Clinical Study of the Pharmacokinetics, Pharmacodynamics, Tolerability, Safety and Immunogenicity of BCD-131 Compared to Mircera and Aranesp in Healthy Volunteers
Phase: PHASE1
Conditions: Reticulocyte Count
Sponsor: Biocad

Clinical Study Protocol 
Protocol ID: BCD-131-1 
NCT02731469 
 
 
 
CONFIDENTIAL 
Version 1.0 of September 21, 2015 
Page 1 of 14 
 
 
CLINICAL STUDY PROTOCOL 
Protocol Title: 
An Open-Label Single Ascending Dose Clinical Study of 
the Pharmacokinetics, Pharmacodynamics, Tolerability, 
Safety and Immunogenicity of BCD-131 in Healthy 
Volunteers as Compared to Mircera® (F. Hoffman-La 
Roche Ltd., Switzerland) and Aranesp® (Amgen Europe 
B.V., Netherlands) 
Protocol Number:: 
BCD-131-1 
Protocol version  
1.0 
Version Date: 
September 21, 2015 
SAP version 
1.0 
SAP version date 
September 21, 2015 
Name and address of the 
clinical study sponsor  
JSC BIOCAD, Russia   
Legal address: 34 A, Ulitsa Svyazi, Strelna, 
Petrodvortsoviy District, Saint Petersburg, Russian 
Federation, 198515 
Postal Address: Petrovo Dalneye, Krasnogorskiy District, 
Moscow Region, Russian Federation, 143422.  
Tel.: +7 (495) 992-66-28 Fax: +7 (495) 992-82-98 
Name and function of 
person(s), authorized to sign 
the protocol and its 
amendments for the sponsor: 
Roman Alexeevich Ivanov, Vice President, Research & 
Development 
Address: Petrovo Dalneye, Krasnogorskiy District, 
Moscow Region,  
Russian Federation, 143422 
Email: ivanov@biocad.ru 
Tel.: + 7 (495) 992-66-28 (ext. 154) 
Name, position, address and 
telephone number of the 
Medical Expert assigned by 
the Sponsor for this Study 
Daria Dmitrievna Bolsun, Medical Expert, Category II 
JSC BIOCAD, 17-A, Ulitsa Italyanskaya, 
Saint-Petersburg, Russian Federation, 198515 
Email: bolsun@biocad.ru 
Tel.: +7 (812) 380 49 33 (ext. 745); +7 (911) 137-89-29 
All information contained in this document is strictly confidential and intended for use by investigators, members of Ethics 
Committees and Health Authority personnel. This information cannot be disclosed to any other persons or entity, submitted 
for publication or used for any purpose other than contemplated herein without the Sponsor`s prior written authorization, 
unless it is necessary to get patient's consent for the participation in the study. 
The above requirements are effective upon the signing of this protocol. 
 

Clinical Study Protocol 
Protocol ID: BCD-131-1 
NCT02731469 
 
 
 
CONFIDENTIAL 
Version 1.0 of September 21, 2015 
Page 2 of 14 
 
SYNOPSIS 
Study Code: 
BCD-131-1  
Study Title: 
An Open-Label Single Ascending Dose Clinical Study of the 
Pharmacokinetics, Pharmacodynamics, Tolerability, Safety and 
Immunogenicity of BCD-131 in Healthy Volunteers as Compared to 
Mircera® (F. Hoffman-La Roche Ltd., Switzerland) and Aranesp® 
(Amgen Europe B.V., Netherlands). 
Study Product: 
BCD-131 — pegylated darbepoetin (JSC BIOCAD, Russia), solution 
for injection 
Reference Drug 1 
Mircera® — methoxy polyethylene glycol-epoetin beta (F. 
Hoffmann-La Roche Ltd., Switzerland) solution for intravenous and 
subcutaneous injection 
Reference Drug 2 
Aranesp® — darbepoetin alfa (Amgen Europe B.V., Netherlands), 
solution for injections 
Population:  
Healthy male volunteers aged 18 to 45 years 
Study Sponsor: 
JSC BIOCAD, Russia.  
Postal address: Petrovo Dalnee, Krasnogorsky District, Moscow 
Region, Russian Federation, 143422. Tel.: +7(495) 992 66 28, fax: 
+7(495) 992 82 98.  
Legal address: 34-A, Ul. Svyazi, Strelna, Petrodvortsoviy District, 
Saint Petersburg, Russian Federation, 198515 
Study Aims and 
Objectives 
Study aim: To evaluate the tolerability, safety, pharmacokinetics, 
pharmacodynamics and immunogenicity of single ascending doses of 
BCD-131 in healthy volunteers as compared to Mircera® and 
Aranesp®. 
Study objectives (Stage I): 
1. 
Establish the frequency and severity of adverse events 
following the administration of single ascending doses of BCD-131 
to healthy volunteers. 
2. 
Establish key pharmacokinetic (PK) parameters (AUC0-1176 h, 
AUC0-∞, Cmax, Тmax, Т½, Кel and CL) of BCD-131 following the 
administration of single ascending doses of the drug product to 
healthy volunteers. 

