Randomized Open-Label Comparative Study of the Efficacy and Safety of BCD-131 (JSC BIOCAD, Russia) and Mircera (F. Hoffmann-La Roche Ltd, Switzerland) in Treatment of Anemia in Chronic Kidney Disease Patients on Dialysis
Phase: PHASE2
Conditions: Anemia
Sponsor: Biocad

Clinical Study Protocol 
Protocol ID: BCD-131-2 
NCT03519243 
 
 
CONFIDENTIAL 
Version 1.0 of June 15, 2017 
Page 1 of 23 
 
 
CLINICAL STUDY PROTOCOL 
 
Protocol Title: 
 
An International, Multicenter, Randomized, Open-Label, 
Comparative Clinical Study of the Efficacy and Safety of 
BCD-131 (JSC BIOCAD, Russia) and Mircera® (F. 
Hoffmann-La Roche Ltd, Switzerland) in the Treatment of 
Anemia in Dialysis Patients with Chronic Kidney Disease  
Protocol ID: 
BCD-131-2, NCT03519243 
Protocol Date: 
June 15, 2017 
Protocol Amendment 
Number: 
Not applicable. 
Protocol Amendment Date: 
Not applicable. 
Protocol Version: 
1.0 
Study Sponsor/Monitor: 
 
JSC BIOCAD, Russia   
Legal address: 34-A, Ul. Svyazi, Strelna, Petrodvortsoviy 
District, Saint Petersburg, Russian Federation, 198515 
Postal address: Petrovo-Dalnee, 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 Alexeevich Ivanov, Vice President for Research & 
Development 
Address: JSC BIOCAD, Petrovo Dalnee, Krasnogorskiy 
District, Moscow Region,  
Russian Federation, 143422 
e-mail: ivanov@biocad.ru 
Tel.: + 7 (495) 992-66-28 (ext. 154) 
Sponsor’s Responsible 
Medical Expert: 
Arina Valeryevna Zinkina-Orikhan, Medical Expert, Category 
II 
JSC BIOCAD, 34-A, Ul. Svyazi, Strelna, Petrodvortsoviy 
District, Saint Petersburg, Russian Federation, 198515 
e-mail: zinkina@biocad.ru 
Tel.: +7 (812) 380-49-33, ext. 744 
The information contained in this document is confidential and intended to be used solely by investigators, ethics 
committee members and health authorities. This information may not be transferred to any third party without the 
prior written permission of JSC BIOCAD, except when necessary for obtaining the patient’s consent to 
participate in the study. The above-mentioned requirements become effective upon the signing of this Protocol. 

Clinical Study Protocol 
Protocol ID: BCD-131-2 
NCT03519243 
 
 
CONFIDENTIAL 
Version 1.0 of June 15, 2017 
Page 2 of 23 
 
1. 
SYNOPSIS 
Protocol ID 
BCD-131-2 
Study Title 
An 
International, 
Multicenter, 
Randomized, 
Open-Label, 
Comparative Clinical Study of the Efficacy and Safety of BCD-131 
(JSC BIOCAD, Russia) and Mircera® (F. Hoffmann-La Roche 
Ltd, Switzerland) in the Treatment of Anemia in Dialysis Patients 
with Chronic Kidney Disease. 
Phase 
II 
Study Sponsor 
JSC BIOCAD  
Postal address: Petrovo-Dalnee, Krasnogorskiy District, Moscow 
Region, Russian Federation, 143422 
Legal address: 34-A, Ul. Svyazi, Strelna, Petrodvortsoviy District, 
Saint Petersburg, Russian Federation, 198515 
Test drug 
BCD-131 — pegylated darbepoetin (JSC BIOCAD, Russia), 
solution for injection. 
Description of the Test 
Drug 
BCD-131 is a covalent conjugate of darbepoetin with the low 
content of sialic acids and linear methoxy-polyethylene glycol with 
the molecular weight of 30 kDa. Pegylated darbepoetin is expected 
to have a longer half-life and higher in vivo activity than the 
available authorized drugs. As a result, the drug will be 
administered to patients less often, the blood concentration of the 
active ingredient will be more stable thus promoting further 
improvement of the patient’s prognosis and quality of life. 
Pegylated darbepoetin (BCD-131) developed by JSC 
BIOCAD is an innovative biotechnology product. To date, a 
comprehensive study of structural, physico-chemical and 
biological properties of BCD-131 has been conducted. The amino 
acid profile, three-dimensional structure, sialylated form profile, 
purity and homogeneity, in vivo potency and stimulating activity of 
pegylated darbepoetin in TF-1 cells have been studied.  
The first step of clinical development of BCD-131 was the 
evaluation of its effects in healthy volunteers in the Phase I study: 
“Open-Label Single Ascending Dose Clinical Trial to Evaluate 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)”. According to the 
results of the Phase I study, the anticipated therapeutic dose range 
of BCD-131 was selected based on the evaluation of the drug 
pharmacodynamic (PD) effect on stimulation of erythropoiesis. 
The pharmacodynamic response reflected by the increased 

Clinical Study Protocol 
Protocol ID: BCD-131-2 
NCT03519243 
 
 
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Version 1.0 of June 15, 2017 
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1. 
SYNOPSIS 
reticulocyte count, which was very similar to that due to the 
comparator Mircera®, was observed in the cohorts of volunteers 
receiving BCD-131 at a dose of 1.05 µg/kg, 1.7 µg/kg, and 
2.75 µg/kg. The further development of BCD-131 includes the 
study of its efficacy and safety for the treatment of renal anemia 
due to the end-stage chronic renal failure (CKD (chronic kidney 
disease) stage 5D) in epoetin or darbepoetin alfa-treated patients. 
Reference Drug 
Mircera® 
— 
methoxy 
polyethylene 
glycol-epoetin 
beta  
(F. Hoffmann-La Roche Ltd., Switzerland) solution for intravenous 
and subcutaneous injection. 
Study Aims and 
Objectives 
Study aim: 
To determine an effective and safe therapeutic dose of 
BCD-131 upon repeated administration of the drug to dialysis 
patients with chronic kidney disease treated for anemia. 
Study objectives 
1. Determine and compare the efficacy variables of 3 different 
doses of BCD-131 upon multiple administration of the test 
drug with those of Mircera®. 
2.      Study and compare the adverse event profile of 3 different 
doses of BCD-131 upon multiple administration of the test 
drug with that of Mircera®. 
3.      Determine and compare the pharmacokinetics (PK) and 
pharmacodynamics (PD) of 3 different doses of BCD-131 
upon multiple administration of the test drug with those of 
Mircera®. 
4.      Determine and compare the proportion of BAb- and NAb-
positive patients in the BCD-131 and Mircera® groups. 
Study Design 
Clinical study BCD-131-2 is an international, multicenter, 
randomized, open-label, comparative two-stage clinical study to 
determine an effective and safe therapeutic dose of BCD-131 upon 
multiple administration of the drug to dialysis patients with chronic 
kidney disease treated for anemia. 
The study will include up to 100 dialysis patients with 
stage 5D chronic kidney disease (end-stage chronic renal failure), 
established efficacy of dialysis and renal anemia without other 
causes of anemia development (such as anemia of chronic disease, 
vitamin B12 deficiency, folic acid deficiency, iron deficiency), 
receiving erythropoiesis-stimulating agents (ESA) and reaching 
target hemoglobin levels. This study is a study of the maintenance 

