation of the membrane attack complex (MAC). 
1.2. Name and description of the investigational product 
1.2.1. Test drug 
Invented name: Not applicable  
Internal code: BCD-148 
International non-proprietary name: eculizumab 
Dosage form: Concentrate for solution for infusion 
Composition: 1 mL of solution contains 
Active ingredient: eculizumab 10 mg 
Excipients: Sodium acetate trihydrate 0.436 mg, trehalose dihydrate 100 mg, poloxamer 188 0.2 
mg, glacial acetic acid ad pH 5.0, water for injection ad 1.0 mL.  
Manufacturer: JSC BIOCAD, Russia. 
Shelf life: 2.5 years. 
Storage and transportation conditions: At 2 to 8 °C, protect from light. Do not freeze. Keep out 
of the sight and reach of children. 
Packaging: 30 mL of the drug product in a vial (grade I colorless neutral glass) with a rubber 
stopper and a seal (aluminum cap) with plastic closure. Each vial has a self-adhesive label. One 
vial in a carton.  
1.2.2. Reference drug: 
Invented name: Soliris® 
International non-proprietary name: eculizumab 
Dosage form: Concentrate for solution for infusion 
Marketing Authorization Holder: Alexion Pharma GmbH5 
Composition:  
1 mL of solution contains 
Active ingredient: eculizumab 10 mg 
Excipients: sodium dihydrogen phosphate monohydrate 0.46 mg, sodium hydrogen phosphate 
1.78 mg, sodium chloride 8.77 mg, polysorbate-80 0.22 mg, water for injection ad 1.0 mL. 
 
5 If the product is not available or difficult to purchase in the Russian Federation, it will be purchased in other countries. 

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Shelf life: 2.5 years. Do not use after the expiry date which is stated on the carton. 
Storage and transportation conditions: At 2 to 8 °C, protect from light. Keep out of the sight 
and reach of children. 
Packaging: This is a marketed drug. The package is in accordance with the approved specification. 
1.2.3. Labeling of the study and reference products in this study 
This study is blind, so the investigational products will be labeled identically. 
Labeling: The secondary package contains the following information (printed in the easily 
readable font): 
- Name of the test/ reference drug 
- Dosage 
- Date of manufacture 
- Shelf life 
- Investigational product lot number. 
- Dosage form  
The secondary package will contain the following information (printed in the easily readable font): 
- Name of the test/ reference drug 
- Dosage 
- Manufacturer/MAH 
- Investigational product lot number 
- Date of manufacture 
- Shelf life 
- Route of administration 
- Dosage form 
- Storage conditions 
- Cautionary labeling 
- Protocol ID. 
The investigator will also put the following information on the secondary package:  
Protocol ID, study site number, and Subject ID. 
Both primary and secondary package will also have the following labeling: “For Clinical 
Trials Only”. 

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1.2.4. Posology and route of administration 
In this clinical study, each healthy volunteer will get one infusion of either the test drug 
BCD-148 or the reference drug Soliris®, depending on the study arm to which the subject is 
randomized. Both eculizumab products (BCD-148/Soliris®) will be administered as a single 900 
mg drip infusion given over 25-45 min. The infusion will be given at the study site.  
The subject should be warned not to smoke for 1 h before the infusion of BCD-148/Soliris® 
and for 3 h following the infusion.  
Route of administration:  
The infusion of BCED-148/Soliris® will be given at the study site. Subjects will stay at the 
study site for monitoring for 48 h post-infusion. The study site where the infusion is given and the 
following monitoring is performed must have all the necessary equipment for emergency care. 
Instructions for reconstitution of the test/reference drug solution 
Take care to ensure aseptic handling when you prepare the infusion. 
According to the storage conditions, vials with BCD-148/Soliris® should be stored at 2 to 
8 °C protected from light (in a refrigerator).  
Before administration, inspect the solution in the vial for particulate matter or discoloration. 
Take the vials with BCD-148/Soliris® from the refrigerator and allow to warm to room 
temperature (not higher than 25°C) for 30 minutes before administration. 
Dilute BCD-148/Soliris® to a final concentration of 5 mg/mL with sodium chloride 9% 
solution for infusion. To do so, remove excessive sodium chloride 9% solution for infusion from 
the infusion bag/vial. The volume of solution remaining in the infusion bag/vial should be 90 mL.  
Use a sterile syringe with a needle to transfer the contents of 3 vials with BCD-148 / 
Soliris® to the vial containing the solution for infusion. 
The final volume of a 5 mg/mL diluted BCD-148 / Soliris®  solution is 180 mL for 900 mg 
doses (refer to Table 1). 
 

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Table 1. Solution reconstitution for certain doses 
Dosage of 
BCD-
148/Soliris® to 
be transferred 
to the infusion 
bag/vial 
Volume (mL) 
of BCD-
148/Soliris® 
solution to be 
transferred to 
the infusion 
bag/vial 
Required number of 
vials of BCD-
148/Soliris® 
Volume 
(mL) of 
0.9% 
sodium 
chloride 
solution for 
infusion 
Final volume of 
5 mg/mL BCD-
148/Soliris® 
solution for 
infusion to be 
administered to 
a subject 
900 mg 
90 mL 
3 vials (take the 
contents of all three 
vials to the syringe) 
90 mL 
180 mL 
The final solution should be clear and colorless. Do not use the solution if it is colored or 
has any visible particles. Administer the infusion immediately after preparation. In exceptional 
circumstances, the solution can be stored for not more than 24 h at a temperature from 2 to 8 °C. 
Before giving an infusion, gently agitate the infusion bag containing the diluted solution to ensure 
thorough mixing of the product and diluent. There is no need to protect the reconstituted solution 
from light during the infusion. During the infusion, the temperature of the solution should be 20–
25 °C.  
BCD-148/Soliris® is administered only as an intravenous infusion. BCD-148/Soliris® must 
not be administered as an intravenous push or bolus injection! 
When the infusion is completed, add 5 mL of normal saline to the catheter to rinse it and 
remove any remaining drug. 
If any adverse events develop during the infusion, the infusion rate may be reduced or the 
infusion can be stopped at the discretion of the investigator.  If reducing the infusion rate, make 
sure that the overall duration of BCD-148/Soliris® infusion does not exceed 2 h. 
The subjects will stay at the study site and will be monitored by the medical team for 2 
days after the infusion. 
1.3. Relevant non-clinical and clinical aspects  
1.3.1. Non-clinical studies 
According to ICH M3(R2)6, clinical studies of single subtherapeutic doses or doses of the 
anticipated therapeutic range should rely on non-clinical pharmacology, safety, single-dose 
toxicokinetics, and mutagenicity studies.  
 
6Guidance on nonclinical safety studies for the conduct of human clinical trials and marketing authorization for 
pharmaceuticals M3(R2) 

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1.4. Summary of the known and potential risks and benefits to human subjects, if any 
(risk/benefit balance) 
Given the mechanism of action, eculizumab is considered safe with regard to the health and 
wellbeing of the study participants. 
The risks for study subjects will be minimized through the protocol-specified 
inclusion/exclusion criteria and procedures. A single dose of BCD-148/Soliris® is not expected to 
cause any severe adverse events. The study participants will be monitored for 59 days, which 
covers five Soliris® half-life periods (the mean half-life of Soliris® is 11.3 days, hence 11.3 х 5 
T1/2 = 56.5 days). 
No medical benefit is expected for the study participants other than a comprehensive 
medical examination and immunization (development of bactericidal antibodies) against 
meningococcus serotypes A, C, W135, and Y.  
Thus, the benefit-risk ratio is expected to be suitable. 
1.5. Description and justification of route of administration, doses, and dosing regimen   
1.5.1 Description and justification of the study design 
The BCD-148-3 trial is a double-blind, randomized clinical study to compare the 
pharmacokinetics, pharmacodynamics, safety, and immunogenicity of single intravenous doses of 
BCD-148 (JSC BIOCAD, Russia) and Soliris® in healthy subjects. The study is planned to involve 
two parallel arms: the BCD-148 arm and the Soliris® arm. 
The suggested double-blind randomized parallel-group design that utilizes a drug with 
demonstrated efficacy (reference drug) as an active control is aimed at proving pharmacokinetic 
equivalence of a biosimilar BCD-148 (test drug) and Soliris® (reference drug) in terms of the key 
PK parameters. This is a common approach in the development of biosimilars, which complies 
with the Russian 7 and international8 regulations. 
 