Clinical Study Protocol 
Protocol ID: BCD-131-1 
NCT02731469 
 
 
 
CONFIDENTIAL 
Version 1.0 of September 21, 2015 
Page 3 of 14 
 
3. 
Establish pharmacodynamic (PD) parameters (AUEC0–1176 h, 
AC-Emax) of BCD-131 based on the absolute reticulocyte count and 
Hb values in the blood of healthy volunteers following the 
administration of single ascending doses of BCD-131. 
4. 
Study serum levels of binding antibodies (BAbs) in the blood 
of healthy volunteers following the subcutaneous administration of 
single ascending doses of BCD-131. 
5. 
Establish main PK (AUC0-1176 h, AUC0-∞, Cmax, Тmax, Т½, Кel 
and CL) and PD parameters (AUEC0–1176 h, AC-Emax based on changes 
in the absolute reticulocyte count and Hb levels in the blood) as well 
as immunogenicity of therapeutic doses of Mircera® and Aranesp® 
given as subcutaneous injections to healthy volunteers. 
6. 
Establish a safe dose of subcutaneous BCD-131 to be used at 
stage II of the study. 
 
Study objectives (Stage II): 
 
1. 
Establish key pharmacokinetic parameters (AUC0-1176 h, 
AUC0-∞, Cmax, Тmax, Т½, Кel and CL) of BCD-131 given as a single 
subcutaneous or intravenous injection to healthy volunteers at a dose 
established at stage I of the study. 
2. 
Establish key pharmacodynamic parameters (AUEC0–1176 h, 
AC-Emax based on changes in the absolute reticulocyte count and Hb 
levels in the blood) of BCD-131 given as a single subcutaneous or 
intravenous injection to healthy volunteers at a dose established at 
stage I of the study. 
3. 
Establish the frequency and severity of adverse events and 
evaluate the level of BAbs to BCD-131 given as a single 
subcutaneous or intravenous injection to healthy volunteers at a dose 
established at stage I of the study. 
4. 
Establish subcutaneous and intravenous doses of BCD-131 to 
be used in a phase II clinical study. 
Study Design: 
Stage I 
Stage I of clinical study BCD-131-1 is an open-label, non-randomized 
clinical study of pharmacokinetics, pharmacodynamics, tolerability, 
safety and immunogenicity of the novel drug product given to healthy 
volunteers at ascending doses (Phase 1, a traditional “3+3” design). 
Also, at stage I the investigators will evaluate the PK and PD 
parameters of the closest analogues of BCD-131 (Mircera® and 
Aranesp®) given as subcutaneous injections at therapeutic doses. 
Volunteers (no more than 54 subjects at stage I) will be included in 
the study after they have signed an informed consent form, completed 
an examination at screening (no more than 14 days) and received the 
approval of the investigator confirming their eligibility for the study.  

