Clinical trial NCT02145026
Conditions: Myelodysplastic Syndromes
Sponsor: Hoffmann-La Roche
Start date: 2014-08-06; Completion date: 2019-04-09
Enrollment: 100 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a Phase IV, prospective, multi-center, open-label study to assess the effectiveness and safety profile of epoetin beta (Recormon®) for treatment of symptomatic anemia in adult participants associated with low/intermediate-1-risk MDS. After screening, eligible participants will be treated with epoetin beta as recommended in the approved label and international guidelines for the use of epoetin in MDS participants and the dosage will be adjusted on the basis of erythroid response.

Detailed description:

Arms: arm 1: Participants will receive epoetin beta at an initial dose of 30,000 International Units (IU) per week administered subcutaneously (SC). Response will be firstly evaluated at Week 4 and the subsequent dose will be based on the response: if hemoglobin level reaches greater than or equal to (\>/=)12 grams per deciliter (g/dL) at any time, epoetin beta will be discontinued until hemoglobin levels are less than or equal to (\</=) 10 g/dL; if the hemoglobin level increases less than (\<) 1 g/dL from screening level and hemoglobin level ˂12 g/dL, a 60,000 IU per week epoetin beta will be administered SC until Week 12; if the hemoglobin level increases \>/=1 g/dL from screening level and hemoglobin level ˂12 g/dL, a 30,000 IU per week epoetin beta will be continued until Week 12.
Interventions: intervention 1: Epoetin beta
Intervention descriptions: intervention 1: Epoetin beta 30,000 or 60,000 IU per week SC injection

Protocol documents:
Prot_000.pdf: 
 
Official Title: 
A PROSPECTIVE OPEN-LABEL STUDY OF THE 
EFFECTIVENESS OF EPOETIN BETA FOR TREATING ANEMIC 
PATIENTS WITH LOW/INTERMEDIATE-1-RISK 
MYELODYSPLASTIC SYNDROME (MDS) 
NCT Number: 
NCT02145026 
Document Date: 
Protocol Version 3: 12-September-2016 
 
 




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PROTOCOL AMENDMENT, VERSION 3.0: 
RATIONALE 
Protocol ML29005 has been amended to extend study duration and to improve 
clarity and consistency on dose adjustment. 
Changes to the protocol, along with a rationale for each change, are summarized 
below: 
 
Protocol synopsis, section the length of study is updated to extend 
recruitment duration to reach original target patients, 120 patients.   
 
Section 4.2.2.1 is updated to clarify criteria for dose adjustment due to 
changes in the level of haemoglobin at week 4 (visit 2)  
 
Section 4.2.4 Post-study access to Recormon® is updated according to 
Roche global post-study access policy  
 
Section 5.4, 5.4.1 and 5.4.2 is updated due to changes in  Medical Monitor 
(Roche Medical Responsible) and local safety responsible person’s contact 
detail  
 
Section 6.2, 6.4 and 6.4.1 is updated in the efficacy analysis population. As 
there is apparently no randomization in the study, the Intent-To-Treat 
population can be applied.  
 
Additional minor changes have been made to improve clarity and consistency.  
Substantive new information appears in italics.  This amendment represents 
cumulative changes to the original protocol. 
 


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PROTOCOL AMENDMENT, VERSION 3.0: 
SUMMARY OF CHANGES 
 
PROTOCOL TITLE PAGE  
VERSION: 23 
FOOTER: 
Recormon—F. Hoffmann-La Roche Ltd 
Protocol ML29005, Version 2.0 dated 28 Nov 2014 Version 3.0 dated 26 July 2016 
 
PROTOCOL SYNOPSIS  
The protocol synopsis has been updated to reflect the changes to the protocol, where 
applicable. 
SECTION 3.1.1: Overview of Study Design 
This is a phase IV, prospective, multi-centre, open label study to assess the efficacy of 
Recormon® for treating anemic patients with low/intermediate-1 risk MDS, in 
approximately 120 adult patients. The primary efficacy endpoint is a proportion of 
patients achieving erythroid response at week 12 according to IWG 2006 definition. The 
trial will be conducted at approximately 78 centres nationwide. 
SECTION 3.3.2: Rational for Patient Population 
Several studies have proven the efficacy of the ESAs in eliciting erythroid response in 
low/int-1 MDS patients. The subset of MDS patients benefiting from ESA therapy is now 
well defined as the low-/int-1-risk group with sEPO of less than 500 mU/ml and a PRBC 
transfusion need of less than two units/month 4 units within 8 weeks prior to screening. 
SECTION 4.2.2.1: Dosage and administration of Recormon®   
Response will be firstly evaluated at 4±1 weeks week 4 (visit 2) 
 
If haemoglobin level reaches ≥ 12 g/dL at any time, Recormon® should be 
discontinued until Hb levels are ≤ 10 g/dL 
 
If the haemoglobin level increases < 1 g/dL from baseline screening level and 
haemoglobin level ˂ 12 g/dL, a 60,000 IU weekly of Recormon® will be 
administered subcutaneously until week 12. 
 
If the haemoglobin level increases ≥ 1 g/dL from baseline screening level and 
haemoglobin level ˂ 12 g/dL, a 30,000 IU weekly of Recormon® will be 
continued until week 12 
SECTION 4.2.4: Post-study Access to Recormon®  
The Sponsor may provide Recormon®  upon physician request to patients who have 
shown a demonstrable benefit from Recormon®  treatment during this study (as showed 
by IWG 2006 response criteria; Hb increase ı 1.5 g/dL from baseline and Hb level at 






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TABLE OF CONTENTS 
PROTOCOL AMENDMENT ACCEPTANCE FORM ............................................ 7 


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PROTOCOL AMENDMENT ACCEPTANCE FORM 
TITLE: 
A PROSPECTIVE OPEN-LABEL STUDY OF THE 
EFFECTIVENESS 
OF 
EPOETIN 
BETA 
FOR 
TREATING 
ANEMIC 
PATIENTS 
WITH 
LOW/INTERMEDIATE-1-RISK MYELODYSPLASTIC 
SYNDROME (MDS) 
PROTOCOL NUMBER: ML29005 
VERSION NUMBER: 
3.0 
EUDRACT NUMBER: 
RO205-3859 
IND NUMBER: 
N/A 
TEST PRODUCT: 
Epoetin beta (RO205-3859) 
MEDICAL MONITOR: 
Dr. 
, MD. 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
I agree to conduct the study in accordance with the current protocol. 
 
 
 
Principal Investigator’s Name  (print) 
 
 
 
 
 
Principal Investigator’s Signature 
 
Date 
Please retain the signed original of this form for your study files.  Please return a copy as 
instructed by your local study monitor 
 
 


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TABLE OF CONTENTS 
1. 
BACKGROUND .......................................................................................... 19 
1.1 
Background on Myelodysplastic Syndromes ......................... 19 
1.2 
Background on Epoetin beta (Recormon® ) .......................... 20 
1.3 
Study Rationale and Benefit–Risk Assessment ..................... 21 
2. 
OBJECTIVES .............................................................................................. 22 
2.1 
Efficacy Objectives ................................................................ 22 
2.2 
Safety Objectives ................................................................... 23 
3. 
STUDY DESIGN ......................................................................................... 23 
3.1 
Description of Study .............................................................. 23 
3.1.1 
Overview of Study Design ..................................................... 23 
3.2 
End of Study .......................................................................... 24 
3.3 
Rationale for Study Design .................................................... 24 
3.3.1 
Rationale for Test Product Dosage ........................................ 24 
3.3.2 
Rationale for Patient Population ............................................ 24 
3.4 
Outcome Measures ............................................................... 24 
3.4.1 
Efficacy Outcome Measures .................................................. 24 
3.4.2 
Safety Outcome Measures .................................................... 25 
4. 
MATERIALS AND METHODS .................................................................... 25 
4.1 
Patients .................................................................................. 25 
4.1.1 
Inclusion Criteria .................................................................... 25 
4.1.2 
Exclusion Criteria ................................................................... 26 
4.2 
Study Treatment .................................................................... 26 
4.2.1 
Formulation, Packaging, and Handling .................................. 26 
4.2.1.1 Recormon® ........................................................................... 26 
4.2.2 
Dosage, Administration and Compliance ............................... 26 
4.2.2.1 Dosage and administration of Recormon® ........................... 26 
4.2.2.2 Assessment of Compliance .................................................. 26 
4.2.3 
Investigational Medicinal Product Accountability ................... 27 
4.2.4 
Post-study Access to Recormon® .......................................... 27 
4.3 
Concomitant Therapy ............................................................ 27 


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4.3.1 
Permitted Therapy ................................................................. 28 
4.3.2 
Prohibited Therapy ................................................................ 28 
4.4 
Study Assessments ............................................................... 28 
4.4.1 
Description of Study Assessments ........................................ 28 
4.4.1.1 Medical History and Demographic Data ............................... 28 
4.4.1.2 Physical Examinations ......................................................... 29 
4.4.1.3 Vital Signs ............................................................................ 29 
4.4.1.4 Laboratory Assessments ...................................................... 29 
4.4.2 
Timing of Study Assessments ............................................... 29 
4.4.2.1 Screening Assessments ....................................................... 29 
4.4.2.2 Assessments during Treatment ............................................ 30 
4.4.2.3 Assessments at End of Study/Early withdrawal visit ............ 31 
4.4.2.4 Assessments at Unplanned Visits ........................................ 31 
4.5 
Patient, Study and Site Discontinuation ................................. 31 
4.5.1 
Patient Discontinuation .......................................................... 31 
4.5.1.1 Discontinuation from Study Drug .......................................... 31 
4.5.1.2 Withdrawal from Study ......................................................... 32 
4.5.2 
Study and Site Discontinuation .............................................. 32 
5. 
ASSESSMENT OF SAFETY ....................................................................... 32 
5.1 
Safety Plan ............................................................................ 32 
5.2 
Safety Parameters and Definitions ........................................ 33 
5.2.1 
Adverse Events ..................................................................... 33 
5.2.2 
Serious Adverse Events (Immediately Reportable to the Sponsor) . 33 
5.3 
Methods and Timing for Capturing and Assessing 
Safety Parameters ................................................................. 34 
5.3.1 
Adverse Event Reporting Period ........................................... 34 
5.3.2 
Assessment of Severity of Adverse Events ........................... 35 
5.3.3 
Assessment of Causality of Adverse Events ......................... 35 
5.3.4 
Procedures for Recording Adverse Events ............................ 35 
5.3.4.1 Diagnosis versus Signs and Symptoms ............................... 36 
5.3.4.2 Adverse Events Occurring Secondary to Other Events ........ 36 
5.3.4.3 Persistent or Recurrent Adverse Events .............................. 36 
5.3.4.4 Abnormal Laboratory Values and Vital Sign Values ............. 36 