7 A.N. Mironov, V.G. Kukes, V.I. Petrov, A.L. Kuznetsov, D.V. Goryachev, R.R. Niyazov, A.B. Prokofyeva, S.V. 
Nedogoda, M.Yu.Frolov, A.Shnayder. Bioequvalence evaluation for generic medicinal products // Guidance on 
evaluation of medicinal products Vol. I – M.: Grif and K, 2013. 
8Rulesfor investigation of biologics (Eurasian Economic Comission)  
https://docs.eaeunion.org/docs/ru-ru/01411969/cncd_21112016_78 

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The EMA9,10 The EMA, guidelines state that for long half-life products (such as 
eculizumab) a parallel-group study design is preferred to crossover ("A parallel group design may 
be necessary due to the long half-life of MAbs and the potential influence of immunogenicity”). 
The study population was selected according to recommendations laid out in the EMA’s 
Guideline on Similar biological medicinal products containing monoclonal antibodies – non-
clinical and clinical issues11 in the Eurasian Economic Unit’s guidelines12 (“…  if feasible, a single 
dose study in healthy volunteers is recommended, which could provide important information on 
biosimilarity.”). 
Blood sampling points for PK assessment were chosen based on the available information 
on eculizumab PK. According to the international guidelines, blood sampling in single-dose 
studies should cover a long-term period including the late-phase elimination. With the knowledge 
of the Soliris® half-life (T½ 11.3±3 days or 272±82 h), this study with multiple blood collections 
for PK, PD, and safety assessment was planned to last for 59 days. This period is approximately 5 
half-lives of eculizumab (56.5 days 1360 h). The sampling time should ensure several collections 
for each fragment of the PK curve - at least 3 samples in the initial increase phase and at least 5 
samples in the decrease phase. With this consideration in mind and with the available data on 
eculizumab PK, the following blood collection timepoints were chosen for the study of BCD-
148/Soliris®: immediately before dosing, then 5 min, 4 h, 8 h, 12 h, 24 h, 48 h, 72 h, 120 h, 192 h, 
264 h, 360 h, 528 h, 696 h, 864 h, 1032 h, 1200 h and 1392 h post-dose.  
The primary endpoint to test the hypothesis (AUC(0-∞) - the area under the Time vs. 
Concentration curve from 0 h to infinity) and secondary PK parameters were chosen as suggested 
in the EMA’s guideline on biosimilar monoclonal antibodies13 (“In a single dose study, the 
primary parameter should be the AUC(0-inf). Secondary parameters such as Cmax, Tmax, volume of 
distribution, and half-life, should also be estimated”). 
This study also includes a thorough assessment and comparison of eculizumab PD marker 
- hemolytic complement activity. This is to provide the most valid and comprehensive data on the 
comparability of BCD-148 and the reference drug Soliris® (“Pharmacokinetic studies should be 
 
9Guideline on similar biological medicinal products containing monoclonal antibodies – non-clinical and clinical 
issues. EMA/CHMP/BMWP/403543/2010, 2012. 
10Guideline on the clinical investigation of the pharmacokinetics of therapeutic proteins (CHMP/EWP/89249/2004) 
11 Guideline on Similar biological medicinal products containing monoclonal antibodies – non-clinical and clinical 
issues, May, 2012. 
12Rules for investigation of biologics (Eurasian Economic Commission) https://docs.eaeunion.org/docs/ru-
ru/01411969/cncd_21112016_78 
13 Guideline on Similar biological medicinal products containing monoclonal antibodies – non-clinical and clinical 
issues, May, 2012. 

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combined with pharmacodynamic (PD) endpoints, where available. This could add valuable 
information for the overall comparability exercise. PD markers are especially valuable if they are 
sensitive enough in order to detect small differences, and if they can be measured with sufficient 
precision) 14. 
1.5.2. Description and justification of the route of administration, doses, and dosage 
regimen 
In this clinical study, healthy subjects will receive a single infusion of 900 mg BCD-148 
or 900 mg Soliris® each. 
The test drug BCD-148 is a biosimilar to Soliris®, a drug used to treat PNH and aHUS. 
Therefore, the dose and route of administration (900 mg given as an IV drip infusion) proposed in 
this study match the standard single therapeutic dose used in the maintenance treatment phase in 
PNH patients as described in the approved Soliris® Instruction for Medical Use15. 
A single dose of the test drug puts the subjects at a minimal risk of any health damage. A 
single dose administration with a subsequent follow-up period allows investigating, as full as 
possible, the PK and PD of the drug. This regimen avoids any carry-over (cumulative) effects, 
which are possible upon repeated dose administration of a monoclonal drug with unknown 
pharmacokinetics. Therefore, such regimen brings to a minimum the risk of data contamination. 
Since there are certain health risks associated with immunosuppression caused by complement C5 
inhibition, assessment of the clinical effects of the repeated-dose regimen in patients is preferred 
in Phase II clinical studies. 
A single drip infusion of eculizumab with subsequent follow-up is to demonstrate whether 
BCD-148 and Soliris® have equivalent PK as well as to investigate and compare their PD and 
safety.  
Eculizumab is used to treat PNH and aHUS. In both diseases, it is used at a 900 mg dose 
(maintenance phase in PNH and initial phase in aHUS. Thus, this dose is the most sensitive one to 
detect the differences (if any) in the PK between BCD-148 and Soliris®. This approach is 
consistent with the international requirements stated in the above listed guidelines (“In principle, 
it is not required to test all therapeutic dosage regimens; the most sensitive dose should be selected 
to detect potential differences in PK between the biosimilar and the reference products”). 
Conclusions 
 
14Rules for investigation of biologics (Eurasian Economic Commission) https://docs.eaeunion.org/docs/ru-
ru/01411969/cncd_21112016_78 
15https://grls.rosminzdrav.ru/Grls_View_v2.aspx?routingGuid=775bf971-249e-427e-9b82-1c5c2a9c2c51&t= 

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The study design, route of administration, dosing regimen, and follow up methodology are 
feasible, ethically and scientifically justified, and do not bring any excessive risk to study subjects. 
1.6. Clinical study compliance with regulatory requirements 
The clinical trial will be conducted according to this Protocol developed in full compliance with 
the current law of the Russian Federation, Federal Law No. 61-FZ of April 12, 2012: On the Circulation of 
Medicines; National Standard of the Russian Federation GOST R 52379-2005 Good Clinical Practice; the 
rules of Good Clinical Practice of the Eurasian Economic Union; the Constitution of the Russian Federation; 
Federal Law No. 323-FZ of November 21, 2011: On Public Health Protection in the Russian Federation; 
the WMA Declaration of Helsinki (Fortaleza 2013), Order No. 200n of April 01, 2016 On Approval of the 
Good Clinical Practice; the GCP principles, and the current law and regulations of the participating 
countries. 
1.7. Study population 
Healthy male subjects aged from 18 to 45 years (inclusive) and meeting the eligibility 
criteria set by the Protocol. 
 1.8. References 
1. 
Janeway CA Jr., Travers P, Walport M, Shlomchik MJ. Immunobiology. 5th ed. — Garland 
Publishing, 2001. 
2. 
A.D. Kulagin, I. A. Lisukov, V.V. Ptushkin, E. Р. Shilova, N. V. Tsvetaeva, E. A. 
Mikhailova. National Clinical Guidelines on Diagnostics and Treatment of Paroxysmal Nocturnal 
Hematuria. Hemoblastoses: Diagnostics, Treatment, and Supportive Therapy. Oncohematology. 
2014; 2: 20-28. 
3. 
SCIENTIFIC DISCUSSION EMEA 2007. 
4. 
Hillmen P., Lewis S. M., Bessler M. et al. Natural history of paroxysmal nocturnal 
hemoglobinuria. N Engl J Med 1995;333:1253-8.  
5. 
Socié G., Mary J. Y., de Gramont A. et al. Paroxysmal nocturnal haemoglobinuria: long-
term 
follow-up 
and 
prognostic 
factors. 
French 
Society 
of 
Haematology. 
Lancet 
1996;348(9027):573–577. 
6. 
Kelly R., Richards S., Hillmen P., Hill A. The pathophysiology of paroxysmal nocturnal 
hemoglobinuria and treatment with eculizumab. Ther Clin Risk Manag 2009;5:911–921. 
7. 
McKeage K. Eculizumab: a review of its use in paroxysmal nocturnal haemoglobinuria. 
Drugs 2011;71: 2327–45.  

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8. 
Lee J., Jun Ho J., Sung Soo Y. et al. High prevalence and mortality associated with 
thromboembolism in Asian patients with paroxysmal nocturnal hemоglobinuria (PNH). 
Haematologica 2010;95:205–206. 
9. 
Hill A., Richards S. J., Hillmen P. Recent developments in the understanding and 
management of paroxysmal nocturnal haemoglobinuria. Br J Haematol 2007;137:181–192. 
10. 
Draft Clinical Guidelines on Diagnostics and Treatment of Atypical Hemolytic Uremic 
Syndrome. Working Group: Prof. N.L. Kozlovskaya Prof. E.I. Prokopenko Associate Prof. Kh.M. 
Emirova, К.м.н. Serikova (PhD) 2014 
11. 
Hillmen P., Muus P., Dührsen U. et al. Effect of the complement inhibitor eculizumab on 
thromboembolism in patients. Blood. 2007 Dec 1;110(12):4123-8.  
12. 
 Extension of indication variation assessment report EMA/CHMP/204109/2015. 