Clinical Study Protocol 
Protocol ID: BCD-131-1 
NCT02731469 
 
 
 
CONFIDENTIAL 
Version 1.0 of September 21, 2015 
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Evaluation of pharmacokinetics, pharmacodynamics and safety 
of ascending doses of BCD-131 
The evaluation of pharmacokinetics, safety and tolerability of BCD-
131 will be conducted in 8 cohorts: 
1. 
Cohort 01 will include no more than 6 volunteers who will 
receive a single subcutaneous injection of BCD-131 at a dose of 
0.05 µg/kg body weight. 
2. 
Cohort 02 will include no more than 6 volunteers who will 
receive a single subcutaneous injection of BCD-131 at a dose of 
0.15 µg/kg body weight. 
3. 
Cohort 03 will include no more than 6 volunteers who will 
receive a single subcutaneous injection of BCD-131 at a dose of 
0.40 µg/kg body weight. 
4. 
Cohort 04 will include no more than 6 volunteers who will 
receive a single subcutaneous injection of BCD-131 at a dose of 
1.05 µg/kg body weight. 
5. 
Cohort 05 will include no more than 6 volunteers who will 
receive a single subcutaneous injection of BCD-131 at a dose of 
1.70 µg/kg body weight. 
6. 
Cohort 06 will include no more than 6 volunteers who will 
receive a single subcutaneous injection of BCD-131 at a dose of 
2.75 µg/kg body weight. 
7. 
Cohort 07 will include no more than 6 volunteers who will 
receive a single subcutaneous injection of BCD-131 at a dose of 
4.45 µg/kg body weight. 
Volunteers will be included in the study in a consecutive order. First, 
three volunteers will be included in Cohort 01 to receive a single 
subcutaneous injection of BCD-131 at a calculated starting safe dose 
of 0.05 µg/kg. If during 14 days after the injection these volunteers 
do not develop any treatment-emergent Grade 3–4 adverse events, the 
next three volunteers will be included in the study (Cohort 02). The 
further inclusion algorithm is as follows: 
If during 14 days after the injection of BCD-131 the subjects do not 
develop any treatment-emergent Grade 3-4 AEs (DLT), the next 
cohort consisting of three volunteers will be included in the study to 
receive an escalated dose of BCD-131 (Cohort 03, Cohort 04, 
Cohort 05 etc.). 
If during 14 days after the injection of BCD-131 only one volunteer 
(of three) develops a treatment-emergent Grade 3-4 AE (DLT), three 
more healthy volunteers will be included in this cohort to receive 
BCD-131. 

Clinical Study Protocol 
Protocol ID: BCD-131-1 
NCT02731469 
 
 
 
CONFIDENTIAL 
Version 1.0 of September 21, 2015 
Page 5 of 14 
 
If two subjects develop treatment-emergent Grade 3-4 AEs (DLT), 
the dose of BCD-131 which resulted in these events is considered to 
be the maximum tolerated dose (MTD). No further dose escalating is 
performed. 
Thus, the dose-limiting toxicity is assessed as close as possible to the 
time of drug administration during the first 14 days after the injection. 
However, follow-up of volunteers does not stop; it will continue up 
to Day 50 from the moment of injection and include the monitoring 
of volunteers’ health as well as safety and PK parameters of BCD-
131. 
 
Evaluation of pharmacokinetics, pharmacodynamics and safety 
of subcutaneous therapeutic doses of Mircera® and Aranesp® 
Simultaneously 
with 
the 
evaluation 
of 
pharmacokinetics, 
pharmacodynamics and safety of ascending doses of BCD-131, the 
investigators will evaluate the pharmacokinetics, pharmacodynamics 
and safety of subcutaneous therapeutic doses of Mircera® and 
Aranesp®. For this purpose, 12 more volunteers will be included in 
the study.  
After having been randomized in a 1:1 ratio, the volunteers will be 
assigned to 2 groups. Six volunteers in Group 1 will receive a single 
subcutaneous injection of Mircera® at a dose of 1.20 µg/kg (Day 1). 
Six volunteers in Group 2 will receive a single subcutaneous injection 
of Aranesp® at a dose of 0.45 µg/kg (Day 1). 
 
