A Randomized, Comparative Study of HEMAX PFS® Versus EPREX/ ERYPO® in the Treatment of Anemia With Epoetin Alfa in Patients With Predialysis Chronic Kidney Disease
Phase: PHASE3
Conditions: Anemia of Chronic Kidney Disease
Sponsor: Bio Sidus SA

Protocol Nº: BIOS-HPFS-0115 
Version 3.0; 26-Jun-2018. 
Study of HEMAX PFS vs EPREX/ERYPO ® in Predialysis Chronic Kidney Disease 
Page 1 of 52 
 
 
BIO SIDUS ARGENTINA S.A. 
 
CLINICAL STUDY PROTOCOL 
 
 
Study title: 
A Randomized, Comparative Study of HEMAX 
PFS® versus EPREX/ ERYPO® in the Treatment 
of Anemia with Epoetin Alfa in Patients with 
Predialysis Chronic Kidney Disease 
 
 
Protocol N°: 
BIOS - HPFS - 0115 (Study of HEMAX PFS VS 
EPREX/ ERYPO® in Predialysis Chronic Kidney 
Disease) 
Clinical phase: 
Phase IIIB 
Protocol version and date:  
 Versión 3.0_Argentina; 26-Junio-2018 
 
Includes General Amendment v1.0, 10-Julio-17 
Includes General Amendment v2.0, 26-Junio-2018 
 
 
Sponsor: 
Biosidus Argentina S.A. 
Constitucion 4234 
(1254) Buenos Aires 
Phone: 54 - 11 - 4909 - 8049 / 8000 
FAX 54 - 11 - 4924 - 3601 
 
 
 
 
 
This clinical study will be conducted in accordance with the current Good Clinical 
Practice (GCP) guidelines, and the relevant ICH (International Conference on 
Harmonization) guidelines. 
 
CONFIDENTIAL 
The information contained in this document is considered privileged and 
confidential and may not be disclosed to third parties except to the extent 
necessary to achieve the approval from the Institutional Review Committees/ 
Ethics Committees, the informed consent and the regulatory authorities. 

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Protocol Nº: BIOS-HPFS-0115, 
Version 3.0; 26-Jun-2018. 
Study of HEMAX PFS vs EPREX/ERYPO ® in Predialysis Chronic Kidney Disease 
 
 
 
 
 
Table of Contents 
1 
CONTACT INFORMATION AND APPROVAL ......................................................5 
2 
SYNOPSIS ...................................................................................................................6 
3 
LIST OF ABBREVIATIONS ....................................................................................12 
4 
INTRODUCTION ......................................................................................................13 
4.1 
CHRONIC KIDNEY DISEASE AND ANEMIA ................................................................................................. 13 
4.2 
TREATMENT WITH ERITROPYESIS STIMULATING AGENTS .................................................................. 13 
4.3 
EPOETINA ALFA (HEMAX AND HEMAX PFS) ............................................................................................. 14 
4.4 
EPOETINA ALFA (EPREX/ ERYPO®) ............................................................................................................. 16 
5 
CURRENT STUDY RATIONALE ...........................................................................16 
6 
STUDY OBJECTIVES ..............................................................................................17 
6.1 
PRIMARY OBJECTIVES: ................................................................................................................................... 17 
6.2 
SECUNDARY OBJECTIVES: ............................................................................................................................. 17 
6.3 
EXPLORATORY OBJECTIVE ........................................................................................................................... 17 
7 
LABORATORIES ......................................................................................................17 
8 
STUDY DESIGN .......................................................................................................18 
9 
STUDY POPULATION .............................................................................................18 
9.1 
PATIENT NUMBER ............................................................................................................................................ 18 
9.2 
INCLUSION CRITERIA ...................................................................................................................................... 18 
9.3 
EXCLUSION CRITERIA ..................................................................................................................................... 19 
9.4 
EARLY TREATMENT TERMINATION ............................................................................................................ 20 
10 
MEDICATIONS/ TREATMENT AND CONCOMITANT MEDICATIONS .........20 
10.1 
MEDICATION/ TREATMENT ........................................................................................................................... 20 
11 
STUDY MEDICATION LABELING .......................................................................22 
11.1 
PRIMARY PACKAGING .................................................................................................................................... 22 
11.2 
SECONDARY PACKAGING .............................................................................................................................. 23 
11.3 
CONCOMITANT MEDICATIONS/ TREATMENT OF ANEMIA .................................................................... 24 
12 
STUDY DEVELOPMENT ........................................................................................24 
12.1 
STUDY PROCEDURES ...................................................................................................................................... 24 
12.2 
STUDY PROCEDURE TABLES ......................................................................................................................... 24 
12.3 
DETAILED STUDY PLAN ................................................................................................................................. 25 
12.3.1 Baseline evaluation visit 1 (week -1) .........................................................................25 
12.3.2 Randomization visit 2 (week 0) .................................................................................26 
12.3.3 Visit 3, 4, 5, 6, and 7 (weeks 2, 4, 6, 8 and 10 respectively) .....................................27 
12.3.4 Visit 8 (week 12) .........................................................................................................27 
12.3.5 Visits 9 and 10 (weeks 16 and 20 respectively) .........................................................28 

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Protocol Nº: BIOS-HPFS-0115, 
Version 3.0; 26-Jun-2018. 
Study of HEMAX PFS vs EPREX/ERYPO ® in Predialysis Chronic Kidney Disease 
 
 
12.3.6 Visit 11 (week 24) or end - of - study visit .................................................................29 
12.3.7 Unscheduled visit .......................................................................................................29 
13 
INVESTIGATIONAL PRODUCT/ STUDY DRUGS ..............................................30 
13.1 
METHOD OF PATIENT ALLOCATION TO A TREATMENT GROUP .......................................................... 30 
13.2 
BLINDING ........................................................................................................................................................... 30 
13.3 
CODE UNBLINDING DUE TO EMERGENCY ................................................................................................. 30 
13.4 
POST STUDY ACCESS....................................................................................................................................... 30 
13.5 
INVESTIGATIONAL PRODUCT/ STUDY DRUGS DESCRIPTION ............................................................... 30 
13.6 
ACCOUNTABILITY AND COMPLIANCE ....................................................................................................... 32 
14 
EVALUATION METHODS ......................................................................................32 
14.1 
METHODS OF EFFICACY EVALUATION ...................................................................................................... 32 
14.2 
SAFETY PARAMETERS .................................................................................................................................... 33 
14.2.1 Adverse events ............................................................................................................33 
14.2.2 Vital signs ...................................................................................................................33 
14.2.3 Medical history ..........................................................................................................33 
14.2.4 Physical exam ............................................................................................................33 
14.2.5 Physical Examination ...............................................................................................33 
14.2.6 Electrocardiogram .....................................................................................................33 
14.2.7 Full laboratory tests ...................................................................................................33 
14.2.8 Complete hemogram ..................................................................................................34 
14.2.9 Blood pregnancy test .................................................................................................34 
15 
SAFETY AND ADVERSE EVENTS .......................................................................34 
16 
STATISTICAL METHODOLOGY ...........................................................................37 
16.1 
SAMPLE SIZE JUSTIFICATION ........................................................................................................................ 37 
16.2 
RANDOMIZATION ............................................................................................................................................. 37 
16.3 
PATIENT DATA ANALYSIS GROUPS ............................................................................................................. 37 
16.3.1 Full Analysis Set (FAS) .............................................................................................37 
16.3.2 Per Protocol (PP) analysis group ..............................................................................37 
16.4 
DATABASE ANALYSIS ..................................................................................................................................... 38 
16.5 
EFFICACY ANALYSIS ....................................................................................................................................... 38 
16.6 
SAFETY ANALYSIS ........................................................................................................................................... 39 
17 
ETHICAL AND REGULATORY CONSIDERATIONS .........................................40 
17.1 
COMPLIANCE 
WITH 
THE 
REGULATIONS 
APPLICABLE 
TO 
CLINICAL 
TRIALS ................................................................................................................................................................ 40 
17.2 
INFORMED CONSENT ...................................................................................................................................... 40 
17.3 
INSTITUTIONAL 
ETHICS 
COMMITTEE 
FOR 
RESEARCH 
(IECR) 
/ 
INSTITUTIONAL REVIEW BOARD (IRB) ....................................................................................................... 41 
17.4 
PROTOCOL AMENDMENTS............................................................................................................................. 42 
17.5 
CLINICAL STUDY COMPLETION STATEMENT ........................................................................................... 42 
17.6 
PATIENT CONFIDENTIALITY ......................................................................................................................... 42 

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Protocol Nº: BIOS-HPFS-0115, 
Version 3.0; 26-Jun-2018. 
Study of HEMAX PFS vs EPREX/ERYPO ® in Predialysis Chronic Kidney Disease 
 
 
17.7 
RESPONSIBILITY AND SAFETY ..................................................................................................................... 42 
18 
DOCUMENTATION .................................................................................................42 
18.1 
STUDY ARCHIVE AND SITE DOCUMENTATION ........................................................................................ 43 
18.2 
STUDY DOCUMENTATION PROVIDED BY THE SPONSOR ....................................................................... 43 
18.3 
DATA MAINTENANCE AND RETENTION ..................................................................................................... 43 
18.4 
DATA MANAGEMENT ...................................................................................................................................... 43 
18.4.1 Data capture through Individual Clinical Record Form (ICRF) ............................44 
18.5 
ADDITIONAL DOCUMENTS AND RECORDS ............................................................................................... 45 
19 
QUALITY ASSURANCE AUDITS ..........................................................................45 
19.1 
QUALITY ASSURANCE PROGRAM ................................................................................................................ 45 
19.2 
REGULATORY INSPECTIONS AND AUDITS ................................................................................................ 45 
20 
STUDY MONITORING ............................................................................................45 
20.1 
MONITORS AND MONITORING VISITS ........................................................................................................ 45 
20.2 
MAIN SOURCE DOCUMENTS .......................................................................................................................... 46 
21 
USE OF INFORMATION AND DATA PUBLICATION ........................................46 
22 
SITE STAFF ...............................................................................................................47 
22.1 
RESEARCH SITE ................................................................................................................................................ 47 
22.2 
PRINCIPAL INVESTIGATOR ............................................................................................................................ 47 
22.3 
STUDY COORDINATOR OR SUBINVESTIGATOR ....................................................................................... 47 
23 
SPONSOR ..................................................................................................................47 
23.1 
BIOSTATISTICS, DATABASE AND PROGRAMMING .................................................................................. 48 
23.2 
CLINICAL MANAGEMENT .............................................................................................................................. 48 
23.3 
MONITOR ............................................................................................................................................................ 48 
23.4 
MEDICAL MONITOR ......................................................................................................................................... 48 
25 
INVESTIGATOR’S AGREEMENT .........................................................................49 
16 
REFERENCES ...........................................................................................................50 
 

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Protocol Nº: BIOS-HPFS-0115, 
Version 3.0; 26-Jun-2018. 
Study of HEMAX PFS vs EPREX/ERYPO ® in Predialysis Chronic Kidney Disease 
 
 
1 
CONTACT INFORMATION AND APPROVAL 
 
 
Job title and contact data 
Name 
Date of 
approva
Clinical Research Manager 
Biosidus Argentina S.A. 
Phone: 54 - 11 - 4909 - 8044 / 8000 
FAX 54 - 11 - 4924 - 3601 
E - mail: r.diez@biosidus.com.ar 
Dr. Roberto A. Diez 
10-Jul-2017 
 
 
 
Clinical Research Coordinator 
Biosidus S.A. 
  Phone: 54-11-4909-404 / 8000 
  FAX 54-11-4924-3601 
  E-mail: c.costas@biosidus.com.ar 
 
Carolina Costas 
10-Jul-2017 
 
 
 
Medical Monitor 
Biosidus S.A. 
  Phone: 54-11-4909-8049 / 8000 
  FAX 54-11-4924-3601 
  E-mail: h.ferro@biosidus.com.ar  
Dr. Hugo H. Ferro 
10-Jul-2017 
 
 
 
Management, Monitoring, Management and 
Analysis of Biostatistical Data 
IC PROJECTS S.R.L. 
Phone: 54 - 11 - 48162396 
FAX 54 - 11 - 4817 - 5617 
E - mail: rbozzo@icresearchgroup.com 
Dr. Raul Bozzo 
10-Jul-2017 
 