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2. STUDY PURPOSE AND OBJECTIVES 
2.1 Study purpose 
To perform a comparative assessment of the pharmacokinetics, pharmacodynamics, safety, 
and immunogenicity of a single intravenous infusion of BCD-148 and Soliris® in healthy subjects. 
2.2 Study objectives 
1. To determine and compare the PK parameters of BCD-148 and Soliris®, each given as a 
single intravenous infusion 
2. To determine and compare the PD parameters of BCD-148 and Soliris®, each given as a 
single intravenous infusion 
3. To determine and compare the adverse event profile with a single infusion of BCD-148 
and Soliris® 
4. To evaluate and compare the proportion of BAb- and NAb-positive subjects in the BCD-
148 and Soliris® arms after a single drug infusion. 
3. STUDY HYPOTHESIS 
The study is to test the hypothesis that the test drug BCD-148 and the reference drug 
Soliris® have equivalent pharmacokinetics. The equivalence hypothesis will be tested for the 
primary PK endpoint – AUC(0-∞) of eculizumab after a single IV infusion of BCD-148/Soliris®. 
BCD-148 will be proved equivalent to Soliris® if the limits of the two-sided 95% CI for the ratio 
of the geometric means of eculizumab AUC(0-∞) values after a single IV infusion of BCD-148 and 
Soliris® fall within 80.00-125.00%. 
4. STUDY DESIGN 
4.1. Primary and secondary outcome measures to be assessed in the study 
4.1.1 PK endpoints 
Pharmacokinetic assessment will be based on the concentration of eculizumab (monoclonal 
antibodies to complement C5) measured in the serum of healthy volunteers. 
The primary endpoint for PK assessment after a single infusion of BCD-148/Soliris®: 
• AUC0-∞ of eculizumab (the area under the Concentration vs. Time curve from 0 to infinity).  

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The secondary endpoints for PK assessment after a single infusion of BCD-
148/Soliris®: 
• Cmax of eculizumab (maximum concentration of eculizumab in the serum) 
• Тmax of eculizumab (time to Cmax) 
• AUC0-1392 of eculizumab (the area under the Concentration vs. Time curve from 0 to 1392 h 
post-infusion) 
• Т1/2 of eculizumab (half-life) 
• Vd of eculizumab (steady-state volume of distribution) 
• Кel  of eculizumab (elimination constant) 
• Cl of eculizumab (clearance). 
Time points for PK blood collections: 
− 5 min before the infusion of BCD-148/Soliris® 
− 5 min, 4 h (±5 min), 8 h (±10 min), 12 h (±15 min), and 24±1 h post-infusion 
− 2 days (48±1 h), 3 days (72±2 h), 5 days (120±3 h), 8 days (192±4 h), 11 days (264±4 h), 
15 days (360±4 h), 22 days (528±4 h), 29 days (696±4 h), 36 days (864±4 h), 43 days 
(1032±4 h), 50 days (1200±4 h), and 58 days (1392±4 h) post-infusion. 
The PK endpoints will be analyzed when all the subjects complete the main study period. 
4.1.2 PD endpoints  
Pharmacodynamics will be investigated by measuring the hemolytic complement activity 
in the serum (CH50), where one unit of hemolytic activity is the reciprocal of the serum dilution 
which causes a 50% hemolysis. 
The secondary endpoints for PK assessment after a single infusion of BCD-
148/Soliris®: 
• ABEC(0-1392) CH50 (the area between the baseline and effect curves for hemolytic activity of 
serum complement from 0 to 1392 h) 
• AUEC(0-1392) CH50 ((area under the Time vs. Effect curve from 0 to 1392 h) 
• Emin CH50 (minimum hemolytic complement activity from 0 to 1392 h) 
• Tmin CH50 (time to minimum hemolytic complement activity within the period from 0 to 
1392 h). 
Time points for PD blood collections: 
− 5 min before the infusion of BCD-148/Soliris® 

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− 5 min, 4 h (±5 min), 8 h (±10 min), 12 h (±15 min), and 24±1 h post-infusion 
− 2 days (48±1 h), 3 days (72±2 h), 5 days (120±3 h), 8 days (192±4 h), 11 days (264±4 h), 
15 days (360±4 h), 22 days (528±4 h), 29 days (696±4 h), 36 days (864±4 h), 43 days 
(1032±4 h), 50 days (1200±4 h), and 58 days (1392±4 h) post-infusion. 
The PD endpoints will be analyzed when all the subjects complete the main study period. 
 
 

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4.1.3. Safety endpoints: 
• 
The proportion of subjects who develop AEs/SAEs that, in the investigator’s opinion, are 
related to eculizumab 
• 
The proportion of subjects who develop СТСАЕ v. 4.03 grade 3/4 AEs that, in the 
investigator’s opinion, are related to eculizumab, by study arms. 
The safety endpoints will be analyzed when all the subjects complete the main study period. 
4.1.4. Immunogenicity endpoints 
• 
The proportion of BAb- and NAb-positive subjects 
Time points for immunogenicity blood collections: 
− 
5 min before the infusion of BCD-148/Soliris® 
− 
29 days after the infusion of BCD-148/Soliris® 
− 
Completion of the main study period (Day 59 of the study). 
The immunogenicity endpoints will be analyzed when all the subjects complete the main 
study period. 
4.2. Study Design 
This is a double-blind, randomized clinical study to compare the pharmacokinetics, 
pharmacodynamics, safety, and immunogenicity of single intravenous doses of BCD-148 (JSC 
BIOCAD, Russia) and Soliris® in healthy volunteers 
The suggested double-blind randomized parallel-group design that utilizes a drug with 
demonstrated efficacy (reference drug) as an active control is aimed at proving pharmacokinetic 
equivalence of a biosimilar BCD-148 (test drug) and Soliris® (reference drug) in terms of the key 
PK parameters. This is a common approach in the development of biosimilars, which complies 
with the Russian 16 and international17 regulations. 
The EMA18,19 guidelines state that for long half-life products (like eculizumab) a parallel-
group study design is preferred to crossover. 
 
16 A.N. Mironov, V.G. Kukes, V.I. Petrov, A.L. Kuznetsov, D.V. Goryachev, R.R. Niyazov, A.B. Prokofyeva, S.V. 
Nedogoda, M.Yu.Frolov, A.Shnayder. Bioequvalence evaluation for generic medicinal products // Guidance on 
evaluation of medicinal products Vol. I – M.: Grif and K, 2013. 
17Rulesfor investigation of biologics (Eurasian Economic Comission)  
https://docs.eaeunion.org/docs/ru-ru/01411969/cncd_21112016_78 
18Guideline on similar biological medicinal products containing monoclonal antibodies – non-clinical and clinical 
issues. EMA/CHMP/BMWP/403543/2010, 2012. 
19Guideline on the clinical investigation of the pharmacokinetics of therapeutic proteins (CHMP/EWP/89249/2004) 

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It is planned to randomized 78 adult healthy volunteers who then will be assigned at a 1:1 
ratio to one of two treatment arms: 39 subjects in the BCD-148 arm and 39 subjects in the Soliris® 
arm.  
During the study, each volunteer will receive a single IV infusion of 900 mg BCD-148 
(test drug) or 900 mg Soliris® (reference drug). 
Before enrollment, all volunteers will be given all the information about this clinical study, 
its purpose and the risks associated with study participation. After signing the informed consent 
form (ICF), each subject will undergo a screening examination (no longer than 20 days), which is 
to find out whether the subject meets the eligibility criteria. 

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4.3. Measures to minimize/eliminate bias 
4.3.1. Inclusion of subjects in the study and assigning the screening and study IDs 
Subjects will be randomized and assigned study IDs according to internal JSC BIOCAD 
procedures. 
The study site will be assigned a two-digit ID (e.g. 01, etc.). 
After the subject signs the ICF, he is assigned a 5-digit screening number consisting of a 
2-digit site number and a 3-digit subject number (continuing numbering in sequence, as subjects 
are enrolled at this site). This information is recorded in the source documents and screening log. 
For example, at the study site 02, the first subject who has signed the ICF will receive the screening 
number 02-01. 
When all screening procedures are completed, and the investigator decides that the subject 
meets all eligibility criteria, the investigator enters all the required information into the eCRF 
(Screening Visit). The Sponsor gets an automatic notification that the investigator filled out these 
pages. If JSC BIOCAD approves the subject, he is then randomized and assigned a Subject ID and 
a drug lot number. The investigator must document the Subject ID and lot number in the source 
documents and eCRF. 
Only those subjects will be assigned the Subject ID, whose lab test results (hemoglobin, 
RBC, WBC, leukocytes, neutrophils, ESR, bilirubin total, ALT, AST) from the Screening Visit 3 
/ Day -3 – -1 are within the reference range, and who have no post-injection complications or signs 
of acute and/or aggravated chronic infections and non-infectious diseases that, in the investigator’s 
opinion, can prevent the subject from further study participation.  
The Subject ID consists of 5 digits with 2 digits for the study site and 3 digits for the 
subject’s number in the study.  
For example, the Subject ID is “01-030”, where “01” is the site number and “030” is the 
order number as the subject was included in the study. 
4.3.2. Stratification procedure  
As this study involves only healthy male subjects all from the same age group, no 
stratification will be performed. 

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4.3.3. Randomization procedure 
Randomization in the study will be centralized. The subjects will be randomized in 1:1 
ratio to the BCD-148 and Soliris® arms. 
During randomization, JSC BIOCAD will monitor the total number of enrolled 
participants.  
4.3.4. Blinding  
Neither subjects nor investigators will be aware of what drug was administered to which 
subject during Visit 1 / Day 1. The study/reference drug will be delivered to the study site in 
identical secondary packaging (cartons) differing only by lot numbers and expiry dates. The lot 
numbers will be subject-specific.  
4.4. Description of the study treatment, dose and dosing regimen for the investigational 
product(s). Pharmaceutical form, packaging, and labeling of investigational products 
4.1.4. Description of the study treatment, dose, and dosing regimen for the investigational 
product(s) 
In this clinical study, each healthy volunteer will get one infusion of either the test drug 
BCD-148 or the reference drug Soliris®, depending on the study arm to which the subject is 
randomized. Both eculizumab products (BCD-148/Soliris®) will be administered as a single 900 
mg drip infusion given over 25-45 min. The infusion will be given at the study site. 
See section 1.2.4. Description and justification of route of administration, doses, and 
dosing regimen. 
4.4.2. Pharmaceutical form, packaging, and labeling of investigational products 
4.4.2.1. Test drug 
See Section 1.2.1. Test Drug and 1.2.3. Labeling of the Study and Reference Products in this Study. 
4.4.2.2. Reference drug 
See section 1.2.2. Reference Drug and 1.2.3. Labeling of the Study and Reference Products in This 
Study. 

