The Clinical Study for Evaluating The Safety And Efficacy Of Epodion® During Maintenance Period Until Evaluation Period On CKD (Chronic Kidney Disease) Patients: An Open Label, Randomized, Active Drug-Comparative, Parallel-Designed, Multi-Center Clinical Study
Phase: NA
Conditions: Chronic Kidney Disease (CKD)
Sponsor: PT. Daewoong Infion

STUDY PROTOCOL 
 
 
The Clinical Study for Evaluating The Safety And 
Efficacy Of Epodion® During Maintenance 
Period Until Evaluation Period On CKD (Chronic 
Kidney Disease) Patients: An Open Label, 
Randomized, Active Drug-Comparative, Parallel- 
Designed, Multi-Center Clinical Study 
 
DW_EPO401 Version 2.1 
(2-April-2020) 
 
dr. Jonny, Sp.PD-KGH, M.Kes, MM1 
dr. Widodo Sutandar, Sp. PD-KGH2 
dr. Kuspuji Dwitanto, Sp. PD-KGH3 
 
 
1 Gatot Soebroto Army Hospital Soebroto, Central Jakarta 
 2 dr. Esnawan Antariksa Airforce Hospital, Est Jakarta  
3 Cempaka Putih Jakarta Islamic Hospital, Central Jakarta 
 
 
 
DAEWOONG PHARMACEUTICAL CO., LTD. 
2019 

Daewoong Pharmaceuticals, Co. Ltd 
DW_EPO401 
Version 2.1 
Protocol 
Effective Date 
2 April 2020 
Confidential 
Page viii of 53 
 
 
 
 
FORM OF AUTHORIZATION 
 
1. Study Title 
: The Clinical Study for Evaluating The Safety And Efficacy 
Of Epodion® During Maintenance Period Until Evaluation 
Period On CKD (Chronic Kidney Disease) Patients: An 
Open Label, Randomized, Active Drug-Comparative, 
Parallel-Designed, Multi-Center Clinical Study 
2. Principal Investigator 
a. Name 
: dr. Jonny, Sp.PD-KGH, M.Kes, MM 
b. Institution 
: Gatot Soebroto Army Hospital 
3. Investigator-1 
a. Name 
: dr. Widodo Sutandar, Sp. PD-KGH 
b. Institution 
: dr. Esnawan Antariksa Airforce Hospital 
4. Investigator-2 
a. Name 
: dr. Kuspuji Dwitanto, Sp. PD-KGH 
b. Institution 
: Cempaka Putih Jakarta Islamic Hospital 
5. Study Location 
: 3 hospitals at Jakarta (Gatot Soebroto Army Hospital, dr. 
Esnawan Antariksa Airforce Hospital, Cempaka Putih 
Jakarta Islamic Hospital ) 
6. Study Duration 
: October 2019 – July 2021 
 
 
 
Jakarta, 2 April 2020 
 
Principal Investigator, 
dr. Jonny, Sp.PD-KGH, M.Kes, MM 
Colonel CKM 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Daewoong Pharmaceuticals, Co. Ltd 
DW_EPO401 
Version 2.1 
Protocol 
Effective Date 
2 April 2020 
Confidential 
Page viii of 53 
 
 
STATEMENT SHEET 
 
I, the undersigned below: 
Principal Investigator 
: dr. Jonny, Sp.PD-KGH, M.Kes, MM 
Study Title 
: The Clinical Study for Evaluating The Safety And Efficacy Of 
Epodion® During Maintenance Periode Until Treatment Evaluation 
Period On CKD (Chronic Kidney Disease) Patients: An Open Label, 
Randomized, Active Drug-Comparative, Parallel-Designed, Multi- 
Center Clinical Study 
Institution 
: Gatot Soebroto Army Hospital 
 
I hereby declare that in this research protocol/proposal no work has ever been submitted for 
approval in other institutions and to the best of my knowledge no work or opinion has ever been 
published or published by another person, except those published are referred to in this manuscript 
and mentioned. in the bibliography. 
Jakarta, 2nd April 2020 
 
Principal Investigaor, 
dr. Jonny, Sp.PD-KGH, M.Kes, MM 
Colonel CKM

Daewoong Pharmaceuticals, Co. Ltd 
DW_EPO401 
Version 2.1 
Protocol 
Effective Date 
2 April 2020 
Confidential 
Page ix of 53 
 
 
GLOSSARY OF TERM 
 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
CBC 
Complete Blood Count 
CKD 
Chronic Kidney Disease 
CI 
Confidence Interval 
CRO 
Contract Research Organization 
CSR 
Clinical Study Report 
CRF 
Case Report Form 
EMA 
European Medicines Agency 
EPO 
Erythropoietin 
GCP 
Good Clinical Practice 
IC 
Informed Consent 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
ITT 
Intent-To-Treat 
IWRS 
Interactive Web Response System 
NAb 
Neutralizing Antibody 
PP 
Per-protocol 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SBP 
Similar Biotherapeutic Product 
SOC 
System Organ Class 
WHO 
World Health Organization 

Daewoong Pharmaceuticals, Co. Ltd 
DW_EPO401 
Version 2.1 
Protocol 
Effective Date 
2 April 2020 
Confidential 
Page xix of 53 
 
 
 
PROTOCOL SYNOPSIS 
 
Study title 
The Clinical Study for Evaluating the Safety and Efficacy Of 
Epodion® During Maintenance Period Until Evaluation Period 
On CKD (Chronic Kidney Disease) Patients: An Open Label, 
Randomized, Active Drug-Comparative, Parallel-Designed, 
Multi- Center Clinical Study 
Sponsor 
 
Daewoong Pharmaceutical Co., Ltd. 
CRO 
 
PT. Equilab International 
Institution and 
Principal 
Investigator 
Gatot Soebroto Army Hospital  
Internal Medicine Department, 
dr. Jonny, Sp. PD-KGH, M.Kes, MM 
Study Period 
Total 36 - 40 weeks 
• 
Screening period (-4) weeks 
• 
Titration period 4~8 weeks 
• 
Baseline evaluation period 4 weeks 
• 
Maintenance period 24 weeks 
• 
Evaluation Period 4 weeks 
Study Population 
Anemia Associated with Chronic Kidney Disease aged ≥ 18 
years and undergoing hemodialysis in hospital site 
Objectives 
To evaluate the safety and efficacy of Epodion® on Chronic 
Kidney Disease (CKD) patients 
Study Phase and 
Design 
An Open Label, Randomized, Active Drug-Comparative, 
Parallel- Designed, Multi-Center Clinical Study, Phase IV Study 
Method 
This clinical study was designed as an open label, randomized, 
active-drug comparator, parallel designed, and multicenter 
study in hemodialysis patients with anemia. 
Once subjects voluntarily consented to participate in the clinical 
study, medical examinations and tests required in the protocol 
will be conducted, eligibility of each subject will be checked, 
and only subjects who meet all of the screening criteria will be 
proceeded for first phase of study which is titration period. 
In Titration period (4 ~ 8 weeks), all eligible subjects will be 
administered with Eprex® at individualized dose. Routine 
hematological (Complete Blood Count, CBC) test will be 
performed every two weeks to monitor Hb level as 
consideration for dose adjustment. Eprex® doses should be 

Daewoong Pharmaceuticals, Co. Ltd 
DW_EPO401 
Version 2.1 
Protocol 
Effective Date 
2 April 2020 
Confidential 
Page xix of 53 
 
 
closely titrated to achieve target Hb range 10-12 g/dL. Subject 
who meets the target range at week 4 will be allowed to skip 
the remaining 4 weeks of titration period and continue to 
Baseline Evaluation Period. 
During the 4 weeks of Baseline Evaluation Period, laboratory 
tests required in the protocol are performed every two weeks 
and recorded as baseline data. 
 
Subjects who meet the inclusion criteria, none of the exclusion, 
and achieve baseline evaluation target criteria will be 
randomized into either test group (Epodion® treatment) or 
control group (Eprex® treatment). 
 
In Maintenance period, the administration dose of Eprex® and 
Epodion® is equal to the previous dose in titration period. Dose 
is allowed to be increased or decreased during maintenance 
period at an appropriate level to maintain Hb level 10-12 g/dL 
according to condition of subjects. During maintenance period, 
blood samples will be collected every two weeks for routine 
hematological test to monitor the efficacy and as consideration 
for dose adjustment. 
 
In the Evaluation period, blood samples will be collected every 
two weeks. The mean of Hb change, weekly dosage, and 
hematocrit between baseline and evaluation period will be 
evaluated as efficacy assessment. 
Investigational 
Product 
Treatment: Recombinant Human Erythropoietin Alfa, Epodion® 
(Daewoong Infion) 
Reference: Recombinant Human Erythropoietin Alpha, Eprex® 
(Janssen) 
Dosage & 
Administration, and 
Route of 
Administration 
Initial Epoetin dose administered according to previous dose. In 
Maintenance period, Epoetin dose may be increased or 
decreased at an appropriate level according to the condition of 
the subjects. 
Number of subjects 
Study 
Group 
(Epodion®) 
Control 
Group 
(Eprex®) 
Total 
Sample 
Size 
Evaluated Case 
50 
50 
100 
Inclusion Criteria: 
a. Male or female patients who are at least 18 years old and 
younger than 75 years of age at the time of screening visit. 

Daewoong Pharmaceuticals, Co. Ltd 
DW_EPO401 
Version 2.1 
Protocol 
Effective Date 
2 April 2020 
Confidential 
Page xix of 53 
 
 
Screening Criteria: 
b. Patients with End-Stage Renal Failure (ESRD) who are 
chronically receiving hemodialysis and have anemia. 
c. Patients with a mean baseline Hb concentration within Hb 
level ≥9 g/dL during the screening period. 
d. Haemodialysis patients with anemia associated with Chronic 
Kidney Disease (CKD) currently receiving stable 
maintenance therapy with Epoetin alfa at least once per 
week. 
e. Adequate iron substitution status (serum ferritin ≥ 100 μg / L 
(100 ng / mL) or saturated transferrin levels ≥ 20%). 
 
f. Patients who understand the information provided to them or 
their representatives and may provide written consent. 
 