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5.3.4.5 Deaths .................................................................................. 36 
5.3.4.6 Preexisting Medical Conditions ............................................ 37 
5.3.4.7 Hospitalization or Prolonged Hospitalization ........................ 37 
5.3.4.8 Overdoses ............................................................................ 37 
5.4 
Immediate Reporting Requirements from Investigator to 
Sponsor ................................................................................. 38 
5.4.1 
Reporting Requirements for Serious Adverse Events ........... 38 
5.4.2 
Reporting Requirements for Pregnancies .............................. 38 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN ....................... 39 
6.1 
Determination of Sample Size ............................................... 39 
6.2 
Analysis Population ............................................................... 39 
6.3 
Interim analysis ...................................................................... 40 
6.4 
Efficacy Analyses .................................................................. 40 
6.4.1 
Primary Efficacy Endpoint ...................................................... 40 
6.4.2 
Secondary Efficacy Endpoints ............................................... 40 
6.5 
Safety Analyses ..................................................................... 40 
7. 
DATA COLLECTION AND MANAGEMENT ............................................... 41 
7.1 
Data Quality Assurance ......................................................... 41 
7.2 
Electronic Case Report Forms ............................................... 41 
7.3 
Source Data Documentation .................................................. 41 
7.4 
Use of Computerized Systems .............................................. 42 
7.5 
Retention of Records ............................................................. 42 
8. 
ETHICAL CONSIDERATIONS .................................................................... 43 
8.1 
Compliance with Laws and Regulations ................................ 43 
8.2 
Informed Consent .................................................................. 43 
8.3 
Institutional Review Board or Ethics Committee .................... 43 
8.4 
Confidentiality ........................................................................ 44 
8.5 
Financial Disclosure .............................................................. 44 
9. 
STUDY DOCUMENTATION, MONITORING, AND ADMINISTRATION ..... 44 
9.1 
Study Documentation ............................................................ 44 
9.2 
Site Inspections ..................................................................... 45 
9.3 
Administrative Structure......................................................... 45 


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9.4 
Publication of Data and Protection of Trade Secrets ............. 45 
9.5 
Protocol Amendments ........................................................... 45 
10. REFERENCES ........................................................................................... 46 
 
 
LIST OF TABLES 
Table 1 
Adverse Event Severity Grading Scale ....................................... 35 
 
 
LIST OF APPENDICES 
Appendix 1 
 Schedule of Assessments ............................................................ 1 
Appendix 2  
 International Prognostic Scoreing System (IPSS)…………………2 
Appendix 3 
 International Working Group (IWG) Response Criteria for MDS…3 
 
   


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PROTOCOL SYNOPSIS 
TITLE: 
A PROSPECTIVE OPEN-LABEL STUDY OF THE 
EFFECTIVENESS OF EPOETIN BETA FOR TREATING ANEMIC 
PATIENTS WITH LOW/INTERMEDIATE-1-RISK 
MYELODYSPLASTIC SYNDROME (MDS) 
PROTOCOL NUMBER: 
ML29005 
VERSION NUMBER: 
3.0 
EUDRACT NUMBER: 
RO205-3859 
IND NUMBER: 
N/A 
TEST PRODUCT: 
Epoetin beta  
PHASE: 
IV 
INDICATION: 
Symptomatic anemia associated with Myelodysplastic Syndromes 
(MDS) 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
Objectives 
Efficacy Objectives 
To assess the efficacy of Recormon® for treating anemic patients with low/intermediate-1 risk MDS, 
as measured by erythroid response 
Safety Objectives  
To assess the safety profile of Recormon® for treating anemic patients with low/intermediate-1 risk 
MDS 
 
Study Design 
Description of Study 
The study consists of a 2-week screening period, a 12-week treatment phase and end-of-study visit 
(see figure 1). After screening, eligible patients will be treated with epoetin beta (Recormon®) as 
recommended in the approved label and international guidelines for the use of epoetin in MDS 
patients, Recormon® dosage will be adjusted on the basis of erythroid response. 
During screening period, serum level of endogenous erythropoietin will be assessed, as well as 
liver and kidney function. Bone marrow morphology analysis and karyotyping are also performed 
during screening if they have not been assessed in the 6 months prior to participation in the study. 
Complete blood count test is performed during screening period and at every patient’s visit until the 
end of study visit. The result should be available on visit date, prior to the Recormon® 
administration 
The patient’s erythroid response will be assessed at week 4 and every 4 weeks thereafter, until 
end-of-study visit. Patients who achieve Hb level ≥ 12 g/dL will stop treatment, while patients with 
Hb level ˂12 g/dL will continue treatment for the total of 12 weeks. Concurrent G-CSF can be 
administered upon physician discretion. 


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Number of Patients 
120 patients expected to be enrolled. 
Target Population 
Adult anemic MDS patients (ı18 years old) in the low or intermediate-1 risk group according to the 
International Prognostic Scoring System (IPSS) 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
1. Able and willing to provide written informed consent and to comply with the study protocol 
2. Adult patients ( ≥ 18 years old) 
3. Low or intermediate-1 risk MDS (having IPSS risk score ≤ 1) confirmed with bone marrow 
morphology analysis and karyotyping within 6 months prior to screening 
4. No previous treatment with hematopoietic growth factors within 3 months prior to screening 
5. Symptomatic  anemia (Hb < 10 g/dL) as determined by investigator 
6. Serum Erythropoietin < 500 mU/ml within 14 days prior to the first dose of study treatment. 
7. Require no red blood cell transfusion or dependent on <4 units within 8 weeks prior to screening 
8. Clinically stable for at least one month prior to entry into the study as determined by investigator 
9. For female patients of childbearing potential and male patients with partners of childbearing 
potential, agree (by patient and/or partner) to use highly effective form(s) of contraception (i.e., 
one that results in a low failure rate [< 1% per year] when used consistently and correctly) 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
10. Contraindications and/or known hypersensitivity to the active substance and/or any of the 
excipients of Recormon® treatment according to the approved package insert. 
11. Poorly controlled hypertension as assessed by the investigator 
12. History of Acute myeloid leukemia (AML) or high risk for AML 
13. Previously documented evidence of Pure red cell aplasia (PRCA) 
14. Current pregnancy or breast-feeding 
15. High likelihood of early withdrawal or interruption of the study 
16. Administration of another investigational drug within 1 month before screening or planned during 
the study period 
Length of Study 
It is expected that approximately 120 patients will be enrolled, over approximately 48 months.  
The study is estimated to last approximately 4.5 years, based on an expected 48-month recruitment 
period, up to 3 months of study treatment and a month of follow-up after the completion of the last 
study treatment 
End of Study 
The end of the study is defined as the date when the last patient, last visit (LPLV) occurs, that is 
when the last patient reaches the end-of-study visit (approximately 4 months after the last patient is 
enrolled). The end-of-study visit will occur 4 weeks after patient’s last dose of study treatment, or 
earlier if one of the following is documented for all treated patients: withdrawal from the study, loss 
to follow up or death 


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Efficacy Outcome Measures 
The efficacy outcome measures for this study are: 
Primary Efficacy Outcomes: 
 The cumulative proportion of patients achieving erythroid response at week 12 according to 
IWG 2006 definition as  
 Hb increase by ı 1.5 g/dL 
 Reduction of units of RBC transfusions by an absolute number of at least 4 RBC 
transfusions/8 weeks compared with the pre-treatment transfusion number in the previous 8 
weeks. Only RBC transfusions given for a Hb of İ 9.0 g/dL pre-treatment will count in the 
RBC transfusion response evaluation 
Secondary Efficacy Outcomes: 
 % patients with platelet response (pre-treatment < 100×109/L) at week 12 defined by IWG 
2006 as following; 
 Absolute increase of ≥ 30 x 109/L for patients starting with > 20 x 109/L platelets (Increase 
from < 20 x 109/L to > 20 x 109/L and by at least 100% ) 
 % patients with neutrophil response (pre-treatment < 1.0 x 109/L) at week 12 defined by IWG 
2006 as following; 
 At least 100% increase and an absolute increase > 0.5 x 109/L 
 
Safety Outcome Measures 
The safety outcome measures for this study are as follows: 
 Tolerability and safety of Recormon®  
 
Investigational Medicinal Products 
Injectable solution of Recormon® (provided free of charge by Roche) 30,000 or 60,000 IU per week 
administered subcutaneously  
The initial dose is 30,000 IU per week administered subcutaneously 
• Response will be firstly evaluated at week 4 (visit 2): 
- 
If haemoglobin level ≥ 12 g/dL at any time, Recormon® should be discontinued until Hb levels 
are ≤ 10 g/dL 
- 
If the haemoglobin level increases < 1 g/dL from screening level and haemoglobin level ˂ 12 
g/dL, a 60,000 IU weekly of Recormon® will be administered subcutaneously until week 12 
- 
If the haemoglobin level increases ≥ 1 g/dL from screening level and haemoglobin level ˂ 12 
g/dL, a 30,000 IU weekly of Recormon®  will be continued until week 12 
 
Non-Investigational Medicinal Products 
Upon physician discretion, G-CSF can be used concurrently 
 


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Statistical Methods 
Descriptive statistics will be used for baseline characteristics. The interim data analysis will be 
performed when the first 30 patients completing 12-week treatment period.  
Determination of sample size 
Sample size based on a 5% significance level and the 80% power with 10% drop out resulting of 
120 patients in total. 
Safety: Assuming a 10% withdrawal rate, 120 patients will be enrolled such that we expect 108 
patients will not withdraw and will remain evaluable.  With 108 evaluable patients in this study, the 
sample size is sufficient to have at least 95% probability of observing a particular adverse event in 
at least one patient in this study, if the true proportion of patients in the target population as a whole 
who experience this event is 0.0274 i.e. approximately 1 in every 37 patients. 
Efficacy: Assuming a 10% withdrawal rate, 120 patients will be enrolled such that we expect 108 
patients will not withdraw and will remain evaluable.  To give an estimate of the precision of this 
study in terms of estimating the proportion of patients with erythroid response, then with 108 
evaluable patients in this study, if the observed proportion of patients with erythroid response in the 
study were 0.25, then the half width of the 95% confidence interval for this proportion would be 
0.0817 (i.e. the 95% confidence interval would be 0.1683 to 0.3317). 
Analysis Population 
The efficacy analysis will be performed based on the intent-to-treat (ITT) population defined as all 
enrolled patients who receive at least one dose of study medication.  
The Safety population will include all patients who receive at least one dose of study medication. 
Interim Analysis 
An interim analysis of primary end point (erythroid response at week 12 according to IWG 2006 
definition) will be undertaken when the first 30 patients have completed their 12-week treatment, 
and safety data will also be summarized at that time.  
Further details regarding the planned interim analysis will be presented in the Statistical Analysis 
Plan (SAP). 
Efficacy Analysis 
The efficacy analyses will include all enrolled patients who receive at least one dose of study 
medication. Efficacy endpoint will be summarized based on ITT population. Subgroup analysis may 
be performed for efficacy analysis.  
Primary Efficacy Endpoint 
Intent-To-Treat (ITT) analysis of the primary outcome variables is planned. Patients who meet the 
evaluable criteria as specified in the analysis plan will be included in the per protocol 
For the primary endpoint of erythroid response, the percentages of patients who achieve the target 
haemoglobin increase by ≥ 1.5 g/dL, or reduction of units of RBC transfusions by an absolute 
number at week 12 will be summarized in table.  
Secondary Efficacy Endpoints 
Secondary efficacy endpoints include platelet and neutrophil response at week 12, defined by the 
following IWG 2006 criteria and will analyzed for the PP population.  
 % patients with platelet response (pre-treatment < 100×109/L) at week 12 defined by IWG 2006 
as following; 
 Absolute increase of ≥ 30 x 109/L for patients starting with > 20 x 109/L platelets (Increase from 
< 20 x 109/L to > 20 x 109/L and by at least 100%) 
 % patients with neutrophil response (pre-treatment < 1.0 x 109/L) at week 12 defined by IWG 
2006 as following; 