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4.4.2.3. Meningococcal vaccine 
Invented name: Menactra® (meningococcal (serotypes А, С, Y and W-135 polysaccharide 
diphtheria toxoid conjugate vaccine).  
Generic Name: Vaccine to prevent meningococcal infection. 
Therapeutic category: Medical immunobiologic vaccine 
Dosage form: Solution for intramuscular injection. 
Composition: 
1 dose (0.5 mL) of the vaccine contains:  
Active substances:  
Meningococcal polysaccharides conjugated with a protein carrier: 
Meningococcal A polysaccharide* – 4 µg 
Meningococcal C polysaccharide* – 4 µg 
Meningococcal Y polysaccharide* – 4 µg 
Meningococcal W-135 polysaccharide* – 4 µg 
* Each polysaccharide in conjugated to diphtheria toxoid protein. One vaccine dose contains 
approximately 48 µg of diphtheria toxoid protein. 
Excipients: 
Sodium chloride 4.35 mg, sodium hydrogen phosphate 0.348 mg, sodium dihydrogen phosphate 
monohydrate 
0.352 mg, water for injection ad 0.5 mL.  
Description:  
Colorless clear or slightly opalescent solution. 
Marketing authorization holder Sanofi Pasteur Inc.20. 
Shelf life: 2 years. 
Storage and transportation conditions: At a temperature from 2 to 8 °С. Do not freeze. Keep 
out of the sight and reach of children. Do not use if the vaccine had been frozen. 
Packaging:  
This is a marketed drug. The package is in accordance with the approved specification. 
Posology and route of administration:  
Menactra® is administered as a 0.5 mL dose. 
 
20 If the product is not available or difficult to purchase in the Russian Federation, it will be purchased in other 
countries. 

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The preferred injection site is the deltoid muscle. Subjects 2 years to 55 years of age should 
receive one dose (0.5) of Menactra®. 
4.5. Expected duration of the study and subjects’ participation in the study 
The study is expected to last for 2 years, which includes subject recruitment, the treatment 
and follow-up period, and statistical processing of results.  
The expected duration of study participation for each particular subject is 82 days from the 
moment the subject signs the ICF. This includes the screening period (20 days maximum), 
maximum of 3 days from randomization to Visit 1/ Day 1, and the main study period (59 days). 
4.6. Study periods 
4.6.1 Study visits and procedures 
The visit schedule and procedures are the same for both study arms. The study includes the 
screening period and 12 visits in the main study period.  
The visits in the main study period cannot be re-scheduled because each of these visits 
involves blood collection for PK/PD assessment. 
 

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Table 6. Schedule of study visits and assessments 
Visit 
Screeni
ng 
- Visit 1 
Scree
ning 
- Visit 
2 
Screen
ing 
Phone 
Call 
Screen
ing 
- Visit 
3 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
Visit 
-20 – -
18 
-17 
-15 
-3 – -1 
Day 1 
Day 2 
Day 3 
Day 4 
Day 6 
Day 9 
Day 
12 
Day 
16 
Day 
23 
Day 
30 
Day 
37 
Day 
44 
Day 
51 
Day 
59 
Signing the ICF 
+ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Life and disease history 
+ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Information 
about 
concomitant therapies 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
Vital signs21 
+ 
+ 
 
+ 
+22 
 
 
 
+ 
 
 
+ 
 
+ 
 
 
 
+ 
Physical examination 
+ 
+ 
 
+ 
+ 
 
 
 
+ 
 
 
+ 
 
+ 
 
 
 
+ 
Chest 
x-ray 
and 
fluorography23 
+ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG 
+ 
 
 
 
 
 
 
 
 
 
 
 
 
+ 
 
 
 
+ 
Venous catheter inserted into 
the vein 
 
 
 
 
+ 
 
 
 
 
 
 
 
 
 
 
 
 
 
Venous catheter removed 
 
 
 
 
 
+ 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology 
+ 
 
 
+ 
 
+ 
 
 
+ 
+ 
 
+ 
+ 
+ 
 
+ 
 
+ 
Chemistry 
+ 
 
 
+ 
 
 
 
 
+ 
 
 
+ 
 
+ 
 
 
 
+ 
Coagulation pattern 
+ 
 
 
 
 
 
 
 
+ 
 
 
+ 
 
+ 
 
 
 
+ 
Urinalysis 
+ 
 
 
 
 
 
 
 
+ 
 
 
+ 
 
+ 
 
 
 
+ 
Blood for PK/PD assessment24 
 
 
 
 
+25 
 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
Blood for immunogenicity 
testing 
 
 
 
 
+26 
 
 
 
 
 
 
 
 
+ 
 
 
 
+ 
 
21BP, wrist pulse, body temperature, body weight, and height (body weight and height are measured on Screening Visit 1). 
22BP, wrist pulse, and body temperature are checked on Day 1 before the infusion, immediately after the infusion, and 1 h, 4 h, 8 h, and 12 h post-infusion. 
23 Results obtained within 2 months before signing the ICF can be used at screening. 
24 Details of timepoints for blood sampling are described in Table 9. 
25Blood samples for PK/PD study on Day 1 are collected 5 min before the infusion and then 5 min, 4 h  (±5 min), 8 h (±10 min), and 12 h (±15 min) post-infusion. 
26Blood is collected before the infusion of BCD-148/Soliris.  

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Visit 
Screeni
ng 
- Visit 1 
Scree
ning 
- Visit 
2 
Screen
ing 
Phone 
Call 
Screen
ing 
- Visit 
3 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
Visit 
-20 – -
18 
-17 
-15 
-3 – -1 
Day 1 
Day 2 
Day 3 
Day 4 
Day 6 
Day 9 
Day 
12 
Day 
16 
Day 
23 
Day 
30 
Day 
37 
Day 
44 
Day 
51 
Day 
59 
Blood tests for HIV, hepatitis 
and syphilis27.28 
+ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol test 
+ 
 
 
 
+29 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine test for psychotropic and 
recreational 
drugs, 
psychoactive medications 
+ 
 
 
 
+30 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vaccination 
 
+31 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Infusion of BCD-148/Soliris® 
 
 
 
 
+ 
 
 
 
 
 
 
 
 
 
 
 
 
 
Documenting SAEs/AEs 
+ 
+32 
+ 
+ 
+33 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
Assess 
conformance 
to 
inclusion/exclusion criteria 
+ 
 
 
+34 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Phone interview 
 
 
+ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
27Results of not earlier than 2 months ago before signing the ICF can be used at screening. 
28 Antibodies to HIV, HBsAg, HCV, syphilis. 
29Alcohol testing on Visit 1 is performed before the first pre-infusion blood sampling. 
30Performed before the first pre-infusion blood sampling. 
31The subject is vaccinated only if he meets all eligibility criteria according to the interview, medical history, physical examination from Screening Visit 1, and laboratory/instrumental 
test results. 
32During the period from vaccination (Screening Visit 2) and until the end of the screening, all AEs (including SAEs) considered by the investigator as post-vaccination complications 
must be captured. 
33Starting from Visit 1 / Day 1 post-infusion, all AEs/SAEs must be captured (regardless of how the investigator assesses the casual relationship to the study drug). 
34On Screening Visit 3, to re-confirm the subject-s eligibility blood will be collected for hematology and chemistry tests and subjects will be evaluated for any post-vaccination 
complications and any signs of acute and/or aggravated chronic infections or non-infectious diseases that may, in the investigator’s opinion, prevent the subject from further participation 
in the study. Only those subjects will be assigned the Subject ID, whose lab test results (hemoglobin, RBC, WBC, leukocytes, neutrophils, ESR, bilirubin total, ALT, AST) from the 
Screening Visit 3 / Day -3 – -1 are within the reference range, and who have no post-injection complications or signs of acute and/or aggravated chronic infections and non-infectious 
diseases that, in the investigator’s opinion, can prevent the subject from further study participation. 