 
 

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Protocol Nº: BIOS-HPFS-0115, 
Version 3.0; 26-Jun-2018. 
Study of HEMAX PFS vs EPREX/ERYPO ® in Predialysis Chronic Kidney Disease 
 
 
 
 
2 
SYNOPSIS 
 
 
Protocol number 
BIOS - HPFS - 0115 
Study title 
A Randomized, Comparative Study of HEMAX PFS® versus 
EPREX/ ERYPO® in the Treatment of Anemia with Epoetin Alfa 
in Patients with Predialysis Chronic Kidney Disease 
Site number 
Multicentric. Argentina, Paraguay and Uruguay. 
The list of Principal Investigators and the centers’ data can be found 
in Annex 01. 
Clinical phase 
IIIB 
Treatment duration 
24 weeks (12 weeks of dose titration and 12 weeks of dose 
maintenance). 
Study population 
Patients with predialysis chronic renal failure (CRF) with indication 
of treatment of anemia and levels of hemoglobin < 10.5 g/ dl that 
have not received previous treatment in the past three months with 
an erythropoiesis stimulating agent. 
Study objectives 
Primary objectives: 
1- Evaluate the efficacy of treatment with epoetin alfa through 
increased levels of hemoglobin from baseline value to the 
mean value of the 8 to 12 weeks of treatment, comparing 
patients treated with HEMAX PFS versus those treated with 
EPREX/ ERYPO®. 
2- Evaluate the safety through the incidence of adverse events 
and adverse reactions after 12 and 24 weeks of treatment, 
comparing patients treated with HEMAX PFS versus those 
treated with EPREX/ ERYPO®. 
Secondary objectives: 
1 - Evaluate the efficacy of treatment with epoetin alfa through the 
percentage of responder patients (increase of Hb ≥ 1g/ dl) after 
12 weeks of treatment, comparing patients treated with HEMAX 
PFS versus those treated with EPREX/ ERYPO®. 
 
2- Evaluate the percentage of transfusion requirement after 12 
weeks of treatment, comparing patients treated with HEMAX PFS 
versus those treated with EPREX/ ERYPO®. 
 
3- Evaluate the intragroup efficacy (HEMAX PFS and EPREX/ 
ERYPO®) of treatment with epoetin alfa through increased levels 
of hemoglobin from baseline in each one of the intermediate visits 
until the week 12 visit. 
 
4- Evaluate the intragroup efficacy (HEMAX PFS and EPREX/ 
ERYPO®) of the change from the twice - a - week dosing during 
the titration phase to a weekly dosing during the maintenance phase

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Protocol Nº: BIOS-HPFS-0115, 
Version 1.0; 15-Oct-2015. 
Study of HEMAX PFS vs EPREX/ERYPO ® in Predialysis Chronic Kidney Disease 
 
 
 
 
 
5- In addition, at week 12 and 24 visits, an anti - erythropoietin alfa 
antibody dosing will be performed to evaluate treatment 
immunogenicity. 
 
6- In an exploratory way, the baseline value of hepcidin will be 
analyzed through ELISA at week 12 and 24, in relation to treatment 
response. 
Study design 
This is a multicenter, open - label, randomized and comparative 
phase IIIB study of two epoetins alfa (HEMAX PFS versus EPREX/ 
ERYPO®). 
Patients older than 18 years with predialysis chronic renal failure 
(CRF) defined by a glomerular filtration rate (calculated through the 
Modification of Diet in Renal Disease Study formula) that is ≥15 
ml/ min by 1.73m2 and <60 ml/ min by 1.73 m2, with an indication 
of treatment of anemia and levels of hemoglobin <10.5 g/ dl, which 
have not received prior treatment with an erythropoiesis stimulating 
agent in the last 3 months. 
The patients that meet all the inclusion criteria and none of the 
exclusion criteria will be randomized in a 1:1 ratio with stratification 
by gender to receive HEMAX PFS or EPREX/ ERYPO® 
subcutaneously with an initial dose of 29 IU/ kg twice a week (2000 
IU twice a week for 70 kg of weight), to be titrated according to the 
scheme that is summarized below. 
There will be a follow - up of patients with visits to the site every 
two weeks during the first 12 weeks of dose titration that will be 
followed by 12 additional weeks of dose maintenance with visits 
every 4 weeks. 
Usual titration scheme and dose management during the titration 
phase: 
• 
If the hemoglobin in any visit increases >1g/ dl in any period 
of 2 weeks prior to the visit, the dose will be reduced by 
25%. 
• 
If the hemoglobin, in any visit, increases to values equal to 
or greater than 11.5 g/ dl the dose will be interrupted and 
resumed when the hemoglobin drops below 10.5 g/ dl, with 
a dose decrease by 25%. 
Only every four weeks (weeks 4 and 8) from treatment initiation 
during the titration period, the dose may be increased according to 
the following scheme: 
• 
If after four or eight weeks, hemoglobin does not increase by 
at least 1 g/ dl as compared to the baseline value, the dose 
will be increased by 25%. 
• 
If after twelve weeks, hemoglobin did not increase during 
the titration phase at any time at least 1 g/ dl as compared to

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Protocol Nº: BIOS-HPFS-0115, 
Version 1.0; 15-Oct-2015. 
Study of HEMAX PFS vs EPREX/ERYPO ® in Predialysis Chronic Kidney Disease 
 
 
 
 
Maintenance phase: 
Patients who have experienced during the titration phase an increase 
of the Hb of at least 1 g/ dl as compared to the baseline value, will 
enter the maintenance phase after week 12 until week 24, with visits 
every 4 weeks. All patients will be switched to a weekly dosing 
scheme in which they will receive the same total dose of epoetin alfa 
administered at the end of the titration phase (for example the 
patients who at the end of the titration phase are with 2000 IU twice 
a week, will receive 4000 IU weekly during the maintenance phase). 
During the maintenance phase, the following medication 
adjustments may be performed: 
• 
During the maintenance phase, despite receiving the 
indicated dose of epoetin alfa, if the Hb drops below 10.5 g/ 
dl, the dose may be adjusted by 25%. 
• 
If the hemoglobin, in any visit, increases to values equal to 
or greater than 11.5 g/ dl the dose will be interrupted and 
resumed when the hemoglobin drops below 10.5 g/ dl, with 
a dose decrease by 25%. 
Patient number 
There are plans to recruit 120 patients in total that will be 
randomized in a 1:1 ratio to receive HEMAX PFS (n: 60) or 
EPREX/ ERYPO® (n: 60). 
Inclusion/ exclusion 
criteria 
Inclusion criteria 
Patients must meet all of the following inclusion criteria to be 
eligible for the study: 
• 
Patients between 18 and 85 years of age of both sexes. 
• 
IRC defined by the glomerular filtration rate through the 
Modification of Diet in Renal Disease Study (MDRD) 
formula that is ≥15 ml/ min and <60 ml/ min by 1.73m2. 
• 
Anemia with indication of treatment and hemoglobin lower 
than 10.5 g/ dl and greater than 7.5 g/ dl. 
• 
Patients who have both the will and the capacity to give 
informed consent in writing. 
• 
Women with at least 2 years of menopause or surgically 
sterile 6 months ago or of childbearing potential that have a 
negative pregnancy test during the baseline visit and are 
willing to receive an effective birth control method. 
 
 
 
Exclusion criteria 
Any of the following criteria exclude the patient from participating 
in the study: 
• 
Patient with scheduled entry to dialysis or kidney transplant 
in the next 6 months. 
•
Transferrin saturation < 20%

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Protocol Nº: BIOS-HPFS-0115, 
Version 1.0; 15-Oct-2015. 
Study of HEMAX PFS vs EPREX/ERYPO ® in Predialysis Chronic Kidney Disease 
 
 
 
 
• 
Cause of renal failure (as the secondary ones to autoimmune 
diseases) that in the opinion of the physician may affect the 
normal development of the Protocol. 
• 
Active bleeding or history of hemorrhage that has caused 
significant decrease of hematocrits in the last 30 days. 
• 
Uncontrolled hypertension (≥160 mm Hg systolic pressure 
and/ or 
≥100mm Hg diastolic pressure with anti - hypertensive 
treatment). 
• 
Anemia due to another cause other than the kidney disease. 
• 
Transfusion in the last 3 months before the baseline or 
screening visit. 
• 
Treatment with an erythropoiesis stimulating agent in the 3 
months prior to the baseline or screening visit. 
• 
Increased risk of thromboembolic disease: Previous history 
of arterial thromboembolism (CVA, TIA, Acute Coronary 
Syndrome or other) in the last 6 months or venous 
thrombosis in the last twelve months prior to the baseline 
visit; surgery in the last month prior to the baseline visit; 
prolonged standstill or orthopedic surgery scheduled in the 
next 6 months or any other factor which in the opinion of the 
investigator may increase the risk of thromboembolism in 
the patient. 
• 
Hematological disease or myelodysplastic syndrome or a 
history of hematologic malignancy or solid tumor in the last 
5 years. 
• 
History of congestive heart failure. 
• 
Pregnancy or breast - feeding. 
• 
Refusal of patient to participate in the protocol or patients 
Route 
of 
administration 
and 
investigational 
product dosage 
HEMAX PFS or EPREX/ ERYPO® (both epoetin alfa) at an initial 
dose of 29 IU/ kg twice a week subcutaneously (2000 IU twice a 
week for 70 kg of weight) during the 12 weeks of titration, followed 
by an equivalent weekly dose during the additional 12 weeks of 
maintenance. 
Concomitant 
treatment of anemia 
Transfusions: Patients will be transfused according to the clinical 
judgment of the investigator, based on the patient's symptoms and 
not on a cutoff value of hemoglobin. The transfused patients will be 
withdrawn from the study for having reached a study endpoint. 
 
Iron intake: All patients will receive concomitant treatment with 
iron orally to maintain the levels of transferrin saturation >20% 
according to the indications of the treating physicians. The 
intravenous iron is also permitted, according to the criterion of the 
t
ti
h
i i

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Protocol Nº: BIOS-HPFS-0115, 
Version 1.0; 15-Oct-2015. 
Study of HEMAX PFS vs EPREX/ERYPO ® in Predialysis Chronic Kidney Disease 
 
 
 
Statistical methods 
Sample size 
A total of 120 patients (60 in each group) will allow, with 80% of 
power, to rule out a difference between treatment groups greater 
than 1g/ dl in hemoglobin increase from baseline value to the mean 
value of the visits between week 8 and 12. 
 
 
 
Efficacy evaluations 
The primary evaluation of efficacy will be carried out through the 
increased levels of hemoglobin from baseline value to the mean 
value of the visits between week 8 and 12, comparing patients 
treated with HEMAX PFS versus those treated with EPREX/ 
ERYPO®. 
 
Additionally, treatment equivalence will be established if the 
difference between the two groups excludes a difference greater 
than 1g/ dl in hemoglobin increase from baseline value to the mean 
value of the visits between week 8 and 12 with a difference ≤20% 
in the mean dose of epoetin alfa in these visits. 
 
The secondary evaluation of efficacy will be carried out through the 
evaluation of the following objectives: 
• 
Percentage of responder patients (increase of Hb ≥ 1g/ dl) 
after 12 weeks of treatment, comparing patients treated with 
HEMAX PFS versus those treated with EPREX/ ERYPO®. 
 
• 
Percentage of transfusional requirement after 12 weeks of 
treatment, comparing patients treated with HEMAX PFS 
versus those treated with EPREX/ ERYPO®. 
 
• 
Intragroup efficacy (HEMAX PFS and EPREX/ ERYPO®) 
of treatment with Epoetin Alfa through increased levels of 
hemoglobin from baseline in each one of the intermediate 
visits until the week 12 visit. 
 
 
• 
Evaluate the intragroup efficacy (HEMAX PFS and 
EPREX/ ERYPO®) of the change from the twice - a - week 
dosing during the titration phase to a weekly dosing during 
the maintenance phase through the variation of hemoglobin 
levels from week 12 to the weeks 16, 20 and 24. 
For missing hemoglobin data, the last observation carried forward 
th d
ill b
d

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Protocol Nº: BIOS-HPFS-0115, 
Version 1.0; 15-Oct-2015. 
Study of HEMAX PFS vs EPREX/ERYPO ® in Predialysis Chronic Kidney Disease 
 
 
 
Safety evaluations 
The safety evaluation to be carried out for the treatment cohort 
will include: 
Incidence, severity and seriousness of adverse events and adverse 
reactions including thromboembolic events, arterial hypertension, 
safety laboratory and other adverse events at 12 and 24 weeks of 
treatment. 
 