Clinical Study Protocol 
Protocol ID: BCD-131-2 
NCT03519243 
 
 
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Version 1.0 of June 15, 2017 
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1. 
SYNOPSIS 
treatment of anemia; therefore, the study population includes 
patients: 
− receiving 
recombinant 
erythropoietin 
(EPO) 
(epoetin alfa or epoetin beta, or darbepoetin alfa) 
for at least 3 months before signing the Informed 
Consent (IC); 
−  receiving a stable dose of recombinant EPO 
(epoetin alfa or epoetin beta, qw, biw, tiw, or 
darbepoetin alfa, qw or q2w) for at least 2 weeks 
before signing the Informed Consent and during the 
screening period; 
− with hemoglobin levels within target values (100-
120 g/L) for at least 2 weeks before signing the 
Informed Consent and at screening.  
 
Randomization and Stratification 
The study plans to include 4 groups: 3 groups will receive 
the test drug BCD-131 at a dose of 1.05 µg/kg, 1.7 µg/kg and 2.75 
µg/kg x conversion ratio (CR)1 based on the previous therapy and 
one group will receive the reference drug Mircera®.  
Before inclusion in the study, all patients will be provided 
with the full information about the clinical study, its aims, and the 
risks associated with the participation in the study. After signing 
the Informed Consent, patients will undergo a screening 
examination (within the screening period of max 4 calendar weeks) 
to confirm that they meet the eligibility criteria. 
After the investigator has decided to include the patient in 
the study, they will be stratified based on the previous therapy 
(epoetin alfa / epoetin beta / darbepoetin alfa) and risk factors for 
AE development due to rHuEPO therapy: age (<60 years / ≥60 
years), availability / absence of vascular implants, need/no need for 
hypoglycemic agents or insulin. 
Study Stages: 
 
1 The dose calculations for BCD-131 and Mircera® are provided in section “Study Therapy” of the Synopsys and 
in section 1.5.1 “Description and Justification of Administration Mode, Doses, Dosage Regimen and Treatment Course” 
of the Study Protocol. 
Monthly doses of BCD-131 and Mircera® depend on a stable dose of recombinant EPO (epoetin alfa or epoetin 
beta, or darbepoetin alfa) received by the patient for at least 2 weeks before signing the Informed Consent and during the 
screening period. 

Clinical Study Protocol 
Protocol ID: BCD-131-2 
NCT03519243 
 
 
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Version 1.0 of June 15, 2017 
Page 5 of 23 
 
1. 
SYNOPSIS 
The study will include the following two stages:  
Stage I 
At stage I, patients will be included successively in each of 
the groups to receive BCD-131. At the same time, patients will be 
included in the reference group to receive Mircera®. Patients will 
be included in the groups in a 3:1 ratio (BCD-131 group : Mircera® 
group).  
First, 9 patients will be included in Group 1 (BCD-131, 
1.05 µg/kg x CR depending on the dose of the previous therapy) 
and 3 patients will be included in the Mircera® group (in a 3:1 ratio). 
After all the enrolled patients from these groups (Group 1 and the 
reference group) have received 2 injections of the test/reference 
drug and completed a 2-week follow-up period after the second 
injection (i.e. 1.5 months (42 days) after the first injection or 14 
days after the second injection), the investigators will consider a 
possibility of including the next 9 patients in Group 2 (BCD-131, 
1.7 µg/kg x CR depending on the dose of the previous therapy). 
At stage I, the Data Safety Monitoring Committee (DSMC) 
will take a decision on a possibility of including the next group of 
patients to receive a higher dose (1.7 µg/kg x CR)2. The decision 
will be based on the pooled data on the safety and 
pharmacodynamics of BCD-131 obtained in patients from Group 1 
for the first 1.5 months (i.e. after two injections and a 2-week 
follow-up period after the second injection). The safety evaluation 
of the test drug will be based on the incidence of Grade 3 AEs, 
having a reasonable suspected causal relationship to the study drug 
(according to the DSMB), in patients from Group 1. To perform the 
preliminary evaluation of the PD effect of the indicated dose of the 
drug product, DSMC members will be additionally provided with 
the data on hemoglobin levels and reticulocyte counts in complete 
blood counts of the patients included in Group 1 at stage I.  
The treatment of patients in Group 1 at stage I and in the 
reference group will not be interrupted and continue according to 
the Study Protocol. 
After the DSMC members have taken a decision about 
further dose escalation, 9 patients will be randomized to Group 2 at 
stage I to receive BCD-131 at a dose of 1.7 µg/kg x CR, and 3 
 