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5. ELIGIBILITY AND EXCLUSION OF STUDY SUBJECTS 
5.1. Inclusion criteria 
1. Signed ICF for participation in the study 
2. Men from 18 to 45 years old (inclusive) at the time of signing the ICF 
3. BMI within the normal limits (18.0 to 30 kg/m2) 
4. The subject is able to follow the Protocol procedures (in the investigator’s opinion) 
5. The subject is verified as “Healthy” according to results of standard clinical, laboratory 
and instrumental tests 
6. Normal hemodynamic parameters: systolic BP from 90 mmHg to 130 mmHg; diastolic BP 
from 60 mmHg to 90 mmHg; HR from 60 bpm to 90 bpm 
7. The subject and his sex partner of childbearing potential consent to implement reliable 
contraceptive methods from the moment the subject signs the ICF and until the subject 
completes the study. This requirement does not apply to those subjects who had undergone 
surgical sterilization. Reliable contraception methods mean one barrier method in 
combination with one of the following: spermicides, intrauterine device and/or oral 
contraceptives used by the subject's partner. 
8. The subject agrees not to drink alcohol for 24 h prior to the infusion of the test/reference 
drug and for the entire period while the subject is in the study. 
5.2 Exclusion criteria 
1. Psychiatric disorders or other conditions that can affect the ability of the subject to follow 
the study protocol 
2. Acute infections within 4 weeks before signing the ICF 
3. Results of laboratory and/or instrumental tests are outside the site’s normal range 
4. Any surgery done within 30 days before the screening or planned within 30 days after the 
subject completes the study 
5. Impossibility to insert an intravenous catheter for blood collection (e.g., because of a skin 
condition at the venipuncture site) 
6. A history of allergies 
7. Known hypersensitivity to any component of BCD-148 or Soliris®, murine proteins or 
other drug components; hypersensitivity to any component of the meningococcal vaccine 
8. The subject had used any medications that significantly affect hemodynamics, liver 

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function, etc. (barbiturates, omeprazole, cimetidine, etc.) within 30 days before signing the 
ICF and/or the subject needs any medications (other than the study drugs) to be taken 
during the entire study period 
9. The subject had previously used eculizumab and/or other therapeutic monoclonal 
antibodies against complement C5 
10. Regular use (oral or parenteral) of any drugs, including OTC products, vitamins or 
biologically active supplements within 14 calendar days before signing the ICF 
11. A history of recurrent/chronic hemorrhages or any hemorrhage within 30 days prior to 
signing the ICF 
12. Acute or chronic infections or other diseases that, in the investigator’s opinion, may affect 
the PK, PD or safety of the study products 
13. HIV, HCV, HBV infection, syphilis. 
14. Meningococcal infection in the past (documented or mentioned verbally by the subject) 
15. Vaccination within 4 weeks before the planned infusion date, except for vaccination 
against Neisseria meningitidis given to all subjects in the screening period 
16. The subject refuses to get a vaccination against Neisseria meningitidis during the screening 
period35. 
17. The subject smokes more than 10 cigarettes per day 
18. The subject consumes more than 10 units of alcohol per week (1 unit equals to 0.5 L of 
beer, 200 mL of wine or 50 mL of a strong alcohol beverage) or has a history of alcohol, 
recreational drug or medication abuse, or tests positive for alcohol and/or psychoactive 
substances during the screening examination 
19. Donation of ≥ 450 mL of blood or plasma within 60 calendar days before signing the ICF. 
20. Participation in any drug clinical studies within 30 calendar days prior to signing the 
informed consent form and through the entire period of study participation. 
5.3. Withdrawal criteria 
Refer to section 4.7. Stop rules and criteria for premature withdrawal for study subjects, 
study periods, and study as a whole. 
The investigator must inform JSC BIOCAD about the subject’s premature withdrawal 
within 24 h and specify the reason. 
 
35 Except for cases when the subject has a documented evidence that he received a tetravalent meningococcal vaccine 
(serogroups A, C, Y, and W-135) within 2 years before signing the informed consent form If the previous vaccination 
was performed with a vaccine other that MCV4, the subject has to be re-vaccinated. 

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5.3.1. Replacing drop-outs 
Those subjects who dropped out after randomization will not be replaced. The sample size 
was calculated with an account for potential dropouts. 
5.4 Follow-up of subjects withdrawn from the study or subjects who discontinued the study 
treatment but remain in the study for follow-up 
5.4.1. Follow-up of subjects who received at least one dose of BCD-148/Soliris® 
If the subject discontinues the study after receiving the test/reference drug, an Early 
Withdrawal Visit is performed and the Early Withdrawal Form is filled out.  
Procedures of the Early Withdrawal Visit: 
1. Information about concomitant therapies 
2. Physical examination 
3. Vital signs (BP, wrist pulse, body temperature) 
4. Hematology, chemistry, and urinalysis 
5. Documenting AEs/SAEs 
If the subject discontinues the study due to an AE/SAE, the investigator should conduct 
further treatment and follow-up after the Early Withdrawal Visit in accordance with the study site 
standards for the treatment of a certain AE or SAE. The subject should be followed up until the 
AE or SAE resolves completely.  
6. ADMINISTRATION OF THE INVESTIGATIONAL PRODUCT  
6.1 Route of administration used in the study 
In this clinical study, each subject will get one infusion of either the test drug BCD-148 or 
the reference drug Soliris®, depending on the study arm to which the subject is randomized. Both 
eculizumab products (BCD-148/Soliris®) will be administered as a single 900 mg drip infusion 
given over 25-45 min. The infusion will be given at the study site. 
See section 1.2.4. Posology and route of administration. 
6.2. Dose modification for the study drug 
Not applicable.  

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6.3. Overdose 
Any dose higher than the dose specified by the Protocol is considered an overdose. 
Repeated administration of the study drug is also considered an overdose, regardless of the dose 
and time of infusion. 
In the case of an overdose, the subject should be monitored for any toxicity signs. If any 
toxicity signs are observed, standard symptomatic therapy should be given. 
In the case of an overdose, either associated or not with an adverse event (serious or non-
serious), the investigator must fill out the Overdose Report Form. An Overdose Report has to be 
immediately (within 24 h) submitted to the Sponsor at safety@biocad.ru (please put “ATTN 
Responsible Pharmacovigilance Officer” in the subject field). 
6.4. Concomitant therapy, medications allowed and prohibited by the Protocol 
The Protocol does not include any medications other than the test/reference drug.  
Symptomatic treatment can be used if the investigator believes it will not affect the 
assessment of eculizumab PK/PD. Instruction on the use of symptomatic treatments are provided 
in the relevant Instructions for Medical Use.  
If during the study, the subject develops an intercurrent illness/condition, a concurrent 
therapy can be prescribed in accordance with the site standard of care. Such therapy can include 
antipyretic drugs, pain-relief drugs, antihistamine, and mucolytic agents, nonsteroidal anti-
inflammatory drugs (NSAIDs), etc. For example, the symptomatic treatment of an acute upper 
respiratory tract infection may include (based on the indication): Ascorbic acid, mucolytic agents, 
expectorants, antipyretics (paracetamol, ibuprofen, etc.), oral/throat antiseptic solutions, nasal 
vasoconstriction sprays, inhaled vasoconstrictors (if the subject has signs of respiratory obstruction 
or has any other indications for inhaled vasoconstrictor therapy), and detoxification therapy. If the 
subject develops a bacterial infection which requires antibiotics actively secreted by the renal 
tubule (e.g. cephalosporins) should be the treatment of choice.   
In the case of any life-threatening complications or conditions that require additional 
medication and/or in the case of severe adverse reactions, the investigator may use any medications 
(including antibacterial and hormonal) needed to stabilize and improve the subject’s health. All 
medications used to treat the complication/condition should be listed in the respective section of 
the eCRF. 

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6.5. Compliance with study procedures 
In this study, the information will be documented about each administration of the 
investigational product, doses, and intervals between the study visits.  
The CRA will review accountability records during the monitoring visits and at the end of 
the study. 
6.6. Compliance 
In this study, a subject will be considered non-compliant if: 
− He did not attend 2 or more visits 
− Time deviations were reported for 2 or more visits36,37. 
7. PK AND PD ASSESSMENT 
7.1. List of pharmacokinetic parameters 
Pharmacokinetic assessment will be based on the concentration of eculizumab (monoclonal 
antibodies to complement C5) in the serum of healthy subjects. 
 
The primary PK endpoint for PK after a single infusion of BCD-148/Soliris®: 
• AUC0-∞ of eculizumab (the area under the Concentration vs. Time curve from 0 to infinity).  
The secondary PK endpoints after a single infusion of BCD-148/Soliris®: 
• Cmax of eculizumab (maximum drug concentration in the serum). 
• Тmax of eculizumab (time to Cmax) 
• AUC0-1392 of eculizumab (area under the Concentration vs. Time curve from 0 to 1392 h post-
infusion) 
• Т1/2 of eculizumab (half-life). 
• Vd of eculizumab (steady-state volume of distribution) 
 
36If the study visit is performed on the scheduled date but outside the acceptable time window, all the visit procedures 
should be performed including blood collections for immunogenicity testing, but no blood should be collected for PK 
and PD assessment. 
If the visit is performed not on a scheduled date (deviation in the visit date), the procedures scheduled for this visits 
are not performed. This visit is considered a missed visit. The subject should attend the next scheduled visit. All other 
situations should be discussed with the Sponsor. 
37If the subject did not attend Visit 1/ Day 1 due to force majeure, this visit can be re-scheduled but has to be performed 
within 5 days from the original visit date. In this case, dates of all subsequent visits will be counted from the actual 
date of Visit 1. 