Exclusion Criteria: 
a. Contraindication with Epoetin therapy. 
b. Documented active bleeding in the last 12 weeks prior to 
screening period. 
c. Any blood transfusion within the last 2 weeks prior Screening 
period. 
d. History of malignancy of any organ system within the last 5 
years. 
e. Patients with uncontrolled hypertension (in case the mean 
value of diastolic blood pressure as measured 4 times during 
the baseline observation period is 110 mmHg or more). 
f. Patients hyporesponsive epoetin treatment or had medical 
history of experiencing pure red blood cell forming failure 
after being administered with Epoetin products. 
g. Known bone marrow fibrosis (osteitis fibrosa 
cystica). 
 
h. Patient with serious cardiovascular disorders: 
myocardial infarction, patients with congestive 
heart failure (NYHA class Ⅲ or higher), ischemic 
vascular disease. 
i. Patient received percutaneous coronary intervention (PCI), 

Daewoong Pharmaceuticals, Co. Ltd 
DW_EPO401 
Version 2.1 
Protocol 
Effective Date 
2 April 2020 
Confidential 
Page xix of 53 
 
 
or coronary artery bypass grafting (CABG) during the last 6 
months prior to screening. 
j. Patients with ALT or AST exceeding the upper limits of the 
normal level by more than 5-folds. 
k. Patients whose kidney transplant is expected or already 
planned for survival. 
l. Secondary anemia to other causes different to the CKD 
(aplastic anemia, hemolytic anemia, sickle cell anemia, 
multiple myeloma, leukemia, myelodysplastic syndrome). 
m. Patients with the following diseases and who are considered 
unfit to enroll in the clinical study: mental system disease, 
mental disease, drug intoxication, epilepsy, lung infarction, 
cerebral infarction, positive HIV antibody, systemic lupus 
erythematosus, immunosuppressive condition and general 
infection. 
 
n. Pregnancy or lactation period in female patients, or 
women of childbearing potential without an effective method 
of birth control. 
 
o. Patients who were considered unfit for study by the principal 
investigators or by the co-investigator. 
Baseline Evaluation 
Period Criteria 
Subject who voluntarily consented to participate in the clinical 
study, meet eligible criteria, stable with Eprex®, will be 
evaluated again to assess the subject eligibility prior 
randomization and maintenance period. Only subjects who meet 
eligible baseline criteria will continue to randomization and 
maintenance period. 
Inclusion criteria: 
 
a. Subject achieved Hb target 10-12 g/dl. 
 
b. Adequate iron substitution status (serum ferritin ≥ 100 μg / L 
(100 ng / mL) or saturated transferrin levels ≥ 20%). 
 
c. Patients who have gone through the baseline evaluation at 
the time of the screening visit or before randomization. 
 
d. Patients with dry weight less than 5% during the baseline 
evaluation period. 
 
e. Subject are reliable and will willingly cooperate during the 
maintenance period and observe the restrictions. 
 

Daewoong Pharmaceuticals, Co. Ltd 
DW_EPO401 
Version 2.1 
Protocol 
Effective Date 
2 April 2020 
Confidential 
Page xix of 53 
 
 
Exclusion Criteria: 
a. Any blood transfusion within the last 2 weeks prior to 
screening period. 
b. In case the EPO administration dose during the baseline 
evaluation period (week 9-12 / 13-16) is increased or 
decreased by 20% or more. 
c. Currently contraindicated with Epoetin therapy. 
d. Subject administered with prohibited drug 
(cyclosporine, androgen, and chemotherapy agents). 
 
e. Occurrence medical condition which can affect 
efficacy data during maintenance period judged by 
principal investigator or sub-investigator. 
Outcome Measures: 
Primary endpoint 
a. Mean change in Hb (hemoglobin) level between the 
baseline period and the evaluation period 
Secondary endpoint: 
b.  Mean change in weekly dosage per kg body weight 
between the baseline period and the evaluation period. 
Instability rate of Hb (hemoglobin) level during maintenance 
and evaluation period as defined when Hb (hemoglobin) level 
dropped below 8 g/dL or increase more than 13 g/dL. 
c. Evaluation Hb (hemoglobin) and hematocrit level during 
maintenance and evaluation period. 
Safety Evaluation: 
Incidence adverse events. 
Study flow 
Study timeline 

Daewoong Pharmaceuticals, Co. Ltd 
DW_EPO401 
Version 2.1 
Protocol 
Effective Date 
2 April 2020 
Confidential 
Page xix of 53 
 
 
1. Subject must achieve baseline target Hb level 10-12 g/dL prior enter
maintenance period. If during 4-week titration period subject did not 
achieve baseline Hb level 10-12 g/dL, titration period will be extended
maximum until week 8. 
 
2. Doses must be individualized to ensure that hemoglobin is maintained 
at an appropriate level for each subject. In the screening period, initial 
dose is 50 IU/Kg body weight three times per week. During titration, 
dose id titrated closely to achieve baseline Hb level 10-12g/dL. In 
maintenance period administer Eprex® and Epodion® equal previous 
stable dose in titration period. Dose is allowed to be increased or 
decreased during maintenance period at an appropriate level according 
to the condition of the subjects. 
3. Only the subjects within the inclusion/exclusion criteria and achieved 
baseline target evaluation criteria should be processed to randomization 
and maintenance period. When the subject achieves baseline target Hb 
level 10- 12 g/dL in 4 weeks titration period randomization will be done 
in week 8, if subject fail achieves Hb 10-12 g/dL in 4 weeks titration 
period, titration period will be extended until week 8. Subject will be 
screened failure and cannot enter maintenance period if during 
maximum 8 week titration cannot achieve target baseline Hb level 10-12 
g/dL. 
 
4. Safety assessment will be evaluated based on comparison incidence of 
adverse event between Epodion® and Eprex®. Incidence of adverse 
events will be recorded during maintenance and evaluation period. 

Daewoong Pharmaceuticals, Co. Ltd 
DW_EPO401 
Version 2.1 
Protocol 
Effective Date 
2 April 2020 
Confidential 
Page 16 of 53 
 
 
 
CHAPTER I. INTRODUCTION 
 
 
1.1 Background of Clinical Study 
 
World Kidney Day (WKD) is celebrated every Thursday on the second week in March. In 2017, 
the theme raised was "Kidney disease and obesity, a healthy lifestyle for healthy kidneys", which 
Chronic Kidney Disease (CKD) is a global public health problem with increased prevalence and 
incidence of kidney failure, poor prognosis, and high cost. Clinically, CKD is defined as kidney 
damage and / or decreased Glomerular Filtration Rate (GFR) of less than 60 ml / minute / 1.73 
m2 for a minimum of 3 months (KDIGO, 2012). 
 
CKD is also a comorbidity of diabetes and hypertension, and can also be caused by chronich 
glomerulonephritis, chronic interstitial nephritis, polycystic kidney disease, urinary tract infections, 
and obesity. CKD also has an indirect impact on increasing deaths from cardiovascular disease, 
diabetes, hypertension, infections in people with HIV, and malaria (Indonesia Ministry of Health, 
2017). 
 
Based on 2015 data by the Global Burden of Disease, 1.2 million deaths are directly correlated 
with a decrease in glomerular filtration ability. In addition, it is also estimated that 2.3-7.1 million 
deaths due to difficulty accessing dialysis, 1.7 million deaths from acute kidney failure, and 5-10 
million deaths from other kidney diseases (Luyckx et al., 2018). 
 
In Indonesia, treatment of CKD patients is second rank after heart disease in the largest funding 
of BPJS health. Based on the results of the 2013 Basic Health Research (Riskesdas), 0.2% of 
the adult population were diagnosed with CKD. This number is lower than the prevalence of CKD 
in other countries based on Indonesia Renal Registry (Pernefri) 2006, which is 12.5%. The 
difference in prevalence rates caused by the diagnosis of CKD patients in Indonesia can only be 
done in the later and final stages (Indonesia Ministry of Health, 2013). 
 
The prevalence of CKD increases as the increasing number of elderly people and the incidence 
of diabetes mellitus and hypertension. CKD is also more common in women because women 
generally have lower muscle mass, so the serum creatinine concentration is also different. 
Calculation of prevalence of CKD generally involves correction factors for women with CKD (Hill 
et al., 2016). 
 
Anemia, which is a complication of chronic kidney disease, is often associated with decreased 
levels of erythropoietin (EPO) in the blood. This results from damage of the cell mass in the 
kidneys responsible for EPO production. Treatment of anemia caused by chronic kidney disease 
which has become the standard is the administration of exogenous EPO together with 
improvement in blood iron levels. 
 
EPO is a glycoprotein hormone produced by renal erythropoietin-producing cells and has a 
function in inducing red blood cell production in the red marrow. Today, EPO has been developed 
on a manufacturing scale using recombinant technology to meet market needs. EPO which is 
developed using recombinant technology is called recombinant human EPO (rhEPO). The first 
recombinant human EPO was developed by Epoetin alpha by Amgen Inc. with the name Epogen 
market. Some other rhEPO products that have been widely used throughout the world include 
Procrit® from Amgen Inc. and Eprex® from Janssen Pharmaceutica (Zadeh, 2017). 

Daewoong Pharmaceuticals, Co. Ltd 
DW_EPO401 
Version 2.1 
Protocol 
Effective Date 
2 April 2020 
Confidential 
Page 17 of 53 
 
 
 
In Indonesia, several RhEPO products that have obtained marketing licenses include Epodion®, 
Epoglobin®, Epotrex®, Hemapo®, Rinofer®, and Recormon® (MIMS, 2019; BPOM, 2019). 
These products are developed by both Indonesian and international pharmaceutical companies. 
The rhEPO products are categorized as biosimilar products. RhEPO products in Indonesia were 
developed referring to the RhEPO originator so that they have the same efficacy and safety as 
the rhEPO originator. 
 
Similar biotherapeutic product (SBP) or can be called similar biological products are biological 
products with efficacy profiles, safety, and quality that are similar to biological products approved 
by the drug safety regulatory authority (BPOM, 2015). Development of biological products that 
are not as simple as synthetic chemical drugs can cause several aspects of similar product 
development to be different. The development of generic drugs from synthetic chemical drugs 
can go through the same stages and produce types of drugs with the same characteristics as the 
originator. However, this does not apply to the development of biological products. 
 
Biological products are complex molecules that are produced using living cells and have very high 
levels of variation depending on the means, tools and materials used in the production process. 
The consistency between batches of production is a challenge in manufacturing biological 
products. Insignificant differences or very small changes in production, transportation or storage 
can result in changes in the safety and efficacy profile of biological products. Two similar biological 
products cannot always be proven to be identical products. 
 