2 The DSMC will include principal investigators (4 persons) and a medical expert assigned for this study. 

Clinical Study Protocol 
Protocol ID: BCD-131-2 
NCT03519243 
 
 
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1. 
SYNOPSIS 
patients will be randomized to the reference group to receive 
Mircera® (randomization in a 3:1 ratio)3. 
After all the patients in Group 2 and 3 patients in the 
reference group (enrolled simultaneously with the patients 
receiving BCD-131 at a dose of 1.7 µg/kg) have received 2 
injections of either BCD-131 at a dose of 1.7 µg/kg x CR or the 
reference drug and completed a 2-week follow-up period after the 
second injection (i.e. 1.5 months (42 days) after the first injection 
or 14 days after the second injection), the investigators will 
consider a possibility of including the next 9 patients in Group 3 
(BCD-131, 2.75 µg/kg x CR depending on the dose of the previous 
therapy).  
At stage I, the decision on a possibility of including the next 
group of patients to receive a higher dose (2.75 µg/kg x CR) will 
be taken in the same way as described for the previous dose level.  
The treatment of patients in Group 2 at stage I and in the 
reference group (the next 3 patients) will not be interrupted and 
continue according to the study protocol. The patients will go on 
receiving the relevant drugs at the same dose or, according to the 
DSMC decision, at a lower dose if the treatment with the same dose 
of BCD-131 does not benefit the patient for safety reasons. 
After the DSMC members have taken a decision about 
further dose escalation, 9 patients will be randomized to Group 3 at 
stage I to receive BCD-131 at a dose of 2.75 µg/kg x CR, and 3 
patients will be randomized to the reference group to receive 
Mircera® (randomization in a 3:1 ratio)4.   
The terms and parameters of safety evaluation of BCD-131 
at a dose of 2.75 µg/kg x CR in patients in Group 3 at stage I will 
be the same as those in Group 1 and Group 2 at stage I. 
 
 
Stage II 
In any of the above-mentioned situations, patients will be 
further enrolled in stage II of the study according to the conditions 
of the screening period and stratification described above for stage 
 
3 If the DSMC members have taken a decision about the risk of including patients in the next dose levels of BCD-
131 (1.7 µg/kg and 2.75 µg/kg x CR) based on the safety data obtained in Group 1 at stage I, new patients will not be 
enrolled in groups to receive the next dose levels of BCD-131. 
4 If the DSMC members have taken a decision about the risk of including patients in the next dose level of BCD-
131 (2.75 µg/kg x CR) based on the safety data obtained in Group 2 at stage I, new patients will not be enrolled in groups 
to receive the next dose levels of BCD-131. 

Clinical Study Protocol 
Protocol ID: BCD-131-2 
NCT03519243 
 
 
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Version 1.0 of June 15, 2017 
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1. 
SYNOPSIS 
I. The total number of patients in each group, approved by the 
DSMC for participation in stage II, should be 25 patients including 
those randomized to the relevant group at stage I of the study. At 
stage I, more patients will be enrolled in the reference group to 
achieve the total number of 25 patients, including those randomized 
to the relevant group at stage I of the study. 
If, based on the decision of the DSMC, all the three dose 
levels (1.05, 1.7, and 2.75 µg/kg x CR) of BCD-131 have 
acceptable safety profiles at stage I, more patients will be enrolled 
in each of these three groups and in the reference group at stage II 
to compare the efficacy and safety of the selected treatment 
regimen for 21 weeks. In this case, stage II of the study will include 
the following groups: 
Planned study groups provided the DSMC has approved 
the further study of the three dose levels of BCD-131: 
• Group 1: Patients in this group (25 patients 
including those randomized to this group at stage I) 
will receive a subcutaneous injection of BCD-131, 
1.05 µg/kg x CR5, depending on the dose of the 
previous therapy, once a month until Week 21. 
• Group 2: Patients in this group (25 patients 
including those randomized to this group at stage I) 
will receive a subcutaneous injection of BCD-131, 
1.7 µg/kg x CR, depending on the dose of the 
previous therapy, once a month until Week 21. 
• Group 3: Patients in this group (25 patients 
including those randomized to this group at stage I) 
will receive a subcutaneous injection of BCD-131, 
2.75 µg/kg x CR, depending on the dose of the 
previous therapy, once a month until Week 21. 
• Group 4: Patients in this group (25 patients 
including those randomized to this group at stage I) 
will receive a subcutaneous injection of Mircera® 
once a month until Week 21, at a dose depending on 
 
5 The dose calculations for BCD-131 and Mircera® are provided in Section 1.5.1 “Description and Justification of 
Administration Mode, Doses, Dosage Regimen and Treatment Course” of the Study Protocol. 
Monthly doses of BCD-131 and Mircera® depend on a stable dose of recombinant EPO (epoetin alfa or epoetin 
beta, or darbepoetin alfa) received by the patient for at least 2 weeks before signing the Informed Consent and during the 
screening period. 

Clinical Study Protocol 
Protocol ID: BCD-131-2 
NCT03519243 
 
 
CONFIDENTIAL 
Version 1.0 of June 15, 2017 
Page 8 of 23 
 
1. 
SYNOPSIS 
that of the previously administered recombinant 
EPO in accordance with the SmPC for Mircera®6. 
 
If, based on the decision of the DSMC, the first two dose 
levels (1.05 and 1.7 µg/kg x CR) of BCD-131 have acceptable 
safety profiles at stage I, more patients will be enrolled only in 
Group 1 and Group 2 of the test drug and in the reference group at 
stage II to compare the efficacy and safety of the selected treatment 
regimen for 21 weeks. Patients who at stage I had received BCD-
131 at a dose of 2.75 µg/kg x CR, which later was not approved by 
the DSMC for stage II, will further receive BCD-131 at a dose of 
1.7 µg/kg x CR (i.e. the preceding dose level) until Week 21; their 
data will be used for additional safety evaluation. In this case, stage 
II of the study will include the following groups: 
Planned study groups provided the DSMC has approved 
the further study of BCD-131, 1.05 and 1.7 µg/kg x CR: 
• Group 1: Patients in this group (25 patients 
including those randomized to this group at stage I) 
will receive a subcutaneous injection of BCD-131, 
1.05 µg/kg x CR7, depending on the dose of the 
previous therapy, once a month until Week 21. 
• Group 2: Patients in this group (25 patients 
including those randomized to this group at stage I) 
will receive a subcutaneous injection of BCD-131, 
1.7 µg/kg x CR, depending on the dose of the 
previous therapy, once a month until Week 21. 
• Group 3: Patients in this group (only 9 patients who 
have been randomized to this group at stage I and 
received BCD-131, 2.75 µg/kg x CR) will receive a 
subcutaneous injection of BCD-131, 1.7 µg/kg x 
CR, depending on the dose of the previous therapy, 
once a month until Week 21, for the purpose of 
additional safety evaluation. 
• Group 4: Patients in this group (25 patients 
including those randomized to this group at stage I) 
 
6 http://grls.rosminzdrav.ru/Grls_View_v2.aspx?routingGuid=24dc1990-f2f5-4991-996b-b4ef599ba2a6&t= 
7 The dose calculations for BCD-131 and Mircera® are provided in Section 1.5.1 “Description and Justification of 
Administration Mode, Doses, Dosage Regimen and Treatment Course” of the Study Protocol. 
Monthly doses of BCD-131 and Mircera® depend on a stable dose of recombinant EPO (epoetin alfa or epoetin 
beta, or darbepoetin alfa) received by the patient for at least 2 weeks before signing the Informed Consent and during the 
screening period. 