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• Кel  of eculizumab (elimination constant) 
• Cl of eculizumab (clearance). 
The PK endpoints will be analyzed when all the subjects complete the main study period. 
7.2. List of pharmacodynamics parameters 
Pharmacodynamics will be investigated by measuring the hemolytic complement activity 
in the serum (CH50), where one unit of hemolytic activity is the reciprocal of the serum dilution 
which causes a 50% hemolysis. 
The secondary endpoints for PD assessment after a single infusion of BCD-
148/Soliris®: 
• ABEC(0-1392) CH50 (the area between the baseline and effect curves for hemolytic activity of 
serum complement from 0 to 1392 h). 
• AUEC(0-1392) CH50 ((area under the Time vs. Effect curve from 0 to 1392 h) 
• Emin CH50 (minimum hemolytic complement activity from 0 to 1392 h) 
• Tmin CH50 (time to minimum hemolytic complement activity within the period from 0 to 
1392 h). 
The PD endpoints will be analyzed when all the subjects complete the main study period. 
8. SAFETY ASSESSMENT  
8.1 List of safety endpoints  
• 
The proportion of subjects who develop AEs/SAEs that, in the investigator’s opinion, are 
related to eculizumab 
• 
The proportion of subjects who develop СТСАЕ v. 4.03 grade 3/4 AEs that, in the 
investigator’s opinion, are related to eculizumab, by study arms. 
Immunogenicity assessment: 
• 
The proportion of BAb- and NAb-positive subjects 

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9. STATISTICAL METHODOLOGY 
9.1 Calculation of PK and PD parameters 
9.1.1. PK parameters 
Eculizumab (anti-C5 MAb) concentrations in the serum of each study subject will be 
measured at timepoints specified by the Protocol, and the following PK parameters will be 
calculated: 
AUC0-∞ of eculizumab (the area under the Concentration vs. Time curve from 0 to infinity). 
𝐴𝑈𝐶0−∞= 𝐴𝑈𝐶0−1392 +
𝐶1392
𝑘𝑒𝑙, where 
C1392 refers to eculizumab concentration in the serum over 1392 h post-infusion, where 𝑘𝑒𝑙 is the 
elimination constant. 
AUC0-1392 (the area under the Concentration vs. Time curve from 0 to 392 h). AUC0-1392 will 
be determined with the trapezoidal rule and the formula where Cp is the concentration of 
eculizumab in the serum at tp (h:) 
𝐴𝑈𝐶(0−1392) = ∑(𝐶𝑝+ 𝐶𝑝−1) ∗(𝑡𝑝−𝑡𝑝−1)
2
18
𝑝=2
 
 𝑡𝑝
∈{0; 0,083; 4;  8; 12; 24; 48; 72; 120; 192; 264; 360; 528; 696; 864; 1032; 1200;  1392 }p=1,…,18 
Cmax is the maximum eculizumab serum concentration achieved during the observation period.  
Tmaxmax is the time to maximum concentration (Cmax). 
AUMC0-1392 is the total area under the first moment curve from 0 to 1392 h. AUMC0-1392 is 
calculated using the following formula: 
𝐴𝑈𝑀𝐶0−1392 = ∑(𝐶𝑝∗𝑡𝑝+ 𝐶𝑝−1 ∗𝑡𝑝−1) ∗(𝑡𝑝−𝑡𝑝−1)
2
18
𝑝=2
, 
 где С𝑝−концентрация экулизумаба  
в сыворотке крови в момент времени 𝑡𝑝 
 𝑡𝑝
∈{0; 0,083; 4;  8; 12; 24; 48; 72; 120; 192; 264; 360; 528; 696; 864; 1032; 1200;  1392}p=1,…,18 
Total clearance (Cl) is the volume of a test tissue from which a drug is completely removed per 
unit time. It is calculated as a drug dose (DOSE) divided by AUC0-1392: 

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𝐶𝐿=
𝐷𝑂𝑆𝐸
𝐴𝑈𝐶0−1392  
Mean residence time (MRT) is calculated as a AUMC0-1392 to AUC0-1392 ratio: 
MRT = AUMC0−1392
AUC0−1392
 
Elimination rate constant (kel) will be calculated as follows: 
𝑘𝑒𝑙=
1
𝑀𝑅𝑇   
Elimination half-life (T1/2) will be calculated as follows: 
 𝑇1/2 = ln (2)
𝑘𝑒𝑙
= ln(2) ∗𝑀𝑅𝑇 
Volume of distribution (Vd) is a proportionality factor that relates the drug concentration in a test 
tissue to the amount of drug in the body. It shows the intensity of drug distribution between a test 
tissue and other tissues: 
𝑉𝑑= 𝐶𝐿∗𝑀𝑅𝑇 
9.1.2. PD parameters 
The hemolytic complement activity (CH50) (where one unit of hemolytic activity is the 
reciprocal of the serum dilution which causes a 50% hemolysis) at protocol-specified endpoints 
will be used to calculate the following PD measures: 
AUEC(0-1392) - the area under the Time vs. Effect curve from 0 to 1392 h) The AUEC0-1392 will be 
calculated using the trapezoidal rule and the following formula: 
𝐴𝑈𝐸𝐶0−1392 = ∑(𝐶𝑝+ 𝐶𝑝−1) ∗(𝑡𝑝−𝑡𝑝−1)
2
18
𝑝=2
, 
Where Cp is the hemolytic complement activity in the serum at tp (h) 
∈{0; 0,083; 4;  8; 12; 24; 48; 72; 120; 192; 264; 360; 528; 696; 864; 1032; 1200;  1392 }p=1,…,18 
ABEC - the area between the baseline and effect curves for hemolytic activity of serum 
complement from 0 to 1392 h. To account for baseline variations, the baseline (pre-infusion) 
values will be subtracted from all subsequent measurements.  
𝐴𝐵𝐸𝐶= 𝐴𝑈𝐸𝐶0−1392 −𝑐0 ∗1392 ,  
Where 𝑐0 is the pre-infusion hemolytic complement activity. 

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Emin CH50 - the minimum hemolytic complement activity from 0 to 1392 h. 
Tmin CH50 - the time to minimum hemolytic complement activity within the period from 0 to 
1392 h. 
9.2.  Statistical methods 
The statistical analysis will be performed using two-tailed hypothesis tests. The statistical 
significance level is 0.05. 
The normally distributed quantitative data will be compared using the following tests: the 
two-tailed Student’s t-test, Welch's t-test, and ANOVA. 
The non-normally distributed quantitative data will be compared by using the Mann-
Whitney test, Wilcoxon test, Kruskal-Wallis test, and Friedman’s test. 
The quantitative data: 
• Safety: 
✓ 
Hematology results 
✓ 
Chemistry results 
✓ 
Coagulation pattern. 
• Assessment of PK and PD 
• Demographics 
Demographic data will be tested for normality using the Shapiro-Wilk test. 
Normally-distributed quantitative variables will be described with the following 
characteristics: Mean values, geometric means (PK/PD), SD, CV, medians, quartiles, Min, and 
Max. In addition, the 90% CIs for the ratio of the geometric means will be calculated for AUC(0-
1392)  and Cmax. 
The categorical data: 
Safety and tolerability: 
• ECG findings 
• Urinalysis results 
• The proportion of subjects with AEs/SAEs 
• The proportion of subjects with a grade 3/4 AE/SAE. 
Immunogenicity: 
• The proportion of BAb- and NAb-positive subjects 

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The categorical data will be processed using the frequency tables, exact Fisher's test, 𝜒2 
test, and Cochran-Mantel-Haenszel test. The categorical data will be described using percentages 
or proportions. 
Statistical methods will be chosen based on the type and distribution of raw data. 
Applicability of certain statistical tests will be evaluated after all the data are collected because it 
is impossible to predict the distribution pattern, data homogeneity and other data characteristics in 
advance. 
9.3. Justification of sample size, including reasoning or calculations to justify statistical 
power and clinical justification of the study 
The study is to test the hypothesis that the test drug BCD-148 and the reference drug 
Soliris® have equivalent pharmacokinetics. The equivalence hypothesis will be tested for the 
primary PK endpoint – AUC(0-∞) of eculizumab after a single IV infusion of BCD-148/Soliris®. 
BCD-148 will be proved equivalent to Soliris® if the limits of the two-sided 95% CI for the ratio 
of the geometric means of eculizumab AUC(0-∞) values after a single IV infusion of BCD-148 and 
Soliris® fall within 80.00-125.00%.  
The sample size sufficient for testing the equivalence of eculizumab AUC(0-∞) was 
calculated. The estimation was based on single-dose eculizumab AUC(0-∞) and  Сmax data available 
from literature. Single-doses of the original eculizumab have not been tested in healthy subjects or 
PNH and aHUS patients, therefore the calculations for this protocol were based on AUC and Сmax 
of single-dose 8 mg/kg eculizumab in rheumatoid arthritis patients (C97-001-01) and SLE patients 
(C97-002-01) 38,39. The 8 mg/kg dose was selected as the one closest to the therapeutic dose of 
eculizumab used in this clinical trial. 
Type I error was set as 5% (α=0.05); type II error was set as 20% (β=0.2); test power was 
80%.  
The 
“sampleN.TOST” 
function 
(PowerTOST 
R 
package).[http://cran.r-
project.org/web/packages/PowerTOST/PowerTOST.pdf] was used to compute the sample size for 
the parallel-group design from the CV and the AUC(0-∞) and Cmax ratios. 
Group coefficients of variation were calculated with the following formula: 
 
38http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Scientific_Discussion/human/000791/WC500054212.pdf 
39https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/125166s0000_ClinPharmR.pdf (table 1, page 10) 

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𝐶𝑉= 𝜎
µ, 
Where: σ is the standard deviation of AUC(0-∞) or Cmax; µ is the mean AUC(0-∞) or Cmax. 
Table 10. Estimated CV values for AUC(0-∞) 
Clinical study 
Mean and standard deviation40 
CV 
C97-001-01 
µ = 37.8 mg*h/mL 
σ = 5.9 mg*h/mL 
𝐶𝑉= 5,9
37,8 = 0,1561 
C97-002-01 
µ = 31.6 mg*h/mL 
σ = 9.1 mg*h/mL 
𝐶𝑉= 9,1
31,6 = 0,288 
The group CV was also estimated for the Сmax. 
 