Dosing of anti - erythropoietin antibodies will be performed to 
evaluate the treatment immunogenicity in the baseline visit and in 
week 12 and 24 visits. 
 
Data analysis and results: 
There will be two formal database analyses. 
A first analysis will be performed after the last study patient 
completes the week 12 visit and the database is clean. This 
analysis will produce all the efficacy and safety results at week 
12. 
 
A second analysis will be performed after the last study patient 

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Protocol Nº: BIOS-HPFS-0115, 
Version 1.0; 15-Oct-2015. 
Study of HEMAX PFS vs EPREX/ERYPO ® in Predialysis Chronic Kidney Disease 
 
 
 
 
 
3 
LIST OF ABBREVIATIONS 
TERM 
 DESCRIPTION 
% 
percentage 
CVA 
cerebrovascular accident 
TIA 
transitional ischemic accident 
DNA 
deoxyribonucleic acid 
ANMAT 
National Administration of Drugs, Food and Medical 
Devices 
RA 
regulatory authority 
IECs 
independent ethics committee 
IECR 
Institutional Ethics Committee for Research 
CKD 
chronic kidney disease 
CRO 
contract research organization 
dl 
deciliter 
DM 
data management 
AE 
adverse event 
SAE 
serious adverse event 
ESA 
erythropoiesis stimulating agent 
ICRF 
individual clinical record form 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice  
Hb 
hemoglobin 
HCG 
human chorionic gonadotropin 
HR 
hazard ratio or risk ratio 
ICH 
International Conference on Harmonization 
IRB 
Institutional Review Board 
CRF 
chronic renal failure 
MDRD 
Modification of Diet in Renal Disease formula 
mg 
milligram 
ml 
milliliter 
SC 
subcutaneous 
TEAE 
treatment - emergent adverse events 

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Protocol Nº: BIOS-HPFS-0115, 
Version 1.0; 15-Oct-2015. 
Study of HEMAX PFS vs EPREX/ERYPO ® in Predialysis Chronic Kidney Disease 
 
 
 
4 
INTRODUCTION 
 
4.1 CHRONIC KIDNEY DISEASE AND ANEMIA 
Chronic kidney disease (CKD) is associated with anemia due mainly to the decline of 
erythropoiesis by deficit of erythropoietin and, potentially, to secondary alterations in oxygen 
level1. The APREDIA study conducted in our country in predialysis population of patients with 
glomerular filtrate levels < 44.4 ml/ min, showed that 72% of the patients had values of 
hemoglobin (Hb) compatible with anemia and that this percentage increases to the extent that 
the deterioration of the renal function is greater2. 
 
The anemia in chronic kidney disease and its lack of treatment is associated with increased 
comorbidity, complications, cardiovascular risk, progression of kidney disease and decreased 
survival 3 - 8.  In addition, the treatment impacts favorably on the exercise capacity and the quality 
of life of patients 9 - 10. In turn, the decrease in the transfusional requirement favorably impacts 
on the reduction of secondary complications to infectious diseases transmissible by blood 
transfusion, hemosiderosis and allosensibilization that may potentially adversely impact on a 
future kidney transplant1. 
 
 
4.2 TREATMENT WITH ERITROPYESIS STIMULATING AGENTS 
Since its advent at the end of the '80s, recombinant erythropoietin became a pillar of the 
treatment of anemia in patients with chronic renal failure1. 
Large - scale controlled studies in patients with anemia and CKD have established an alert as to 
what is the level of hemoglobin and the ideal dose of erythropoiesis stimulating agents (ESA). 
 
In these controlled clinical studies, when comparing the target higher levels of Hb (13 - 14 g/ 
dl) with the lower levels (9 - 11.3 g/ dl), it was noted that by titrating ESAs to the highest levels 
of hemoglobin, an increased risk of mortality, myocardial infarction, cerebrovascular accident, 
heart failure and other thromboembolic events11 - 13 were obtained, as seen in the table shown 
below in this section. 
 
 
In addition, the use of ESAs in other populations, such as cancer patients with curable tumors 
and anemia induced by chemotherapy or patients undergoing orthopedic surgery or coronary 
revascularization surgery, demonstrated the possibility of several problems, including in some 
cases increased mortality, increased risk of tumor progression or recurrence and 
thromboembolic events, so the use of ESA in some of these indications1 is not recommended. 

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Protocol Nº: BIOS-HPFS-0115, 
Version 1.0; 15-Oct-2015. 
Study of HEMAX PFS vs EPREX/ERYPO ® in Predialysis Chronic Kidney Disease 
 
 
 
 
 
Study 
Normal 
Hematocrit 
Study (NHS)11 
CHOI
R12 (N = 
1432) 
TREA
T13 (N = 
4038) 
Population 
CKD on 
dialysis with 
coronary heart 
disease or heart 
failure 
CKD Not on 
dialysis 
with 
Hb < 11 g/ dL 
CKD Not on 
dialysis with 
diabetes type II 
and Hb ≤ 11 g/ 
dL 
ESA 
Epoetin Alfa 
Epoetin Alfa 
Darbepoetin Alfa 
Target Hb 
(in g/ dl) 
14.0 vs. 10.0 
13.5 vs. 11.3 
13.0 vs. ≥ 9.0 
Median 
Hb 
(quartile 1 
12.6 (11.6; 13.3) 
13.0 (12.2; 13.4) 
12.5 (12.0; 12.8) 
Results 
Increased 
mortality 
HR=1.27; 95% CI 
(1.04, 1.54); 
Increase in 
major 
cardiovascular 
events (death, 
infarction, CVA 
or 
hospitalization 
due to heart
Increased CVA 
HR 1.92; 95% CI: 
(1.38, 2.68) 
 
Based on this evidence, the current guidelines for the management of anemia in patients with 
CKD recommend treatment initiation with ESAs in the following cases1: 
1.3.1 
Patients with clinical individualized treatment indication (symptoms, 
decreased hemoglobin, risk of transfusion and inadequate response to the 
iron) with levels of hemoglobin <10 g/ dl. In patients with Hb levels >10 g/ 
dl the decision of treatment initiation must be individualized according to the 
potential risk/ benefit balance. 
2.3.1 
During treatment, the levels of Hb 11.5 g/ dl should not be exceeded. 
3.3.1 
Use the minimum necessary doses to maintain the Hb in the ranges 
described. 
 
 
4.3 EPOETINA ALFA (HEMAX AND HEMAX PFS) 
HEMAX® is a medication that contains epoetin alfa (human recombinant erythropoietin) as 
active pharmaceutical ingredient14. Epoetin is a glycoprotein of 165 amino acids produced by 
recombinant DNA technology, obtained from a genetically modified mammal cell line. Epoetin 
has a peak level of purity and is indistinguishable from natural human erythropoietin. 

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Erythropoietin induces the erythropoiesis by inhibiting apoptosis and stimulating the division and 
differentiation of erythropoietic stem cells in bone marrow, which results in an increase in the red blood 
cell volume and, consequently, the hematocrit. Erythropoietin also induces the release of reticulocytes 
from the bone marrow towards the bloodstream, where they mature to erythrocytes. 
The normal concentration of endogenous erythropoietin is 10 - 30 mU/ ml and is influenced by the levels 
of oxygen to tissue level. When tissue oxygen levels decrease, the concentration of erythropoietin 
increases between 100 and 
1,000 times This situation can also be seen in the patients with anemia. 
Epoetin alfa, drug substance of HEMAX®, is administered parenterally (subcutaneous or intravenous). 
The initial increase in reticulocyte count occurs within 7 to 10 days after the administration. Clinically 
significant increases were found in the red blood cell, hematocrit and hemoglobin count, usually in 2 to 
6 weeks after the administration of epoetin alfa. The range and extent of the response depends on the 
dose and on the availability of iron reserves. 
The peak plasma concentration is achieved after 15 minutes following a single intravenous dose and 
between 5 to 24 hours following administration of a single dose subcutaneously. In the latter case, peak 
concentrations can be maintained for 12 to 16 hours and present detectable amounts for at least 24 hours 
following administration. 
The half - life of epoetin alfa is 4 to 13 hours following intravenous or subcutaneous administration. The 
elimination half - life is generally higher following the first dose after two or more weeks of treatment. 
In general, after 24 h plasma levels of erythropoietin return to their baseline level. Following 
subcutaneous administration of epoetin, the peak concentration of the drug was observed between 5 and 
24 hours after administration, and its decline is slower. 
In studies conducted in healthy adult volunteers, it was observed that the half - life following intravenous 
administration of epoetin is 20 % lower in patients with renal failure. Furthermore, in a study conducted 
in healthy volunteers, it was noted that the half - life of HEMAX® administered subcutaneously was 
20.8 ± 6.3 hours. 
Once treatment is interrupted, the hematocrit may begin to decrease after 2 weeks. 
The experience with HEMAX® in Argentina is more than 20 years, being one of the most widely used 
products in the treatment of anemia in patients with chronic kidney disease. 
 
 
On the other hand, HEMAX PFS is a medication that also contains epoetin alfa (human recombinant 
erythropoietin) as active pharmaceutical ingredient (the same content in HEMAX®, differing in the 
primary packaging and mainly, in that it does not contain human albumin as an excipient15, which is 
usually perceived as an improvement. The lack of albumin, that is a hemoderivative, decreases the risk 
of hypersensitivity reactions in patients who are allergic to albumin or to similar products derived from 
human blood and reduce the chance of infections transmissible through blood. 
 
All studies conducted with HEMAX PFS® in the comparability exercise with the innovative epoetin 
alfa product have shown that both are biosimilar (Registration Dossier of Hemax PFS submitted to 
ANMAT, dossier n° 1 - 47 - 1110 - 793 - 14 - 6). Given that the drug active pharmaceutical ingredient 
is the same, any kind of difference between this formulation and the current formulation with albumin 

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(HEMAX®) is not expected. Given that the registration dossier of the new formulation (which was 
submitted at the end of 2014 but still has not been approved for marketing), this study is considered 
Phase IIIB and not Phase IV for the time being. 
 
 
4.4 EPOETINA ALFA (EPREX/ ERYPO®) 
EPREX® and ERYPO® are tradenames for a same medication that also contains epoetin alfa, obtained 
from a genetically modified mammal cell line16. EPREX/ ERYPO® are products with epoetin alfa 
developed by Janssen Cilag, in Belgium, which have been approved there by the local authority and by 
the ANMAT in our country (re - certification 3107 / 2011), being frequently used as an international 
reference product. 
 
 
5 
CURRENT STUDY RATIONALE 
 
In order to obtain more scientific evidence on the use of epoetin alfa in the context of the current 
treatment of anemia in patients with predialysis CKD, it is of interest to perform a randomized study of 
HEMAX® controlled with a reference medication such as EPREX/ ERYPO®. 
Based on this context and to conform to the current recommendations, we designed a study that will 
include patients with clinical indication for treatment and levels of hemoglobin <10.5 g/ dl with dose 
adjustment in aliquots of 25% and interruption of treatment if the Hb reaches values equal to or greater 
than 11.5 g/ dl so as to maintain the hemoglobin concentration between 10.4 and 11.4g/ dl. Patients with 
increased thromboembolic risk will be excluded from the study. 
The initial dose of epoetin alfa currently recommended for treatment initiation in patients with 
predialysis CKD are 50 - 100 IU/ kg three times a week subcutaneously. However, these doses are not 
the ones used in the usual clinical practice in our country, where treatment is initiated with lower doses 
of 20 to 40 IU/ kg twice a week. This therapeutic approach has the advantage of being more in line with 
the current recommendations, exposing the patient to lower initial doses, in addition to the convenience 
to the patient of administering the medication only twice a week instead of three times a week. In 
addition, it is frequent during the maintenance phase or even from the start to administer epoetin in a 
single weekly dose. This dosing scheme is founded on that the clinically relevant pharmacodynamic 
effect of epoetin alfa does not depend on its plasma half - life but on the half - life of the red blood cells. 
Several clinical studies have demonstrated the equivalence and safety of epoetin administration schemes 
weekly, every two weeks and every 3 weeks17 - 23.  
It is interesting to note that the mean weekly dose of epoetin alfa used in more recent studies has been 
5000 ± 2500 IU/ week, a dose that is in the range of our initial dose24.  
For these reasons, our study will use a scheme that is frequently used in the practice in our country using 
lower initial doses administered twice a week subcutaneously in the initial titration phase of 12 weeks, 
switching then to the same weekly dose but administered once a week during the maintenance phase. 
Thus, local additional evidence on the efficacy and safety of this dosing scheme will be obtained. 
 