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 At least 100% increase and an absolute increase > 0.5 x 109/L 
The percentages of patient who achieve the above hematologic responses at week 12, according to 
the IWG 2006 criteria will be presented in summary tables.   
Safety Analyses 
All patients who have received at least one dose of study medication, whether prematurely 
withdrawal or not will be included in the safety analysis.  
The safety parameters will be vital signs, AEs, SAEs and the safety laboratory assessments 
including serum ferritin. All clinical AEs and SAEs as well as laboratory abnormalities will be 
recorded and graded according to the NCI-CTCAE version 4.0.  
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). The 
incidence of all AEs/SAEs will be summarized according to the primary system-organ class and by 
preferred terms.  
Safety laboratory parameters will be summarized and at least presented descriptively, and the 
selected laboratory parameters may also be displayed graphically.   
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
AE 
Adverse event 
ALT/SGPT 
Alanine Aminotransferase 
AST/SGOT 
Aspartate Aminotransferase 
AML 
Acute Myeloid Leukemia 
ATRA 
All-Trans Retinoic Acid 
MDS 
Myelodysplastic Syndromes 
CBC 
Complete Blood Count 
CHO 
Chinese Hamster Ovary 
CKD 
Chronic Kidney Disease 
CRO 
Contract Research Organization 
CTCAE 
Common Terminology Criteria for Adverse Events 
EC 
Ethics Committee 
ECG 
Electrocardiography 
eCRF 
electronic Case Report Form 
ESA 
Erythropoiesis-stimulating agent 
FDA 
Food and Drug Administration 
G-CSF 
Granulocyte Colony-Stimulating Factor 
GCP 
Good Clinical Practice 
Hb 
Haemoglobin 
EPO 
Recombinant Erythropoietin 
HSCT 
Hematopoietic Stem Cell Transplantation 
ICH 
International Conference on Harmonization 
IMP 
Investigational Medicinal Product 
IND 
Investigational New Drug 
int-1 
intermediate-1 
int-2 
intermediate-2 
IPSS 
International Prognostic Scoring System 
IRB 
Institutional Review Board 
IWG 2006 
International Working Group 2006 
LPLV 
last patient, last visit 
NCI 
National Cancer Institute 
PRBCs 
PRCA 
Packed Red Blood Cells 
Pure Red Cell Aplasia 
QoL 
Quality of Life 
RBC 
Red Blood Cells 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
sEPO 
Serum Erythropoietin 


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Abbreviation 
Definition 
ULN 
Upper Limit of Normal 
WBC 
White Blood Cell 
WHO 
World Health Organization 
X-ray 
X-radiation 
 


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1. 
BACKGROUND 
1.1 
BACKGROUND ON MYELODYSPLASTIC SYNDROMES  
Myelodysplastic syndromes (MDS) are a group of hematological neoplastic diseases with  
a heterogeneous clinical presentation and, most probably, heterogeneous pathophysiology. 
Their common shared clinical feature is the presence of severe peripheral blood cytopenias, 
especially anaemia, and by frequent evolution to acute myeloid leukaemia (AML)  
(Fenaux 2004).  In more than two thirds of MDS cases, anemia is present at diagnosis. 
Improving erythropoiesis, and thus eliminating fatigue and symptoms, is the main 
therapeutic target for the majority of MDS patients, because >50% of patients present with 
anemia with an Hb level <10 g/dL. Some 85% of patients develop more serious anemia as 
MDS progresses and >80% require red blood cell (RBC) transfusion. In a mainly geriatric 
population of patients, anemia leads to co-morbidities that include cardiac complications, 
increased fatigue, diminished quality of life (QoL), and the need for chronic RBC 
transfusion. Well-known problems associated with RBC transfusions are iron overload, 
fluctuating haemoglobin levels, and persistently low haemoglobin levels (usually <10 g/dL), 
in addition to the intrinsic risks related to intolerance reactions, alloimmunization, and 
infections. 
 
Diagnostic 
and 
prognostic 
evaluations 
of 
MDS 
patients 
are 
based 
on 
the  
French–American–British classification (Bennett 1986), the derived International Prognostic 
Score System (IPSS) (Greenberg 1998), the World Health Organization (WHO) 
classification (Swerdlow et al. 2008), or the derived WHO classification-based prognostic 
scoring system, WPSS (Malcovati et al. 2007). These prognostic systems are strongly 
dependent on the morphological detection of immature cells and on the presence of 
cytogenetic abnormalities. 
 
The International Prognostic Scoring System (IPSS) that accounts for cytogenetic, number 
of lineages involved in dysplasia and the bone marrow blast counts, divides MDS into four 
categories; low, intermediate-1 (int-1), intermediate-2 (int-2) and high risk for leukemic 
transformation and survival (Komrokji and Bennett 2007). The median survival is estimated 
at 5.7, 3.5, 1.2 and 0.4 years, respectively. The median time for leukemic transformation in 
at least 25% of patients is 9.4, 3.3, 1.1 and 0.2 years respectively. 
 
Management of MDS is based on expectations of treatment tolerability and quality of life, 
as well as on the risks imposed by the disease itself. However, because MDS differs from 
many hematologic malignancies in terms of its chronic nature and in the morbidity and 
mortality associated with cytopenias, alleviating disease-related symptoms is an important 
therapeutic goal. Therapy can be optimized for each patient based on IPSS risk category 
as well as age, performance status, and comorbidities, all of which determine the likelihood 
of a patient tolerating treatments of different intensities. Relying on the major IPSS risk, 
groups of “lower-risk” disease encompasses low- and intermediate (Int)-1-risk categories, 
and “higher-risk” MDS incorporates those patients with Int-2-and High-risk disease.  
 
A “watch and wait” approach is generally recommended for patients with lower-risk disease, 
a haemoglobin level >10 g/dL, and with no transfusion needs. Higher-risk patients usually 
require treatment immediately (Ria et al. 2009). Given that Hematopoietic stem cell 
transplantation (HSCT) is the only potentially curative treatment for MDS (Cheson et al. 
2000), any initial decision must be made around the eligibility of the patient for 
transplantation. A key consideration in any patient with MDS is the need to avoid chronic 
transfusion dependency, because this is associated with iron overload and its attendant 
potential risk of organ damage and dysfunction (Ria et al. 2009 and Goldberg et al. 2010). 
 


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It is known that, at some point in the natural history of the disease, every MDS patient 
requires regular transfusions of packed red blood cells (PRBCs) and/or platelets to 
maintain peripheral blood cell counts. The proportion of PRBC transfusion-dependent 
patients increases with the severity of the disease from low- to high-risk MDS categories. 
Approximately 40–50% of patients are PRBC-transfusion-dependent in low-/int-1-risk 
groups, while the number rises to 65–80% in the int-2-/high-risk groups (Balducci 2006). 
 
Transfusion dependency affects quality of life and predicts shortened survival (Goldberg et 
al. 2010 and Malcovati et al. 2007). Best supportive care for all patients includes clinical 
monitoring, red blood cell (RBC) and platelet transfusions for symptomatic anemia or 
thrombocytopenia, psychosocial support, and quality-of-life assessments.  Daily iron 
chelation with subcutaneous deferoxamine or oral deferasirox should be considered to 
decrease iron overload in patients receiving >20 to 30 RBC transfusions. In addition, 
hematopoietic growth factor support, such as erythropoietin, granulocyte colony-stimulating 
factor, or granulocyte/macrophage colony-stimulating factor, should be considered for 
symptomatic cytopenias that are unresponsive to correction of all other identifiable causes 
of the low blood counts. 
 
1.2 
BACKGROUND ON EPOETIN BETA (RECORMON® )  
Recormon® (epoetin beta) is a sterile, purified, stable recombinant human erythropoietin 
concentrate produced from genetically engineered chinese hamster ovary (CHO) cells 
containing a cloned human erythropoietin gene. Recormon® is provided as lyophilisate and 
solvent for solution for injection in cartridge, and as solution for injection in pre-filled 
syringes. The reconstituted product is a colorless, clear to slightly opalescent solution. 
Epoetin beta is a glycoprotein that stimulates the proliferation and differentiation processes 
of the erythroid stem cell compartment and also has a stimulatory effect on the proliferation 
and maturation compartment of the erythron. Epoetin beta therefore leads to an increase in 
haemoglobin formation and an associated acceleration of cell maturation with reduction in 
the cell cycle time. A further effect of epoetin beta is the acceleration of reticulocyte 
maturation and an increase in the release of reticulocytes into the bloodstream. 
Recormon® has been approved by Thai FDA for the following therapeutic Indication(s) 
 
Treatment of symptomatic anemia associated with chronic kidney disease 
(CKD) in patients on dialysis. 
 
Treatment of symptomatic renal anemia in patients not yet undergoing dialysis. 
 
Prevention of anemia of prematurity in infants with a birth weight of 750 to 
1500 g and a gestational age of less than 34 weeks. 
 
Treatment of symptomatic anemia in adult patients with non-myeloid 
malignancies receiving chemotherapy. 
 
Increasing the yield of autologous blood from patients in a pre-donation 
program. 
 
Its use in this indication must be balanced against the reported increased risk 
of thromboembolic events. Treatment should only be given to patients with 
moderate anemia (Hb 10 - 13 g/dL [6.21 - 8.07 mmol/l], no iron deficiency) if 
blood conserving procedures are not available or insufficient when the 
scheduled major elective surgery requires a large volume of blood (4 or more 
units of blood for females or 5 or more units for males). 
 
Treatment 
of 
symptomatic 
anemia 
associated 
with 
Myelodysplastic 
Syndromes (MDS) patients, including other ineffective erythropoiesis 
See the local prescribing information for more details. 
 


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1.3 
STUDY RATIONALE AND BENEFIT–RISK ASSESSMENT 
Chronic refractory anemia and long-term use of blood transfusions pose a tremendous 
clinical and economic burden to the management of MDS patients. Thus, treatment options 
aimed at maintaining transfusion independence or delaying transfusion dependence play 
an important role in the management of low-risk early disease.  
 
Of the currently available therapeutic options, Erythropoiesis-stimulating agents (ESAs) 
alone or in combination with GCSF appear to fulfill this goal in a significant proportion of 
MDS patients. In contrast to the application of these growth factors to treat the side effects 
of chemotherapy in other cancers, their use in MDS appears to serve a therapeutic role 
since ineffective hematopoiesis, and specifically defective erythropoiesis, constitute the 
basic pathology in MDS. By promoting survival and differentiation ESAs overcome 
excessive apoptosis of erythroid progenitors and, hence, are therapeutic in alleviating the 
basic pathology of these disorders. 
 
Recombinant erythropoietin (EPO) can correct anaemia in about 20% of MDS when used 
alone and 40% when combined with recombinant human granulocyte colony-stimulating 
factor (G-CSF), and the response rate to EPO + G-CSF is higher than that of symptomatic 
treatment (Economopoulos et al. 1999, Remacha et al. 1999, Hellstrom-Lindberg et al. 
2003, and Casadevall et al. 2004). Major prognostic factors for a favourable response to 
EPO ± G-CSF are low endogenous serum EPO levels (<200 or 500 U/l) and relatively low 
transfusion requirement. In patients with a serum EPO level below 500 U/l, response rates 
to EPO + G-CSF reach 60% (Hellstrom-Lindberg et al. 2003 and Casadevall et al. 2004). 
 