Table 11. Estimated CV values for Cmax 
Clinical study 
Mean and standard 
deviation41 
CV 
C97-001-01 
Μ = 182 µg/mL 
σ = 19 µg/mL 
𝐶𝑉= 19
182 = 0,1044 
C97-002-01 
µ = 160 µg/mL 
σ = 10 µg/mL 
𝐶𝑉= 10
162 = 0,0625 
The table below summarizes the statistical data for the sample size based on the CVs for 
AUC(0-∞) and Cmax. 
 
Table 12. Power and sample size (“sampleN.TOST”) 
Variable 
Ratio of mean 
values 
CV 
Sample size (N) 
Power 
C97-001-01 clinical study 
 
40https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/125166s0000_ClinPharmR.pdf 
41https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/125166s0000_ClinPharmR.pdf 

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Variable 
Ratio of mean 
values 
CV 
Sample size (N) 
Power 
AUC(0-∞) 
µТ
µС = 0.95 
0.1561. 
NAUC 0-∞ = 24 
subjects (12 
subjects/arm) 
83.18% 
Cmax 
µТ
µС = 0.95 
0.1044. 
NCmax = 12 
subjects (6 
subjects/arm) 
83.96% 
C97-001-01 clinical study 
AUC(0-∞) 
µТ
µС = 0.95 
0,288 
NAUC 0-∞ = 70 
subjects (35 
subjects/arm) 
80.01% 
Cmax 
µТ
µС = 0.95 
0,0625 
NCmax = 6 subjects 
(3 subjects/arm) 
86.11% 
Thus, statistical estimate based on the С97-001-01 study shows that this protocol should 
include N= max{NAUC 0-∞, NCmax} =  
= max{24.12}=24 subjects (12 subjects per study arm). 
Statistical estimate based on the С97-002-01 study shows that this protocol should include 
N= max{NAUC 0-∞, NCmax} =  
= max{70.6}=70 subjects (35 subjects per study arm). 
It was shown that to get the full and valid data for testing the hypothesis of PK equivalence 
(the primary PK endpoint of AUC(0-∞)) 70 subjects have to be enrolled in total (35 subjects in each 
arm). This sample size will be sufficient to demonstrate with the 80% power that the two-sided CI 
for the AUC(0-∞) ratio between BCD-148 and Soliris® falls within the range from 80.00% to 
125.00%. The expected dropout rate due to reasons not related to the study drugs is approximately 
10%. Therefore, 8 more volunteers will be enrolled to compensate for the premature withdrawal 
of randomized subjects. Thus, the overall number of study participants will be 78 subjects (39 in 
each study arm). 
9.4. Statistical analysis steps and timelines for reports 
Clinical study results will be analyzed after all protocol-specified data of the last study 
subject have been received (i.e. after all subjects have completed the trial). 

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9.5. Study termination criteria 
JSC BIOCAD can suspend or terminate the study due to safety or ethical issues, Protocol 
compliance issues, or due to other reasons. If JSC BIOCAD suspends or terminates the study, the 
study site will be notified in advance. In case of suspension or termination, JSC BIOCAD and the 
investigator have to inform Ethics Committees and regulatory authorities in due time. If the study 
is suspended or terminated, all study information must be transferred to and all unused 
investigational product must be returned to JSC BIOCAD. 
9.6. Handling of missing, unevaluable or uncertain data  
All information specified in the eCRF has to be confirmed by appropriate data in the source 
documents. To collect missing data or correct wrong data, the BIOCAD’s CRA or clinical trial 
specialist generates queries, which are study- and site-specific, i.e. generated for each subject 
individually. 
The investigator must respond within 5 working days from the date when the query was 
received.  
None of the missing, non-evaluable, or uncertain data will be replaced with available data 
or projected. 
9.7. Reporting any deviations from the initial statistical plan 
If the initial study plan requires modifications, all changes will be described and explained 
in a protocol amendment or final clinical study report. 
9.8 Selection of subjects for analysis 
Demographics and baseline clinical and laboratory characteristics will be evaluated in all 
subjects included in the study.  
PK/PD analysis: 
The PK/PD analysis will include data from all subjects who received the test drug/ reference 
drug. However, subjects who had two or more PK/PD blood samples missed/lost/spoiled will be 
removed from the analysis. 
To obtain valid results, individual concentration values will be excluded from analysis if a 

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technical issue occurs during the concentration analysis due a human error (e.g., a whole 
biospecimen is compromised because a wrong reagent or wrong amount of an appropriate reagent 
was added; a sample was re-frozen after thawing: a sample was contaminated with foreign 
substances, etc.) or due to an unexpected technical problem, and it is impossible to retest the 
sample. If, with the inappropriate sample excluded from the analysis, a subject has two or more 
blood samples missed/lost/spoiled over the entire study period, this volunteer will be completely 
removed from the PK assessment. 
Safety analysis 
The safety analysis will include all subjects dosed with BCD-148/Soliris®. 
Immunogenicity analysis 
The immunogenicity analysis will include data from all subjects who received BCD-
148/Soliris® except for those whose pre-infusion sample and at least one post-infusion sample are 
missed/lost/spoiled. 
10. DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
The investigator/institution involved in the study must ensure direct access to source 
data/documents by the monitor, the auditor, the LEC/IRB or regulatory authorities. 
11. QUALITY CONTROL AND QUALITY ASSURANCE 
11.1. Data quality assurance 
According to the National Standard “Good Clinical Practice”, ICH GCP, and regulatory 
requirements, the Sponsor, a third party on behalf of the Sponsor, regulatory authorities, or 
LEC/IRB may perform audits/inspections to assure the quality of the study. Audits/inspections can 
be performed at any time during the study or after its completion. The investigator must give the 
auditor/inspector direct access to all study documents (including source documents) and discuss 
(personally, or designate someone from the study team) the audit/inspection results and other 
matters with the auditor/inspector. 
11.2. Investigator adherence to the Protocol 
Before beginning the study, the investigator must read and accept all provisions of this 
Protocol. The investigator must conduct the study in accordance with this Protocol, the current law 
of the Russian Federation, Federal Law #61-FZ of April 12, 2012: On the Circulation of 

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Medicines; National Standard of the Russian Federation GOST R 52379-2005 Good Clinical 
Practice; the rules of Good Clinical Practice of the Eurasian Economic Union; the Constitution of 
the Russian Federation; Federal Law #323-FZ of November 21, 2011: On Public Health 
Protection in the Russian Federation; the WMA Declaration of Helsinki (Fortaleza 2013), Order 
#200n of April 01, 2016 On Approval of the Good Clinical Practice; the GCP principles, and the 
applicable regulations. 
No protocol deviations are allowed during the study without a previous written approval 
from JSC BIOCAD, the Ministry of Healthcare of the Russian Federation and Local Ethics 
Committees, except for the cases when the deviation is necessary to protect a subject from an 
immediate hazard.  
The investigator should have enough time to accurately perform and complete the study 
within the timeframes specified by JSC BIOCAD, enough employees of appropriate qualification, 
and adequate equipment to conduct the study according to the Protocol. 
Each sub-investigator participating in the study must read the Protocol and be aware of 
his/her responsibilities/functions in the study. If the principal investigator delegates some of 
his/her functions to sub-investigators, this must be documented in a relevant section of the 
Investigator's File. 
11.3. Investigator responsibility to comply with the Protocol 
If the investigator decides to withdraw a subject from the study, he/she must notify the 
responsible Clinical Trial Manager (CTM) or CRA at JSC BIOCAD via e-mail within 48 h after 
making this decision. The e-mail should contain the Subject ID, reason and date of withdrawal 
from the study. The fact of withdrawal must be captured in the eCRF. 
If the subject missed the scheduled visit, or if any study drug dose modification was 
revealed other than those allowed by the Protocol, the investigator must notify the responsible 
CTM or CRA at JSC BIOCAD via e-mail within 24h of event discovery. The event must be 
captured in the eCRF. 
If the investigator fails to follow these procedures or if multiple Protocol violations occur, 
JSC BIOCAD may suspend or terminate the study at this particular study site. 
11.4. Study monitoring 
Before the study start(during the Study Initiation Visit or Investigators’ Meeting), a 
CRA/CTM of JSC BIOCAD or an authorized CRO will explain the Protocol, IB, eCRF, and other 