Biosimilar products can be produced by the pharmaceutical industry after the originator's product 
patent period has expired. At present, various biosimilar products are under development or have 
received marketing licenses in many countries. Development of science as well as the growth of 
pharmaceutical industry in Indonesia has an impact on improving domestic biosimilar products. 
Various biosimilar products that have been developed in Indonesia include erythropoietin, 
monoclonal antibodies, and several growth factor products. 
 
Epodion® research has been carried out in several countries including Korea and Thailand with 
good results. Phase III studies in Korea evaluated the safety and efficacy of Eposis® in 198 CKD 
patients (Eposis®: 101, reference product: 97) using dose: ≤ 2000 IU / kg, 3 times/week. The 
efficacy of Eposis® is the same and or better than the reference product. Eposis also shows lower 
frequency of Adverse Events compared to reference products. Whereas in the Post Marketing 
Surveillance study in Korea with the number of subjects 640 CKD patients for 4 years. In the 
results of the safety assessment, 55 and 13 cases of adverse event occurred in the general PMS 
study and the long-term PMS study, respectively (An incidence of adverse events was 9.02% and 
18.57%, respectively; in the exact 95% confidence level). All the reported adverse events were 
considered that there was no causal relationship with product and therefore there were no 
adverse drug reactions. 
 
Phase IV study begins after drug approval. Therapeutic use studies go beyond the prior 
demonstration of the drug’s safety, efficacy and dose definition. Studies in Phase IV are all studies 
(other than routine surveillance) performed after drug approval and related to the approved 
indication. They are studies that were not considered necessary for approval but are often 
important for optimizing the drug's use. They may be of any type but should have valid scientific 
objectives. 
 

Daewoong Pharmaceuticals, Co. Ltd 
DW_EPO401 
Version 2.1 
Protocol 
Effective Date 
2 April 2020 
Confidential 
Page 18 of 53 
 
 
1.2 Rationale for Clinical Study 
 
1.2.1 Non-clinical Study 
 
Nonclinical study was conducted based on “Guideline on non-clinical and clinical development of 
similar biological medicinal products containing recombinant erythropoietin” released by 
European Medicines Agency (EMEAjansse/CHMP/BMWP/301636/2008). In pharmacology 
studies, biosimilarity and bioequivalence of test product and reference product was confirmed in 
the regular animal model, acute blood loss induction model, and renal failure model. Both 
articles’s effects were determined to be equivalent. In pharmacokinetic studies, all parameters, 
blood concentration curve area (AUClast), maximum blood concentration (Cmax), and half-life (T½), 
met the criteria for biosimilarity evaluation. 
 
Biosimilarity and bioequivalence of reference and test product on the absorption was confirmed 
in intravenous and subcutaneous administration in rats. In the case of toxicology study, no 
abnormality was observed in the single dose toxicity studies in rats and beagle dogs. To 
investigate the toxicity caused by the 4-week repeated intravenous administration of test product, 
it was repeatedly administered intravenously to Sprague-Dawley rats for 4 weeks. 
 
As a result of the test, there was no death rate or any abnormality in the ophthalmologic test, 
urinalysis, autopsy, and clinical signs caused by the administration of test product. When 
compared to reference product, test product showed that equivalent or non-inferior toxicological 
profile. For analysis of antigenicity, active systemic anaphylaxis test (ASA) and passive cutaneous 
anaphylaxis (PCA) were conducted in guinea pigs. Both articles had similar pattern in anaphylaxis 
reaction. 
 
From the pharmacodynamics, pharmacokinetic and toxicology study results of test product and 
comparison with reference product, test product was proven that has similar pharmacokinetics, 
pharmacodynamic effect and toxicological profile with reference. In conclusion, no harmful effect 
is expected to be observed when test product is administered into human. 
 
1.2.2 Clinical Safety Study 
 
Post-marketing data was collected from December 4, 2007 to December 3, 2011 in Korea. A 
target number of subjects were more than 600 and the total number of collected CRFs was 640. 
Detailed report was attached in 5.3.6 Report of post-marketing experiences. In the results of 
safety assessment, 55 and 13 cases of adverse event occurred in the general PMS study and the 
long-term PMS study, respectively (An incidence of adverse events was 9.02% and 18.57%, 
respectively; in the exact 95% confidence level). All the reported adverse events were considered 
that there was no causal relationship with product and therefore there were no adverse drug 
reactions. 
 
1.2.2 Efficacy Study 
 
Therapeutic confirmatory study for evaluating the safety and efficacy of EPO PRODUCT on CRF 
(Chronic Renal Failure) patients: a double-blinded, randomized, active drug-comparative, 
parallel-designed, multi-center clinical study has been conducted on 192 patients in Korea. To 
verify the effects of treating anemia patients suffering from chronic renal failure, the indications of 
the test product and the reference product and trends in changes in RBC (Red Blood Cell), 
Hemoglobin, Hematocrit, and Reticulocyte, were examined during the period of clinical study. 

Daewoong Pharmaceuticals, Co. Ltd 
DW_EPO401 
Version 2.1 
Protocol 
Effective Date 
2 April 2020 
Confidential 
Page 19 of 53 
 
 
During the process of the clinical study, the test group posted somewhat higher values compared 
with the reference group in 3 items, i.e., RBC, Hemoglobin, and Hematocrit. 
 
1.3 Objective and Hypothesis 
 
The objective of this study is to evaluate the safety and efficacy of Epodion® on Chronic Kidney 
Disease (CKD) patients. 
 
1.3.1 Study Objectives 
 
1.3.1.1 Efficacy Outcome 
 
A. Primary Objectives 
To demonstrate that the Epodion® treatment is equivalence to Eprex® by evaluating Hb 
level change between baseline and evaluation period. 
 
B. Secondary Objectives 
1. Obtain data mean change in weekly dosage per kg body weight between the baseline 
period and the evaluation period. 
 
2. Calculating instability rate of Hb (hemoglobin) level during maintenance and evaluation 
period as defined when Hb (hemoglobin) level dropped below 8 g/dL or increase more 
than 13 g/dL. 
 
3. Evaluating Hb (hemoglobin) and Hematocrit level during maintenance and evaluation 
period. 
 
1.3.1.1 Safety Outcome 
 
Obtain safety data (side effects, adverse events, and serious adverse events) hemodialysis 
patients during the use of Epodion®. 
 
 
1.3.2 Hypothesis 
 
Efficacy and safety of Epodion® was therapeutically equivalence to the reference product 
(Eprex®) in dialysis patients with renal anemia. 
 
1.4 Research Benefit 
 
This study will provide treatment in the form of hemodialysis three times a week during the study 
period to consenting and committed patients marked by signing on the explanation sheet after 
approval. In addition, subjects will receive routine Epoetin treatment during the study period. 

Daewoong Pharmaceuticals, Co. Ltd 
DW_EPO401 
Version 2.1 
Protocol 
Effective Date 
2 April 2020 
Confidential 
Page 20 of 53 
 
 
 
CHAPTER 2. LITERATURE REVIEW 
 
 
2.1 Chronic Kidney Disease (CKD) 
 
Chronic Kidney Disease (CKD) is kidney damage due to structural or kidney function 
abnormalities that occurs for more than 3 months. The kidneys have various functions including 
excretion, endocrine and other metabolic functions. Glomerular filtration rate (GFR) is one 
component of excretion that is generally used as an index of renal function because in general 
kidney function will decline after damage to the spread structure and decrease in other kidney 
function decreases with glomerular filtration rate in CKD (KDIGO, 2013). The criteria for Chronic 
Kidney Disease (CKD) can be seen in the following table: 
 
Table 1. CKD criteria (KDIGO, 2013) 
 
 
 
 
 
 
 
 
 
Parameters of kidney damage 
(one or more) 
● Albuminuria (AER> 30 mg / 24 hours; ACR> 
30 mg / g [> 3mg / mmol]) 
● Urinary sediment abnormalities 
● Electrolyte abnormalities and others due to 
tubular damage 
● Abnormalities detected by histology 
● Structural damage detected by imaging 
● History of kidney transplants 
Decreasing Glomerular Filtration Rate (LFG) 
< 60 mL/minute/1.73 m2 

Daewoong Pharmaceuticals, Co. Ltd 
DW_EPO401 
Version 2.1 
Protocol 
Effective Date 
2 April 2020 
Confidential 
Page 21 of 53 
 
 
 
Based on the National Kidney Foundation Kidney Disease Improving Global Outcomes (NKF- 
KDIGO) in 2012, the classification of Chronic Kidney Disease (CKD) was divided based on 
glomerular filtration rate and albuminuria (Figure 1). 
 
 
Figure 1. Classification of Chronic Kidney Disease based on Glomerular Filtration Rate and 
albuminuria (KDIGO, 2012) 
 
In patients with CKD, a decrease in the glomerular filtration rate causes a buildup of chemicals 
such as potassium and urea. Hemodialysis therapy, which is a blood cleansing process using a 
kidney replacement in the form of a dialyzer machine, is given to patients with CK level 5 or the 
final level or GFR <15 mL / minute / 1.73 m2. This process involves the use of a dialysate 
containing sodium bicarbonate, sodium chloride, acid concentrate, and water distilled as an 
osmosis medium. The physiological working principle of hemodialysis is filtration, diffusion, 
osmosis, and ultrafiltration which are influenced by temperature, viscosity, and size of the 
molecule itself (Vadakedath & Kandi, 2017). 
 
People with CKD often also suffer from anemia complications caused by a decrease in kidney 
function. Anemia diagnosis is given to adult PGK patients if the Hb concentration is <13 g / dl in 
men or <12 g / dl in women. This condition can occur when a decrease in kidney function is up to 
50%. Iron therapy can be performed on CKD patients with anemia who have low iron levels, which 
is known by conducting laboratory tests for ferritin <200 ng / L and transferrin saturation <30%. In 
addition, CKD patients with anemia can be given Epoetin therapy to increase levels of red blood 
cells or erythrocytes in the blood (Pollock et al. 2008). 
 
 

Daewoong Pharmaceuticals, Co. Ltd 
DW_EPO401 
Version 2.1 
Protocol 
Effective Date 
2 April 2020 
Confidential 
Page 22 of 53 
 
 
 
Giving Epoetin in patients with CKD who undergo hemodialysis begins after symptoms of uremia, 
excess fluid, and stable hypertension. In addition, administration of Epoetin can only be done after 
all causes of anemia except erythropoietin deficiency are overcome, especially iron deficiency, 
folic acid, vitamin B12, and the presence of bleeding (Pollock et al. 2008). 
 