 

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6 
STUDY OBJECTIVES 
The study has as a general objective the evaluation of the efficacy and safety of HEMAX PFS compared 
with EPREX/ ERYPO®, following a dose titration and maintenance scheme similar to that used in the 
clinical practice in our country, being the specific objectives the following. 
 
6.1 PRIMARY OBJECTIVES: 
Evaluate the efficacy of treatment with epoetin alfa through increased levels of hemoglobin from 
baseline value to the mean value of the 8 to 12 weeks of treatment, comparing patients treated with 
HEMAX PFS versus those treated with EPREX/ ERYPO®. 
 
 
Evaluate the safety through the incidence of adverse events and adverse reactions after 12 and 24 weeks 
of treatment, comparing patients treated with HEMAX PFS versus those treated with EPREX/ 
ERYPO®. 
 
 
6.2 SECUNDARY OBJECTIVES: 
Evaluate the efficacy of treatment with epoetin alfa through the percentage of responder patients 
(increase of Hb ≥ 1g/ dl) after 12 weeks of treatment, comparing patients treated with HEMAX PFS 
versus those treated with EPREX/ ERYPO®. 
 
 
Evaluate the percentage of transfusion requirement after 12 weeks of 
treatment, comparing patients treated with HEMAX® PFS versus those treated with EPREX/ ERYPO®. 
 
Evaluate the intragroup efficacy (HEMAX® PFS and EPREX/ ERYPO®) of treatment with epoetin alfa 
through increased levels of hemoglobin from baseline in each one of the intermediate visits until the 
week 12 visit. 
 
Evaluate the intragroup efficacy (HEMAX® PFS and EPREX/ ERYPO®) of the change from the twice 
- a - week dosing during the titration phase to a weekly dosing during the maintenance phase through 
the variation of the hemoglobin levels from week 12 to weeks 16, 20 and 24. 
 
In addition, at week12 and 24 visits, an anti - erythropoietin antibody dosing will be performed to 
evaluate treatment immunogenicity. 
 
 
6.3 
EXPLORATORY OBJECTIVE 
Evaluate the baseline value of hepcidin through ELISA at 12 and 24 weeks, in relation to treatment 
response. 
 
 
7 
LABORATORIES 

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Hemoglobin levels will be analyzed at each center’s local laboratory. 
Anti-erythropoietin antibodies and hepcidin level will be analyzed at BIOSIDUS S.A. located at 
Constitución N°4216/24/34, Mármol N°1213/23 and Tarija N°4243/45/51/57/63, Ciudad Autónoma de 
Buenos Aires. 
 
 
8 
STUDY DESIGN 
This is a multicenter, open - label, randomized and comparative phase IIIB study of two epoetins alfa 
(HEMAX PFS versus EPREX/ ERYPO®). 
Patients older than 18 years with predialysis chronic renal failure (CRF) defined by a glomerular 
filtration rate through the Modification of Diet in Renal Disease Study formula that is ≥15 ml/ min by 
1.73 m2 and <60 ml/ min by 1.73 m2, with an indication of treatment of anemia and levels of hemoglobin 
<10.5 g/ dl, which have not received prior treatment with an erythropoiesis stimulating agent in the last 
3 months. 
The patients that meet all the inclusion criteria and none of the exclusion criteria will be randomized in 
a 1:1 ratio with stratification by gender to receive HEMAX® PFS or EPREX/ ERYPO® subcutaneously 
with an initial dose of 29 IU/ kg twice a week (2000 IU twice a week for 70 kg of weight), to be titrated 
according to the scheme that is summarized in Section 7. 
There will be a follow - up of patients with visits to the site every two weeks during the first 12 weeks 
of dose titration that will be followed by 12 additional weeks of dose maintenance with visits every 4 
weeks. 
 
 
9 
STUDY POPULATION 
Patients with kidney disease and predialysis chronic renal failure (CRF) with indication of treatment of 
anemia and levels of hemoglobin < 10.5 g/ dl that have not received previous treatment in the past three 
months with an erythropoiesis stimulating agent. 
 
9.1 PATIENT NUMBER 
There are plans to recruit 120 patients in total that will be randomized in a 1:1 ratio to receive HEMAX 
PFS (n = 60) or EPREX/ ERYPO® (n = 60). 
 
 
9.2 INCLUSION CRITERIA 
Patients must meet all of the following inclusion criteria to be eligible for the study: 
 
 
1) Patients between 18 and 85 years of age of both sexes. 
2) IRC defined by the glomerular filtration rate through the Modification of Diet in Renal 
Disease Study (MDRD) formula that is ≥15 ml/ min and <60 ml/ min by 1.73 m2. 
3) Anemia with indication of treatment and hemoglobin lower than 10.5 g/ dl and greater 

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than 7.5 g/ dl. 
4) Patients who have both the will and the capacity to give informed consent in writing. 
5) Women with at least 2 years of menopause or surgically sterile 6 months ago or of 
childbearing potential that have a negative pregnancy test during the baseline visit and 
are willing to receive an effective birth control method (diaphragm or prophylactic 
associated with a spermicide since at least 21 days before the first treatment; or 
intrauterine device in place for at least 3 months before the first dose of epoetin alfa: or 
hormonal birth control method, in pills, patch or implant, initiated at least 3 months 
before the first treatment). 
 
 
 
 
9.3 EXCLUSION CRITERIA 
Any of the following criteria exclude the patient from participating in the study: 
1) Patient with scheduled entry to dialysis or kidney transplant in the next 6 months. 
2) Transferrin saturation < 20%. 
3) Cause of renal failure (as the secondary ones to autoimmune diseases) that in the opinion 
of the physician may affect the normal development of the Protocol. 
4) Active bleeding or history of hemorrhage that has caused significant decrease of 
hematocrits in the last 30 days. 
5) Uncontrolled hypertension (≥160 mm Hg systolic pressure and/ or ≥100mm Hg diastolic 
pressure with anti - hypertensive treatment). 
6) Anemia due to another cause other than the kidney disease. 
7) Transfusion in the last 3 months before the baseline or screening visit. 
8) Treatment with an erythropoiesis stimulating agent in the 3 months prior to the baseline 
or screening visit. 
9) Increased risk of thromboembolic disease: Previous history of arterial thromboembolism 
(CVA, TIA, Acute Coronary Syndrome or other) in the last 6 months or venous 
thrombosis in the last twelve months prior to the baseline visit; surgery in the last month 
prior to the baseline visit; prolonged standstill or orthopedic surgery scheduled in the next 

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6 months or any other factor which in the opinion of the investigator may increase the 
risk of thromboembolism in the patient. 
10) Hematological disease, including myelodysplastic syndrome or a history of hematologic 
neoplasia or solid tumor in the last 5 years. 
11) History of congestive heart failure. 
12) Pregnancy or breast - feeding. 
13) Refusal of patient to participate in the protocol or patients with a medical condition that 
the investigator considers significantly relevant to prevent their participation in the study. 
 
 
 
9.4 EARLY TREATMENT TERMINATION 
 
The termination visit should be performed in all patients that completed the study prematurely. 
Patients who decide not to continue with the visits must perform the termination visit before completion. 
A patient may leave or be excluded from the study due to the following reasons: 
 
• Death. 
• Adverse event that in the opinion of the investigator requires early withdrawal 
(specify principal AE in the AE form). 
• Revocation of informed consent. 
• At the request of the investigator or physician primarily responsible for the care of 
the patient. 
• Due to major protocol violation that required discontinuation. 
• Loss of follow - up, including the fact that patient does not return to the site. 
• Positive pregnancy test at any time during the study. 
• Patient transfusion or lack of response after 12 weeks of treatment. 
• If after twelve weeks the hemoglobin did not increase during the titration phase by at 
least 1 g/dL from baseline, the patient will be withdrawn from the study. 
 
10 MEDICATIONS/ TREATMENT AND CONCOMITANT MEDICATIONS 
 
10.1 MEDICATION/ TREATMENT 
 
HEMAX PFS or EPREX/ ERYPO® (both epoetin alfa) at an initial dose of 29 IU/ kg twice a week 

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subcutaneously (2000 IU twice a week for 70 kg of weight) during the 12 weeks of titration, followed 
by an equivalent weekly dose during the additional 12 weeks of maintenance. 
 
 
Usual titration scheme and dose management during the titration phase: 
• If the hemoglobin in any visit increases >1 g/ dl in any period of 2 weeks prior to the 
visit, the dose will be reduced by 25%. 
• If the hemoglobin, in any visit, increases to values equal to or greater than 11.5 g/ dl 
the dose will be interrupted and resumed when the hemoglobin drops below 10.5 g/ 
dl, with a dose decrease by 25%. 
Only every four weeks (weeks 4 and 8) from treatment initiation and during the titration 
period, the dose may be increased according to the following scheme: 
 
 
• If after four or eight weeks, hemoglobin does not increase by at least 1 g/ dl as 
compared to the baseline value, the dose will be increased by 25%. 
• If after twelve weeks, hemoglobin did not increase during the titration phase at least 
1 g/ dl as compared to the baseline value, the patient will be withdrawn from the 
study. 
 
 
Maintenance phase: 
Patients who have experienced during the titration phase an increase of the Hb of at least 1 
g/ dl as compared to the baseline value, will enter the maintenance phase after week 12 until 
week 24, with visits every 4 weeks. All patients will be switched to a weekly dosing scheme 
in which they will receive the same total dose of epoetin alfa administered at the end of the 
titration phase (for example the patients who at the end of the titration phase are with 2000 
IU twice a week will receive 4000 IU weekly during the maintenance phase). During the 
maintenance phase, the following medication adjustments may be performed: 
• If despite receiving the indicated dose of epoetin alfa, the Hb drops below 10.5 g/ dl, 
the dose may be adjusted by 25%. 
• If the hemoglobin, in any visit, increases to values equal to or greater than 11.5 g/ dl, 
the dose will be interrupted and resumed when the hemoglobin has dropped below 
10.5 g/ dl, with a dose decrease by 25%. 
 
Application of Medication:  
According to the above titration scheme the different medication presentations described in section 9.5 
will be used to facilitate application and avoid risks related to potential overdosing. During the titration 
phase, responder patients (hemoglobin increases greater than 1 g/dL) who require a dose reduction may 
receive the reduced dose in a single weekly application in order to facilitate application and avoid the 

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potential risks of overdosage. In the (rare) cases in which the patient has sustained hemoglobin 
increases greater than 1 g/dL and requires doses less than 1000IU/week, the dose will be suspended 
and restarted at 1000IU/week when the hemoglobin is < 10.5 g/dL to avoid the potential risk of 
overdosing in responders.    
 
 
11 STUDY MEDICATION LABELING 
 
11.1 PRIMARY PACKAGING 
 
 

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11.2 SECONDARY PACKAGING 
 
 

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11.3 CONCOMITANT MEDICATIONS/ TREATMENT OF ANEMIA 
 
Transfusions: Patients will be transfused according to the clinical judgment of the investigator, based 
on the patient's symptoms and not on a cutoff value of hemoglobin. The transfused patients will be 
withdrawn from the study for having reached a study endpoint. 
 
 
Iron intake: All patients will receive concomitant treatment with iron orally to maintain the levels of 
transferrin saturation >20% according to the indications of the treating physicians. The intravenous iron 
is also permitted, according to the criterion of the treating physicians. 
 
 
 
12 STUDY DEVELOPMENT 
 
12.1 STUDY PROCEDURES 
This study will include a screening or baseline visit (a week before randomization), a 
randomization visit (week 0), a treatment titration phase (week 0 to week 12) and a 
maintenance period (between week 12 and 24). The visit windows are ± 7 days post - 
randomization. In the table below, there is a detailed summary of the activities. 
 