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study documentation to the investigators and members of the study teams. The CRA will 
periodically come to the study site during the study to check that the rights and wellbeing of the 
study subjects are being protected, the data submitted are valid, complete, and supported by 
appropriate source documents, and that the study is being conducted according to the current 
approved Protocol version/amendment, GCP, and regulations. During these visits, key members 
of the study team should be available to assist the CRA and resolve arising issues (if any). 
Study monitoring is performed according to appropriate SOPs of JSC BIOCAD. 
For each study subject, the investigator should keep source documents containing the 
subject data and records made during visits (medical records of the study center), including 
demographics, medical information, laboratory findings, ECG, and all other tests or examinations. 
Any information contained in the eCRF should be also recorded in the subject’s source documents. 
The investigator must keep the original ICF. A copy of the signed ICF will be given to the subject. 
The investigator has to provide the CRA with all relevant subject source documents to 
confirm that data in the source documents is consistent with the data in the eCRF. The investigator 
should ensure the timely completeness of the eCRFs before the CRA’s visit. 
To confirm the conformance of the study to the Declaration of Helsinki, Russian National 
Standard Good Clinical Practice, ICH GCP, regulatory requirements, and the Study Protocol, as 
well as the authenticity, accuracy, and completeness of data, the CTM will check the eCRFs and 
other study-related documents by verifying raw data. 
Upon the study completion, a BIOCAD representative (CTM/CRA) should visit the study 
site to perform the study closeout visit. During this visit, the Sponsor’s representative will collect 
all necessary documentation in accordance with the SOP of JSC BIOCAD. 
11.5. Data management and quality control 
In the trials that involve eCRFs, JSC BIOCAD employees (or employees of an authorized 
CRO) will check the data entered by the study team members for accuracy and completeness. If 
there are any inconsistent or missing data points, queries will be generated with a request for 
clarification. All queries are sent to the study site. A designated member of the study team must 
immediately answer the request and make all required changes to the database. 
At the end of the study, any protocol deviations will be determined. After all these actions 
have been taken and the completeness and accuracy of study data have been verified, the database 
is locked. 

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11.6. Study termination  
JSC BIOCAD can suspend or terminate the study due to safety or ethical issues, Protocol 
compliance issues, or due to other reasons. If JSC BIOCAD suspends or terminates the study, the 
study site will be notified in advance. In case of suspension or termination, JSC BIOCAD and the 
investigator have to inform Ethics Committees and regulatory authorities in due time. If the study 
is suspended or terminated, all study information must be transferred to and all unused 
investigational product must be returned to JSC BIOCAD. 
12. ETHICS 
12.1. Ethical aspects of the study 
This clinical study will be conducted in accordance with the ethical principles laid out in 
the WMA Declaration of Helsinki (Fortaleza 2013); Federal Law #61-FZ of April 12, 2012: On 
the Circulation of Medicines; Order #200n of April 01, 2016 On Approval of the Good Clinical 
Practice; National Standard of the Russian Federation GOST R 52379-2005 Good Clinical 
Practice; the rules of Good Clinical Practice of the Eurasian Economic Union; the Constitution of 
the Russian Federation; Federal Law #323-FZ of November 21, 2011: On Public Health 
Protection in the Russian Federation; the GCP principles, and the applicable regulations. 
The final version of the Protocol, including the Subject Information Sheet with the 
Informed Consent Form, will be submitted to regulatory authorities and local ethics committees 
for approval before the study start. 
All subsequent protocol amendments (other than administrative amendments) must be 
approved before implementation. 
Informed consent must be obtained from the subject before any study procedures are 
initiated. The Subject Information Sheet contains all the information that a subject may need to 
make a conscious and independent decision about whether to participate.  
During the study, all cases of SAEs will be reported to JSC BIOCAD within 24 hours. JSC 
BIOCAD will analyze the reports and may suspend the study if considered necessary. Local Ethics 
Committees will also be notified of all SAEs that are related, in the investigator’s opinion, to the 
investigational product. 
All subject personal information is confidential and can be disclosed only if required by 
law (including court decisions).  

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All study subjects will be insured. If a subject gets injured directly due to the investigational 
product, the Sponsor will cover all reasonably justified treatment expenses. 
12.2. Confidentiality of study subjects 
The investigator should keep confidentiality concerning subjects’ identity, the text of this 
Protocol, and all other study materials and results.  
The investigator should ensure subjects’ confidentiality. Subjects should be identified in 
the CRFs and other documents provided by JSC BIOCAD using identification numbers and/or 
initials, but not with their complete names.  
The investigator should keep a separate log with volunteers’ identification numbers, last 
names, addresses, telephone and medical record numbers (if applicable). The investigator must 
keep confidentiality of the data not intended for submission to JSC BIOCAD. 
All study materials proprietary to JSC BIOCAD cannot be transferred to a third party unless 
required by the law of the Russian Federation. 
13. DATA HANDLING AND RECORD KEEPING 
13.1. Record keeping at the study site 
All study documents must be archived at the study site or at the central archive of the 
institution. A list of all study subject identifiers should be made.  
According to the ICH GCP, essential documents include: signed Protocol and amendments; 
signed ICFs for all subjects; medical records and other source documents; approvals from LECs 
and regulatory authorities and all correspondence including approved documents; drug 
accountability records; study correspondence; and the list of subject names and addresses. These 
are the essential documents that must be kept in the Investigator’s File. 
The investigator must keep all the essential documents over a period of time specified by 
applicable regulations. 
By the end of this period, the Sponsor will inform the investigator(s) about the date when 
the documents may be destroyed. 
Study subject documentation will be archived in accordance with the site in-house SOPs. 
The investigator must inform the Sponsor about the place where essential documents are 
stored and request an approval from JSC BIOCAD before destroying any of the essential 
documents. Appropriate measures must be taken to prevent the accidental or premature destruction 
of these documents. 

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13.2. Confidentiality of data 
All information about study subjects will be kept confidential. The information will be 
processed in compliance with all applicable laws and regulations. These regulations require 
informing study subjects and obtaining their written authorization regarding the following: 
questions: 
• What protected health information will be collected in this study? 
• Who will have access to this information and on what grounds? 
• Who will use or disclose this information? 
• Do study subjects have the right to recall their consent for using their confidential 
health information? 
According to the current regulations, if the subject recalls his/her authorization to collect 
or use his/her protected health information, the investigator still can use all information obtained 
before the authorization was withdrawn. If the subject recalls authorization to collect or use his/her 
protected health information, the investigator should do as much as possible to get subject’s 
permission for collecting at least the safety information (i.e. onset of new or aggravation of existing 
adverse events) until the scheduled end of the study period. 
To prevent unauthorized access to protected subject information, the data management 
system uses integrated safety elements encrypting all the data when sending them in both 
directions. The access to the system will be controlled with a sequence of individually assigned 
identification codes and user passwords. These codes and passwords will be given only to 
authorized members of the study team who have received a special training. 
13.3. Collection of data 
This trial uses an electronic data capture (EDC) system. Designated study team members 
will enter the data required by the Protocol to eCRFs. The eCRFs have been developed with a 
validated and safe web-based software. The study team members will get access to the EDC system 
only after being appropriately trained. An automated validation program inspects the eCRFs for 
inconsistencies and allows the study team members to change or verify the entered data. 
The principal investigator is responsible for completeness and accuracy of all the data 
entered to the eCRFs and for entering and updating the information in a timely manner. 
The study site personnel will collect PK/PD/IG blood samples and send them to the central 
laboratory for processing. 

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14. FINANCE AND INSURANCE 
Study subjects will receive a monetary compensation for participating in the study. 
The compensation for study participation is 65 000 (sixty-five thousand) Russian Rubles. The 
total amount is paid to the subjects who have completed the entire study. If the subject 
discontinues the study due to a safety issue but not due to any non-compliance issue or violation 
of the Protocol, he will be paid the full compensation. In all other cases the compensation 
amount will be pro-rated according to the number of actual blood collections. Blood samples for 
PK and blood samples for PD will be collected at the same time over the entire study. Thus, the 
study includes 18 blood collections for PK and PD assessment, and the compensation for each 
PK/PD blood collection is 3600 Russian Rubles. No payments are provided for the screening 
examination and vaccination.  
The Sponsor will not provide any special compensation for the subject’s travel to the study site 
or other expenses. 
During the study, each study subject will be insured as a study participant according to the 
applicable law of the Russian Federation. In the Russian Federation, subjects will be insured by 
the Russian company SPAO Ingosstrakh. The investigator will provide the subject a certificate 
of compulsory insurance of the life and health of a drug clinical study participant. If the subject 
needs to make changes to the compulsory insurance certificate, he will need to return the 
previously issued certificate and receive a new one. 
The insurance policy covers only claims regarding life and health harmed as a result of study 
participation. The insurance object is the subject’s property interest related to the harm to the 
subject’s life or health due to his/her participation in the clinical trial if there is a causal 
relationship between the event and subject’s participation in the clinical trial. The Insurer shall 
pay the following compensations according to the Compulsory Insurance Contract (insurance 
payment): 
a) If the insured person dies: 2 million Russian Rubles. Insurance payment in the specified size is 
distributed among beneficiary parties in equal parts. 
b) If the insured person gets injured, and the injury results in: 
Group I disability - 1.5 million Russian Rubles 
Group II disability - 1 million Russian Rubles 
Group III disability - 500 000 Russian Rubles 
c) If the insured person gets injured, and the injury does not result in disability: not more than 300 000 
Russian Rubles. 
15.0. PUBLICATIONS 

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After completion of the study, its results will be summarized and prepared for publication. 
The investigator must not publish any study results, including those obtained at his/her study site, 
without a permission from JSC BIOCAD. Results from individual study sites must not be 
published before the publication of the overall study results.