2.2 Biosimilar 
 
Biological products contain active compounds derived from living cells or organisms and are very 
necessary for the treatment of various serious and chronic conditions. Most biological products 
used clinically are groups of proteins with varying sizes and complexity. The production process 
of biological products is more complicated than medicinal products produced through a synthesis 
process with chemical reactions, because it often involves the engineering process of DNA 
recombination. 
 
In the production process, the biological products produced can vary between batches which can 
affect the safety and efficacy of the product as a whole. Determination of standard variations is 
needed to ensure that active compounds can work in accordance with the objectives and at the 
intended level. Strict control of the quality of biological products is applied to each batch of 
production, both from physicochemical properties, biological activities, activity, purity, degree of 
sterilization, and stabilization. 
 
Biosimilar products are products that are similar to other biological products whose period of 
protection has ended. Biosimilar products must have similarities and sequences of amino acids 
or proteins and protein folding structures that determine their biological activity. In addition, 
biosimilar products are also not allowed to have different posology and administrative routes 
unless they have an effect on product safety and efficacy. Based on the level of similarity with the 
originator, biosimilar products are divided into 4 levels (Figure 2) (EMA, 2017). 
 
Figure 2. Similarity level of biosimilar product toward the originator (EMA, 2017) 

Daewoong Pharmaceuticals, Co. Ltd 
DW_EPO401 
Version 2.1 
Protocol 
Effective Date 
2 April 2020 
Confidential 
Page 23 of 53 
 
 
 
Biosimilar products are different from generic products because the production of generic 
products is carried out through a chemical synthesis process and does not involve variability so 
that the end product can have a similarity level of up to 100% (Table 2). 
 
Table 2. Comparison of generic products with biosimilar products (EMA, 2017) 
Generic product 
Biosimilar product 
Production process 
Chemically synthesized 
Biological process 
Final result 
The exact same molecule 
Molecules with high similarity 
levels 
Molecule size 
Small, can be easily 
characterized 
Large, complex structures 
require technology for 
characterization 
Development process 
Emphasizes the bio- 
equivalence (speed of release 
of active compounds) 
Emphasizing biosimilarity 
(structure, biological functions, 
efficacy, safety, and 
immunogenicity) 
 
 
The biosimilar regulation was first compiled by the European Union in 2006 with the approval of 
the first biosimilar product, the somatotropin hormone. Approval of biosimilar products is given 
based on a balance between positive benefits and risks based on biosimilarity with the originator. 
 
This is obtained through comparative studies to find out clinical data between biosimilar products 
and their originators. 
 
Based on applicable regulations in the European Union, biosimilar producers must be able to 
show data as proof that the product has been produced to applicable standards and is intended 
for certain clinical uses. Some requirements include characteristic structure, physicochemical 
properties, purity, biological activity, product composition, formulation, manufacturing process, 
and stability of active ingredients and products during storage (EMA, 2017). 
 
Clinical trials for biosimilar products do not need to be done for all important stages (phase 1, 2, 
and 3 clinical trials) to find out analytical and functional data because these two aspects have 
been carried out by the originator. The comparability, security, and efficacy between biosimilar 
products and the originator are preferred (EMA, 2017). 
 
2.3 Erythropoietin 
 
Erythropoietin (EPO), otherwise known as epoetin is a glycopeptide hormone (figure 3) produced 
by renal erythropoietin producing cells in the kidneys. This hormone is functioning as a stimulator 
to produce red blood cells in the human red marrow. Increased hormone production is happening 
when low-oxygen level detected in kidney. EPO in humans was first isolated from anemic patients 
in 1977. The gene that encodes EPO in humans was first isolated in 1983. After one year later, 
the EPO gene was successfully cloned for the first time shown in the Chinese Hamster Ovary 
(CHO) cell. This cloning technology then became a stepping stone in the development of 
recombinant human EPO (rhEPO) as an anemia drug in patients with chronic kidney disease. 

Daewoong Pharmaceuticals, Co. Ltd 
DW_EPO401 
Version 2.1 
Protocol 
Effective Date 
2 April 2020 
Confidential 
Page 24 of 53 
 
 
 
 
Figure 3. Amino acid sequence and Erythropoietin primary structure 
 
 
Erythropoietin is known to cause physiological effects if it binds to EPO receptors (EpoR). EPO 
binds to its receptors on the surface of stem cells which will differentiate into red blood cells. EPO 
is known to have a mechanism of action on cells by activating the JAK2 signal cascade. The 
initiation of the JAK2 pathway will also activate the signal cascade on the STAT5, PIK3, and 
MAPK lines. The signaling causes erythroid cell differentiation and division. In addition, the 
SOCS1, SOCS3 and CIS paths are also activated and play an antagonistic role as a negative 
regulator of EPO. EPO receptors (EpoR) are found most frequently in stem cells in the red marrow. 
Even so, EpoR is also found in other tissues, such as the heart, muscles, kidneys, peripheral 
nerve networks and central nervous networks. 
 
 
The level of EPO in blood in normal humans is around 10 mU/mL. Meanwhile, in conditions of 
hypoxia or lack of oxygen, EPO production has increased up to 1000 times to reach 10,000 
mU/mL in blood. In adults, EPO is produced mainly in cells in the kidney, but a small fraction of 
the fraction of EPO in the blood is also produced by the liver and pericyte cells in the brain. 
 
Regulation of EPO production is governed by a reciprocal mechanism of oxygen and iron levels 
in the blood. 
 
2.4 Epodion® 
 
Epodion® is an alpha rhEPO product produced by PT. Daewoong Pharmaceutical Company 
Indonesia. This product is used in conjunction with other clinical treatments for anemic patients 
due to chronic kidney disease or due to chemotherapy. Yellowish transparent Epodion® injection 
solution which can be injected intravenously or subcutaneously. Epodion® has four products with 
different EPO content, including 2000 IU, 3000 IU, 4000 IU, and 10000 IU. 
 
At the beginning of Epodion® use, patients are given a dose of 50 units/kg of body weight three 
times a week which can be done intravenously or subcutaneously. If needed, the dose can be 
increased to 75 units/kg at 4-week intervals from the initial administration. If the increase in 
hemoglobin level increases by more than 2 gr/dL at the initial dose, the administration of Epodion® 
must be reduced to 2 times a week. Repair doses can be continued until the patient's hemoglobin 
level becomes 10 gr/dL. Anemia that has been overcome can be continued with a maintenance 

Daewoong Pharmaceuticals, Co. Ltd 
DW_EPO401 
Version 2.1 
Protocol 
Effective Date 
2 April 2020 
Confidential 
Page 25 of 53 
 
 
dose of between 25 to 50 units/kg, 2 or 3 times a week. The expected hemoglobin range for 
treatment is 10-12 gr/dL. The initial hemoglobin level determines the treatment dose. In addition, 
the patient's age is also important in determining the dose. The dosage for the use of Epodion® 
should not exceed 200 units/kg and the frequency of administration is not more than 3 times a 
week. During treatment, the patient's iron levels need to be controlled. Chronic kidney failure 
patients who do not undergo hemodialysis, a dose of 70-150 units/kg per week is proven to 
maintain hematocrit levels 36-38% for more than 6 months. 
 
Research on the effects of Epodion® on human bone marrow cell culture shows that Epodion® 
stimulates the formation of red blood cells and does not affect the formation of white blood cells. 
Animal studies using Epodion® showed in vivo efficacy in test animals. In addition, no cytotoxic 
effects were detected, changes in behavior, locomotor activity, circulation or breathing in test 
animals. 
 
The time needed to reach maximum concentration in uremia patients averages 12-28 hours with 
subcutaneous administration. The bioavailability of Epodion® by subcutaneous administration is 
23-42% compared with intravenous administration. Half-life of Epodion® given intravenously to 
healthy volunteers and kidney failure patients ranges from 4-12 hours with a distribution volume 
reaching 1 to 2 times the plasma volume. This is similar to the results found in studies in mice 
with uremia and normal mice. The half-life of the terminal Epodion® by subcutaneous 
administration in uremia patients averages 13-28 hours, longer than intravenous administration. 
 
The most common side effect is hypertension or worsening hypertension. This increase in blood 
pressure can be treated with antihypertensive agents. If the hypertension that occurs cannot be 
overcome with anti-hypertensive drugs, it is recommended to temporarily stop giving Epodion®. 
Therefore, it is recommended to monitor the possibility of a hypertensive crisis with symptoms 
resembling encephalopathy (eg, headache, confusion, sensorimotor disorders, tonic clonic 
(seizures), including in patients with normal or low blood pressure. 
 
In addition, leukocytosis, eosinophilia can sometimes occur. Granulocytopenia can sometimes 
occur in premature infants. Increases in serum potassium, BUN, creatinine and gout have been 
reported to occur occasionally. Although rare, thrombocytosis can occur. Reported red cell 
hypoplasia after administration of Epodion® product in patients with chronic kidney failure from 
several months to several years is rare. In addition, there may be an increase in platelet counts 
during Epodion® therapy, especially if given IV. This increase in platelet counts associated with 
the dose of Epodion® given is usually within normal limits and will improve if Epodion® therapy is 
given. The incidence of thrombocytosis is very rare. However, it is recommended to monitor 
platelet levels during the first 8 weeks of Epodion® therapy. 
 
Often, a higher dose of heparin is needed during hemodialysis due to an increase in hematocrit 
levels. In addition, a dialysis system blockage may occur if heparinization is not optimal. Shunt 
thrombosis can occur in patients who tend to be hypotensive or patients with complications of the 
arteriovenous fistula (eg, aneurysm, stenosis). In these patients it is recommended to give 
thrombosis prophylaxis to administration of acetalisalate. In some patients, there is a decrease in 
serum ferritin levels together with an increase in hematocrit. For this reason, it is recommended 
to provide 200 mg / day of oral iron (Fe2 +) substitution in patients with serum ferritin levels <100 
ug / L or transferrin saturation <20%. Then, there is a temporary increase in serum serum 
potassium and phosphate levels. Therefore, it is recommended to monitor these parameters 
regularly. 

Daewoong Pharmaceuticals, Co. Ltd 
DW_EPO401 
Version 2.1 
Protocol 
Effective Date 
2 April 2020 
Confidential 
Page 26 of 53 
 
 
 
CHAPTER 3. STUDY DESIGN OVERVIEW 
 
3.1 Study Design 
This study is an open label, randomized, active drug-comparative, parallel-designed, multi-center 
study in hemodialysis patients with anemia. 
 