Result from prospective randomized phase III trial by the Eastern Cooperative Oncology 
Group (E1996) confirm earlier studies by demonstrating the efficacy of adding G-CSF to 
EPO and higher EPO dose for enhancing erythroid responses in MDS (Greenberg et al. 
2009). Mo yo et al. (Mo yo et al. 2007) also suggest increasing EPO dose may have a 
greater impact on erythroid responses than addition of G/GM-CSF. 
 
Three ESAs have been used in MDS, epoetin-α and darbepoetin-α in the USA, and in 
addition epoetin-β outside of the USA. Several studies have proven the efficacy of these 
ESAs in eliciting erythroid response in low/int-1 MDS patients (MundLe 2006). A pretherapy 
endogenous serum erythropoietin (sEPO) level of less than 500 mU/ml and transfusion 
requirement of less than two units/month appear to predict the best response to ESA 
therapy, particularly in low/int-1 disease. As reviewed previously, with the use of these 
criteria for patient selection and that of the standardized response evaluation criteria 
recommended by the International Working Group in MDS, erythroid response rates have 
significantly improved to nearly 60–65% from approximately 20% in the past with their 
earlier use in unselected all-comer MDS patients evaluated for response with variable 
criteria (MundLe 2006). The responses to ESA alone, or in combination with granulocyte 
colony-stimulating factor (GCSF), appear to be remarkably durable with a median of 23 
months in the absence of transfusions (Jadersten et al. 2005). The responses are observed 
both in transfusion-dependent patients in terms of transfusion avoidance and Hb 
improvement, as well as in transfusion-independent patients in terms of Hb improvement. 
 
It is evident that complete transfusion independence is achieved in 30–50% of patients, 
with a noticeable decrease in the mean number of PRBC units required to maintain Hb in 
others. 
 
To date, no treatment-related side effects have been noted with ESA therapy and treatment 
with ESAs appears to be well-tolerated. In fact, the only largest randomized placebo-


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controlled trial with ESA in MDS conducted thus far showed that the patients treated with 
EPO as a single agent had numerically lower rates of adverse events (32%) compared with 
those on placebo (43%) (ITALIAN COOPERATIVE STUDY GROUP 1998). Furthermore, 
encouragingly, no treatment-related episodes of thrombosis or seizures were reported in 
this trial or even after long-term administration of EPO to MDS patients in another large, 
single-arm trial (Terpos et al. 2002). The noticeable absence of therapy-related thrombotic 
events with EPO treatment of MDS in several clinical trials so far is indeed distinguished 
from even the minimum acceptable risk of thrombotic complications of ESAs when used in 
chemotherapy-induced anemia as listed in the drug prescribing information for epoetin-α or 
darbepoetin-α. Thus, treatment of MDS with ESA in general seems to be well tolerated with 
significant clinical benefits in MDS. 
 
ESA use in MDS is widespread; recent estimates suggest that 60% of MDS patients 
received ESAs (Sekeres et al. 2008). The last update of the 2011 National Comprehensive 
Cancer Network guidelines (Greenberg et al. 2011) acknowledges the fact that anemia is a 
major issue in MDS patients to be addressed even more carefully than in the past with 
parallel statements by the Italian Society of Hematology (Alessandrino et al 2002), the 
United Kingdom (UK) MDS Guidelines Group (Bowen et al. 2003), Nordic MDS Group 
(Guideline by NMDS group), and the Thai MDS study group (Guideline by The Thai Society 
of Hematology). 
 
As improvements in haemoglobin are usually noted 6–8 weeks after initiation of an 
adequate dose of ESA, a minimum 8-week therapeutic trial was considered to be indicated. 
Moreover, it should be noted that ESA doses found to impact the anemia of MDS are 
substantially higher than those used in chronic renal insufficiency (Oliva et al. 2010). The 
addition of granulocyte colony-stimulating factor (G-CSF), thought to synergize with ESA in 
producing an erythropoietic effect in MDS patients, is suggested for patients who do not 
manifest a response to ESA (Jadersten et al. 2008 and Hellstrom-Lindberg et al. 2003). 
 
The relative durable clinical benefits and lack of adverse effects on survival or rate of 
leukemic transformation may uniquely position ESAs as the eminent therapeutic choice. 
Importantly, the subset of MDS patients benefiting from ESA therapy is now well defined as 
the low-/int-1-risk group with sEPO of less than 500 mU/ml and a PRBC transfusion need 
of less than two units/month. From a benefit–risk perspective, the positive long-term 
outcomes demonstrated with ESAs in a specified group of MDS patients have yet to be 
shown with other therapies. ESAs thus remain a treatment of choice for low-/int-1 MDS 
patients when considered against the significant risks and estimated high costs associated 
with complicated chronic blood transfusions. 
 
However, the majority of clinical studies of ESAs in MDS patients use EPO-alpha. Few 
data have been published for EPO-beta. This prospective study aim to provide the 
additional effectiveness and safety profile of Recormon® (EPO-beta) for treatment of 
symptomatic anemia associated with MDS patients for all epoetin formulations review by 
Thai FDA. 
2. 
OBJECTIVES 
2.1 
EFFICACY OBJECTIVES 
The primary efficacy objective for this study is: 
 
To assess the efficacy of Recormon® for treating anemic patients with 
low/intermediate-1 risk MDS, as measured by erythroid response 
  


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2.2 
SAFETY OBJECTIVES 
The safety objective for this study is: 
 
To assess the safety of Recormon®  for treating anemic patients with low/intermediate-1 
risk MDS 
 
3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF STUDY 
3.1.1 
Overview of Study Design  
This is a phase IV, prospective, multi-centre, open label study to assess the efficacy of 
Recormon®  for treating anemic patients with low/intermediate-1 risk MDS, in approximately 
120 adult patients. The primary efficacy endpoint is a proportion of patients achieving 
erythroid response at week 12 according to IWG 2006 definition. The trial will be conducted 
at approximately 8 centres nationwide. 
All potential study patients must provide signed written informed consent approved by the 
relevant independent Ethics Committee before undergoing any study-specific procedures. 
Results of the screening assessments must be available and patients must meet all 
eligibility criteria prior to enrolment into the study. The study design is shown in Figure 1. 
 
Figure 1 
Study Scheme 
The study consists of a 2-week screening period, a 12-week treatment phase and end-of-
study visit (see figure 1). After screening, eligible patients will be treated with epoetin beta 
(Recormon®) as recommended in the approved label and international guidelines for the 
use of epoetin in MDS patients, Recormon® dosage will be adjusted on the basis of 
erythroid response. 
During screening period, serum level of endogenous erythropoietin will be assessed,  
as well as liver and kidney function. Bone marrow morphology analysis and karyotyping are 
also performed during screening if they have not been assessed in the 6 months prior to 
participation in the study. Complete blood count test is performed during screening period 
and at every patient’s visit until the end of study visit. The result should be available prior to 
dosing of Recormon®. 
The patient’s erythroid response will be assessed at week 4 and every 4 weeks thereafter, 
until end-of-study visit. Patients who achieve Hb level ≥ 12 g/dL will stop treatment, while 


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patients with Hb level ˂ 12 g/dL will continue treatment for the total of 12 weeks. 
Concurrent G-CSF can be administered upon physician discretion. 
Patients can withdraw from the study at any time as per section 4.5.1  
Study oversight will be assured by a steering committee to guide study conduct, to review 
the results at the end of the study, to approve and sign-off the study report and to prepare 
and submit a publication to a peer-review journal. The steering committee will be made up 
of investigators and Roche representatives and will meet at regular intervals. 
A schedule of assessments is provided in Appendix 1. 
3.2 
END OF STUDY 
The end of the study is defined as the date when the last patient, last visit (LPLV) occurs, 
that is when the last patient reaches the end-of-study visit (approximately 4 months after 
the last patient is enrolled). The end-of-study visit will occur 4 weeks after patient’s last 
dose of study treatment, or earlier, if one of the following is documented for all treated 
patients: withdrawal from the study, loss to follow up or death. 
 
3.3 
RATIONALE FOR STUDY DESIGN 
3.3.1 
Rationale for Test Product Dosage 
The study treatment dosing is consistent with the approved label of Recormon® and 
standard treatment guidelines. 
As improvements in haemoglobin are usually noted 6–8 weeks after initiation of an 
adequate dose of ESA, a minimum 8-week treatment period was considered to be 
indicated. 
3.3.2 
Rationale for Patient Population 
Several studies have proven the efficacy of the ESAs in eliciting erythroid response in 
low/int-1 MDS patients. The subset of MDS patients benefiting from ESA therapy is now 
well defined as the low-/int-1-risk group with sEPO of less than 500 mU/ml and a PRBC 
transfusion need of less than 4 units within 8 weeks prior to screening. 
3.4 
OUTCOME MEASURES  
3.4.1 
Efficacy Outcome Measures 
The efficacy outcome measures for this study are as follows: 
Primary Efficacy Outcomes: 
 
The cumulative proportion of patients achieving erythroid response at week 12 
according to IWG 2006 definition as  
 Hb increase by ı 1.5 g/dL 
 Reduction of units of RBC transfusions by an absolute number of at least 4 RBC 
transfusions/8 weeks compared with the pre-treatment transfusion number in the 
previous 8 weeks. Only RBC transfusions given for a Hb of İ 9.0 g/dL pre-
treatment will count in the RBC transfusion response evaluation 
 


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Secondary Efficacy Outcomes: 
 
% patients with platelet response (pre-treatment < 100×109/L) at week 12 defined by 
IWG 2006 as following; 
 Absolute increase of ≥ 30 x 109/L for patients starting with > 20 x 109/L platelets 
(Increase from < 20 x 109/L to > 20 x 109/L and by at least 100%) 
 
% patients with neutrophil response (pre-treatment < 1.0 x 109/L) at week 12 defined 
by IWG 2006 as following; 
 At least 100% increase and an absolute increase > 0.5 x 109/L 
 
3.4.2 
Safety Outcome Measures 
The safety outcome measures for this study are as follows: 
Tolerability and safety of Recormon®  (Incidence, nature, and severity of adverse events) 
Safety assessments will include AEs, SAEs, routine safety laboratory tests, vital signs 
measurements, and recording of concomitant medications. All clinical AEs and SAEs as 
well as laboratory abnormalities will be recorded and graded according to the NCI-CTCAE 
version 4.0. 
Patients will undergo an end-of-study safety assessment 4 weeks after the last Recormon®  
administration or after early withdrawal (unless the reason for early withdrawal is 
withdrawal of consent) 
4. 
MATERIALS AND METHODS  
4.1 
PATIENTS 
Adult anemic MDS patients (ı18 years old) in the low or intermediate 1 risk group 
according to the International Prognostic Scoring System (IPSS) 
4.1.1 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
 
Able and willing to provide written informed consent and to comply with the study 
protocol 
 
Adult patients  (≥ 18 years old) 
 
Low or intermediate-1 risk MDS (having IPSS risk score ≤ 1) confirmed with bone 
marrow morphology analysis and karyotyping within 6 months prior to screening  
 
No previous treatment with hematopoietic growth factors within 3 months prior to 
screening 
 