Clinical Study Protocol 
Protocol ID: BCD-131-2 
NCT03519243 
 
 
CONFIDENTIAL 
Version 1.0 of June 15, 2017 
Page 9 of 23 
 
1. 
SYNOPSIS 
will receive a subcutaneous injection of Mircera® 
once a month until Week 21, at a dose depending on 
that of the previously administered recombinant 
EPO in accordance with the SmPC for Mircera®8. 
 
If, based on the decision of the DSMC, only the first dose 
level (1.05 µg/kg x CR) of BCD-131 has an acceptable safety 
profile at stage I, more patients will be enrolled only in Group 1 of 
the test drug and in the reference group at stage II to compare the 
efficacy and safety of the selected treatment regimen for 21 weeks. 
Patients who at stage I had received BCD-131 at a dose of 
1.7 µg/kg x CR, which later was not approved by the DSMC for 
stage II, will receive BCD-131 at a dose of 1.05 µg/kg x CR (i.e. 
the preceding dose level) until Week 21; their data will be used for 
additional safety evaluation. In this case, stage II of the study will 
include the following groups: 
Planned study groups provided the DSMC has approved 
the further study of BCD-131, 1.05 µg/kg x CR: 
• Group 1: Patients in this group (25 patients 
including those randomized to this group at stage I) 
will receive a subcutaneous injection of BCD-131, 
1.05 µg/kg x CR9, depending on the dose of the 
previous therapy, once a month until Week 21. 
• Group 2: Patients in this group (only 9 patients who 
have been randomized to this group at stage I and 
received BCD-131, 1.7 µg/kg x CR) will receive a 
subcutaneous injection of BCD-131, 1.05 µg/kg x 
CR, depending on the dose of the previous therapy, 
once a month until Week 21, for the purpose of 
additional safety evaluation. 
• Group 4: Patients in this group (25 patients 
including those randomized to this group at stage I) 
will receive a subcutaneous injection of Mircera® 
once a month until Week 21, at a dose depending on 
 
8 http://grls.rosminzdrav.ru/Grls_View_v2.aspx?routingGuid=24dc1990-f2f5-4991-996b-b4ef599ba2a6&t= 
9 The dose calculations for BCD-131 and Mircera® are provided in Section 1.5.1 “Description and Justification of 
Administration Mode, Doses, Dosage Regimen and Treatment Course” of the Study Protocol. 
Monthly doses of BCD-131 and Mircera® depend on a stable dose of recombinant EPO (epoetin alfa or epoetin 
beta, or darbepoetin alfa) received by the patient for at least 2 weeks before signing the Informed Consent and during the 
screening period. 

Clinical Study Protocol 
Protocol ID: BCD-131-2 
NCT03519243 
 
 
CONFIDENTIAL 
Version 1.0 of June 15, 2017 
Page 10 of 23 
 
1. 
SYNOPSIS 
that of the previously administered recombinant 
EPO in accordance with the SmPC for Mircera®10. 
Study Periods 
The study will include the following periods: 
1. Screening period (up to 28 days from the moment of signing 
the Patient Information Sheet and the Informed Consent 
Form, inclusive); 
2. Treatment period (Week 1 – Week 21, inclusive); 
3. Follow-up (28 days from the last injection of the 
test/reference drug at Week 21 of the study). 
Study Population 
Adult dialysis patients with renal anemia due to the end-
stage chronic renal failure (stage 5D CKD), aged 18 to 75 years 
(inclusive) on the day of signing the ICF, with the established 
efficacy of dialysis (dialysis dose (Kt/v) ≥1.2 for patients on 
hemodialysis and Kt/v ≥1.7 for patients on peritoneal dialysis)11. 
For dialysis patients, the need for the standard hemodialysis 
procedure should be at least 12 hours per week. 
Patients receiving recombinant EPO therapy (epoetin alfa 
or epoetin beta, or darbepoetin alfa) for at least 3 months before 
signing the Informed Consent, with the stable recombinant EPO 
dosing (epoetin alfa or epoetin beta, qw, biw, tiw, or darbepoetin 
alfa, qw or q2w) for at least 2 weeks before signing the Informed 
Consent and during the screening period, with the hemoglobin level 
within target values (100-120 g/L, inclusive) for at least 2 weeks 
before signing the Informed Consent and at screening, will be 
eligible for inclusion. 
Planned Sample Size 
Maximum number of patients: 100 patients 
 
Inclusion Criteria 
1. Signed ICF to participate in the study. 
2. Men and women aged 18 to 75 years inclusive at the 
moment of signing the ICF. 
3. Documented end-stage renal failure. 
4. Need for dialysis for at least 3 months before signing the 
ICF. 
 
10 http://grls.rosminzdrav.ru/Grls_View_v2.aspx?routingGuid=24dc1990-f2f5-4991-996b-b4ef599ba2a6&t= 
11 Kt/V = -Ln (R - 0.008 x t) + (4 - 3.5 x R) x UF/W  
where Ln - natural logarithm; R - post-dialysis to pre-dialysis blood urea nitrogen (BUN) (or urea) ratio; t - dialysis 
duration in h; UF - ultrafiltration volume in L; W - post-dialysis weight of the patient. 
 