3.2 Number of Research Subjects and Estimated Number of Samples 
3.2.1. Number of Subjects 
 
The total number of subjects in this study is 100 subjects. Only subject who achieve baseline 
target Hb level 10-12 g/dL will continue to maintenance period. Subject will be randomized into 2 
study arms. For the randomized allocation code between reference product (Eprex®) and test 
product (Epodion®) will be maintained ratio 1:1. 
 
Study Group 
Epodion® 
Eprex® 
Evaluated 
50 Subjects 
50 Subjects 
 
 
3.2. Rationale Number of Subject 
 
A sample size of 90 subjects will be determined with difference 0 g/dL, standard deviation 0.8 
g/dL, statistical power 90%, randomization ratio 1:1 to demonstrate equivalence at 5% 
significance level and equivalence margin ±0.5 g/dL. Assumption of difference and standard 
deviation for sample size estimation in this study was derived from PDA10 ITT set. Difference 
between treatment groups in PDA10 ITT set was -0.009, but this study assumed to be 0. Standard 
deviation 0.8 was an approximate estimation derived from two-sided 90% confidence interval [- 
0.189, 0.171]. After an assumption of 10% drop-out rate for this trial, about 100 subjects will be 
enrolled to the trial. The sample size calculated using the POWER procedure (Proc Power 
procedure) of SAS ver. 9.4 (SAS Institute, Cary, NC, USA). 
 
 
 
Figure 4. SAS code used in determining study subject number 

Daewoong Pharmaceuticals, Co. Ltd 
DW_EPO401 
Version 2.1 
Protocol 
Effective Date 
2 April 2020 
Confidential 
Page 27 of 53 
 
 
 
Figure 5. SAS output 
 
3.3 Institutions Participating in the Clinical Study 
 
1. Gatot Soebroto Army Hospital 
2. dr. Esnawan Antariksa Airforce Hospital 
3. Cempaka Putih Jakarta Islamic Hospital 
 
3.4 Allocation of Treatment Group 
To guarantee scientific appropriateness of the clinical study, investigator’s subjective opinion shall 
not intervene in assignment of subjects into each treatment group, and randomization procedure 
will be used, based on the concrete probabilistic theory. 
 
Randomization is done using envelopes. The envelope contains information about the product 
that the subject will receive. Once randomization envelope is opened, it cannot be re-issued to 
another subject. Randomized allocation code between reference product (Eprex®) and test 
product (Epodion®) will be maintained ratio 1:1. 

Daewoong Pharmaceuticals, Co. Ltd 
DW_EPO401 
Version 2.1 
Protocol 
Effective Date 
2 April 2020 
Confidential 
Page 28 of 53 
 
 
CHAPTER 4. ASSESSMENT AND PROCEDURE OF STUDY 
 
 
4.1 Efficacy Evaluation 
 
4.1.1 Primary Endpoint 
 
To demonstrate that the Epodion® treatment is equivalence to Eprex® by evaluating Hb level 
change between baseline (Week 5-8/9-12) and evaluation period (Week 33-36/37-40). 
 
4.1.2 Secondary Endpoint 
 
1. Obtain data mean change in weekly dosage per kg body weight between the baseline 
period and the evaluation period. 
 
2. Calculating instability rate of Hb (hemoglobin) level during maintenance and evaluation 
period as defined when Hb (hemoglobin) level dropped below 8 g/dL or increase more 
than 13 g/dL. 
 
3. Evaluating Hb (hemoglobin) and hematocrit level during maintenance and evaluation 
period. 
 
4.2 Safety Evaluation 
 
Safety was evaluated based on incidence of adverse event. 
 
Reported any symptoms from subject or other health care practitioner defined adverse event if 
appear after subject administered with investigational product (both Eprex® or Epodion®), and 
divided into local reactions and general reactions, and the details are as mentioned below: 
a. Local reaction: Pain, Tenderness, Erythema/Redness, Induration/Swelling 
b. Systemic reaction: Fever, Nausea/vomiting, Diarrhea, Headache, Fatigue, Myalgia. 
Vital sign abnormalities are defined as adverse event if there are any clinical significance increase 
or decrease value including blood pressure, body temperature, heart rate, and respiratory rate 
after subject administered with investigational product (both Eprex® or Epodion®. 
Laboratory test findings defined as adverse event if there are any clinical significance increase or 
decrease laboratory results including hematology test, blood chemistry test, and urinalysis after 
subject administered with investigational product (both Eprex® or Epodion®). If any findings after 
subject administered with investigational product disease temporary, finding abnormalities of 
electrocardiogram, X-ray, MRI also recorded as adverse event. 
 
4.3 Others 
4.3.1 Demographic Investigation 
 
Prior to participation in the clinical study, objective and content of this clinical study shall be 
explained to the subjects and LAR in detail, informed consent shall be obtained from them, 
screening number shall be given according to the sequence of receiving informed consent, and 
then demographic information shall be recorded. Records include written consent, date of consent, 
gender, date of birth, and age. 
 

Daewoong Pharmaceuticals, Co. Ltd 
DW_EPO401 
Version 2.1 
Protocol 
Effective Date 
2 April 2020 
Confidential 
Page 29 of 53 
 
 
4.1.3 Investigation of medical and medication history 
Medical history and medication history of the subject shall be investigated and recorded in detail 
by medical interview. Content that must be included in the medical history and medication history 
is as mentioned below. 
 
For medical history, past history and current illness including surgical history, and hypersensitivity 
during 6 months before screening period shall be investigated. Time of onset (year or date of 
onset), investigator’s opinion, etc. shall be written. 
 
For medication history, medication history and current status of erythropoietin administration 
(dosage, dose, period, etc.) during the 4 weeks prior to screening period shall be investigated. 
Also, history of medication with cyclosporin and androgen during 3 months prior to screening 
period, shall be recorded. 
 
If there is any change of concomitant medication compared to the medication investigated at 
screening, the information shall be documented in the CRF in detail. 
 
4.4 Study Procedure 
 
This research consists of a screening period (4 weeks), titration period (4~8 weeks) baseline 
evaluation period (4 weeks), maintenance period (24 weeks) and 4 weeks for evaluation period. 
For each subject, the end of the study was the last day of evaluation. In the case of a subject that 
has left the study (withdrawn), the exit date will be the end of the study. 
 
 
 
Figure 6. Study method 
 

Daewoong Pharmaceuticals, Co. Ltd 
DW_EPO401 
Version 2.1 
Protocol 
Effective Date 
2 April 2020 
Confidential 
Page 30 of 53 
 
 
 
Figure 7. Study flow 
 
4.4.1 Subject screening (-4 weeks) 
 
Patient eligibility was assessed before study begins based on screening criteria and before 
entering maintenance period based on inclusion and exclusion criteria of study as stated in the 
protocol. Once subjects voluntarily consented to participate in the clinical study, medical 
examinations and tests required in the protocol will be conducted, eligibility of each subject will 
be checked, and only subjects who meet all of the screening criteria will be proceeded for first 
phase of study which is titration period. 
 
4.4.2 Titration Period (Week 0-4/0-8) 
 
In the Titration period (4 ~ 8 weeks), all eligible subjects will be given Eprex® at individualized 
dose for 3 times a week through intravenous injection. In this period, the Hb level of the subject 
was controlled to reach the target range of 10-12 g / dL. Patient demographics, patient medical 
history, and routine hematological test will be obtained in this period. 
4.4.3 Baseline Evaluation Period (Week 5-8/9-12) 
 
Week 5-8/9-12 is the baseline evaluation period. Hemoglobin mean data and mean weekly 
Epoetin dose will be used as efficacy assessment parameter. 
 
Before entering the maintenance period, subject inclusion and exclusion criteria are examined 
before subjects received a randomization number and were allocated into a test or control group. 
 
4.4.4 Maintenance Period (Week 9-32/13-36) 
 
During the maintenance period (Week 9-32/13-36), subjects who met the criteria were given 
Epoetin treatment according to the randomization allocation. Administration of Eprex® or 
Epodion® will be done with same doses regimen during titration period through intravenous 
injection. Epoetin dose may be increased or decreased at an appropriate level according to the 
condition of the subjects. Subject Hb levels were controlled to reach a range of 10-12 g/dL. Blood 
collection is carried out once every two weeks for the purposes of routine hematological test. 
Adverse event concomitant medication, and instability rate of Hb data is observed during the 
maintenance period. Concomitant medication during the study were recorded in the Case Report 
Form (CRF). 
 

Daewoong Pharmaceuticals, Co. Ltd 
DW_EPO401 
Version 2.1 
Protocol 
Effective Date 
2 April 2020 
Confidential 
Page 31 of 53 
 
 
4.4.5 Treatment Evaluation Period (Week 33-36/37-40) 
 
The week 33-36/37-40 is the treatment evaluation period. Hemoglobin mean data, weekly Epoetin 
dose, and hematocrit will be compared with the baseline period as an efficacy evaluation 
parameter. Adverse events, concomitant medication, and instability rate of Hb data is observed 
during the maintenance period. 
 
4.4.6 Dose Information 
 
Doses must be individualized to ensure that hemoglobin is maintained at an appropriate level 
for each subject. Screening period initials dose 50 IU/Kg body weight three times per week. 
During titration, titrated dose closely to achieve baseline Hb level 10-12g/dL. In maintenance 
period administer Eprex® and Epodion® equal previous stable dose in titration period. Dose is 
allowed to be increased or decreased during maintenance period at an appropriate level 
according to the condition of the subject. 

Daewoong Pharmaceuticals, Co. Ltd 
DW_EPO401 
Version 2.1 
Protocol 
Effective Date 
2 April 2020 
Confidential 
Page 32 of 48 
 
 
 
CHAPTER 5. SELECTION OF SUBJECTS AND DROPOUT CRITERIA 
 
 
5.1 Screening Period Criteria 
 
Inclusion: 
 
a. Male or female patients who are at least 18 years old and younger than 75 years of age at 
the time of screening visit 
 
b. Patients with End-Stage Renal Failure (ESRD) who are chronically receiving hemodialysis 
and have anemia 
 
c.  Patients with a mean baseline Hb concentration within Hb level ≥9 g/dL during the 
screening period 
 
d. Haemodialysis patients with anemia associated with Chronic Kidney Disease (CKD) currently 
receiving stable maintenance therapy with Epoetin at least once per week 
 
e. Adequate iron substitution status (serum ferritin ≥ 100 μg / L (100 ng / mL) or saturated 
transferrin levels ≥ 20%) 
 
f. Patients who understand the information provided to them or their representatives and may 
provide written consent. 
 