Symptomatic anemia (Hb < 10 g/dL) as determined by investigator 
 
Serum Erythropoietin < 500 mU/ml  within 14 days prior to the first dose of study 
treatment 
 
Require no red blood cell transfusion or dependent on < 4 units within 8 weeks prior to 
screening 
 
Clinically stable for at least one month prior to entry into the study as determined by 
investigator 
 
For female patients of childbearing potential and male patients with partners of 
childbearing potential, agree (by patient and/or partner) to use highly effective form(s) 


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of contraception (i.e., one that results in a low failure rate [< 1% per year] when used 
consistently and correctly) 
 
4.1.2 
Exclusion Criteria 
 
Patients who meet any of the following criteria will be excluded from study entry: 
 
Contraindications and/or known hypersensitivity to the active substance and/or any of 
the excipients of Recormon® treatment according to the approved package insert 
 
Poorly controlled hypertension as assessed by the investigator 
 
History of Acute myeloid leukemia (AML) or high risk for AML 
 
Previously documented evidence of Pure red cell aplasia (PRCA) 
 
Current pregnancy or breast-feeding 
 
High likelihood of early withdrawal or interruption of the study 
 
Administration of another investigational drug within 1 month before screening or 
planned during the study period 
 
4.2 
STUDY TREATMENT  
4.2.1 
Formulation, Packaging, and Handling 
4.2.1.1 
Recormon®   
Recormon® will be supplied by the sponsor as solution for injection in pre-filled syringes. 
For further details, see the local prescribing information. 
4.2.2 
Dosage, Administration and Compliance 
4.2.2.1 
Dosage and administration of Recormon®  
Injectable solution of Recormon 30,000 or 60,000 IU per week administered 
subcutaneously  
The initial dose is 30,000 IU per week administered subcutaneously 
Response will be firstly evaluated at week 4 (visit 2): 
 
If haemoglobin level reaches ≥ 12 g/dL at any time, Recormon® should be 
discontinued until Hb levels are ≤ 10 g/dL 
 
If the haemoglobin level increases < 1 g/dL from screening level and haemoglobin 
level ˂ 12 g/dL, a 60,000 IU weekly of Recormon® will be administered 
subcutaneously until week 12. 
 
If the haemoglobin level increases ≥ 1 g/dL from screening level and haemoglobin 
level ˂ 12 g/dL, a 30,000 IU weekly of Recormon®  will be continued until week 12 
4.2.2.2 
Assessment of Compliance 
Accountability and subject compliance will be assessed by maintaining adequate drug 
dispensing and return records. Subjects will be instructed on how to self-inject at the 
screening visit and re-instructed at each visit if deemed necessary by the 
Investigator/delegate. 
A Drug Inventory/Dispensing Log provided by Roche must be kept current and should 
contain the following information at a minimum: 


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 
the identification of the subject to whom the study medication was dispensed 
 
the date[s], quantity of the study medication dispensed to the subject 
 
the initials of the person confirming administration of the study medication 
 
the date[s] and quantity of the study medication returned by the subject 
 
This inventory must be available for ongoing inspection by the Monitor. In case of home 
administrations, for assessment of compliance, subjects will be asked to return all used and 
unused drug supply boxes to the investigational site at each visit. The compliance will be 
assessed by reconciliation of the number of unused syringes and empty drug supply boxes 
returned. Immediately after self-injection by the subject, the used syringes must be placed 
in a safety container provided by Roche. This safety container should be returned to the 
investigational site at each visit for immediate disposal by site staff in accordance with the 
study site’s institutional standard operating procedure 
 
4.2.3 
Investigational Medicinal Product Accountability 
Recormon® will be provided by the Sponsor.  The investigational site will acknowledge 
receipt of IMPs to confirm the shipment condition and content.  Any damaged shipments 
will be replaced.  
IMPs will either be disposed of at the study site according to the study site’s institutional 
standard operating procedures or returned to the Sponsor with the appropriate 
documentation.  The site's method of IMP destruction must be agreed upon by the Sponsor.  
The site must obtain the written authorization from the Sponsor before any IMP is 
destroyed, and IMP destruction must be documented on the appropriate form. 
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on the Drug Inventory Log. 
4.2.4 
Post-study Access to Recormon®  
The Sponsor will offer post-study access to the study drug (Recormon®) free of charge to 
eligible patients in accordance with the Roche Global Policy on Continued Access to 
Investigational Medicinal Product, as outlined below. 
A patient will be eligible to receive study drug after completing the study if all of the 
following conditions are met: 
•  
The patient has a life-threatening or severe medical condition and requires 
continued study drug treatment for his or her well-being 
 
There are no appropriate alternative treatments available to the patient 
•  
The patient and his or her doctor comply with and satisfy any legal or regulatory 
requirements that apply to them 
 


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A patient will not be eligible to receive study drug after completing the study if any of the 
following conditions are met: 
•  
The study drug is commercially marketed in the patient's country and is 
reasonably accessible to the patient (e.g., is covered by the patient's insurance or 
wouldn't otherwise create a financial hardship for the patient) 
•  
The Sponsor has discontinued development of the study drug or data suggest that 
the study drug is not effective for low/intermediate-1 risk MDS 
•  
The Sponsor has reasonable safety concerns regarding the study drug as 
treatment for low/intermediate-1 risk MDS  
•  
Provision of study drug is not permitted under the laws and regulations of the 
 patient's country 
The Roche Global Policy on Continued Access to Investigational Medicinal Product is 
available at the following Web site: 
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf 
 
4.3 
CONCOMITANT THERAPY 
4.3.1 
Permitted Therapy  
Concomitant therapy includes any medication (e.g., prescription drugs, over-the-counter 
drugs, herbal/homeopathic remedies, nutritional supplements) used by a patient from 4 
weeks prior to screening to the end-of-study visit/early termination visit. 
Throughout the study, patient could be treated with any concomitant medications or 
treatment necessary to provide adequate supportive care except for those treatments listed 
in the prohibited therapy. Upon physician discretion and their normal practice, G-CSF can 
be used. 
All RBC transfusions administered during the study should be documented (i.e., specified 
by number of units transfused) and recorded on the eCRF. 
All concomitant medications should be reported to the investigator and recorded on the 
Concomitant Medications electronic Case Report Form (eCRF).  
4.3.2 
Prohibited Therapy 
The following treatments are prohibited during study treatment: 
Investigational or unlicensed/unapproved agents of any type 
Patients receiving any of the prohibited therapies will be discontinued and assessed for 
safety at end-of study visit 
 
4.4 
STUDY ASSESSMENTS  
4.4.1 
Description of Study Assessments 
For the timing of each assessment listed in this section, refer to Section 4.4.2 and Appendix 1. 
4.4.1.1 
Medical History and Demographic Data 
Medical history includes clinically significant diseases and all medications (e.g., prescription 
drugs, over-the-counter drugs, herbal or homeopathic remedies, nutritional supplements) 


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used by the patient within 4 weeks prior to the screening visit. RBC transfusion needed 
within 8 weeks prior to the screening will be recorded. 
Demographic data will include weight, height, age and gender. 
4.4.1.2 
Physical Examinations 
A complete physical examination should include an evaluation of the head, eyes, ears, 
nose, and throat, and the cardiovascular, dermatological, musculoskeletal, respiratory, 
gastrointestinal, genitourinary, and neurological systems.  Any abnormalities identified at 
screening should be recorded on the General Medical History and Baseline Conditions 
eCRF. 
At subsequent visits (or as clinically indicated), limited, symptom-directed physical 
examinations should be performed.  Changes from baseline abnormalities should be 
recorded in patient notes.  New or worsened clinically significant abnormalities should be 
recorded as adverse events on the Adverse Event eCRF. 
4.4.1.3 
Vital Signs 
Vital signs will include measurements of respiratory rate, pulse rate, and systolic and 
diastolic blood pressure while the patient is in a seated position, and body temperature. 
4.4.1.4 
Laboratory Assessments 
Samples for the following standard laboratory tests will be sent to the study site's local 
laboratory for analysis. The results from these assessments should be available on visit 
date, prior to the Recormon® administration: 
 
Haematology parameters will include haemoglobin (Hb), red blood cell count (RBC), 
white blood cell count (WBC) and differentials, and platelet count. 
 
Biochemistry parameters at screening will include serum EPO, serum creatinine, 
alanine aminotransferase (ALT/SGPT) and aspartate aminotransferase (AST/SGOT). 
Biochemistry parameters at any further time point during the study will include 
ALT/SGPT, AST/SGOT, and serum creatinine. Serum ferritin will include at screening 
and end-of-study visit. 
 
4.4.2 
Timing of Study Assessments 
4.4.2.1 
Screening Assessments 
Written informed consent for participation in the study must be obtained before performing 
any study-specific screening tests or evaluations.  Informed Consent Forms for enrolled 
patients and for patients who are not subsequently enrolled will be maintained at the study 
site.   
Screening tests and evaluations will be performed within 14 days prior to the start of study 
drug administration, unless otherwise specified. 
Results of standard-of-care tests or examinations performed prior to obtaining informed 
consent and within 14 days prior to the start of study drug administration may be used; 
such tests do not need to be repeated for screening. These will include the following: 


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 
Review and documentation of demographics data and medical history 
 
Review and documentation of MDS diagnosis 
 
IPSS score   
 
Physical examination 
 
Vital sign measurements 
 
Haematology and biochemistry laboratory tests 
 
AE recording (Note: after informed consent has been obtained but prior to initiation of 
study drug, only SAEs caused by a protocol-mandated intervention should be reported). 
 
Recording concomitant treatments and therapies 
 
Recording RBC transfusion needed within the past 8 weeks 
 
Serum pregnancy test for female patients of childbearing potential. Patients who are 
amenorrheic for at least 12 months are not considered of childbearing potential. 
All screening evaluations must be completed and reviewed to confirm that patients meet all 
eligibility criteria before enrolment.  The investigator will maintain a screening log to record 
details of all patients screened and to confirm eligibility or record reasons for screening 
failure, as applicable. 
Patients who fail screening may be re-screened if it is considered likely that they could later 
become eligible. There is a limit of 2 screening attempts for each patient. Re-consenting 
process must be performed. 
Please see Appendix 1 for the schedule of screening assessments. 
4.4.2.2 
Assessments during Treatment 
All assessments must be performed on the day of the specified visit (V1 – V4), unless 
a time window is specified in the schedule of assessments (see Appendix 1).  Assessments 
scheduled on the visit date should be performed prior to administration of study treatment, 
unless otherwise noted in the schedule of assessments. 
At each treatment visit, patients will undergo the following assessments: 
 
Physical examination and measurements of vital signs  
 
Routine laboratory tests (see section 4.4.1.4 for details about individual laboratory 
assays). The results from these tests should be available on visit date prior to the 
Recormon® administration. 
 
AE recording  
 
Recording concomitant treatments and therapies 
 
Recording RBC transfusion needed from previous visit 
 
Recormon® dose adjustment will be performed at week 4±1 (see section 4.2.2.1 for 
details about dose adjustment) 
Please see Appendix 1 for the schedule of assessments performed during the treatment 
period. 