Clinical Study Protocol 
Protocol ID: BCD-131-2 
NCT03519243 
 
 
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1. 
SYNOPSIS 
5. For dialysis patients, according to the investigator, the need 
for the standard hemodialysis procedure should be at least 
12 hours per week. 
6. Documented treatment with recombinant EPO (epoetin 
alfa, epoetin beta, or darbepoetin alfa) for at least 3 months 
before signing the ICF. 
7. Documented stable dose of recombinant EPO (epoetin alfa 
or epoetin beta, qw, biw, tiw, or darbepoetin alfa, qw or 
q2w) for at least 2 weeks before signing the ICF and during 
the screening period. 
8. Documented 
target 
hemoglobin 
level 
(100-120 g/L 
inclusive) for 2 weeks before signing the ICF and at 
screening. 
9. Efficacy of dialysis established at screening (dialysis dose 
(Kt/v) ≥1.2 for patients on hemodialysis, and Kt/v ≥1.7 for 
patients on peritoneal dialysis)12. 
10. Transferrin saturation ≥20%, ferritin level > 100 ng/mL at 
screening. 
11. Willingness of patients and their sexual partners with 
preserved 
reproductive 
function 
to 
use 
reliable 
contraception starting from signing the ICF and up to 4 
weeks after the final dose of the drug product given within 
the clinical study. This requirement does not apply to 
patients after surgical sterilization or ≥ 2 years post-
menopausal. Reliable methods of contraception include one 
barrier method in combination with one of the following 
methods: 
spermicides, 
intrauterine 
device/oral 
contraceptives.  
12. Patient’s ability (in the investigator’s opinion) to follow the 
Protocol procedures. 
Exclusion Criteria: 
1. Any other diagnosed forms of anemia, except for renal 
anemia, including anemia of chronic disease (C-reactive 
protein (CRP) level >20 mg/L at screening). 
2. Proven diagnosis of lupus nephritis or CKD due to systemic 
vasculitis13. 
 
12 Kt/V = -Ln (R - 0.008 x t) + (4 - 3.5 x R) x UF/W  
where Ln - natural logarithm; R - post-dialysis to pre-dialysis blood urea nitrogen (BUN) (or urea) ratio; t - dialysis 
duration in h; UF - ultrafiltration volume in L; W - post-dialysis weight of the patient. 
 
13 A note of the absence of this pathology should be made by the investigator in the source documents. 

Clinical Study Protocol 
Protocol ID: BCD-131-2 
NCT03519243 
 
 
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1. 
SYNOPSIS 
3. Platelet count <100х109/L at screening. 
4. Planned (i.e. there are data on a tentative date of surgery 
and/or availability of a suitable donor) kidney transplant 
surgery during the expected period of participation in the 
study. 
5. History of allergies (anaphylactic shock or multiple drug 
allergy 
syndrome) 
as 
told 
by 
the 
patient, 
and 
hypersensitivity to darbepoetin alfa or any components of 
the study drugs, or iron(III)-hydroxide sucrose complex. 
6. Vaccination within 8 weeks prior to signing the ICF (as told 
by the patient). 
7. Diagnosed liver cirrhosis complicated with portal 
hypertension and/or splenomegaly and/or ascites. 
8. HIV-infection, acute hepatitis В, С, syphilis14. 
9. ALT, AST levels >3xULN at screening. 
10. Decompensated heart disorders (chronic heart failure 
(CHF), NYHA Class IV). 
11. Resistant hypertension15. 
12. Unstable angina pectoris. 
13. Proven diagnosis of hemoglobinopathies, myelodysplastic 
syndrome, malignant blood or lymphoid disorders, pure red 
cell aplasia. 
14. Severe secondary hyperparathyroidism (intact parathyroid 
hormone (PTH)>1000 pg/mL at screening). 
15. Documented episodes of gastrointestinal bleeding within 3 
weeks prior to signing the ICF. 
16. Documented episodes of thrombosis in past medical history 
(acute myocardial infarction, stroke, transient ischemic 
attacks, deep venous thrombosis, pulmonary embolism) 
within 6 months prior to signing the ICF. 
 
14 The patient with anti-HCV antibodies detected at screening can be included in the study if all of the following conditions 
are met: negative qualitative PCR results for HCV RNA (this test is performed only if anti-HCV antibodies have been 
detected); no increased transaminase and bilirubin concentrations shown by blood biochemistry tests; the medical 
infections specialist has provided a documented conclusion that the patient has no HCV/cured HCV; and the Sponsor has 
approved the enrollment of this particular patient. 
HBsAg test is performed during the examination for hepatitis B. In case of positive results for HBsAg, the patient cannot 
be included in the study.  
In case of a positive reaction for syphilis, the patient can be included in the study by the decision of the Sponsor if the 
Dermatologist/Venerologist has provided a documented conclusion that the patient has no syphilis/cured syphilis. 
Additional examination may be required to confirm the diagnosis (at the discretion of dermatologist).  
15 Resistant hypertension is defined as high blood pressure above the target range despite the concurrent use of three anti-
hypertensive drugs of different classes. In case blood pressure can be controlled using four or more antihypertensive 
drugs, such hypertension is still considered to be resistant. 

Clinical Study Protocol 
Protocol ID: BCD-131-2 
NCT03519243 
 
 
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1. 
SYNOPSIS 
17. Seizure disorders, including a history of epilepsy. 
18. Documented major surgery within 1 month prior to signing 
the ICF. 
19. Documented blood transfusion within 3 months prior to 
signing the ICF. 
20. Any acute infections, relapses of chronic infections or any 
other chronic diseases that are present on the day of signing 
the Informed Consent and can, as judged by the 
Investigator, negatively affect the patient’s safety during the 
study treatment. 
21. History of severe depression, suicidal thoughts or suicide 
attempts16. 
22. Documented malignancies except for cured basal-cell 
carcinoma and/or cervical cancer in situ. 
23. Known alcoholic or drug dependence or signs of present 
alcoholic/drug dependence that, in the investigator's 
opinion, can be contraindications for the treatment with the 
test/reference drug products or limit the treatment 
compliance. 
24. Participation in other clinical studies within 90 calendar 
days prior to signing the Informed Consent. 
25. Pregnancy and breastfeeding. 
Study Therapy 
BCD-131 will be administered to patients in 3 of 4 groups. 
Patients in Group 1 will receive BCD-131 at a dose of 1.05 µg/kg 
х CR, in Group 2 – 1.7 µg/kg х CR, in Group 3 – 2.75 µg/kg х CR. 
In all the BCD-131 groups, a conversion ratio will be additionally 
used to calculate a monthly dose depending on the previous dose of 
epoetin (alfa or beta) or darbepoetin alfa.  
The calculated doses of BCD-131, the frequency (once a 
month) and route of administration (subcutaneous) have been 
selected based on the data from non-clinical studies and a Phase I 
clinical study of BCD-131 as well as on their comparison with the 
data and recommendations for use available for other recombinant 
epoetins. The ease of administration and applicability in clinical 
practice have been taken into account as well. 
BCD-131 and Mircera® will be injected on Day 1 of 
Week 1, Day 1 of Week 5, Day 1 of Week 9, Day 1 of Week 13, 
 