 
Exclusion: 
 
a. Contraindication with Epoetin therapy 
 
b. Documented active bleeding in the last 12 weeks prior to screening period 
 
c. Any blood transfusion within the last 2 weeks prior Screening period 
 
d. History of malignancy of any organ system within the last 5 years 
 
e. Patients with uncontrolled hypertension (in case the mean value of diastolic blood pressure 
as measured 4 times during the baseline observation period is 110 mmHg or more). 
 
f. Patients hyporesponsive epoetin treatment or had medical history of experiencing pure red 
blood cell forming failure after being administered with Epoetin products 
 
g. Known bone marrow fibrosis (osteitis fibrosa cystica) 
 
h. Patient with serious cardiovascular disorders: myocardial infarction, patients with congestive 
heart failure (NYHA class Ⅲ or higher), ischemic vascular disease 
 
i. 
Patient received percutaneous coronary intervention (PCI), or coronary artery bypass grafting 
(CABG) during the last 6 months prior to screening 

Daewoong Pharmaceuticals, Co. Ltd 
DW_EPO401 
Version 2.1 
Protocol 
Effective Date 
2 April 2020 
Confidential 
Page 33 of 48 
 
 
 
j. 
Patients with ALT or AST exceeding the upper limits of the normal level by more than 5-folds 
 
k. Patients whose kidney transplant is expected or already planned for survival 
 
l. 
Secondary anemia to other causes different to the CKD (aplastic anemia, hemolytic anemia, 
sickle cell anemia, multiple myeloma, leukemia, myelodysplastic syndrome) 
 
m. Patients with the following diseases and who are considered unfit to enroll in the clinical study: 
mental system disease, mental disease, drug intoxication, epilepsy, lung infarction, cerebral 
infarction, positive HIV antibody, systemic lupus erythematosus, immunosuppressive 
condition and general infection 
n. Pregnancy or lactation period in female patients, or women of childbearing potential without 
an effective method of birth control 
 
o. Patients who were considered unfit for study by the principal investigators or by the co- 
investigator 
 
5.2 Baseline Evaluation Period Criteria 
 
Subject who voluntarily consented to participate in the clinical study, meet eligible criteria, stable 
with Eprex®, will be evaluated again to assess the subject eligibility prior randomization and 
maintenance period. Only subjects who meet eligible baseline criteria will continue to 
randomization and maintenance period. 
 
Inclusion criteria 
 
a. Subject achieved Hb target 10-12 g/dl 
 
b. Adequate iron substitution status (serum ferritin ≥ 100 μg / L (100 ng / mL) or saturated 
transferrin levels ≥ 20%. 
 
c. Patients who have gone through the Baseline period at the time of the screening visit or before 
randomization 
 
d. Patients with dry weight less than 5% during the baseline evaluation period 
 
e. Subject are reliable and will willingly cooperate during the maintenance period and observe 
the restrictions 
 
 
Exclusion 
 
a. Any blood transfusion within the last 2 weeks prior to screening period 
 
b. In case the EPO administration dose during the baseline evaluation period is increased or 
decreased by 20% or more 
 
c. Currently contraindicated with Epoetin therapy 

Daewoong Pharmaceuticals, Co. Ltd 
DW_EPO401 
Version 2.1 
Protocol 
Effective Date 
2 April 2020 
Confidential 
Page 34 of 48 
 
 
 
d. Subject administered with prohibited drug (androgen, cyclosporin, and chemotherapy 
agents) 
 
e. Occurrence medical condition which can affect efficacy data during maintenance period 
judged by principal investigator or sub-investigator 
 
5.3 Discontinuation and Dropout Criteria 
 
The subject may discontinue participation in this clinical study at any time by his/her request, or 
by the investigator or sponsor’s discretion for a safety, action or administrative reason. The 
investigator shall ask the subject dropout reason, ask them to perform the final visit. If applicable, 
the investigator shall make utmost efforts to follow up the subject’s unresolved adverse events. 
 
Patients who dropped out of this study were patients in one of the following cases: 
1. Withdrawn of the consent. 
2. Subject receives kidney transplantation during the study period. 
3. Subjects that are unable to continue the study because of side effects. 
4. Subject do not receive investigational product 4 week consecutively. 
5. Not able to participate or continue the study or for any reason based on the assessment 
of the principal investigator. 
 
5.4 Temporary Discontinuation 
 
If the following situation occurs, the investigator shall delay investigational product administration 
until the situation will be settled. Then, investigational product administration shall be delayed to 
the extent of investigational product administration schedule indicated. 
 
The following condition when investigational product should be delayed are detailed below: 
● 
Increase blood pressure systole ≥ 180 mmHg and/or diastole ≥ 120 mmHg. 
● 
Hb level exceed 13 g/dL, investigational product should be reinitiated at approximately 25% 
lower than the previous dose after haemoglobin levels fall to 12 g/dl (7.45 mmol/l) or below. 
● 
Any reason based on the assessment of the principal investigator. 
 
5.5 Management of Compliance and Deviations from Protocol 
 
The Principal Investigator and sub investigator of this clinical study shall become fully aware of 
the protocol and perform the study so that the protocol is not violated. To follow the administration 
and test schedule of the investigational product in this study, the sub investigator shall take proper 
measures so that the subject makes an outpatient visit on the relevant date (for example, written 
notice of the next visit time or phone monitoring). 
In case of major protocol violation, the subject shall be dropped out from analysis (Excluded from 
PP analysis) in principle and the following apply to this. 
1. In case of no acquiring the informed consent 
2. In case of violation of the inclusion/exclusion criteria 
3. If the subject takes contraindicated drugs during study period 
4. In case of an error in randomization 
 

Daewoong Pharmaceuticals, Co. Ltd 
DW_EPO401 
Version 2.1 
Protocol 
Effective Date 
2 April 2020 
Confidential 
Page 35 of 48 
 
 
For minor protocol violations which are not deemed to influence the analysis of study results, the 
degree of violation or delay shall be exactly mentioned, and when a final report is written, whether 
or not the study has been influenced by the investigator, sponsor, monitor, and statistician shall 
be comprehensively evaluated in PP analysis. 

Daewoong Pharmaceuticals, Co. Ltd 
DW_EPO401 
Version 2.1 
Protocol 
Effective Date 
2 April 2020 
Confidential 
Page 36 of 48 
 
 
 
CHAPTER 6. INVESTIGATIONAL PRODUCT 
 
 
6.1 Overview of the Investigational Product 
 
6.1.1 Study drug 
 
1. Brand name 
: Epodion® 2000 IU 
2. Manufacturer 
: PT. Daewoong Infion 
3. Appearance 
: Colorless yellowish pre-filled syringe 
4. Storage 
: 2-8 °C 
 
6.1.2 Control drug 
Control drug that is used as a comparator is Eprex® (Janssen). 
 
6.2 Dosage, Administration, and Administration Period 
 
The drug dose should be individualized, during titration period Eprex® doses should be closely 
titrated to achieve target Hb range 10-12 g/dl. During maintenance period, the administration dose 
of Eprex® and Epodion® is equal to the previous dose in titration period. Dose is allowed to be 
increased or decreased during maintenance period at an appropriate level to maintain Hb level 
10-12 g/dl according to condition of subjects. Route of administration for this study is Intravenous 
injection (IV). Investigational product will be administered when subject enrolled until the end of 
the study. 
 
6.3 Management of Investigational Products 
 
6.3.1 Shipment and storage conditions of study drug 
 
The study drug shall be kept in a safe place with limited access. The study drug shall be 
refrigerated at 2°C - 8°C. Temperature shall be closely observed throughout the clinical study and 
recorded in the specified form. If the drug is frozen, or if refrigeration has stopped, the drug shall 
not be given. In such case, the investigator or sub-investigator shall make inquiries to the monitor 
to take actions. 
 
The clinical trial pharmacist shall store and manage study drugs to ensure guaranteed drug quality 
until given to patients. 
 
6.3.2 Inventory of study drug 
 
 
The clinical trial pharmacist responsible for drug procurement and control shall record must record 
the amount of drug used for research and reporting to sponsors for reimbursement purposes. If 
shortage of drugs is expected during the study period, clinical trial pharmacist shall be 
immediately reported to the clinical study monitor to avoid delays in drug supply. The sponsor’s 
monitor shall make sure that there is consistency between the drug control record of the institution 
and record of the case report form. 
 

Daewoong Pharmaceuticals, Co. Ltd 
DW_EPO401 
Version 2.1 
Protocol 
Effective Date 
2 April 2020 
Confidential 
Page 37 of 48 
 
 
6.4 Concomitant Medication and Treatment 
 
6.4.1 Concomitant medication 
 
The following drugs may be concomitantly administered during the study period. 
 
a. Any drug the subject has been on medication prior to participating in the clinical trial, the 
drug which is considered not to affect the study result analysis shall be permitted during 
the study period by the clinician’s judgement. 
b. Any drug to be used temporarily for the purpose of treating other diseases or adverse 
events incurred during the study period shall be concomitantly administered through 
discussion with the investigator or physician. 
 
All the information (commercial name, indication, daily dose, administration period etc.) of 
concomitant medications (including medication to treat other diseases or adverse events) shall 
be recorded in the CRF in detail. 
 
6.4.2 Contraindications 
Epodion is contraindicated in patients with the following conditions: 
 
a. Hypersensitivity to other drugs or Erythropoietin products 
b. Patients who develop pure red cell aplasia (PRCA) following treatment with any 
erythropoietin 
c. Uncontrolled hypertension 
d. Hypersensitivity to derivative products from mammalian cells or albumin 
e. Patients experience events that result in severe damage to coronary, peripheral, carotid 
or cerebral vessels. 
f. Patients scheduled to follow any surgery who for any reason cannot receive adequate 
antithrombotic prophylaxis or treatment 

Daewoong Pharmaceuticals, Co. Ltd 
DW_EPO401 
Version 2.1 
Protocol 
Effective Date 
2 April 2020 
Confidential 
Page 38 of 48 
 
 
 
CHAPTER 7. STATISTICAL ANALYSIS PLAN 
 
7.1 Definition of analysis group 
 
7.1.1 Safety Set 
 
The Safety Set will consist of all enrolled subjects who received at least 1 dose of the 
investigational product. In the case of dosing administration error, analyses on the Safety Set will 
be conducted according to actual treatment received. 
 
7.1.2 Full Analysis Set (FAS) 
 
The Full Analysis Set will be consisting of all randomized subjects who treated for at least 4 weeks 
of the investigational product, and for whom at least 1 Hb level for the evaluation period will be 
available. In the case of dosing administration error, analyses on the FAS will be conducted 
according to randomized treatment. 
 