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4.4.2.3 
Assessments at End of Study/Early withdrawal visit 
End of study/early withdrawal visit will occur at 4 weeks after last dose of Recormon®. This 
visit will include the following evaluations: 
 
Physical examination and vital sign measurements 
 
Safety laboratory assessments (see section 4.4.1.4 for details about individual 
laboratory assays) 
 
AE recording 
 
Recording of concomitant treatments and therapies 
 
Recording of RBC transfusion needed from previous visit 
Please see Appendix 1 for the schedule of assessments performed at the end-of-study 
visit/early termination visit. 
4.4.2.4 
Assessments at Unplanned Visits 
Assessments other than those specified in Appendix 1, Schedule of Assessments, may be 
performed as clinically indicated. These assessments should be adequately documented. 
 
4.5 
PATIENT, STUDY AND SITE DISCONTINUATION 
4.5.1 
Patient Discontinuation 
The investigator has the right to discontinue a patient from study drug or withdraw a patient 
from the study at any time.  In addition, patients have the right to voluntarily discontinue 
study drug or withdraw from the study at any time for any reason.  In case of such 
withdrawal, the reason(s) for withdrawal must be documented. Reasons for discontinuation 
of study drug or withdrawal from the study may include, but are not limited to, the following: 
 
Patient withdrawal of consent at any time 
 
Any medical condition that the investigator or Sponsor determines may jeopardize the 
patient’s safety if he or she continues in the study 
 
4.5.1.1 
Discontinuation from Study Drug 
Reasons for study drug discontinuation may include, but are not limited to the following: 
 
Evolution into high-risk MDS or overt leukemia as determined by Investigator 
 
Withdrawal of consent by the patient 
 
Any significant AE that compromises the patient’s ability to participate in the study 
 
Investigator or Sponsor determines it is in the best interest of the patient 
 
Intercurrent illness 
 
Treatment unresponsiveness 
 
Need for prohibited treatment 
 
Protocol violation 
 
Pregnancy 
Patients who discontinue study drug prematurely will be asked to return to the clinic for the 
end-of-study visit (see Section 4.4.2.3).The primary reason for premature study drug 


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discontinuation should be documented on the appropriate eCRF.  Patients who discontinue 
study drug prematurely will not be replaced. 
4.5.1.2 
Withdrawal from Study 
Every effort should be made to obtain information on patients who withdraw from the study.  
The primary reason for withdrawal from the study should be documented on the 
appropriate eCRF.  Patients will not be followed for any reason after consent has been 
withdrawn.  Patients who withdraw from the study will not be replaced. 
4.5.2 
Study and Site Discontinuation 
The Sponsor has the right to terminate this study at any time.  Reasons for terminating the 
study may include, but are not limited to, the following: 
 
The incidence or severity of adverse events in this or other studies indicates a potential 
health hazard to patients. 
 
Patient enrollment is unsatisfactory. 
 
Steering committee decision 
 
The Sponsor will notify the investigator if the study is placed on hold, or if the Sponsor 
decides to discontinue the study.   
 
The Sponsor has the right to replace a site at any time.  Reasons for replacing a site 
may include, but are not limited to, the following: 
 
Excessively slow recruitment 
 
Poor protocol adherence 
 
Inaccurate or incomplete data recording 
 
Non-compliance with the International Conference on Harmonization (ICH) guideline 
for Good Clinical Practice 
 
5. 
ASSESSMENT OF SAFETY  
5.1 
SAFETY PLAN 
Patients will be assessed by prior medical history, vital signs (including resting blood 
pressure, heart rate, and body temperature), weight and height, physical examination, AEs 
and concomitant medications. A complete medical history (including prior treatments for 
MDS) will be documented at screening. A general physical exam will be performed at 
screening, and at every treatment visit and end-of-study visit (see Appendix 1, Schedule of 
Assessments). 
AEs will be monitored and documented continuously during the study. SAEs will also be 
documented and reported according to the ICH E2 Guideline for Clinical Safety Data 
Management, Definitions and Standards for Expedited Reporting. All AEs and SAEs 
(including patients’ symptoms and signs of toxicity and clinically significant haematological 
and biochemical parameters) will be graded according to NCI CTCAE version 4.0.  
Changes in concomitant medication will be recorded at each study visit. 
 


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5.2 
SAFETY PARAMETERS AND DEFINITIONS 
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events; measurement of protocol-specified safety laboratory assessments; 
and other protocol-specified tests that are deemed critical to the safety evaluation of the 
study. 
Certain types of events require immediate reporting to the Sponsor, as outlined in Section 
5.4. 
5.2.1 
Adverse Events 
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product, regardless of causal attribution.  An adverse event can therefore 
be any of the following: 
 
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product 
 
Any new disease or exacerbation of an existing disease (a worsening in the character, 
frequency, or severity of a known condition) 
 
Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline 
 
Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug 
 
Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive procedures 
such as biopsies) 
 
5.2.2 
Serious Adverse Events (Immediately Reportable to the Sponsor) 
A serious adverse event is any adverse event that meets any of the following criteria: 
 
Fatal (i.e., the adverse event actually causes or leads to death) 
 
Life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death) 
 
This does not include any adverse event that had it occurred in a more severe form or 
was allowed to continue might have caused death. 
 
Requires or prolongs inpatient hospitalization 
 
Results in persistent or significant disability/incapacity (i.e., the adverse event results in 
substantial disruption of the patient’s ability to conduct normal life functions) 
 
Congenital anomaly/birth defect in a neonate/infant born to a mother exposed to study 
drug 
 
Significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above) 
 


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The terms “severe” and “serious” are not synonymous.  Severity refers to the intensity of an 
adverse event (rated as mild, moderate, or severe, or according to NCI CTCAE criteria; see 
Section 5.3.2); the event itself may be of relatively minor medical significance (such as 
severe headache without any further findings). 
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF. 
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4 for 
reporting instructions) via appropriate SAE reporting form. 
Related SAEs MUST be collected and reported regardless of the time elapsed from the last 
study treatment administration, even if the study has been closed. 
Unrelated SAEs must be collected and reported during the study and for up to 28 days 
after the last dose of study medication. 
5.3 
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS 
The investigator is responsible for ensuring that all adverse events (see Section 5.2.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Sections 5.4. 
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity (see 
Section 5.3.2), and causality (see Section 5.3.3).   
5.3.1 
Adverse Event Reporting Period 
Investigators will seek information on adverse events at each patient contact.  All adverse 
events, whether reported by the patient or noted by study personnel, will be recorded in the 
patient’s medical record and on the Adverse Event eCRF. 
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported  
After initiation of study drug, all adverse events, regardless of relationship to study drug, 
will be reported until 4 weeks (28 days) after the last dose of study drug (End of study/early 
withdrawal visit)     
Resolution of adverse events and serious adverse events including dates should be 
followed-up until it is known or end of study/early withdrawal visit, whichever occurs first 
and documented on the Adverse Events eCRF and in the patient’s medical record to 
facilitate source data verification.   


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5.3.2 
Assessment of Severity of Adverse Events 
The adverse event severity grading scale for the NCI CTCAE (v4.0) will be used for 
assessing adverse event severity.  Table 1 will be used for assessing severity for adverse 
events that are not specifically listed in the NCI CTCAE. 
Table 1 
Adverse Event Severity Grading Scale 
Grade 
Severity 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
or intervention not indicated 
2 
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a 
3 
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living b,c 
4 
Life-threatening consequences or urgent intervention indicated d 
5 
Death related to adverse event d 
NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events. 
Note: 
 
Based 
on 
the 
NCI 
CTCAE 
(v4.0), 
which 
can 
be 
found 
at:  
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf 
 
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc. 
b Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding one's self, using the toilet, and taking medications, as performed by patients who are 
not bedridden. 
c If an event is assessed as a "significant medical event," it must be reported as a serious 
adverse event (see Section 5.4. for reporting instructions), per the definition of serious 
adverse event in Section 5.2.2. 
d Grade 4 and 5 events must be reported as serious adverse events (see Section 5.4. for 
reporting instructions), per the definition of serious adverse event in Section 5.2.2. 
 
5.3.3 
Assessment of Causality of Adverse Events 
Investigators should use their knowledge of the patient, the circumstances surrounding the 
event, and an evaluation of any potential alternative causes to determine whether or not an 
adverse event is considered to be related to the study drug, indicating "yes" or "no" 
accordingly. 
 
For patients receiving combination therapy, causality will be assessed individually for each 
protocol-mandated therapy. 
5.3.4 
Procedures for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations. 
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF. 


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5.3.4.1 
Diagnosis versus Signs and Symptoms 
A diagnosis (if known) should be recorded on the Adverse Event eCRF rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather than 
jaundice, asterixis, and elevated transaminases).  However, if a constellation of signs 
and/or symptoms cannot be medically characterized as a single diagnosis or syndrome at 
the time of reporting, each individual event should be recorded on the Adverse Event eCRF.  
If a diagnosis is subsequently established, all previously reported adverse events based on 
signs and symptoms should be nullified and replaced by one adverse event report based 
on the single diagnosis, with a starting date that corresponds to the starting date of the first 
symptom of the eventual diagnosis. 
5.3.4.2 
Adverse Events Occurring Secondary to Other Events 
In general, adverse events occurring secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of severe 
or serious secondary events.  However, medically significant adverse events occurring 
secondary to an initiating event that are separated in time should be recorded as 
independent events on the Adverse Event eCRF.   
5.3.4.3 
Persistent or Recurrent Adverse Events 
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should only be recorded once on the Adverse 
Event eCRF.  The initial severity of the event should be recorded, and the severity should 
be updated to reflect the most extreme severity any time the event worsens.  If the event 
becomes serious, the Adverse Event eCRF should be updated to reflect this. 
A recurrent adverse event is one that resolves between patient evaluation timepoints and 
subsequently recurs.  Each recurrence of an adverse event should be recorded separately 
on the Adverse Event eCRF. 
5.3.4.4 
Abnormal Laboratory Values and Vital Sign Values 
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria: 
Accompanied by clinical symptoms 
Results in a change in study treatment  
Results in a medical intervention or a change in concomitant therapy 
Clinically significant in the investigator’s judgment  
 
It is the investigator’s responsibility to review all laboratory findings and vital sign findings.  
Medical and scientific judgment should be exercised in deciding whether an isolated 
laboratory abnormality or an isolated vital sign abnormality should be classified as an 
adverse event. 
5.3.4.5 
Deaths 
All deaths that occur during the protocol-specified adverse event reporting period (see 
Section 5.3.1), regardless of relationship to study drug, must be recorded on the Adverse 
Event eCRF and immediately reported to the Sponsor (see Section 5.4).   


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Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be reported.  
If the death is attributed to progression of MDS, "MDS progression” should be recorded on 
the Adverse Event eCRF. 
5.3.4.6 
Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF. 
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors.  
5.3.4.7 
Hospitalization or Prolonged Hospitalization 
Any adverse event that results in hospitalization or prolonged hospitalization should be 
documented and reported as a serious adverse event (per the definition of serious adverse 
event in Section 5.2.2), except as outlined below.   
The following hospitalization scenarios are not considered to be serious adverse events: 
 
Hospitalization for respite care 
 
Planned hospitalization required by the protocol 
 
Hospitalization for a preexisting condition, provided that all of the following criteria are 
met: 
 
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected normal 
progression of the disease 
 
The patient has not suffered an adverse event 
 
5.3.4.8 
Overdoses 
Study drug overdose is the accidental or intentional use of the drug in an amount higher 
than the dose being studied.  An overdose or incorrect administration of study drug is not 
an adverse event unless it results in untoward medical effects.   
Any study drug overdose or incorrect administration of study drug should be noted on the 
Study Drug Administration eCRF.  
All adverse events associated with an overdose or incorrect administration of study drug 
should be recorded on the Adverse Event eCRF.  If the associated adverse event fulfills 
serious criteria, the event should be reported to the Sponsor immediately (i.e., no more 
than 24 hours after learning of the event; see Section 5.4). 