16 This exclusion criterion can be confirmed or rejected on the basis of documents or as told by the patient. 

Clinical Study Protocol 
Protocol ID: BCD-131-2 
NCT03519243 
 
 
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Page 14 of 23 
 
1. 
SYNOPSIS 
Day 1 of Week 17, Day 1 of Week 21, i.e. each patient will receive 
6 injections of the test or reference drug. 
It should be noted that during the discussion of this clinical 
study design with leading Russian experts having extensive 
practical experience in using erythropoietins in dialysis patients 
with CKD, this approach was found to be optimal in terms of 
patients’ safety and prevention of potential adverse events. 
The table below shows the starting doses of BCD-131 in 
Groups 1, 2, 3 and the dose of Mircera® in the Mircera® group 
depending on the type and dose of previous treatment. 
Dose 
Level 
Previous 
dose of 
epoetin 
Previous dose 
of darbepoetin 
alfa 
Mircera® 
dose 
BCD-131 dose 
in Group 1 
(1.05 µg/kg x 
CR), 
subcutaneously 
BCD-131 dose 
in Group 2 
(1.7 µg/kg x 
CR), 
subcutaneously 
BCD-131 dose 
in Group 3 
(2.75 µg/kg x 
CR), 
subcutaneously 
No. 
IU/week 
µg/week 
µg/month 
µg/month 
µg/month 
µg/month 
1 
1000 - 2000 
   5 - 10 
40 
40 
60 
80 
2 
>2000 - 4000 
> 10 - 20 
75 
60 
100 
160 
3 
> 4000 - 6000 
> 20 - 30 
120 
100 
160 
260 
4 
> 6000 - 8000 
> 30 - 40 
150 
120 
200 
340 
5 
> 8000 - 
10000 
> 40 - 50 
200 
160 
280 
440 
6 
> 10000 - 
12000 
> 50 - 60 
250 
200 
340 
560 
7 
> 12000 - 
14000 
> 60 - 70 
300 
260 
420 
680 
8 
> 14000 - 
16000 
> 70 - 80 
350 
300 
480 
800 
9 
> 16000 
> 80 
>350 
>300 
>480 
>800 
Dose Management: 
Due to intra-patient variability, occasional individual 
hemoglobin values for a patient above and below the desired 
hemoglobin level may be observed. Hemoglobin variability should 
be addressed through dose management (adjustment) with 
consideration for the hemoglobin target range of 100 to 120 g/L, 
inclusive.  
In this clinical study, 9 dose levels have been calculated for 
each of the BCD-131 and Mircera® groups depending on the 
dose/type of the previous treatment received by the participant. 
When situations described in the table below occur, dose 

Clinical Study Protocol 
Protocol ID: BCD-131-2 
NCT03519243 
 
 
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1. 
SYNOPSIS 
adjustment is required (i.e. the dose of the drug product used should 
be increased or decreased by one level). For example, if the starting 
monthly dose of BCD-131 given to a patient in Group 1 (1.05 µg/kg 
x CR) was set as 100 µg/month (third dose level), then when the 
hemoglobin level increases from >125 to <130 g/L, it is necessary 
to reduce the dose of the drug product to the previous dose level i.e. 
to 60 µg/month (second dose level). Or, for example, when a patient 
in Group 2 (BCD-131, 1.7 µg/kg x CR) receives the drug product 
at a dose of 200 µg/month (fourth dose level) and two sequential 
blood tests show the variation in the hemoglobin level from ≥95 to 
<100 g/L, it is necessary to increase the product dose to the next 
dose level, i.e. the next injected dose should be 280 µg/month (fifth 
dose level). 
If, according to the investigator, a situation requiring a 
different approach to dose adjustment of the test/reference drug 
occurs, this should be discussed with the Sponsor. 
The dose adjustment of the test/reference drug is required, 
if one of the situations described in the table below occur: 
Hemoglobin level 
in complete blood 
count (CBC), g/L 
Change in hemoglobin level 
since the last CBC 
Required measures 
<75 
Any change over time 
Repeat the CBC. If hemoglobin level 
remains <75 g/L, it is recommended 
that the dose is increased to the next 
dose level. 
75 to <95 
Decreased level or without 
change 
It is recommended that the dose is 
increased to the next dose level. 
75 to <95 
Increased level 
Maintenance dose (no dose 
adjustment is required) 
≥95 до <100  
during two 
sequential complete 
blood counts 
Decreased level or without 
change 
It is recommended that the dose is 
increased to the next dose level. 
≥100 to ≤120 
Any change over time 
Maintenance dose (no dose 
adjustment is required) 
>120 to ≤125 
during two 
sequential complete 
blood counts 
Increased level or without 
change 
Maintenance dose (no dose 
adjustment is required) 
>125 to <130 
Decreased level 
Maintenance dose (no dose 
adjustment is required) 
>125 to <130 
Increased level or without 
change 
It is recommended that the dose is 
decreased to the previous dose level 
≥130 
Any change over time 
Repeat the CBC. If the hemoglobin 
of ≥130 g/L is confirmed, the dose 
should be temporarily withheld until 
the hemoglobin decreases to 
115 g/L, at which point therapy 
should be reinitiated at one dose 
level lower than the previous one.  

Clinical Study Protocol 
Protocol ID: BCD-131-2 
NCT03519243 
 
 
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SYNOPSIS 
Any 
Increase by >20 g/L from the 
baseline for 4 weeks (or by 
>10 g/L for 2 weeks) 
Repeat the CBC. It is recommended 
that the dose is decreased to the 
previous dose level  
Any 
Reduction by >20 g/L from 
the baseline for 4 weeks (or by 
>10 g/L for 2 weeks)  
Repeat the CBC. It is recommended 
that the dose is increased to the next 
dose level. 
Study Procedures 
Patients will be given the injections of the test/reference 
drug during their visits to the study site. During the clinical study, 
dialysis sessions will be conducted as scheduled according to the 
recommendations approved by the treating physician.  
The efficacy of the drug products will be evaluated upon the 
completion of all the study periods based on the comparison of 
hemoglobin values obtained throughout the evaluation period vs. 
baseline (primary efficacy endpoint) and based on secondary 
endpoints. Secondary efficacy endpoints will include changes in the 
hemoglobin over time, a proportion of patients with the target 
hemoglobin maintained throughout the entire study, a proportion of 
patients who required dose adjustment or blood transfusion, and the 
mean hemoglobin throughout the entire study. 
Safety evaluation will be based on the frequency and 
severity of AEs and SAEs in the treatment groups, laboratory and 
instrumental findings, and the analysis of the vital signs. The 
investigators will monitor main hematology and biochemistry 
markers, ECG results, vital signs as well as the results of general 
examination of the patients. Safety parameters will be analyzed 
throughout the study. 
To evaluate the immunogenicity of the study drugs, 
patients will take blood tests for binding or neutralizing antibodies 
to BCD-131 or Mircera®, depending on the treatment group.  To 
detect antibodies to pegylated darbepoetin / methoxy polyethylene 
glycol-epoetin beta and analyze changes in their production over 
time, blood sampling will be performed before the first injection at 
Visit 1/Day 1, then at Week 9 and Week 23, and when pure red cell 
aplasia (PRCA) is suspected17. 
 