After the last volunteer enrolled in stage I of the study has completed 
all the procedures specified in the Study Protocol, an interim analysis 
of the data obtained will be performed. Based on the comparison of 
pharmacokinetics, pharmacodynamics and safety of different doses of 
the test drug and active comparators, the investigators will establish a 
dose of BCD-131 which ensures PD effects similar to those of the 
closest analogues (Mircera®, Aranesp®) given as subcutaneous 
injections at therapeutic doses. The established dose of BCD-131 will 
be used at stage II of the study. 
 

Clinical Study Protocol 
Protocol ID: BCD-131-1 
NCT02731469 
 
 
 
CONFIDENTIAL 
Version 1.0 of September 21, 2015 
Page 6 of 14 
 
Subjects will be asked to stay at the study site for the first 24 h after 
the injection because multiple blood samples are to be collected over 
this period. 
Regardless of the group/cohort to which a volunteer has been 
assigned, s/he will be followed-up for 50 days during which 16 visits 
will be performed. 
 
Stage II 
Stage II of the study aims to further evaluate pharmacokinetics, 
pharmacodynamics and safety of subcutaneous and intravenous 
injections of BCD-131 at a dose which ensures PD effects similar to 
those of the closest analogues (Mircera®, Aranesp®) given as 
subcutaneous injections at therapeutic doses. For this purpose, 12 
volunteers will be included in the study after they have signed an 
informed consent form, completed an examination at screening (no 
more than 14 days) and received the approval of the investigator 
confirming their eligibility for the study. 
After having been randomized in a 1:1 ratio, the volunteers will be 
assigned to 2 groups.  
• Six volunteers in Group 1 will receive a single intravenous 
injection of BCD-131 at a dose established at stage I of the 
study (Day 1).  
• Six volunteers in Group 2 will receive a single subcutaneous 
injection of BCD-131 at a dose established at stage I of the 
study (Day 1). 
 
Subjects will be asked to stay at the study site for the first 24 h after 
the injection because multiple blood samples are to be collected over 
this period. Regardless of the group/cohort to which a volunteer has 
been assigned, s/he will be followed-up for 50 days during which 16 
visits will be performed. 
Use of BCD-131 at 
Stage I 
The test drug and reference drugs will be used in accordance with the 
study design: 
Evaluation of pharmacokinetics, pharmacodynamics and safety 
of ascending doses of BCD-131 

Clinical Study Protocol 
Protocol ID: BCD-131-1 
NCT02731469 
 
 
 
CONFIDENTIAL 
Version 1.0 of September 21, 2015 
Page 7 of 14 
 
1. 
Cohort 01 will include no more than 6 volunteers who will 
receive a single subcutaneous injection of BCD-131 at a dose of 
0.05 µg/kg body weight. 
2. 
Cohort 02 will include no more than 6 volunteers who will 
receive a single subcutaneous injection of BCD-131 at a dose of 
0.15 µg/kg body weight. 
3. 
Cohort 03 will include no more than 6 volunteers who will 
receive a single subcutaneous injection of BCD-131 at a dose of 
0.40 µg/kg body weight. 
4. 
Cohort 04 will include no more than 6 volunteers who will 
receive a single subcutaneous injection of BCD-131 at a dose of 
1.05 µg/kg body weight. 
5. 
Cohort 05 will include no more than 6 volunteers who will 
receive a single subcutaneous injection of BCD-131 at a dose of 
1.70 µg/kg body weight. 
6. 
Cohort 06 will include no more than 6 volunteers who will 
receive a single subcutaneous injection of BCD-131 at a dose of 
2.75 µg/kg body weight. 
7. 
Cohort 07 will include no more than 6 volunteers who will 
receive a single subcutaneous injection of BCD-131 at a dose of 
4.45 µg/kg body weight. 
 