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6.3 
INTERIM ANALYSIS  
An interim analysis of primary end point (erythroid response at week 12 according to IWG 
2006 definition) will be undertaken when the first 30 patients have completed their 12-week 
treatment, and safety data will also be summarized at that time.  
Further details regarding the planned interim analysis will be presented in the Statistical 
Analysis Plan (SAP). 
6.4 
EFFICACY ANALYSES 
The efficacy analyses will include all enrolled patients who receive at least one dose of 
study medication.  Efficacy endpoint will be summarized based on ITT population. 
Subgroup analysis may be performed for efficacy analysis. 
6.4.1 
Primary Efficacy Endpoint 
The Intent-To-Treat (ITT) analysis of the primary outcome variables is planned. Patients 
who meet the evaluable criteria as specified in the analysis plan will be included in the per 
protocol 
 
For the primary endpoint of erythroid response, the percentages of patients who achieve 
the target haemoglobin increase by ≥1.5 g/dL, or reduction of units of RBC transfusions by 
an absolute number at week 12 will be summarized in the table.  
 
6.4.2 
Secondary Efficacy Endpoints 
Secondary efficacy endpoints include platelet and neutrophil response at week 12, defined 
by the following IWG 2006 criteria and will analyzed for the PP population.  
 
% patients with platelet response (pre-treatment < 100×109/L) at week 12 defined by 
IWG 2006 as following; 
 Absolute increase of ≥ 30 x 109/L for patients starting with > 20 x 109/L platelets 
(Increase from < 20 x 109/L to > 20 x 109/L and by at least 100%) 
 
 
% patients with neutrophil response (pre-treatment < 1.0 x 109/L) at week 12 defined 
by IWG 2006 as following; 
 At least 100% increase and an absolute increase > 0.5 x 109/L 
 
The percentages of patient who achieve the above hematologic responses at week 12, 
according to the IWG 2006 criteria will be presented in summary tables.   
6.5 
SAFETY ANALYSES 
All patients who have received at least one dose of study medication, whether prematurely 
withdrawal or not will be included in the safety analysis.  
The safety parameters will be vital signs, AEs, SAEs and the safety laboratory 
assessments including serum ferritin. All clinical AEs and SAEs as well as laboratory 
abnormalities will be recorded and graded according to the NCI-CTCAE version 4.0.  


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Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). The incidence of all AEs/SAEs will be summarized according to the primary 
system-organ class and by preferred terms.  
Safety laboratory parameters (Section 4.4.1.4) will be summarized and at least presented 
descriptively, and the selected laboratory parameters may also be displayed graphically.   
Further details about planned safety analyses will be presented in Statistical Analysis Plan 
(SAP)   
 
7. 
DATA COLLECTION AND MANAGEMENT 
7.1 
DATA QUALITY ASSURANCE 
The Sponsor will supply electronic eCRF specifications for this study.  A contract research 
organization (CRO) will be responsible for data management of this study, including quality 
checking of the data.  Data entered manually will be collected via EDC using eCRFs.  Sites 
will be responsible for data entry into the EDC system.  In the event of discrepant data, the 
CRO will request data clarification from the sites, which the sites will resolve electronically 
in the EDC system. 
The Sponsor will perform oversight of the data management of this study, including 
approval of the CRO’s data management plans and specifications.  Data will be periodically 
transferred electronically from the CRO to the Sponsor, and the Sponsor’s standard 
procedures will be used to handle and process the electronic transfer of these data.   
eCRFs and correction documentation will be maintained in the EDC system’s audit trail.  
System backups for data stored at the CRO and records retention for the study data will be 
consistent with the CRO’s standard procedures.  
7.2 
ELECTRONIC CASE REPORT FORMS  
eCRFs are to be completed using a designated EDC system.  Sites will receive training 
and have access to a manual for appropriate eCRF completion.  eCRFs will be submitted 
electronically to the Sponsor and should be handled in accordance with instructions from 
the Sponsor. 
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee. 
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format on a compact disc that must be kept with the study records.  
Acknowledgement of receipt of the compact disc is required. 
7.3 
SOURCE DATA DOCUMENTATION 
Study monitors will perform ongoing source data verification to confirm that critical protocol 
data (i.e., source data) entered into the eCRFs by authorized site personnel are accurate, 
complete, and verifiable from source documents.  


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Source documents (paper or electronic) are those in which patient data are recorded and 
documented for the first time.  They include, but are not limited to, hospital records, clinical 
and office charts, laboratory notes, memoranda, patient-reported outcomes, evaluation 
checklists, pharmacy dispensing records, recorded data from automated instruments, 
copies of transcriptions that are certified after verification as being accurate and complete, 
microfiche, photographic negatives, microfilm or magnetic media, X-rays, patient files, and 
records kept at pharmacies, laboratories, and medico-technical departments involved in a 
clinical trial. 
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be entered 
directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data. 
Source documents that are required to verify the validity and completeness of data entered 
into the eCRFs must not be obliterated or destroyed and must be retained per the policy for 
retention of records described in Section 7.6. 
To facilitate source data verification, the investigators and institutions must provide the 
Sponsor direct access to applicable source documents and reports for trial-related 
monitoring, Sponsor audits, and IRB/EC review.  The investigational site must also allow 
inspection by applicable health authorities. 
7.4 
USE OF COMPUTERIZED SYSTEMS 
When clinical observations are entered directly into an investigational site’s computerized 
medical record system (i.e., in lieu of original hardcopy records), the electronic record can 
serve as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research.  An 
acceptable computerized data collection system allows preservation of the original entry of 
data.  If original data are modified, the system should maintain a viewable audit trail that 
shows the original data as well as the reason for the change, name of the person making 
the change, and date of the change. 
7.5 
RETENTION OF RECORDS 
Records and documents pertaining to the conduct of this study and the distribution of IMP, 
including eCRFs, Informed Consent Forms, laboratory test results, and medication 
inventory records, must be retained by the Principal Investigator for at least 15 years after 
completion or discontinuation of the study, or for the length of time required by relevant 
national or local health authorities, whichever is longer.  After that period of time, the 
documents may be destroyed, subject to local regulations.   
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to another 
party or moving them to another location. 


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8. 
ETHICAL CONSIDERATIONS 
8.1 
COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in full conformance with the ICH E6 guideline for Good Clinical 
Practice and the principles of the Declaration of Helsinki, or the laws and regulations of the 
country in which the research is conducted, whichever affords the greater protection to the 
individual.  The study will comply with the requirements of the ICH E2A guideline (Clinical 
Safety Data Management:  Definitions and Standards for Expedited Reporting).   
8.2 
INFORMED CONSENT 
The Sponsor’s sample Informed Consent Form will be provided to each site.  If applicable, 
it will be provided in a certified translation of the local language.  The Sponsor or its 
designee must review and approve any proposed deviations from the Sponsor's sample 
Informed Consent Forms or any alternate consent forms proposed by the site (collectively, 
the “Consent Forms”) before IRB/EC submission.  The final IRB/EC-approved Consent 
Forms must be provided to the Sponsor for health authority submission purposes according 
to local requirements. 
The Consent Forms must be signed and dated by the patient or the patient’s legally 
authorized representative before his or her participation in the study.  The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study. 
The Consent Forms should be revised whenever there are changes to study procedures or 
when new information becomes available that may affect the willingness of the patient to 
participate.  The final revised IRB/EC-approved Consent Forms must be provided to the 
Sponsor for health authority submission purposes. 
Patients must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study.  For any updated or revised Consent 
Forms, the case history or clinical records for each patient shall document the informed 
consent process and that written informed consent was obtained using the updated/revised 
Consent Forms for continued participation in the study. 
A copy of each signed Consent Form must be provided to the patient or the patient’s legally 
authorized representative.  All signed and dated Consent Forms must remain in each 
patient’s study file or in the site file and must be available for verification by study monitors 
at any time. 
8.3 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE 
This protocol, the Informed Consent Forms, any information to be given to the patient, and 
relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB/EC.  


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The Principal Investigator is responsible for providing written summaries of the status of the 
study to the IRB/EC annually or more frequently in accordance with the requirements, 
policies, and procedures established by the IRB/EC.  Investigators are also responsible for 
promptly informing the IRB/EC of any protocol amendments (see Section 9.5). 
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports or 
other safety-related communications from the Sponsor.  Investigators are responsible for 
ensuring that such reports are reviewed and processed in accordance with health authority 
requirements and the policies and procedures established by their IRB/EC, and archived in 
the site’s study file.  
8.4 
CONFIDENTIALITY 
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location. 
Patient medical information obtained by this study is confidential and may only be disclosed 
to third parties as permitted by the Informed Consent Form (or separate authorization for 
use and disclosure of personal health information) signed by the patient, unless permitted 
or required by law. 
Medical information may be given to a patient’s personal physician or other appropriate 
medical personnel responsible for the patient’s welfare, for treatment purposes. 
Data generated by this study must be available for inspection upon request by national and 
local health authorities, Sponsor monitors, representatives, and collaborators, and the 
IRB/EC for each study site, as appropriate. 
8.5 
FINANCIAL DISCLOSURE 
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study. 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION 
9.1 
STUDY DOCUMENTATION 
The investigator must maintain adequate and accurate records to enable the conduct of the 
study to be fully documented, including but not limited to the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and governmental 
approval.  In addition, at the end of the study, the investigator will receive the patient data, 
which includes an audit trail containing a complete record of all changes to data. 


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9.2 
SITE INSPECTIONS 
Site visits will be conducted by the Sponsor or an authorized representative for inspection 
of study data, patients’ medical records, and eCRFs.  The investigator will permit national 
and local health authorities, Sponsor monitors, representatives, and collaborators, and the 
IRBs/ECs to inspect facilities and records relevant to this study. 
9.3 
ADMINISTRATIVE STRUCTURE 
Please refer to the separate contact list for the contact information of the Sponsor CRO 
designee study personnel. This information can be found at the Roche Thailand Ltd. office, 
and within the Investigator Site File. 
9.4 
PUBLICATION 
OF 
DATA 
AND 
PROTECTION 
OF 
TRADE 
SECRETS 
The results of this study may be published or presented at scientific meetings.  If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to the Sponsor prior 
to submission.  This allows the Sponsor to protect proprietary information and to provide 
comments based on information from other studies that may not yet be available to the 
investigator. 
The Sponsor will comply with the requirements for publication of study results.  In 
accordance with standard editorial and ethical practice, the Sponsor will generally support 
publication of multicenter trials only in their entirety and not as individual center data.  In 
this case, a coordinating investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication of 
the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the appropriate 
Sponsor personnel. 
Any inventions and resulting patents, improvements, and/or know-how originating from the 
use of data from this study will become and remain the exclusive and unburdened property 
of the Sponsor, except where agreed otherwise. 
9.5 
PROTOCOL AMENDMENTS 
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will be 
submitted to the IRB/EC and to regulatory authorities in accordance with local regulatory 
requirements. 
Approval must be obtained from the IRB/EC and regulatory authorities (as locally required) 
before implementation of any changes, except for changes necessary to eliminate an 
immediate hazard to patients or changes that involve logistical or administrative aspects 
only (e.g., change in Medical Monitor or contact information). 