17 Diagnostic criteria for pure red cell aplasia 
Main signs: 
rHuEPO therapy for at least 3 weeks; 
Hemoglobin reduction by at least 1 g/L/day without blood transfusions; 
Reticulocyte count below 10x109/L; 
No significant reduction in WBC and platelets. 
Additional signs: 
Skin and/or systemic allergic reactions. 
Supporting assessment: 
Bone marrow aspiration shows normal cellularity and <5% erythroblasts with evidence of a maturation block; 

Clinical Study Protocol 
Protocol ID: BCD-131-2 
NCT03519243 
 
 
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SYNOPSIS 
A limited number of patients (not more than 15 patients in 
each group) will have additional blood samples collected to study 
pharmacokinetics (PK) (serum concentrations of the drug product) 
and pharmacodynamics (PD) (absolute reticulocyte count). Based 
on the investigator’s decision, during the period of intensive blood 
sampling for PK analysis (after injection 1), patients in the PK/PD 
subset may be hospitalized to the study site (this hospitalization will 
not be reported as a SAE). Since patients included in the PK/PD 
subset will have to make multiple additional visits to the study site 
for blood sampling, this may cause certain inconveniences. 
Therefore, the study provides compensation to these patients. 
Overall Duration of the 
Study 
The expected duration of the study is 30 months, including 
the periods of enrollment (12 months), 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 28 
weeks maximum, including the screening (4 weeks), treatment and 
follow-up periods. 
Efficacy Evaluation 
Primary endpoint: 
• Change in the hemoglobin vs. baseline during the 
evaluation period. 
The baseline hemoglobin will be calculated as the 
arithmetic mean of hemoglobin values obtained at screening and at 
Visit 1. The final hemoglobin value during the evaluation period 
will be calculated as the arithmetic mean of hemoglobin values 
obtained at Week 21 and Week 23. 
Secondary endpoints: 
• Relative number of patients (%) with the target hemoglobin 
level (100-120 g/L, inclusive) during Weeks 1-23; 
• Relative number of patients (%) who required dose 
adjustment during Weeks 1-23; 
• Relative number of patients (%) who required blood 
transfusion during Weeks 1-23; 
• Mean hemoglobin level during Weeks 1-23. 
Methods of efficacy assessment: 
The efficacy analysis will be based on the comparison of 
hemoglobin values obtained throughout the evaluation period vs. 
baseline, a proportion of patients with the target hemoglobin, a 
 
Serum assay shows the presence of anti-erythropoietin NAbs. 

Clinical Study Protocol 
Protocol ID: BCD-131-2 
NCT03519243 
 
 
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SYNOPSIS 
proportion of patients who required blood transfusion and dose 
adjustment, and the mean hemoglobin.  
To evaluate the efficacy of BCD-131 and Mircera®, patients 
will take CBC tests to determine hemoglobin levels. The first test 
for hemoglobin will be taken at screening. During the treatment 
period, the hemoglobin will be determined once every 2 weeks 
during the first 2 months of the study, and then every 4 weeks. 
The primary efficacy endpoint will be analyzed after the 
clinical study completion. 
Safety Evaluation 
Safety endpoints: 
• The proportion of patients who developed AEs/SAEs 
that were treatment-emergent in the opinion of the 
investigator; 
• The proportion of patients in each group who developed 
Grade 3-4 AEs (СТСАЕ v.4.03) that were treatment-
emergent in the opinion of the investigator; 
• The proportion of patients in each group who 
discontinued the study due to AEs/SAEs. 
The safety endpoints will be analyzed after the completion 
of all periods of the study.  
Methods of safety evaluation: 
The safety assessment will include periodic evaluation of 
vital signs (blood pressure, pulse, body temperature), hematology 
(RBC, Hb, reticulocytes, platelets, WBC differential etc.) and 
biochemistry (glucose, total bilirubin, AST, ALT, ferritin, 
transferrin saturation etc.), ECG monitoring, AE/SAE reporting. 
Immunogenicity 
Assessment 
• The proportion of BAb- and NAb-positive patients. 
Blood sampling for immunogenicity assessment (BAbs and 
NAbs) will be performed in all the patients included in the study 
before the first injection and then at Week 9 and Week 23. 
Immunogenicity endpoints will be analyzed after the study 
completion.  
PK and PD Assessment 
(for a limited number of 
patients, max n=60) 
1) PK/PD endpoints: 
PK endpoints: 
✓ AUC0–672 h (area under the concentration vs. time curve 
from the moment of injection to 672 h [28 days]) and AUC0-
∞ (to infinity) after the first injection of the test/reference 
drug, 

Clinical Study Protocol 
Protocol ID: BCD-131-2 
NCT03519243 
 
 
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SYNOPSIS 
✓ Cmax (maximum serum concentration of the drug product) 
after the first injection of the test/reference drug, 
✓ Cmin (minimum serum concentration of the drug product) at 
Weeks 5, 9, 13, 17, 21, 
✓ Тmax (time to maximum serum concentration) after the first 
injection of the test/reference drug, 
✓ Т½ (half-life) after the first injection of the test/reference 
drug, 
✓ Кel (elimination rate constant) after the first injection of the 
test/reference drug, 
✓ CL (total clearance) after the first injection of the 
test/reference drug. 
PD endpoints: 
✓ AUEC0-672 h (area under the effect vs. time curve from the 
moment of injection to 672 h [28 days]) based on the change 
in the absolute reticulocyte count after the first injection of 
BCD-131/Mircera®, 
✓ AC-Emax (maximum absolute reticulocyte count after the 
first injection of BCD-131/Mircera®). 
The PK analysis of the test drug will be based on the serum 
concentration of BCD-131 (pegylated darbepoetin). The PD 
analysis of BCD-131 will be based on the absolute reticulocyte 
count. 
The PK/PD study will include a limited number of patients 
(max 60 patients, i.e. 15 patients per group). Additional blood 
samples will be collected in these patients for PK/PD study. 
 