7.1.3 Per-Protocol Set (PPS) 
 
The Per-Protocol Set will be defined as all subjects who completed the study without any major 
protocol deviations. The subjects who committed a major protocol deviation will be finally 
determined in the blind meeting before database lock. 
 
In the study, the efficacy assessment will have the PPS as the primary analysis set, and the FAS 
will be additionally analyzed and the results of the two analysis sets will be compared. 
 
7.2 General principle of statistics 
 
The summary statistics will be presented with descriptive statistics including number of subjects, 
mean, standard deviation, median, minimum and maximum values for continuous variables. For 
categorical variables, number and percentage of subjects with event will be presented. For the 
test of significance between the two treatment groups, the two-sided test will be conducted at 5% 
significance level. 
 
7.3 Analysis of demographic data and baseline characteristics 
 
Demographic data and baseline characteristics will be summarized by treatment groups and 
overall. For continuous variables, the summary will be presented by number of subjects, mean, 
standard deviation, median, minimum and maximum value. For categorical variables, the 
summary will be presented by number and percentage of subjects in each category. 
 
7.4 Efficacy Analysis 
 
Efficacy analysis will be performed using the Full Analysis Set and Per-Protocol Set. 
 
 
 
 
 

Daewoong Pharmaceuticals, Co. Ltd 
DW_EPO401 
Version 2.1 
Protocol 
Effective Date 
2 April 2020 
Confidential 
Page 39 of 48 
 
 
7.4.1 Primary Endpoint 
 
Change in Hb levels from baseline to the evaluation period 
 
Descriptive statistics will be provided by treatment group. The difference between treatment 
groups will be determined by ANCOVA (analysis of covariance) model with treatment as factor, 
and baseline Hb level and the change in weekly dosage per kg body weight from baseline to 
the evaluation period of Epodion® or Eprex® as covariates. 
Therapeutic equivalence of Epodion® to the comparator Eprex® will be demonstrated if the 
two-sided 90% confidence interval of the difference of mean changes in Hb levels between 
treatment groups lay within the interval of ± 0.5 g/dL. 
 
7.4.2 Secondary Endpoint 
 
(1) Change in weekly dosage per kg body weight from baseline to the evaluation period. 
 
Descriptive statistics will be provided treatment group. The difference between treatment 
groups will be analyzed by ANCOVA model with treatment as factor, and baseline Hb level 
and baseline weekly dosage per kg body weight value as covariates. 
 
(2)  Instablity rate of Hb level during maintenance and evaluation period 
 
The number of subjects with Hb level <8 g/dl or Hb level >13 g/dl during maintenance and 
evaluation period will be provided by treatment groups along with rates and the two-sided 
95% confidence intervals. Also, the difference in the rates between the treatment groups 
and two-sided 95% confidence interval will be provided. 
 
(3) Hb and Hematocrit level during maintenance and evaluation period 
 
Descriptive statistics will be provided treatment groups for Hb and Hematocrit levels at 
baseline and at each bi-week during maintenance and evaluation period. The time course 
figure of Hb levels will be presented using mean and standard deviation throughout 
maintenance and evaluation period. 
 
7.5 Safety Analysis 
 
Safety analysis will be performed using the Safety Set. 
 
(1) Adverse events (AEs) 
 
The incidence of the following events will be summarized by treatment group for all 
observed adverse events, local reactions and systemic reactions. 
• Treatment-emergent adverse events (TEAEs) 
• Adverse Drug Reactions (ADRs) 
• Serious TEAEs/ADRs 
• TEAEs/ADRs leading to investigational product discontinuation 
• TEAEs/ADRs leading to death 
 
(2) Vital sign, Laboratory test 
Summary statistics for change from baseline in vital signs and the laboratory test 
evaluation will be provided. Clinically significant abnormal results in laboratory test will 

Daewoong Pharmaceuticals, Co. Ltd 
DW_EPO401 
Version 2.1 
Protocol 
Effective Date 
2 April 2020 
Confidential 
Page 40 of 48 
 
 
also be summarized. If needed, laboratory re-tests may be carried out outside the 
schedule to monitor the patient's condition. 
 
7.6 Handling of dropout or missing values 
 
Analysis for efficacy variables will be performed for subjects who have at least 1 Hb level for the 
evaluation period. For by visit analysis (ANCOVA, Hb and Hematocrit level), missing data will be 
imputed by LOCF (last observation carried forward) method. For calculating the instability rate, only 
observed data will be used. For safety analysis, no imputation will be made for missing data. 

Daewoong Pharmaceuticals, Co. Ltd 
DW_EPO401 
Version 2.1 
Protocol 
Effective Date 
2 April 2020 
Confidential 
Page 41 of 48 
 
 
 
CHAPTER 8. ADVERSE EVENTS 
 
 
8.1 Definition of Adverse Event 
 
a. Adverse event (AE) 
Any untoward medical occurrence in a patient or subject administered a pharmaceutical product 
and which does not necessarily have a causal relationship with this treatment. An adverse event 
(AE) can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medicinal (investigational) 
product, whether or not related to the medicinal (investigational) product (see the ICH Guideline 
for Clinical Safety Data Management: Definitions and Standards for Expedited Reporting). 
 
b. Adverse Drug Reaction (ADR) 
In the pre-approval clinical experience with a new medicinal product or its new usages, particularly 
as the therapeutic dose(s) may not be established: all noxious and unintended responses to a 
medicinal product related to any dose should be considered adverse drug reactions. The phrase 
responses to a medicinal product means that a causal relationship between a medicinal product 
and an adverse event is at least a reasonable possibility, i.e., the relationship cannot be ruled out. 
 
Regarding marketed medicinal products: a response to a drug which is noxious and unintended 
and which occurs at doses normally used in man for prophylaxis, diagnosis, or therapy of diseases 
or for modification of physiological function (see the ICH Guideline for Clinical Safety Data 
Management: Definitions and Standards for Expedited Reporting). 
 
c. Serious Adverse Event (SAE) or Serious Adverse Drug Reaction (SADR) 
 
Any untoward medical occurrence that at any dose: 
1. Results in death 
2. Is life-threatening 
3. Requires inpatient hospitalization or prolongation of existing hospitalization 
4. Results in persistent or significant disability/incapacity, or 
5. Is a congenital anomaly/birth defect 
 
d. Unexpected Adverse Drug Reaction 
 
It means that there is a difference in the aspect or risk of adverse drug reaction in view of available 
medication information such as from IB, insert paper or label. 
 
8.2 Collection and Documentation of Adverse Events 
 
If an adverse event is present, investigator should assess the type, start date, end date, severity 
of the symptoms, relevance to the test drug, measures related to the test drug, treatment, results 
and significance and record in Case report form (CRF). 
 
 
 
 
 

Daewoong Pharmaceuticals, Co. Ltd 
DW_EPO401 
Version 2.1 
Protocol 
Effective Date 
2 April 2020 
Confidential 
Page 42 of 48 
 
 
8.3 Evaluation of Adverse Events 
 
8.3.1 Severity 
 
1. Mild: causes minimal discomfort without interfering with the normal daily life (function) of 
the subject, and can be easily tolerated by the subject 
2. Moderate: It causes discomfort that significantly disturb the normal daily life (function) of 
the subject 
3. Severe: If the person's daily life (function) becomes impossible 
 
8.3.2 Causal relation with study drug 
Investigator will examine the relationship between the adverse reaction and the study drug in 
terms of the patient’s past history, health status, administration time, dosage status, etc. 
 
a. Relevant: Relevant or potentially relevant 
 
1) Definitely Related 
1. If there is evidence that the test drug has been administered 
2. If the time order of test drug administration and adverse events is reasonable 
3. The adverse event is most likely explained by the administration of the test drug 
for any other reason 
4. Adverse events disappear with discontinuation 
5. If re-administration is possible, if the outcome is positive 
6. If the adverse event is consistent with the information already known about the 
test drug or the same series of test drug. 
 
2) Related 
1. If there is evidence that the drug has been administered for study 
2. If the timing of the administration of the drug and the adverse reaction is 
reasonable 
3. Adverse events are more likely to be explained by the administration of the drug 
than for other reasons 
4. Adverse events disappear with discontinuation 
 
3) Possibly Related 
1. If there is evidence that this drug has been administered 
2. If the adverse event is judged to be due to the administration of the test drug at 
the same level as other potential causes 
3. Adverse events disappear with discontinuation 
 
4) Not Related 
1. If there are other causes of the Adverse Event 
2. If the discontinuation result is negative or ambiguous 
3. If the re-administration of the test drug is negative or ambiguous 
 
5) 
Definitely Not Related 
1. If the subject does not receive investigational drug 
2. If the time sequence between drug administration and side effects is not possible 
3. If there are other obvious causes (such as the use of other drugs, latent diseases, 

Daewoong Pharmaceuticals, Co. Ltd 
DW_EPO401 
Version 2.1 
Protocol 
Effective Date 
2 April 2020 
Confidential 
Page 43 of 48 
 
 
other factors, etc.) and there is a reasonable explanation for the adverse reaction 
 
4) Unknown 
If some information about the adverse reaction received but can not assess its 
relevance. 
 
8.3.3 Treatment for Adverse Reaction 
a. No treatment for adverse event 
b. Medication for adverse event 
c. Non-medication for adverse event 
8.3.4 Results of Adverse Reaction 
a. Resolve 
b. Continuous 
c. Revolve, but the effect is remain 
d. Death 
8.4 Reporting of Serious Adverse Events 
The investigator should report any serious adverse events (SAEs) in the study immediately to 
sponsor and Ethics Comitee. The definition of a serious adverse event is a medical event which 
at any dose takes the form of: 
a. Results in death 
b. Is life-threatening 
c. Requires inpatient hospitalization or prolongation of existing hospitalization 
d. Results in persistent or significant disability/incapacity 
e. A congenital anomaly/birth defect. 
All SAEs above are reported to the sponsor no later than 24 hours since they are known and 
reporting to the ethics committee a maximum of 3 calendar days since they are known. Sponsors 
must report to the regulatory authority no later than 7 calendar days from the time it is first known 
(for the occurrence of death), 15 days for other serious adverse events. In this study the 
investigator immediately contacts the safety report and provides further and detailed reporting 
through. 
Fax: +82 2 550 9900 
E-mail: safety@daewoong.co.kr 

Daewoong Pharmaceuticals, Co. Ltd 
DW_EPO401 
Version 2.1 
Protocol 
Effective Date 
2 April 2020 
Confidential 
Page 44 of 48 
 
 
 
CHAPTER 9. ETHICAL CONSIDERATIONS AND ADMINISTRATIVE 
PROCEDURES 
 
 
 
9.1 Protocol Compliance 
 
The investigator shall conduct a clinical study in compliance with the protocol. The clinical study 
shall not be carried out contrary to the protocol with the exception that a risk factor incurred in the 
subject is required to be removed immediately, and upon a violation, the fact and the reason shall 
be stated. Even if the investigator thinks that violation of the protocol can improve the performance 
of the clinical study, this shall not be executed before consent by the Sponsor to the change and 
approval of the Institutional Review Board (including the National Agency of Drug and Food 
Control, if needed) will be obtained. 
 