 
 
12.2 STUDY PROCEDURE TABLES 
 
 
 
 
PROCEDURES - SITE VISITS 
 
V1 
Scree
 
V2 
Rando
 
 
V3 
 
 
V
 
 
V5 
 
 
V
 
 
V7 
 
 
V
 
 
V9 
 
 
V10 
 
V11 
or 
Study weeks 
 - 
0 
S2 
S
S6 
S
S10 
S1
S1
S20 
S24 
INVESTIGATOR ACTIVITIES 
 
 
 
 
 
 
 
 
 
 
 
Obtain the informed consent in writing 
 
 
X 
 
 
 
 
 
 
 
 
 
 

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Evaluate the inclusion and exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
Blood pregnancy test HCG beta subunit 
(only in women of childbearing potential) 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
Medical 
history 
(with 
concomitant 
medication) and physical examination 
 
X 
 
 
 
 
 
 
 
 
 
 
Blood pressure and pulse 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Electrocardiogram 
X 
 
 
 
 
 
 
 
 
 
 
Complete 
laboratory 
test 
(hemogram; 
hepatogram; blood glucose; renal function; 
ionogram; lipids; iron metabolism) 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
Control laboratory test: hemogram 
 
 
X 
X 
X 
X 
X 
 
X 
X 
 
Laboratory measurement of antibodies and 
hepcidin 
X 
 
 
 
 
 
 
X  
 
X 
Dosing and dose adjustment 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Administration of subcutaneous medication 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Delivery of medication and dosage record 
card 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Medication control and dose recording 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
AEs recording 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
12.3 DETAILED STUDY PLAN 
 
12.3.1 Baseline evaluation visit 1 (week -1) 
 
Before performing any study procedure/ evaluation, the patient must have been duly informed on all 
aspects of the study, including scheduled visits and activities and must sign an informed consent. The 
patient will be given a signed copy of the informed consent. 
The following tasks will be carried out during the baseline visit: 
 
▪ 
Review and sign the informed consent with delivery of a signed copy for the patient. 
▪ 
Evaluate the inclusion and exclusion criteria. 
▪ 
Samples for full local laboratory test, consisting of: 
▪ 
Complete hemogram with reticulocyte (through cytometry or automatic counter) 
and platelet count. 
▪ 
Hepatogram, 
▪ 
Glycemia, lipid profile (HDL, LDL and triglycerides) 

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▪ 
Ionogram, calcium, phosphorus, urea and creatinine, 
▪ 
Serum iron, transferrin, transferrin saturation, and ferritin 
▪ 
Beta subunit of chorionic gonadotropin only in women of childbearing potential 
▪ 
Serum sample for antibodies and hepcidin dosage (the sample will be collected and 
an aliquot will be stored at - 20º C for further analysis) 
▪ 
Medical history (with concomitant medication) and a physical examination (with weight 
and height), registering only the clinically relevant findings. 
▪ 
Pulse: the radial pulse will be measured as an estimate of the heart rate after the patient 
has rested for 5 minutes. 
▪ 
Blood pressure: 3 measurements separated by 5 minutes each will be taken, for which 
the patient should be at rest and sitting. The first measurement will be discarded and the 
values obtained at the second and third measurements will be averaged, a mean value 
that will be recorded in the medical history and in the case report form (CRF). 
▪ 
Electrocardiogram 
▪ 
The patient will be scheduled for visit 2, which corresponds to randomization. 
 
 
12.3.2 Randomization visit 2 (week 0) 
 
Visits will be scheduled a week after the baseline screening visit with a window of ± 3 days from the 
respective date. 
The following tasks will be carried out in the consultation during this visit: 
 
▪ 
Review the inclusion and exclusion criteria. 
▪ 
Pulse, will be measured after the patient has rested during 5 minutes. 
▪ 
Blood pressure: 3 measurements separated by 5 minutes each will be taken, for which 
the patient should be at rest and sitting. The first measurement will be discarded and the 
values obtained at the second and third measurements will be averaged, a mean value 
that will be recorded in the medical history and in the case report form (CRF). 
▪ 
Patient will be randomized. A randomization number and treatment with HEMAX PFS 
or EPREX/ ERYPO® will be assigned to each eligible patient. 
▪ 
Study medication will be dispensed. Patients will receive the study medication 
(including oral iron supplement) free of charge; in addition, patients will be instructed 
on the administration of the medication and will be given a card to register dose 
administration. 
▪ 
Subcutaneous administration of HEMAX PFS or EPREX/ ERYPO® will be performed. 
▪ 
The prescribed doses of HEMAX PFS or EPREX/ ERYPO® will be recorded. 

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▪ 
The patient will be scheduled for the next visit, that corresponds to study week 2. 
 
 
12.3.3 Visit 3, 4, 5, 6, and 7 (weeks 2, 4, 6, 8 and 10 respectively) 
 
Visits will be scheduled two weeks after the prior visit with a window of ± 1 week from the respective 
date. 
The following tasks will be carried out in the consultation in each of these visits: 
 
▪ 
Blood pregnancy test (only in women of childbearing potential) 
▪ 
Pulse, will be measured after the patient has rested for 5 minutes. 
▪ 
Blood pressure: 3 measurements separated by 5 minutes each will be taken, for which 
the patient should be at rest and sitting. The first measurement will be discarded and the 
values obtained at the second and third measurements will be averaged, a mean value 
that will be recorded in the medical history and in the case report form (CRF). 
 
 
▪ 
Complete hemogram. The result of the local hemoglobin test should be within the 
same day or before, so as to be able to adjust the study medication dose, if required. 
▪ 
The study medication will be counted and dispensed, and patients will be given a card 
to record the application of the doses. 
▪ 
Subcutaneous administration of HEMAX PFS or EPREX/ ERYPO® will be performed. 
▪ 
The prescribed doses of HEMAX PFS or EPREX/ ERYPO® will be recorded, 
controlling the returned empty boxes and the dose recording cards. 
▪ 
Adverse events will be recorded and will be registered in the medical history and in the 
CRF. 
▪ 
The patient will be scheduled for the next study visit. 
 
 
12.3.4 Visit 8 (week 12) 
 
The following tasks will be carried out in the consultation during this visit: 
 
▪ 
Review the criteria for entry in the maintenance phase. 
▪ 
Blood pregnancy test (only in women of childbearing potential) 
▪ 
Samples for full local laboratory test, consisting of: 
▪ 
Complete hemogram with reticulocyte and platelet count. 
▪ 
Hepatogram, 

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▪ 
Glycemia, lipid profile (HDL, LDL and triglycerides) 
▪ 
Ionogram, calcium, phosphorus, urea and creatinine, 
▪ 
Serum iron, transferrin, transferrin saturation, and ferritin 
▪ 
Serum sample for antibodies and hepcidin dosage (the sample will be collected and 
stored for further analysis) 
▪ 
Pulse, will be measured after the patient has been at rest during 5 minutes. 
▪ 
Blood pressure: 3 measurements separated by 5 minutes each will be taken, for which 
the patient should be at rest and sitting. The first measurement will be discarded and the 
values obtained at the second and third measurements will be averaged, a mean value 
that will be recorded in the medical history and in the case report form (CRF). 
▪ 
The study medication will be counted and dispensed, and patients will be given a card 
to record the application of the doses. 
▪ 
Subcutaneous administration of HEMAX® PFS or EPREX/ ERYPO® will be performed. 
 
 
▪ 
The prescribed doses of HEMAX® PFS or EPREX/ ERYPO® will be recorded, 
controlling the returned empty boxes and the dose recording cards. 
▪ 
Adverse events will be recorded and entered in the medical history and in the CRF. 
▪ 
The patient will be scheduled for the next study visit. 
 
12.3.5 Visits 9 and 10 (weeks 16 and 20 respectively) 
 
The visits will be scheduled four weeks after the previous visit with a window of ± 1 week from the 
respective date. 
The following tasks will be carried out in consultation during these visits: 
▪ 
Blood pregnancy test (only in women of childbearing potential) 
▪ 
Pulse, will be measured after the patient has been at rest during 5 minutes. 
▪ 
Blood pressure: 3 measurements separated by 5 minutes each will be taken, for which 
the patient should be at rest and sitting. The first measurement will be discarded and the 
values obtained at the second and third measurements will be averaged, a mean value 
that will be recorded in the medical history and in the case report form (CRF). 
▪ 
Complete hemogram. The result of the local hemoglobin test must be within the same 
day or before so as to be able to adjust the study medication dose, if required. 
▪ 
The study medication will be counted and dispensed, and patients will be given a card 
to record the application of the doses. 
▪ 
Subcutaneous administration of HEMAX PFS or EPREX/ ERYPO® will be performed. 

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▪ 
The prescribed doses of HEMAX PFS or EPREX/ ERYPO® will be recorded, 
controlling the returned empty boxes and the dose recording cards. 
▪ 
Adverse events will be recorded and entered in the medical history and in the CRF. 
▪ 
The patient will be scheduled for the next study visit. 
 
 
12.3.6 Visit 11 (week 24) or end - of - study visit 
 
This visit will be scheduled four weeks after the previous visit with a window of ± 1 week from the 
respective date. 
The following tasks will be carried out in the consultation during this visit: 
 
▪ 
Blood pregnancy test (only in women of childbearing potential) 
 
 
▪ 
Samples for full local laboratory test, consisting of: 
▪ 
Complete hemogram with reticulocyte and platelet count. 
▪ 
Hepatogram, 
▪ 
Glycemia, lipid profile (HDL, LDL and triglycerides) 
▪ 
Ionogram, calcium, phosphorus, urea and creatinine, 
▪ 
Serum iron, transferrin, transferrin saturation, and ferritin 
▪ 
Serum sample for antibodies and hepcidin dosage (the sample will be collected and 
stored for further analysis) 
▪ 
Pulse, will be measured after the patient has been at rest during 5 minutes. 
▪ 
Blood pressure: 3 measurements separated by 5 minutes each will be taken, for which 
the patient should be at rest and sitting. The first measurement will be discarded and the 
values obtained at the second and third measurements will be averaged, a mean value 
that will be recorded in the medical history and in the case report form (CRF). 
▪ 
The prescribed doses of HEMAX PFS or EPREX/ ERYPO® will be recorded, 
controlling the returned empty boxes and the dose recording cards. 
▪ 
Medication accounting will be performed 
▪ 
Adverse events will be recorded and entered in the medical history and in the CRF. 
 
 
12.3.7 Unscheduled visit 
 
An unscheduled visit can be made at any time during the study, if the patient requests so or in the event 
that the investigator deems it necessary. The date and the reason for the unscheduled visit will be 

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recorded in the medical history. The following items will be recorded in the CRF: 
▪ 
adverse events,  
▪ 
changes in medication and concomitant medications. 
All the other activities and evaluations are optional according to the investigator's judgment. 
 
 
 
13 INVESTIGATIONAL PRODUCT/ STUDY DRUGS 
 
13.1 METHOD OF PATIENT ALLOCATION TO A TREATMENT GROUP 
 
All patients will be randomized by an electronic randomization system, stratified by sex and in blocks 
by site. 
 
13.2 BLINDING 
This is not applicable as this is an open-label study. 
 
13.3 CODE UNBLINDING DUE TO EMERGENCY  
This is not applicable as this is an open-label study. 
 
13.4 POST STUDY ACCESS  
If at the end of the study, the patient has the indication to continue with the treatment with epoetin and 
his current healthcare provider does not provide it, BIOSIDUS will provide the patient with epoetin 
(Hemax PFS® or Hemax®) free of charge until it becomes available through patient’s healthcare 
provider. 
 