Blood sampling points for PK assessment: 
• 2 h, 1 h and 5 min before injection 1 (Day 1 of Week 1), 
• 3, 6, 12, 24, 48, 72, 96, 168, 336, 504 h after injection 1, 
• 672 h after injection 1 (i.e. immediately before injection 2 
at Week 5), 
• Before injections 3, 4, 5, 6 (Weeks 9, 13, 17, 21). 
Blood sampling points for PD assessment: 
• 5 min before injection 1 (Week 1), 
• 3, 6, 12, 24, 48, 72, 96, 168, 336, 504 h after injection 1, 
• 672 h after injection 1 (i.e. immediately before injection 2 
at Week 5). 

Clinical Study Protocol 
Protocol ID: BCD-131-2 
NCT03519243 
 
 
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SYNOPSIS 
Based on the investigator’s decision, during the period of 
intensive blood sampling for PK/PD analysis (after injection 1), 
patients in the PK/PD subset may be hospitalized to the study site 
(this hospitalization will not be reported as a SAE). 
The PK/PD endpoints will be analyzed after the completion of 
all periods of the study. 
Statistical Analysis 
Calculation of sample size 
The number of patients to be enrolled in the study was 
calculated using literature data on the therapeutic efficacy of 
Mircera® obtained from a multicenter, randomized, open-label 
clinical study of the maintenance treatment of anemia in dialysis 
patients with chronic kidney disease18.  
While the study was being planned, a hypothesis about the 
equivalent efficacy of the test and reference drugs (H0: |ε| ≥𝛿, H1: 
|ε| < δ, where ε is the true difference in the mean efficacy between 
the groups, δ is the equivalence margin of the efficacy of the test 
and reference drugs) was tested using the following values of 
errors: type I error: 5% (α=0.05), type II error: 20% (β=0.2), with 
the 80% power. The efficacy variable used to calculate the sample 
size was set as the change in the hemoglobin level throughout the 
treatment in patients participating in the above-mentioned Phase II 
study19. 
To calculate the sample size, the investigators estimated the 
sample mean value and standard deviation for the efficacy 
parameter using median values and quartiles given in the above-
mentioned study. The estimate was based on the approach 
described in the article by X.Wan, W.Wang20. 
The calculated number of patients was 10 subjects per 
group. Taking into account the evaluation of the primary efficacy 
endpoint of the test drug with the dose selection for subsequent 
phases and high probability of patient’s early withdrawal (due to 
the main disease), 25 patients will be included in each group to get 
more accurate and relevant efficacy data. Thus, the study will 
 
18 F.Locatelli, G.Villa, A.L.M. de Francisco, et al. Effect of a continuous erythropoietin receptor activator 
(C.E.R.A.) on stable haemoglobin in patients with CKD on dialysis: once monthly administration. Current medical 
research and opinion, 2007, Vol. 23, No., 2007, 969–979 
19 F.Locatelli, G.Villa, A.L.M. de Francisco, et al. Effect of a continuous erythropoietin receptor activator 
(C.E.R.A.) on stable haemoglobin in patients with CKD on dialysis: once monthly administration. Current medical 
research and opinion, 2007, Vol. 23, No., 2007, 969–979. 
20 X.Wan, W.Wang, J. Liu, T.Tong. Estimating the sample mean and standard deviation from the sample size, 
median, range and/or interquartile range. BMC Medical Research Methodology, 2014. 

Clinical Study Protocol 
Protocol ID: BCD-131-2 
NCT03519243 
 
 
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SYNOPSIS 
include up to 100 patients (25 patients in each group of BCD-131, 
if all the three groups are formed, and 25 patients in the reference 
group). 
Selection of populations for analysis 
Efficacy analysis 
The per-protocol analysis will be used to assess the efficacy 
of treatment using the primary endpoint. This analysis will include 
all the patients who completed the treatment according to the 
Protocol. 
The mITT-analysis will be used to evaluate the efficacy of 
treatment using secondary endpoints. The mITT-analysis will 
include all the patients who were randomized to receive at least one 
dose of the study drugs and were not withdrawn at the beginning of 
the study due to serious violations of the Protocol rules and 
inclusion/exclusion criteria. 
Safety analysis 
The safety population will include all the patients who 
received at least one dose of the test/reference drug. 
Immunogenicity analysis 
The immunogenicity analysis will include all the patients 
who received at least one dose of the test/reference drugs and who 
have samples (suitable for analysis) taken before the first injection 
and at least at one of the subsequent visits. 
PK/PD Analysis 
The PK/PD analysis will include patients with no missed / 
lost / damaged blood samples as follows: 
• Samples taken before injection 1 (at least 1 blood 
sample); 
• Not more than 2 blood samples taken after injection 
1 to 672 h, inclusive; 
• Not more than 2 blood samples taken at visits of 
Week 9, Week 13, Week 17, Week 21 (for PK 
analysis).  
Methods of Statistical Analysis 
The efficacy analysis for the primary endpoint will be 
performed by calculating the 95% confidence interval for the 
difference in the frequencies and by its comparison with the 
selected equivalence margin of 10 g/L. 

Clinical Study Protocol 
Protocol ID: BCD-131-2 
NCT03519243 
 
 
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Statistical methods for other variables will be selected based 
on the type and distribution of raw data. The following tests will be 
used to compare quantitative data with normal distribution: two-
tailed Student's test, Welch's test, ANOVA. The non-normally 
distributed quantitative data will be analyzed using the Mann-
Whitney test, Wilcoxon test, Kruskal-Wallis test, and the Friedman 
test. The categorical data will be processed with frequency tables, 
contingency tables, exact Fisher’s test, test for equality of 
frequencies, 𝜒2 Pearson’s test, and Cochran-Mantel-Haenszel test. 
Reporting: 
Upon the completion of all the study periods, the final report 
will be prepared. It will contain the data on the efficacy and safety 
of BCD-131 obtained in this study. 
 
 

Clinical Study Protocol 
Protocol ID: BCD-131-2 
NCT03519243 
 
 
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