Evaluation of pharmacokinetics, pharmacodynamics and safety 
of subcutaneous therapeutic doses of Mircera® and Aranesp® 
Group 1: Six volunteers will receive a single subcutaneous injection 
of Mircera® at a dose of 1.20 µg/kg. 
Group 2: Six volunteers will receive a single subcutaneous injection 
of Aranesp® at a dose of 0.45 µg/kg. 
Use of BCD-131 at 
Stage II 
BCD-131 will be used in accordance with the study design: 
Group 1: Six volunteers will receive a single intravenous injection of 
BCD-131 at a dose established at stage I of the study. 
Group 2: Six volunteers will receive a single subcutaneous injection 
of BCD-131 at a dose established at stage I of the study. 
Time Points for Blood 
Sampling to Evaluate 
PK at Stage I of the 
Study  
In the groups of volunteers receiving BCD-131 and Mircera®, blood 
sampling for the PK evaluation will be performed as follows: 
1. PK1-1 — 5 min before the injection of BCD-131/Mircera® 
2. РК2-1 — 30 ± 5 min after the injection of BCD-131/Mircera® 
3. РК3-1 — 2 h ± 10 min after the injection of BCD-131/Mircera® 
4. PK4-1 — 8 h ± 15 min after the injection of BCD-131/Mircera® 
5. PK5-1 — 24 h ± 20 min after the injection of BCD-131/Mircera® 
6. PK6-1 — 48 h ± 30 min after the injection of BCD-131/Mircera® 

Clinical Study Protocol 
Protocol ID: BCD-131-1 
NCT02731469 
 
 
 
CONFIDENTIAL 
Version 1.0 of September 21, 2015 
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7. PK7-1 — 72 h ± 30 min after the injection of BCD-131/Mircera® 
8. PK8-1 — 96 h ± 60 min after the injection of BCD-131/Mircera® 
9. PK9-1 — 120 h ± 60 min after the injection of BCD-
131/Mircera® 
10. PK10-1 — 168 h ± 60 min after the injection of BCD-
131/Mircera® 
11. PK11-1 — 216 h ± 120 min after the injection of BCD-
131/Mircera® 
12. PK12-1 — 288 h ± 120 min after the injection of BCD-
131/Mircera® 
13. PK13-1 — 336 h ± 120 min after the injection of BCD-
131/Mircera® 
14. PK14-1 — 504 h ± 120 min after the injection of BCD-
131/Mircera® 
15. PK15-1 — 672 h ± 120 min after the injection of BCD-
131/Mircera® 
16. PK16-1 — 840 h ± 120 min after the injection of BCD-
131/Mircera® 
17. PK17-1 — 1008 h ± 120 min after the injection of BCD-
131/Mircera® 
18. PK18-1 — 1176 h ± 120 min after the injection of BCD-
131/Mircera® 
 
In the group of volunteers receiving Aranesp®, blood sampling for the 
PK evaluation will be performed as follows: 
1. PK1-1 — 5 min before the injection of Aranesp® 
2. РК2-1 — 30 ± 5 min after the injection of Aranesp® 
3. РК3-1 — 2 h ± 10 min after the injection of Aranesp® 
4. РК3-1 — 8 h ± 15 min after the injection of Aranesp® 
5. PK5-1 — 16 h ± 20 min after the injection of Aranesp® 
6. PK6-1 — 24 h ± 20 min after the injection of Aranesp® 
7. РК7-1 — 36 h ± 30 min after the injection of Aranesp® 
8. PK8-1 — 48 h ± 30 min after the injection of Aranesp® 
9. PK9-1 — 72 h ± 30 min after the injection of Aranesp® 
10. PK10-1 — 96 h ± 60 min after the injection of Aranesp® 
11. PK11-1 — 120 h ± 60 min after the injection of Aranesp® 
12. PK12-1 — 168 h ± 60 min after the injection of Aranesp® 
13. PK13-1 — 216 h ± 120 min after the injection of Aranesp® 
14. PK14-1 — 288 h ± 120 min after the injection of Aranesp® 
15. PK15-1 — 336 h ± 120 min after the injection of Aranesp® 
16. PK16-1 — 504 h ± 120 min after the injection of Aranesp® 
17. PK17-1 — 672 h ± 120 min after the injection of Aranesp® 
18. PK18-1 — 840 h ± 120 min after the injection of Aranesp® 
19. PK19-1 — 1008 h ± 120 min after the injection of Aranesp® 
20. PK20-1 — 1176 h ± 120 min after the injection of Aranesp® 