13.5 INVESTIGATIONAL PRODUCT/ STUDY DRUGS DESCRIPTION 
 
HEMAX PFS will be used in prefilled syringe in 1000 IU/ 0,5ml, 2000 IU/0,5ml, 3000 IU/0,3ml and  
4000 UI/0,4ml presentations. 
The sponsor Biosidus Argentina SA, is responsible for the manufacture of HEMAX PFS in accordance 
with the Good Manufacturing Practice (GMP) guidelines. 
The solution for injection should be kept in the refrigerator, at a temperature between 2°C and 8°C. 
EPREX/ ERYPO® injectable in prefilled syringe in 1000 IU/0,5ml, 2000 IU/0,5ml, 3000 IU/0,3ml and 
4000 IU/0,4ml.presentations will be used as reference. 
The manufacturer Janssen Cilag, Germany, is responsible for the 
 manufacture of Eprex/ ERYPO® 
in accordance with the Good Manufacturing Practice (GMP) guidelines. 
The solution for injection should be kept in the refrigerator, at a temperature between 2°C and 8°C. The 
study drugs will be dispensed according to the following diagram: 

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Medication 
Presentation to be 
dispensed 
Titration phase 
(week 0 to week 
12) 
Maintenance 
phase (week 12 to 
week 24) 
HEMAX® 
Injectable, 2000 
IU/ 0.5ml and 4000 
IU/ 0.4 ml in a 
sufficient 
amount 
depending on the 
dose 
to 
be 
administered. 
The initial dose 
will be 29IU/ kg 
estimated for an 
average weight of 
70 
Kg, 
what 
equals to 2000IU 
twice a week.  
 
 
 
 
 
 
 
Dose 
adjustments 
will be in aliquots 
of 25% of the dose 
that the patient was 
receiving  
 
It is estimated that 
the mean weekly 
dose will be 5000 
IU ± 2500 IU/ ml. 
 
 
Given that visits are 
every 2 weeks and 
that in each visit the 
medication will be 
administered at the 
site, 
only 
the 
necessary 
amount 
for the biweekly 
dose (3 doses) will 
be dispensed which 
will 
not 
be 
administered at the 
site. 
The weekly dose 
will be estimated 
based on the total 
dose that the patient 
was receiving until 
week 12. That is to 
say, a patient that 
was 
receiving 
2000IU/ 0.05 ml 
twice a week will 
start 
to 
receive 
4000IU/ 0.4ml on a 
weekly basis 
 
Dose 
adjustments 
will be in aliquots 
of 25% of the dose 
that the patient was 
receiving  
 
It is estimated that 
the mean weekly 
dose will be similar 
to the weekly dose 
administered twice 
a week. 
 
Given that visits are 
every 4 weeks and 
that in each visit the 
medication will be 
administered at the 
site, 
only 
the 
necessary 
amount 
for the weekly dose 
(3 doses) will be 
dispensed 
which 
will 
not 
be 
administered at the 

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site. 
 
 
The drug supplies should be stored in a safe place, in a refrigerator with limited access and in 
appropriate conditions, with temperatures between 2º C and 8º C. Only authorized staff will have access 
to the study drug at study sites. 
Patients will also be administered supplements of: 
•Ferrous sulphate, tablets of 200 mg that will be presented in the packaging with the 
approved package insert for use in our country and which will be administered 
according to the criterion of the investigator in order to maintain the transferrin 
saturation above 20% during the study. 
 
 
13.6 ACCOUNTABILITY AND COMPLIANCE 
The patient will return all the study drugs both used and not used. The site staff will only 
record in the source document and in patient’s individual accountability record the patient 
number and the number of study drug packages returned. 
During the study, the monitor will continuously review all the study drugs (bottles used 
and unused) and the corresponding accountability forms. Also the card where the patient 
will record the administered medication doses will be reviewed at each visit. The 
accountability records of the study drugs will be filed at all times at the sites. At the end of 
the study, a final accountability will be performed and all the remaining drugs will be 
removed for destruction according to the current regulations. 
 
14 EVALUATION METHODS 
 
14.1 METHODS OF EFFICACY EVALUATION 
 
The following parameters will be evaluated for treatment efficacy, according to the objectives defined 
by the protocol at each visit: 
• Levels of hemoglobin and its variation at each visit, with intragroup and intergroup 
comparison 
• Percentage of responder patients, defined as the increase of Hb ≥1g/ dl without 
transfusion requirement. 
• Number and percentage of patients that require at least one transfusion. 
 

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14.2 SAFETY PARAMETERS 
 
14.2.1 Adverse events 
Adverse events will be recorded from the moment in which the patient signs the informed consent and 
will be recorded throughout the study. These should be reviewed and updated at each subsequent visit 
and during any telephone contact with the patient. 
 
14.2.2 Vital signs 
Pulse and blood pressure measurements will be made at each visit. 
 
 
14.2.3 Medical history 
At baseline visit (week - 1), a medical history will be made and all clinically relevant data will be 
recorded in the source documents of the patient and in the individual case record form (ICRF). The 
medical history will include the registration of the concomitant medication which will be recorded in 
the source documents of the patient and in the individual case record form (ICRF), which will be 
updated as changes occur at each visit. 
 
14.2.4 Physical exam 
At baseline visit (week - 1), a physical examination will be performed and all clinically relevant data 
will be recorded in the source documents of the patient and in the individual case record form (ICRF). 
 
14.2.5 Physical Examination  
A brief physical examination will be performed at the baseline visit (week -1) and all clinically relevant 
data should be recorded in the patient's source documents and on the individual case record form 
(ICRF). 
 
14.2.6 Electrocardiogram 
At baseline visit (week - 1) an electrocardiogram will be performed and all clinically relevant data will 
be recorded in the source documents of the patient and in the individual case record form (ICRF). 
 
14.2.7 Full laboratory tests 
A full laboratory test will be performed at the baseline visit (week - 1) and at the  
week 12 and week 24 visits or at study completion visit and all clinically relevant data will be recorded 
in the source documents of the patient and in the individual case record form (ICRF). Samples for full 
local laboratory test will consist of: 
▪ 
Complete hemogram with reticulocyte (through flow cytometry or hematologic 
counter) and platelet count. 
▪ 
Hepatogram, 
▪ 
Glycemia, lipid profile (HDL, LDL and triglycerides) 

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▪ 
Ionogram, calcium, phosphorus, urea and creatinine, 
▪ 
Serum iron, transferrin, transferrin saturation, and ferritin 
▪ 
Beta subunit of chorionic gonadotropin only in women of childbearing potential 
▪ 
Serum/ plasma sample for antibodies and hepcidin dosage (the sample will be 
collected and stored frozen at - 20º C for further analysis) 
 
 
14.2.8 Complete hemogram 
A complete hemogram will be performed at week 4, 6, 8, 10, 16 and 20 visits and all clinically relevant 
data will be recorded in the source documents of the patient and in the individual case record form 
(ICRF). The result of the local hemoglobin test must be within the same day or before so as to be able 
to adjust the study medication dose, if required. 
 
14.2.9 Blood pregnancy test 
 
A blood pregnancy test will be performed only in women of childbearing potential at week -1, 2, 4, 6, 
8, 10, 12, 16, 20 and 24 visits. All clinically relevant data will be recorded in the patient's source 
documents and in the individual case record form (ICRF). 
 
 
15 SAFETY AND ADVERSE EVENTS   
Adverse events 
An adverse event (EA) is defined as any undesirable medical condition, in a patient in a clinical trial 
to whom a medical product was administered, without necessarily having to present any causal 
relationship with the treatment. 
In the study, any event that occurs once the patient included in the clinical trial has signed the study 
informed consent and has received at least one dose of the study medication should be recorded and 
reported as an AE. 
An adverse event can therefore be any unfavorable and unintended sign (including abnormal laboratory 
findings), symptom, or disease temporally associated with the use of a medicinal product under 
investigation, whether or not considered related to that medical product. 
For adverse events with a causal relationship to the investigational product, the investigator will be 
required to follow up until the event or its sequelae resolve or stabilize to a level acceptable to the 
investigator. 
A new problem or the worsening of a preexisting one will be considered as an AE. A stable chronic 
problem, such as arthritis that exists before the start of the study and that does not worsen during the 
same will not be considered an AE. 
An abnormal result from a diagnostic procedure, including abnormal laboratory findings, will be 
considered as an AE when: 
▪ It results in the withdrawal of the patient by the investigator 
▪ It is associated with a serious adverse event (SAE) 

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▪ It is associated with clinical signs or symptoms 
▪ The physician considers it clinically relevant 
 
 
The investigator will establish, according to his own criterion, if the AEs do or do not have a causal 
relationship with the study drug, in accordance with the following assessment of causality of adverse 
reactions possibly related to the study drug. 
 
The following 4 - point scale will be used to establish the causality relationship: 
• Unrelated: Events that do not follow a reasonable temporal sequence from the 
administration of the study drug or that can be reasonably explained by the base 
disease, complications, concomitant medication or treatment or environmental 
factors. 
• Possible: Event that follows a reasonable temporal sequence from the 
administration of the study drug (including study medication suspension or dose 
reduction) with reasonable possibility that the adverse event has been caused by the 
study medication but also may have been caused by the base disease, complications, 
concomitant medication or treatment or environmental factors. 
• Probable: Event that presents a clear temporal relationship, with improvement upon 
study medication suspension or dose reduction and when the causality due to other 
factors such as the base disease, complications, concomitant medication or treatment 
or environmental factors can be reasonably excluded. 
• Defined: Event with clear temporal relationship, with improvement upon study 
medication suspension or dose reduction and recurrence upon treatment reinitiation. 
 
Depending on its intensity or degree of severity, the AEs are classified as follows: 
• Mild: It does not significantly interfere with the daily activities of the subject, 
disappears without leaving any residual effect. 
• Moderate: It significantly interferes with the study and/ or with the daily activities 
of the subject, and may or may not require treatment. 
• Severe: It significantly interferes with the study and/ or with the daily activities of 
the subject, it requires treatment or suspension of the study medication and is 
considered as unacceptable at the physician or the patient’s criterion and may 
require withdrawal from the study. 
 
 
A serious adverse event (SAE) is defined as an AE that results in any of the following results: 
• Death; 
• Life threat; 
• Requires or prolongs hospitalization; 

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• Causes persistent or significant inability / disability; 
• It is a congenital anomaly or birth defect; 
• It is a major medical event that requires a medical intervention to prevent the results 
mentioned in the previous points. 
 
 
Important medical events are those that may not be immediately life threatening but that may 
endanger the patient and require an intervention to prevent one of the other serious results listed above. 
Examples would be an intensive treatment in the emergency room or at home due to an allergic 
bronchospasm, blood dyscrasia or seizures that do not result in hospitalization but that, if not treated, 
would have threatened the life or resulted in death; an adverse event of this type, resolved, will be 
considered as serious according to this criterion. 
 
The hospital admission or the prolongation of an existing hospitalization means that the patient's 
admission to the hospital for more than 24 hours and/ or the prolongation of the hospitalization was 
necessary for the treatment of an AE or that it occurred as a result of the event. It does not refer to a 
preplanned elective hospital admission for the treatment of a preexisting disorder that has not 
significantly worsened, nor to diagnostic procedures. 
The term "life - threatening" in the definition of "serious" refers to an event in which the patient ran 
a risk of death at the time of the event; it does not refer to an event which hypothetically could have 
caused the death had it been more severe. 
Any new SAE that occurs after the study period and is considered related (reasonable possibility) with 
the study drug or with the participation in the study, must be registered and reported immediately. The 
study period for SAE reporting is defined as the period from the time of the signing of an informed 
consent until the end of the follow - up period (30 days after the last dose). 
 
 
SAE reporting: To comply with the regulatory requirements, any serious adverse event, considered 
related or not with the study drug, should be brought to the attention of the sponsor or designee as soon 
as the investigator or the coordinator becomes aware of the same. The SAE form must be completed 
and sent without delay, even if not all information was available at the time of the initial contact. 
The SAE must be reported to the sponsor or designee within 24 hours after becoming aware of the 
event. 
The SAEs occurred in Argentina will be sent directly or through the person responsible for monitoring 
the clinical study to: 
 
 
Biosidus, Departamento de Investigación Clinica  
Constitucion 4234 
(1254) Buenos Aires 
Phone: 54 - 11 - 4909 - 8049 / 8000 
FAX 54 - 11 - 4924 - 3601 
 

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Any relevant additional follow - up information on a SAE that was not possible to provide in the initial 
report will be sent by the site within 24 hours from the moment on which the new information is 
obtained. 
The Unidad de Seguridad de Medicamentos of Biosidus S.A. will make a pharmacovigilance report 
for those cases that require so, in order to notify to the appropriate authorities, in accordance with the 
current regulations. 
 