9.2 Approval and Amendment of Protocol 
 
If the clinical study which is being approved will be modified, the protocol or protocol amendment 
shall be approved by the Institutional Review Board (IRB) per phase of the clinical study, and if 
necessary, approved by the National Agency of Drug and Food Control. Prior to approval, any 
subject is not allowed to participate in the clinical study. 
 
9.3 Procedure of Consent by Subject 
 
The subject information and the informed consent form are available only after they are approved 
by the IRB. The investigator shall obtain consent from each subject in accordance with the ethical 
principles under the Declaration of Helsinki and the Good Clinical Practice. Prior to execution of 
all of the study related procedures, the investigator shall fully explain the clinical study to each 
subject (or his/her representative) and obtain written consent from the subject. The investigator 
shall keep the signed original of the informed consent form in the investigator’s file and offer 
copies of the signed informed consent form and subject information to the subject (or his/her 
representative). The patient consent procedure shall be stated in the supporting document. If it is 
impossible for the subject to consent, consent shall be obtained from the subject’s representative. 
If both the subject and his/her representative are not able to read words, a witness shall participate 
in all consent processes. As the subject and his/her representative verbally consent to participate 
in the clinical study and sign their own autograph in the informed consent form if possible, and 
then the witness signs the informed consent form, this demonstrates that information in the 
informed consent form is exactly explained and understood. 
 
If the subject information and informed consent form are changed, this shall be approved by the 
Institutional Review Board (IRB), as well as the ongoing subject (or his/her representative). Then, 
the investigator shall record the subject, date, and content of notification in the supporting 
document. The subject information and informed consent form of this clinical study can be viewed 
in separate document. 
 
 
 
 

Daewoong Pharmaceuticals, Co. Ltd 
DW_EPO401 
Version 2.1 
Protocol 
Effective Date 
2 April 2020 
Confidential 
Page 45 of 48 
 
 
9.4 Measures for the Protection of Subject’s Safety 
 
The investigator shall carry out the clinical study in consideration of the subject’s rights and 
welfare/well-being on the basis of the Declaration of Helsinki, and the investigators who 
participate in the clinical study shall be familiar with the Good Clinical Practice, Protocol, etc. 
before conducting the clinical study. The investigator shall take enough time for each subject and 
thoroughly assess eligibility of each subject and onset of adverse event through discussion and 
examination. 
 
The Principal Investigator shall report AEs, study progress, and results to the Sponsor on a 
periodic basis, and the Sponsor shall routinely control the study progress. 
 
9.5 Post-study Treatment of Subject and Treatment Criteria 
 
The investigator shall make sure that a person who dropped out of the study or did not show 
response can receive proper treatment based on needs. 
 
9.6 Subject Indemnification 
 
The Sponsor, upon an adverse event incurred from the study drug or damage incurred during 
corrective treatment of an adverse event, or damage directly caused by the study drug, will 
indemnify the subject for such damages as subject indemnification detailed outside of the Protocol. 
 
9.7 Keeping of Study Related Documents and Records 
 
9.7.1 CRF and supporting document 
 
Data of this clinical study will be collected in CRF. Data of CRF based on supporting document 
shall coincide with the supporting document, and the investigator shall make sure that all data 
entered in CRF are exact, complete, easy to read, and timely. 
 
Whenever modifying or correcting contents of CRF, the original content shall be identifiable. 
 
The monitor shall compare CRF with supporting document, notify the investigator of inconsistency, 
if any, and ask the investigator to make proper corrections. Only the investigator or a designated 
person can enter and correct CRF and supporting document. 
 
9.7.2 Peruse of supporting data 
 
The sponsor, monitor, and auditor involved in this study can peruse subject’s records for the 
purposes of monitoring, audit, and progress management of this study. The investigator shall be 
aware of the fact that as the clinical study contract is concluded, the sponsor or monitor or auditor 
may review or copy relevant documents to verify the subject’s chart and CRF record. Such 
information shall be kept confidential. The investigator shall ensure necessary support for the 
CRO and sponsor. 
 
 
 
 

Daewoong Pharmaceuticals, Co. Ltd 
DW_EPO401 
Version 2.1 
Protocol 
Effective Date 
2 April 2020 
Confidential 
Page 46 of 48 
 
 
9.7.3 Keeping of clinical study data 
 
The investigator shall keep data and records related to execution of the clinical study in a safe 
place, maintain their security, and keep them for 3 years from the date when the clinical study is 
completed or discontinued. After a clinical study report is completed, study related documents 
shall be transferred to the data keeping manager, and if the investigator is to discard study related 
records or to move them to another place, the investigator shall notify the sponsor in advance. 
 
9.7.4 Audit and inspection 
 
To ensure that the GCP and all related regulations are observed, the sponsor or a person 
authorized by the sponsor can perform quality assurance audit for this study, and the National 
Agency of Drug and Food Control can conduct inspection. After a relevant notice is given to the 
investigator, the investigator shall respond to such audit or inspection, allow the auditor or 
inspector to have personal access to all clinical study related documents, and consent to take the 
time to discuss all observations and related issues. 
 
9.8 Confidentiality of Clinical Study Documents and Subject Records 
 
All clinical study results and documents shall be kept confidential. The investigator, CRO, and the 
staff of the sponsor shall not expose any study related information without Sponsor’s written 
approval. 
 
Records that are capable of finding out subject’s identity will be kept confidential, and all study 
related documents such as CRF etc. will be recorded with not the subject’s name but the subject’s 
identification code for differentiation. Even if the results of the clinical study are published, 
subject’s identity will be kept confidential, too. 
 
9.9 Monitoring of Institution 
 
To protect subject’s rights and well-being, confirm the accuracy, integrity, and verifiability of data 
through comparison between reported study related data and supporting document, and check if 
the clinical study is performed in compliance with the approved protocol, monitoring of the 
institution shall be conducted. 
 
The monitor shall monitor the clinical study by routine site visits and phone, evaluate the study 
progress, and check whether the investigator’s duty was fulfilled as per the protocol and 
regulations. When visiting the institution, the monitor shall check whether the originals of subject’s 
records, CRFs, drug control records, and study-related data are being kept, and upon 
inconsistency or problem in the clinical study records, will discuss with the investigator. 
 
 
 
 
 
 
 
 
 

Daewoong Pharmaceuticals, Co. Ltd 
DW_EPO401 
Version 2.1 
Protocol 
Effective Date 
2 April 2020 
Confidential 
Page 47 of 48 
 
 
9.10 Withdrawal of Study 
 
If the institution or investigator, or a person authorized by the sponsor fails to observe the GCP, 
protocol, and terms and conditions of the contract, the sponsor will immediately correct this and 
takes measures. If continues violation of the said matter is found or the enrollment target is not 
achieved, or efficacy and safety information occurs which is likely to have a critical effect on 
continuation of the clinical study, the sponsor may direct the institution to withdraw the study. 
 
9.11 Clinical Study Report and Publication 
 
Once all the data of the institution are completely analysed, the sponsor shall prepare a clinical 
study report and notify the investigator of the results of the clinical study. 
 
All the data and result arising out of this clinical study shall be owned by Daewoong 
Pharmaceuticals, Co. Ltd, and the sponsor has the right to publish the results of this study at any 
time. The investigator or any personnel from the institution shall not publish, announce, or disclose 
information related with the result of this study without Sponsor’s prior written consent. In order to 
use only exact and verified data, the investigator shall necessarily submit all publication drafts or 
manuscripts to the sponsor prior to publication or announcement for discussion and withhold 
publication until approval in writing is obtained. 
 
For a multicenter study, the investigator shall consent not to publish the study results before the 
other investigator publishes the results gathered from all institutions, with the exception that it is 
officially recognized by the principal investigator and sponsor. 

Daewoong Pharmaceuticals, Co. Ltd 
DW_EPO401 
Version 2.1 
Protocol 
Effective Date 
2 April 2020 
Confidential 
Page 48 of 48 
 
 
 
CHAPTER 10. REFERENCES 
 
1) Hill NR, Fatoba ST, Oke JL, Hirst JA, O’Callaghan CA, Lasserson DS, Hobbs FDR. 2016. 
Global Prevalence of Chronic Kidney Disease - A Systematic Review and Meta-Analysis. 
PLoS One 11(7):e0158765. 
2) Kemenkes. 2013. Riset kesehatan dasar. 
3) Kemenkes. 2017. Situasi penyakit ginjal kronis. Pusat Data dan Informasi Kementerian 
Kesehatan RI. 
4) KDIGO. 2012. Clinical Practice Guideline for the Evaluation and Management of Chronic 
Kidney Disease. 
5) Luyckx VA, Tonelli M, Stanifer JW. 2018. The global burden of kidney disease and the 
sustainable development goals. Bulletin of the WHO 96:414-422. 
6) EMEA. 2007. Guideline on immunogenicity assessment of biotechnology-derived therapeutic 
proteins. EMEA: London. 
7) EMA. 2017. Biosimilars in the EU - information guide for healthcare professionals. 
8) Zadeh KK. 2017. History of Erythropoiesis-Stimulating Agent, the Development of Biosimilars, 
and the Future of Anemia Treatment in Nephrology. 
9) Bennet CL, Luminari S, Nissenson AR, Talman MS, Klinge SA, et al. 2004. Pure red-cell 
aplasia and epoetin therapy. N Engl J Med 351:1403-1408. 
10) Pollock C, Johnson DW, Horl WH, Rossert J, Casadevall N, et al. 2008. Pure red cell aplasia 
induced by erythropoiesis-stimulating agents. 
11) Vadakedath S, Kandi V. 2017. Dialysis: a review of the mechanisms underlying complications 
in the management of chronic renal failure. Cureus 9(8): e1603.