Clinical Study Protocol 
Protocol ID: BCD-131-1 
NCT02731469 
 
 
 
CONFIDENTIAL 
Version 1.0 of September 21, 2015 
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Time Points for Blood 
Sampling to Evaluate 
PK at Stage II of the 
Study 
1. PK1-2 — 5 min before the injection of BCD-131 
2. РК2-2 — 15 ± 3 min after the injection of BCD-131  
3. РК3-2 — 30 ± 5 min after the injection of BCD-131 
4. РК4-2 — 60 ± 5 min after the injection of BCD-131  
5. РК5-2 — 2 h ± 10 min after the injection of BCD-131 
6. РК6-2 — 4 h ± 15 min after the injection of BCD-131 
7. РК7-2 — 8 h ± 15 min after the injection of BCD-131 
8. РК8-2 — 24 h ± 20 min after the injection of BCD-131 
9. PK9-2 — 48 h ± 30 min after the injection of BCD-131 
10. PK10-2 — 72 h ± 30 min after the injection of BCD-131 
11. РК11-2 — 96 h ± 60 min after the injection of BCD-131 
12. PK12-2 — 120 h ± 60 min after the injection of BCD-131 
13. PK13-2 — 168 h ± 60 min after the injection of BCD-131 
14. PK14-2 — 216 h ± 120 min after the injection of BCD-131 
15. PK15-2 — 288 h ± 120 min after the injection of BCD-131 
16. PK16-2 — 336 h ± 120 min after the injection of BCD-131 
17. PK17-2 — 504 h ± 120 min after the injection of BCD-131 
18. PK18-2 — 672 h ± 120 min after the injection of BCD-131 
19. PK19-2 — 840 h ± 120 min after the injection of BCD-131 
20. PK20-2 — 1008 h ± 120 min after the injection of BCD-131 
21. PK21-2 — 1176 h ± 120 min after the injection of BCD-131 
Planned Sample Size: 
Up to 66 healthy volunteers 
Inclusion Criteria: 
1. Signing of the Informed Consent Form; 
2. Male sex; 
3. Age of 18 to 45 years, inclusive; 
4. BMI within normal limits (18.5–24.9 kg/m2); 
5. Healthy patients, which is proved by their medical history, 
physical examination and laboratory findings: 
• No clinically significant abnormalities of circulatory, 
respiratory, nervous, hematopoietic, endocrine and 
digestive systems, liver and kidneys in the past medical 
history and at screening; 
• No history of cardiovascular disorders or thyroid 
disorders; 
• No history of hematologic disorders, including but not 
limited to any type of anemia, myelodysplastic syndrome, 
blood cancers, hemolytic syndrome, hemoglobinopathies, 
coagulopathies; 
• CBC results within normal limits, including: 
o Hemoglobin within 132–173 g/L; 
o Hematocrit (based on CBC results) within 39–
49%; 
o Platelet count within 150–400*109/L; 
o Absolute reticulocyte count within 30.4–93.5 * 
109/L; 
• Blood biochemistry and urinalysis results within normal 
limits; 

Clinical Study Protocol 
Protocol ID: BCD-131-1 
NCT02731469 
 
 
 