 
Pregnancy reports: Pregnancy reports should be sent to the Unidad de Seguridad de Medicamentos 
of Biosidus S.A. so as to be included in the safety database. This also includes the normal pregnancies 
without AEs. 
A pregnancy follow - up must be made in order to determine pregnancy results, including spontaneous 
or voluntary interruption, the birth details, the presence or absence of any birth defect, congenital 
anomalies or complications in the mother or in the newborn. The pregnancy follow - up report should 
be registered in the specific ICRF, provided by the sponsor. 
The procedure for pregnancy reporting must be the same as the procedure for SAE reporting. 
 
 
16 STATISTICAL METHODOLOGY  
 
16.1 SAMPLE SIZE JUSTIFICATION 
 
A total N of 120 patients (60 in each group) will allow, with 80% of power, to rule out a difference 
between treatment groups greater than 1g/ dl in hemoglobin increase from baseline value to the mean 
value of the visits between week 8 and 12. 
 
16.2 RANDOMIZATION 
All patients will be randomized by an electronic randomization system, stratified by sex and in blocks 
by site. 
 
 
16.3 PATIENT DATA ANALYSIS GROUPS 
  
The data analysis groups or populations are listed below. 
 
16.3.1 Full Analysis Set (FAS) 
The full data analysis group will consist of all patients enrolled in this study that have been randomized 
and who have received at least one dose of the study medication. 
 
16.3.2 Per Protocol (PP) analysis group  
The per protocol data analysis group will consist of all patients enrolled in this study who have received 
at least one dose of the study medication, who have completed at least one follow - up visit and that do 
not have major protocol violations. 
 
 

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16.4 DATABASE ANALYSIS  
  
 
There will be two formal database analyses. 
• A first analysis will be performed after the last study patient completes the week 
12 visit and the database is clean. This analysis will produce all the efficacy and 
safety results at week 12. 
 
 
• A second analysis will be performed after the last study patient completes the 
week 24 visit and the database is clean. This analysis will produce all the safety 
results, including immunogenicity, at week 24. 
 
 
16.5 EFFICACY ANALYSIS 
 
The efficacy analysis will be performed for both FAS and PP populations. Descriptive statistics and 
inferential statistics will be performed through intergroup analysis (ANCOVA covariance analysis)- 
comparing each treatment group (patients treated with HEMAX PFS versus those treated with EPREX/ 
ERYPO®) and an additional intragroup analysis analyzing the variations in hemoglobin (increase from 
baseline to the average of the visits between weeks 8 and 12) adjusted for the baseline value, using a 
significance level of 5%. Statistical analysis will be performed with SPSS software or equivalent. 
 
 
The following parameters will be evaluated for treatment efficacy, according to the objectives defined 
by the protocol. 
 
 
The primary efficacy assessment will be carried out through the levels of hemoglobin increase from 
baseline value to the mean value of the visits between week 8 and 12, comparing patients treated with 
HEMAX PFS versus those treated with EPREX/ ERYPO®. 
 
 
Additionally, treatment equivalence will be established if the difference between the two groups 
excludes a difference between treatment groups greater than 1g/ dl in hemoglobin increase from 
baseline value to the mean value of the visits between week 8 and 12 with a difference in the mean 
dose of epoetin alfa in these visits no greater than 20%. 
 
 
The secondary efficacy assessment will be carried out through the evaluation of the following 
objectives: 
• Percentage of responder patients (increase of Hb ≥ 1g/ dl) after 12 weeks of 
treatment, comparing patients treated with HEMAX PFS versus those treated with 
EPREX/ ERYPO®. 
 
 

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• Percentage of transfusion requirement after 12 weeks of treatment, comparing 
patients treated with HEMAX PFS versus those treated with EPREX/ ERYPO®. 
 
 
• Intragroup efficacy (HEMAX PFS and EPREX/ ERYPO®) of treatment with 
Epoetin Alfa through increased levels of hemoglobin from baseline in each one of 
the intermediate visits until the week 12 visit. 
 
 
• Evaluate the intragroup efficacy (HEMAX PFS and EPREX/ ERYPO®) of the 
change from the twice - a - week dosing during the titration phase to a weekly dosing 
during the maintenance phase through the variation of the hemoglobin levels from 
week 12 to the weeks 16, 20 and 24. 
 
 
For missing hemoglobin data, the last observation carried forward method will be used. 
 
 
In an exploratory way, the basal level of hepcidin at 12 and 24 weeks will be evaluated in relation to 
the response to treatment in order to observe the relationship between the basal levels of hepcidin with 
the fall in filtrate and the hemoglobin level. We will also observe the response of hepcidin levels to 
treatment with erythropoietin and finally we will see if there is any type of association between hepcidin 
levels and the subgroup of patients who do not respond to erythropoietin. 
 
16.6 SAFETY ANALYSIS 
 
The evaluation of safety shall be carried out using the entire population (FAS) of data, making focus 
on adverse events (AE). 
As primary safety objective, the incidence of adverse events and adverse reactions will be evaluated 
after 12 and 24 weeks of treatment, comparing patients treated with HEMAX PFS versus those treated 
with EPREX/ ERYPO®. 
An AE shall be considered as treatment - emergent adverse event (TEAE), if it presents after the first 
dose administered of the investigational product or if, preexistent prior to the administration of the first 
dose, it worsens after the administration of the same. 
All TEAEs will be presented summarized through the use of Tables, for each organ class and preferred 
term to denominate them. The Tables will present the number of patients for which events occurred, 
and the incidence rate, expressed as a percentage calculated on the number of patients from the entire 
population included in the safety FAS. 
The TEAEs will be presented by causality (relationship with the study drug), intensity (mild, moderate, 
severe). Treatment - emergent events that are serious and that lead to treatment discontinuation will 
also be summarized using the preferred term and the class organ system involved. 
In addition, and with focus on safety, the following will be discussed: 
• Incidence 
of 
thromboembolic 
events 
(myocardial 
infarction, 
cerebrovascular accident, deep vein thrombosis and other thromboembolic 
events). 

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• Incidence of hypertension as TEAE. 
• Blood pressure values at each visit. 
• Complete baseline laboratory data and at week 12 and 24 visits, 
• Antibody dosages, baseline and at weeks 12 and 24. 
 
For safety analysis, descriptive statistics will be performed mainly to evaluate the incidence of adverse 
events and adverse reactions after 12 and 24 weeks of treatment and x2 test will be performed to 
compare the incidence of adverse events and adverse reactions of patients treated with HEMAX® PFS 
versus those treated with EPREX/ERYPO®. 
 
17 ETHICAL AND REGULATORY CONSIDERATIONS 
 
17.1 COMPLIANCE WITH THE REGULATIONS APPLICABLE TO CLINICAL TRIALS 
 
The study will be carried out in accordance with the laws, regulations and administrative requirements 
related to the implementation of Good Clinical Practice in the conduct of clinical trials with 
medications for human use, as determined by the current national/ local regulations, applicable 
ANMAT dispositions, the current version of the Declaration of Helsinki and the ICH guidelines. 
 
17.2 INFORMED CONSENT 
 
The principles of informed consent will be followed, in accordance with the national/ local current 
regulations, the current version of the Declaration of Helsinki and the ICH guidelines. A patient should 
not enter into the clinical trial or perform any study - related procedure until he/ she has been duly 
informed, has been given time to consider his/ her participation and has given his/ her consent freely 
by signing and dating the informed consent approved by the Institutional Ethics Committee of Clinical 
Research (IECR). This must occur before any study - related procedure is performed. 
The proposed consent form and any of the other documents relevant to the consent process, must be 
submitted to the IECR together with the protocol and must be approved prior to study initiation. 
A signed and dated copy of the informed consent form and any other document in relation to the consent 
process will be given to the patient; the original document will be kept at the site.  
The Informed Consent details some aspects of special interest that are listed below: 
 
POTENTIAL EXPECTED BENEFITS.  
You may not get any benefit from participating in this study, the potential benefits are in 
the future for patients with the same disease. However, it is expected that you will obtain 
the same effect with HEMAX PFS® as the one described with the previous formulation 
HEMAX® and EPREX/ERYPO®, which is the increase in red blood cell levels in patients 
with chronic kidney disease and anemia.  
 
COSTS 

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For the patient 
This study is being funded by Biosidus S.A. who has established a contract with your 
doctor/center for all costs and professional fees associated with your participation in this 
study. Your participation in this study will not result in any costs to you or your medical 
coverage.   Biosidus S.A. will provide you with study medication (including oral iron 
supplements if indicated) at no charge. Medical visits, physical examinations, procedures, 
treatments (including contraceptive methods required by the study) or tests that are not 
included in your usual medical care, and that are required only for the purposes of this 
study, will be provided at no charge to you or your health care system. In addition, if after 
the study, you have indication to continue with epoetin treatment and your current health 
system does not provide it, Biosidus S.A. will provide you with epoetin (Hemax PFS® if 
approved by ANMAT or Hemax® which is the formulation currently marketed) free of 
charge until it is available through your health system.   
 
Payment for participation in the study 
You will not receive any payment for your participation in this study. However, you will 
be reimbursed for travel expenses related to study visits upon signature of the 
acknowledgement of receipt and/or presentation of the original receipts for expenses 
incurred for this study.  
 
COVERAGE IN CASE OF DAMAGE WHAT HAPPENS IF YOU SUFFER AN 
ADVERSE EVENT AND/OR REACTION OR DAMAGE TO YOUR HEALTH? 
If during the study you suffer an adverse event or a consequence to your health related to 
the medication or procedures of the study, Biosidus S.A. will provide you with all the 
immediate and necessary medical assistance for your treatment. The costs of such 
assistance will be borne by the sponsor. Likewise, Biosidus S.A. will be responsible for 
any damage to your health resulting from your participation in the study. Biosidus S.A. 
has taken out an insurance policy (policy #44927) with the firm CHUBB ARGENTINA 
DE SEGUROS S.A. with address at Hipólito Bouchard 710, 11th and 12th floors, Ciudad 
Autónoma de Buenos Aires, telephone 54-11-4510-1500, in case of any damage to your 
person. By signing the informed consent form, you do not waive your rights under the 
Civil and Commercial Code and Argentine laws regarding civil liability for damages.   
If you agree, your primary care physician will be informed about your participation in this 
study. 
 
 
17.3 INSTITUTIONAL ETHICS COMMITTEE FOR RESEARCH (IECR) / INSTITUTIONAL 
REVIEW BOARD (IRB) 
 
The study must have written approval from the IECR. Before the beginning of the study, the sponsor 
or its designee must receive a copy of the letter of approval from the IECR, which will contain the 
specific identification of the approved documents. 
Any relevant amendments to the protocol or subsequent changes in the informed consent form as a 

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result of the changes in the protocol and/ or Investigator’s Brochure approved by the sponsor must also 
be approved by the IECR and the documentation of this approval will be provided to the sponsor. The 
records of the IECR review and the approval of all the documents relevant to this study will be kept in 
the file of the investigator and will be subject to an audit by the sponsor and/ or the regulatory authority 
during or after study completion. All study documents should be kept for a period of ten years or more 
according to the current regulations. 
In addition, the investigator or sponsor will communicate to the IECR any serious adverse event (SAE) 
or other according to its regulations. 
As needed, periodic reports of the trial progress as well as the notification of study end and a final 
report, where applicable, will be submitted to the IECR. A copy of all reports submitted to the IECR 
will also be sent to the sponsor. 
 
 
17.4 PROTOCOL AMENDMENTS 
 
Protocol changes should only be performed by an approved amendment to the protocol. Protocol 
amendments must be approved by the sponsor, the IECR of reference and the IECR of each site (if 
applicable), prior to their implementation. 
 
17.5 CLINICAL STUDY COMPLETION STATEMENT 
  
 
For all the sites participating in the trial, there will be an end of clinical trial notification to the IECR. 
 
17.6 PATIENT CONFIDENTIALITY 
  
 
All patient data are identified only by a patient identification number and the existing laws on personal 
data protection will be respected. 
After obtaining the consent from the patient, the investigator will enable the study monitor, the 
independent auditor or the regulatory agency staff to review the part of the medical history of the patient 
that is directly related to the study. This will cover all relevant study documentation, including the 
medical history of the patient, to verify eligibility, summaries of hospitalization/ discharge from any 
hospitalization that could occur during patient’s participation in the study and the reports of autopsies 
of deaths occurring during the study (if applicable). 
 