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Version 1.0 of September 21, 2015 
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• Serum ferritin within 20–250 µg/L; 
• Serum endogenous erythropoietin within 4.3–29.0 
MIU/mL; 
• Hemodynamic parameters within normal limits: systolic 
blood pressure within 100–139 mmHg; diastolic blood 
pressure within 60–90 mmHg; heart rate within 50–90 
bpm; 
• No history of chronic infections (tuberculosis) or chronic 
inflammation; 
• No hepatitis B or C, HIV, or syphilis; 
• No acute infections within 4 weeks prior to inclusion in 
the study; 
• No psychiatric disorders and other conditions (including 
depression) that can interfere with the volunteer's ability 
to follow the study protocol; 
• Well-being (in the volunteer's opinion) within 30 days 
prior to inclusion in the study; 
6. No history of or current (at baseline) alcohol or drug abuse; 
7. Ability of the volunteer, in the investigator's opinion, to follow the 
study protocol procedures; 
8. Willingness of volunteers and their sexual partners with preserved 
reproductive potential to use reliable contraception within 2 
weeks before inclusion in the study and up to 7 weeks after the 
injection of the test product. This criterion is not applicable to 
subjects who underwent surgical sterilization. Reliable methods 
of contraception include one barrier method in combination with 
one of the following methods: spermicides, intrauterine 
device/oral contraceptives (for sexual partners). 
9. Willingness of volunteers to avoid alcohol intake within 24 hours 
before and 8 days after each injection of the test drug; 
Exclusion Criteria: 
1. History of treatment with erythropoietins or any other ESAs; 
2. Acute bleeding, blood/plasma donation or blood transfusion 
within 2 months before inclusion in the study; 
3. History of chronic bleeding; 
4. Standard laboratory and instrumental findings outside normal 
limits at screening; 
5. History of allergies (anaphylactic shock or multiple drug allergy 
syndrome); 
6. Known allergy or intolerance to any components of the 
investigational product; 
7. Major surgery within 30 days prior to screening, or surgery being 
scheduled for any time during the study; 
8. Impossibility to install a venous catheter for blood sampling (e.g. 
because of skin disorders at the sites of venipuncture);  
9. Diseases or other conditions that can interfere with the 
pharmacokinetics of the investigational drug (e.g. chronic liver, 
kidney, blood, circulatory system, lung or neuroendocrine 
diseases, including diabetes mellitus and others); 

Clinical Study Protocol 
Protocol ID: BCD-131-1 
NCT02731469 
 
 
 
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Version 1.0 of September 21, 2015 
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10. History of fever of 40 °C or more; 
11. History of elevated hepatic transaminases (above 2.5xULN); 
12. Episodes of thrombosis and/or thromboembolia in past medical 
history (myocardial infarction, stroke, transient ischemic attacks, 
deep vein thrombosis, pulmonary embolism within 6 months prior 
to inclusion in the study) as well as an increased risk of deep vein 
thrombosis; 
13. History of epileptic attacks or seizures; 
14. History or current (at screening) depression, suicidal thoughts/ 
attempts; 
15. Regular oral or parenteral use of any medications including over-
the-counter drugs, vitamins and nutritional additives within 2 
weeks before a scheduled injection of the test drug;  
16. Use of drugs, including OTC products, that significantly affect the 
hemodynamics, hepatic function, etc. (barbiturates, omeprazole, 
cimetidine, etc.) within 30 days before a scheduled injection of 
the test drug; 
17. Vaccination within 4 weeks before a scheduled injection of the 
test drug; 
18. Smoking more than 10 cigarettes per day;  
19. Consumption of more than 10 portions of alcohol per week (one 
portion equals to 0.5 L of beer, 200 mL of wine or 50 mL of 
ethanol) or a history of alcohol, drug or medication abuse; 
20. Participation in other clinical studies within 1 month before 
screening or simultaneous participation in another clinical study; 
21. Previous participation in this study. 
Overall Duration of 
the Study:  
 
The expected duration of the study is 12 months, including the periods 
of enrollment, screening, treatment and follow-up as well as data 
collection and statistical analysis of the results. Each subject is 
expected to participate in the study for no more than 64 days, 
including the screening period (up to 2 weeks) and the active phase 
of the study (50 days). 
Endpoints to Evaluate 
Single-Dose PK: 
Primary: 
✓ AUC0–1176 h (area under the concentration vs. time curve from 
the moment of injection to 1176 h [Day 50 of follow-up]) and 
AUC0-∞ (to infinity). 
Secondary: 
✓ Cmax (maximum serum concentration), 
✓ Тmax (time to Cmax), 
✓ Т½ (half-life), 
✓ Кel (elimination constant), 
✓ CL (total clearance). 
PD Endpoints 
Primary: 

Clinical Study Protocol 
Protocol ID: BCD-131-1 
NCT02731469 
 
 
 
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Version 1.0 of September 21, 2015 
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✓ AUEC0-1176 h (total area under the effect vs. time curve from 
the moment of injection to 1176 h [Day 50 of follow-up]) 
based on the change in the absolute reticulocyte count after a 
single-dose injection of the drug product. 
✓ AC-Emax (absolute maximum increase in the test parameter vs. 
baseline) based on the change in the absolute reticulocyte 
count in the blood after a single-dose injection of the drug 
product. 
 
Secondary: 
✓ AUEC0-1176 h (total area under the effect vs. time curve from 
the moment of injection to 1176 h [Day 50 of follow-up]) 
based on the change in the Hb level in the blood after a single-
dose injection of the drug product. 
✓ AC-Emax (absolute maximum increase in the test parameter vs. 
baseline) based on the change in the Hb level in the blood after 
a single-dose injection of the drug product. 
 
Endpoint for Pain 
Assessment 
✓ The average VAS score evaluating the pain during the 
injection. 
Safety Endpoints: 
✓ Total SAEs. 
✓ Total AEs.  
✓ Incidence of administration site reactions. 
✓ Incidence of Grade 3-4 AEs and SAEs.  
✓ Frequency of early withdrawals due to AEs and SAEs. 
Immunogenicity 
Endpoints 
✓ Incidence of BAbs to the drug product on Day 50 from the 
moment of a single-dose injection of the drug. 
Statistical Analysis 
Sample size calculation 
The sample size for the study was calculated based on the “3+3” 
design used in the study of doses and additional test parameters: 
 
Cohort 
Dose, 
μg/kg 
Number of 
volunteers to be 
enrolled 
(obligatory) 
Number of 
volunteers who 
can be enrolled 
if DLT signs 
develop 
01 
0.05 
3 
3 
02 
0.15 
3 
3 

Clinical Study Protocol 
Protocol ID: BCD-131-1 
NCT02731469 
 
 
 
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03 
0.40 
3 
3 
04 
1.05 
3 
3 
05 
1.70 
3 
3 
06 
2.75 
3 
3 
07 
4.45 
3 
3 
 
To assess the PK and PD of the closest analogues of BCD-131, 6 more 
volunteers will be included in the study to receive Mircera® and 
6 more volunteers will be enrolled to receive Aranesp®. 
To assess the PK and PD of BCD-131 given as a subcutaneous or 
intravenous injection at a dose established at stage I of the study, 6 
more volunteers will be included in the study to receive BCD-131 as 
an intravenous injection and 6 more volunteers will be enrolled to 
receive BCD-131 as a subcutaneous injection. 
 
Methods of analysis 
The data will be statistically processed with Statistica 10.0 software. 
The following tests will be used to compare data with normal 
distribution: two-tailed Student's test and ANOVA. The Mann-
Whitney test and ANOVA will be used to compare non-normally 
distributed data.  The regression analysis will be used for quantitative 
efficacy data. The categorical data will be processed using the 
Fisher’s exact test, Yates-corrected Pearson’s test 𝜒2 and Cochran-
Mantel-Haenszel test. 
PK analysis 
The PK analysis will include data of all volunteers who have received 
one dose of BCD-131 or reference drugs. If a subject has had more 
than two PK serum samples missed / lost / spoilt and skipped blood 
sampling time points more than twice, his/her data will not be 
included in the PK analysis. 
PD analysis 
The PD analysis will include data of all volunteers who have received 
one dose of BCD-131 or reference drugs. If a subject has had more 
than two PK serum samples missed / lost / spoilt and skipped blood 

Clinical Study Protocol 
Protocol ID: BCD-131-1 
NCT02731469 
 
 
 
CONFIDENTIAL 
Version 1.0 of September 21, 2015 
Page 14 of 14 
 
 
sampling time points more than twice, his/her data will not be 
included in the PD analysis. 
Safety analysis 
The safety analysis will include all patients who have received one 
dose of the test/reference drug. 
Immunogenicity analysis 
The immunogenicity analysis will include data of all volunteers who 
have received one dose of BCD-131 or reference drugs. If a subject 
has had serum samples taken on Day 1 and Day 50 missed / lost / 
spoilt, his/her data will not be included in the immunogenicity 
analysis.