17.7 RESPONSIBILITY AND SAFETY 
 
Biosidus Argentina SA will provide a Certificate of Insurance Policy of Clinical Trial to the study sites 
with the corresponding coverage according to the local current regulations. 
 
18 DOCUMENTATION  
 

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18.1 STUDY ARCHIVE AND SITE DOCUMENTATION  
Before the start of the study, the following documents must be received by the sponsor 
from the site: 
1)   Confidentiality Agreement. 
2) Signed protocol pages, amendments and notifications. 
3) Curriculum Vitae of the principal investigator and medical license. 
4) Investigator’s statement. 
 
5) Clinical Trial Agreement signed. 
6) Written approval of the IECR for the protocol, amendment(s), informed consent form, 
patient information sheet (if applicable) and advertising (if applicable). 
7) List of the IECR members. Committee SOPs. 
8) Other forms that are applicable according to the local current regulations. 
 
18.2 STUDY DOCUMENTATION PROVIDED BY THE SPONSOR 
  
The sponsor will provide the investigator with the following documents: 
▪ Protocol final version. 
▪ Informed consent (final version). 
▪ Current version of HEMAX PFS package insert project and EPREX/ ERYPO® package 
insert, which will constitute the product information. 
▪ A printed copy of the ICRF. 
▪ Regulatory document files. 
▪ Certificate of insurance and/ or insurance policy. 
 
 
18.3 DATA MAINTENANCE AND RETENTION   
It is the responsibility of the site investigator to maintain, in an exhaustive and centralized manner, a 
system for collecting all the relevant information. 
Investigators will be informed that they should keep all study records in a safe place and with limited 
access during a period of ten years or more according to the applicable current regulations. 
Investigators will be informed that before eliminating any study data/ document, they have 
to consult it with the Sponsor, as well as to notify in writing any change in location, 
availability or custody of the study files. 
 
 
18.4 DATA MANAGEMENT 
 

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18.4.1 Data capture through Individual Clinical Record Form (ICRF) 
 
18.4.1.1 Data capture 
 
The sponsor will provide each study site with a printed copy of the reference template for data capture 
(ICRF) in carbonless paper or digital form, sending a copy to the site and another to the sponsor. 
Data entry at the site will be made by the investigator, study coordinator or other study staff properly 
trained and designated. 
The ICRFs are used to keep the study data and are an integral part of the study and subsequent reports. 
Therefore, the ICRFs must be completed for each patient recruited in accordance with the source data 
of the patient at every visit. 
Patients should not be identified by the name. An appropriate coded identification will be used so that 
they cannot be identified (if applicable). The site investigator should maintain a separate form with the 
names of the patients, the non - identifying initials (if applicable) and the addresses of the patients (a 
patient identification form). 
Each completed ICRF must be verified by the site investigator at each visit and should be contrasted 
with the source documents of the patient by the clinical trial monitor. Each entry must be monitored by 
the monitor and by the staff from the Procesamiento de Datos department (DM). 
 
 
18.4.1.2 Discrepancy Management 
 
The internal consistency and the integrity of the data entered in the study database are defined by a 
series of validations. A deviation from these predefined and automated validations, may create an 
inconsistency in the database that can be resolved by using a data correction form. 
There are 2 main types of discrepancies: 
• 
Automatic discrepancies automatically generated during data entry or following data 
logical execution. 
• 
Manual discrepancies, that can be generated by a system user at any time. 
It will be the responsibility of the investigator and his team to resolve any data discrepancy in due time 
and manner. The study monitors will perform the follow - up to confirm that these discrepancies are 
resolved. 

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18.5 ADDITIONAL DOCUMENTS AND RECORDS 
  
1) Patient selection and allocation form: A list of all patients who have signed the informed 
consent and that have been selected. 
2) Patient identification form: Allows the investigator to associate the selected patient with the 
study. This information will include, but will not be limited to only: patient name, date of 
birth, contact information and non - identifying patient initials (if applicable). This 
confidential list must be kept at the research site and will not be sent to the sponsor. 
3) Drug accountability form: This form reflects the total amount of study drug that has been 
dispensed and returned by each patient in the relevant study visits. 
 
19 QUALITY ASSURANCE AUDITS 
 
19.1 QUALITY ASSURANCE PROGRAM   
This clinical trial can be audited in accordance with the Quality Assurance (QA) Program 
of the sponsor. 
The purpose of these audits is to determine if this study is being conducted or monitored in 
accordance with both the Protocol, and with the GCP guidelines and local regulations. 
These audits will also increase the credibility of the study data, so that any type of study 
documentation may be required by any regulatory authority for inspection. These audits, if 
performed, will be scheduled with the site and will be carried out in a reasonable period of 
time. 
 
19.2 REGULATORY INSPECTIONS AND AUDITS 
 
The study may be inspected by regulatory agencies and audited by ethics committees. These 
inspections/ audits will take place at any time during or after the study and will be performed 
in accordance with the national regulations as well as the ICH guidelines. 
 
20 STUDY MONITORING 
 
20.1 MONITORS AND MONITORING VISITS  
 
 
The study monitor will be responsible for ensuring compliance with the current Good Clinical Practice 
guidelines, the ICH guidelines and the standard operating procedures of the sponsor or designee. The 
study monitors will be designated by the sponsor. The monitors will observe the current Good Clinical 
Practice guidelines, the ICH guidelines and the standard operating procedures of the sponsor or designee. 

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Regular monitoring of the study data in accordance with the specific study monitoring plan will be 
conducted. Individual sites will be monitored to check the pace of recruitment, data and protocol 
compliance. The frequency of monitoring of individual sites may depend on the pace of recruitment, the 
quantity of data collected and the complexity of the study, variables that will be documented in the 
monitoring plan. 
These monitoring visits will be carried out with the purpose of verifying the protocol compliance as well 
as the accuracy of the data and that these are collected in the ICRF. The study monitor will verify the 
entries in the ICRF comparing them with the main source of information (hospital/ clinic/ official 
records), which must be available for this purpose. The monitor will review the maintenance of official 
documentation and the study medication accountability. The monitor will periodically review study 
progress along with the site investigator and the other people participating in the study. At study end, 
there will be a monitoring closure visit. Monitoring visits will be scheduled in advance with the site staff 
by mutual agreement and at an acceptable time for both. The site staff should provide sufficient time to 
the monitor for the review of the ICRFs as well as of the source documents. The coordinator and/ or 
investigator will answer any question or provide any clarification in relation to the data. The site 
investigator must provide a place and a time suitable for those visits to be performed. 
 
20.2 MAIN SOURCE DOCUMENTS 
 
The investigator should retain the primary documentation sources for data entry in the ICRF. These 
documents, considered as "source documents", should include, but will not be limited to: 
▪ Anthropometric and demographic information. 
▪ Evidence that supports the diagnosis/ condition for which the patient is being studied. 
▪ General information to support patient participation in the study. 
▪ Medical information and physical examination findings. 
▪ Records of hospitalizations or emergency visits (if applicable). 
▪ Each study visit must be dated including any relevant finding/ note found by the 
investigator; occurrence (or absence) of adverse events, as well as changes in the use of 
the medication, including the start and end date of drug administration. 
▪ Any additional visit during the study. 
▪ Any relevant telephone conversation with the patient related to the study or to a possible 
adverse event. 
 
▪ The original informed consent form signed for study participation. 
The investigator must also keep all those printed documents/ test/ procedure reports performed that are 
requested in this study. During the monitoring visits, the monitor will need to verify the ICRF data, 
comparing them with the source information. 
 
21 USE OF INFORMATION AND DATA PUBLICATION 
  
All information provided by the sponsor in connection with this study, which has not been previously 

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published, is considered confidential information. This information includes, but is not limited to, the 
Investigator’s Brochure (if applicable), clinical protocol, data capture notebooks and other scientific 
data. Any data collected during the study are also considered confidential. This confidential information 
will remain the exclusive property of the sponsor, it will not be disclosed to third parties without the 
written consent of the sponsor, and it will not be used for other purposes than study conduct. 
The information developed during the conduct of this clinical study is also considered confidential and 
will be used by the sponsor in connection with the development of the drug. The information must be 
disclosed as considered by the sponsor. To allow the use of information derived from this clinical trial, 
the investigator is obliged to provide the sponsor with the complete results and all data developed in this 
study. The information obtained during this study may be available for other investigators who are 
conducting similar studies. 
If the investigator wishes to publish the data from this study, he must deliver a manuscript to the sponsor 
for review 60 (sixty) days before its publication. In the event that the sponsor chooses to publish this 
study data, it will deliver a copy to the investigator at least 30 days before the presumed date of delivery 
to the defined editor. Any publication resulting from this research should include the investigators who 
participated on behalf of the sites and Biosidus, according to the usual criteria of authorship of scientific 
publications set forth in the Uniform Requirements for Manuscripts submitted to biomedical journals: 
Writing and editing for biomedical publication, from the International Committee of Medical Journal 
Editors. 
The sponsor maintains the right to eliminate the confidential information from the manuscript and may 
make any objection to or suggestion regarding its publication and/ or the time of the publication (at the 
sponsor’s full discretion). 
 
 
22 SITE STAFF 
 
22.1 RESEARCH SITE 
The staff from each research site will consist at least of a Principal Investigator and a clinical study 
coordinator or sub-investigator. 
 
22.2 PRINCIPAL INVESTIGATOR 
At each research site, a physician will be designated to act as Principal Investigator and will bear overall 
responsibility for the management of the team of the site where the study will be conducted and for the 
study aspects at the appropriate site. The Principal Investigator will supervise the recruitment of patients, 
the correct conduct of the trial in accordance with the protocol and the requested data capture. 
 
22.3 STUDY COORDINATOR OR SUBINVESTIGATOR  
The study coordinator or sub-investigator will be appointed by the Principal Investigator and will be 
responsible for assisting the principal investigator in all those tasks that have been delegated to him. 
 
23 SPONSOR 
 
 

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23.1 BIOSTATISTICS, DATABASE AND PROGRAMMING 
  
The departments of Biostatistics, Database and Programming are responsible for the proper use of the 
data management application, of the completion of the common data management procedures and 
statistical analysis, as detailed in this Protocol. All procedures will be carried out in accordance with the 
local and ICH guidelines. 
Based on the sponsor criterion, the biostatistics, database and programming tasks can be performed by 
a CRO. 
 
23.2 CLINICAL MANAGEMENT 
The local Gerenciamiento Clinico department (project leader or manager) is responsible for the daily 
activities of the local study and for ensuring that the sites and the Sponsor comply with all applicable 
regulations related to the clinical research. 
Based on the sponsor criterion, this task can be performed by a CRO. 
 
 
23.3 MONITOR 
The monitor is responsible for monitoring the study in the participating sites. Monitoring visits will be 
agreed in advance and by mutual agreement at a time acceptable to both the monitor and the site staff. 
Based on the sponsor criterion, this task can be performed by a CRO. 
 
 
23.4 MEDICAL MONITOR 
The Medical Monitor will be responsible for the periodic review of the clinical safety data and for the 
resolution of study - related medical issues. 
 
 
 
 
 

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25 INVESTIGATOR’S AGREEMENT 
 
 
BIOSIDUS ARGENTINA SA 
Protocol Nº BIOS - HPFS - 0115 
I have carefully read beforehand the protocol, including all appendices and I agree that it 
contains all the information necessary for this study to be conducted safely. 
I agree to conduct this study as indicated in the Protocol and in accordance with the 
Declaration of Helsinki (including its updates) and the current Good Clinical Practice 
Guidelines in force and applicable in each territory where the Clinical Study will be 
conducted, and I will try to complete the study within the defined deadline. 
I agree to provide copies of the Protocol and any other information related to the preclinical 
and clinical trial experience to all team members that participate in the study. I agree to 
discuss with them this information and ensure that they are adequately informed in relation 
to the medication and the development of study. 
I agree to keep all data and patient information (data capture notebooks, forms and 
medication dispensing and return forms and all the information generated during this study) 
by complying with the current Good Clinical Practice guidelines and local regulations. 
 
 
 
Signature of the Principal Investigator: 
  
 
 
 
Name of the Principal Investigator: 
  
 
 
 
Date: 
  
 

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