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10. 
REFERENCES 
 
Alessandrino EP, Amadori S, Barosi G, et al. Italian Society of Hematology. Evidence-
and consensus-based practice guidelines for the therapy of primary myelodysplastic 
syndromes. A statement from the Italian Society of Hematology. Haematologica. 
2002;87:1286–306. 
 
Balducci L. Transfusion independence in patients with myelodysplastic syndromes: 
impact on outcomes and quality of life. Cancer. 2006;106:2087–2094. 
 
Bennett JM. Classification of the myelodysplastic syndromes. Clin Haematol 1986;15: 
909-923. 
 
Bowen D, Culligan D, Jowitt S, et al. Guidelines for the diagnosis and therapy of adult 
myelodysplastic syndromes. Br J Haematol. 2003;120:187–200.  
 
Casadevall N, Durieux P, Dubois S, et al. (2004) Health, economic, and quality-of-life 
effects of erythropoietin and granulocyte colony-stimulating factor for the treatment of 
myelodysplastic syndromes: a randomized, controlled trial. Blood. 2004; 104: 321–327. 
 
Cheson BD, Bennett JM, Kantarjian H, et al. Report of an international working group 
to standardize response criteria for myelodysplastic syndromes. Blood. 2000; 96: 
3671-3674. 
 
Economopoulos T, Mellou S, Papageorgiou E, et al. Treatment of anemia in low risk 
myelodysplastic syndromes with granulocytemacrophage colony-stimulating factor plus 
recombinant human erythropoietin. Leukemia. 1999; 13: 1009–1012. 
 
Fenaux P. Myelodysplastic syndromes: from pathogenesis and prognosis to treatment. 
Semin Hematol. 2004; 41: 6–12. 
 
Goldberg SL, Chen E, Corral M, et al. Incidence and clinical complications of 
myelodysplastic syndromes among United States Medicare beneficiaries. J Clin Oncol. 
2010; 28: 2847–2852. 
 
Greenberg PL. Risk factors and their relationship to prognosis in myelodysplastic 
syndromes. Leuk Res 1998;22 Suppl 1:S3-S6. 
 
Greenberg PL, Sun Z, Miller KB, et al. Treatment of myelodysplastic syndrome 
patients with erythropoietin with or without granulocyte colony-stimulating factor: 
results of a prospective randomized phase 3 trial by the Eastern Cooperative Oncology 
Group (E1996) Blood. 2009;114:2393–2400. 
 
Greenberg PL, Attar E, Bennett J, et al. NCCN clinical practice guidelines in oncology: 
myelodysplastic syndromes. J Natl Compr Canc Netw. 2011;9(1):30-56. 
 
Hellström-Lindberg E, Gulbrandsen N, Lindberg G, et al. A validated decision model 
for treating the anaemia of myelodysplastic syndromes with erythropoietin + 
granulocyte colony-stimulating factor: significant effects on quality of life. Br J 
Haematol. 2003; 120: 1037–1046. 
 
Italian Cooperative Group for rHuEpo in myelodysplastic syndromes: A randomized 
double-blind placebo-controlled study with subcutaneous recombinant human 
erythropoietin 
in 
patients 
with 
low-risk myelodysplastic 
syndromes. 
Br. 
J. 
Haematol.1998; 103:1070–1074. 
 
Jädersten M, Malcovati L, Dybedal I, et al. Erythropoietin and granulocyte-colony 
stimulating factor treatment associated with improved survival in myelodysplastic 
syndrome. J Clin Oncol. 2008; 26: 3607–3613. 
 
Jädersten M, Montgomery SM, Dybedal I, et al. Long-term outcome of treatment of 
anemia in MDS with erythropoietin and G-CSF. Blood. 2005; 106: 803–811. 
 
Komrokji RS, Bennett JM. Evolving classifications of the myelodysplastic syndromes. 
Curr Opin Hematol. 2007;14: 98–105. 
 
Malcovati L, Germing U, Kuendgen A, et al. Time-dependent prognostic scoring 
system for predicting survival and leukemic evolution in myelodysplastic syndromes. J 
Clin Oncol 2007; 25: 3503-3510. 


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47 
 
Moyo VM, Lefebvre P, Duh M, et al. Treating the anemia of MDS with erythropoietin: 
Impact of higher dose compared to combination with G/GM-CSF. Proceeding from the 
American Society of Clinical Oncology Conference. Chicago, IL. 2007. Abstract # 7082. 
 
MundLe SD. Advances in erythropoietic growth factor therapy for myelodysplastic 
syndromes. Expert Opin. Biol. Ther. 2006; 6:1099–1104. 
 
Nordic MDS Group. Guidelines for the diagnosis and treatment of Myelodysplastic 
Syndromes and Chronic Myelomonocytic Leukemia. Issue 6. 5th update, 1st of 
December 2011 (http://www.nmds.org/Nordic-Care-Programme) 
 
Oliva EN, Nobile F, Alimena G, et al. Darbepoetin alfa for the treatment of anemia 
associated with myelodysplastic syndromes: efficacy and quality of life. Leuk 
Lymphoma. 2010; 51:1007–1014 
 
Remacha AF, Arrizabalaga B, Villegas A, et al. (1999) Erythropoietin plus granulocyte 
colony-stimulating factor in the treatment of myelodysplastic syndromes. Identification 
of a subgroup of responders. The Spanish Erythropathology Group. Haematologica. 
1999; 84: 1058–1064. 
 
Ria R, Moschetta M, Reale A, et al. Managing myelodysplastic symptoms in elderly 
patients. Clin Interv Aging. 2009; 4: 413–423. 
 
Sekeres MA, Schoonen WM, Kantarjian H, et al. Characteristics of US patients with 
myelodysplastic syndromes: results of six cross-sectional physician surveys.J Natl 
Cancer Inst, 2008; 100: 1542–1551. 
 
SwerdLow S, Campo E, Harris N, et al. Lyon: IARC Press; 2008. WHO classification of 
tumors of hemopoietic and lymphoid tissues. 
 
Terpos E, Mougiou A, Kouraklis A, et al. Prolonged administration of erythropoietin 
increases erythroid response rate in myelodysplastic syndromes: a Phase II trial in 281 
patients. Br. J. Haematol.2002; 118: 174–180. 
 
The Thai Society of Hematology. Guideline for diagnosis and management of 
Myelodysplatic Syndrome (www.tsh.or.th/files_news/newsFile_20110512140230.doc) 
 


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Appendix 1  
Schedule of Assessments 
 
Screening 
treatment phase 
End-of-
Study 
visit 
Visit 
S1 
V1 
V2 
V3 
V4 
F 
Week 
-2 
0 
4 
8 
12 
15a 
Visit window ±  (week) 
 
 
1 
1 
1 
1 
Informed consent b 
X 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
Physical 
examination/vital signs 
X 
X 
X 
X 
X 
X 
CBCc 
X 
X 
X 
X 
X 
X 
Liver function test d 
X 
X 
X 
X 
X 
X 
Creatinine 
X 
X 
X 
X 
X 
X 
Serum EPO 
X 
 
 
 
 
 
Serum Ferritin 
X 
 
 
 
 
X 
Serum pregnancy e 
X 
 
 
 
 
 
Record of RBC 
Transfusion  
X 
X 
X 
X 
X 
X 
Concomitant treatment 
X 
X 
X 
X 
X 
X 
Adverse event 
 
X 
X 
X 
X 
X 
Drug dispensing f 
 
X 
X 
X 
 
 
 
a In case of early discontinuation, end-of-study for safety follow up must be undertaken 4 weeks 
after the last study drug administration  (unless the reason for early withdrawal is withdrawal of 
consent) 
b Written informed consent is required before performing any study-specific tests or procedures. 
Signing of the Informed Consent Form can occur outside the 14-day screening period.  
c Parameters will include haemoglobin (Hb), red blood cell count (RBC), white blood cell count 
(WBC) and differentials, and platelet count  
d Liver function test includes alanine aminotransferase (ALT/SGPT), aspartate aminotransferase 
(AST/SGOT) 
All women of childbearing potential (including those who have had a tubal ligation) will have a 
serum pregnancy test at screening. Patients who are amenorrheic for at least 12 months are not 
considered of childbearing potential. 
f  If haemoglobin level reaches ≥ 12 g/dL at any time, Recormon® should be discontinued until Hb 
levels are  10 g/dL. 
 


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Appendix 2  
International Prognostic Scoring System (IPSS)  
(Greenberg et.al, 1997) 
The 1997 International Prognostic Scoring System (IPSS) for De Novo Myelodysplastic 
Syndrome  
 
Prognostic 
Factor 
Category Score a 
0 (best) 
0.5 
1 
1.5 
2 (worst) 
Marrow 
Blasts 
˂ 5% 
5% - 10% 
- 
11% - 20% 
21% - 30% 
Karyotype 
Good: 
Normal 
isolated –Y, 
isolated 
del(5q) 
or 
isolated 
del(20q) 
Intermediate: 
All karyotypes 
not defined as 
Good or Poor 
Poor: 
Abnormal 
chromosome 
7 
or 
A complex 
karyotype (3 
or more 
anomalies) 
- 
- 
Peripheral 
blood 
cytopenias b 
0 or 1 
2 or 3 
- 
- 
- 
 
a sum all 3 for overall IPSS score  
 
b IPSS definition of Peripheral Blood Cytopenias: Haemoglobin ˂ 10 g/dL, Absolute neutrophil count ˂ 
1,500/mm3, Platelet count ˂ 100,00/mm3  
 
 
 
 


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Appendix 3  
International Working Group (IWG) Response Criteria for MDS  
(Cheson et al. Blood. 2006;108:419‐425) 
 

SAP_001.pdf: 
 
Official Title: 
A PROSPECTIVE OPEN-LABEL STUDY OF THE 
EFFECTIVENESS OF EPOETIN BETA FOR TREATING ANEMIC 
PATIENTS WITH LOW/INTERMEDIATE-1-RISK 
MYELODYSPLASTIC SYNDROME (MDS) 
NCT Number: 
NCT02145026 
Document Date: 
SAP Version 2: 21-June-2019 
 
 


Clinical Study Report: epoetin beta - F. Hoffmann-La Roche Ltd
Protocol ML29005     Report Number 1097901
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CONFIDENTIAL 
 
This is an F. Hoffmann-La Roche Ltd document that contains confidential information.  Nothing 
herein is to be disclosed without written consent from F. Hoffmann-La Roche Ltd. 
 
Recormon—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan ML29005 
STATISTICAL ANALYSIS PLAN 
TITLE: 
A PROSPECTIVE OPEN-LABEL STUDY OF THE 
EFFECTIVENESS 
OF 
EPOETIN 
BETA 
FOR 
TREATING 
ANEMIC 
PATIENTS 
WITH 
LOW/INTERMEDIATE-1-RISK 
MYELODYSPLASTIC SYNDROME (MDS) 
PROTOCOL NUMBER: 
ML29005 
STUDY DRUG: 
Epoetin beta (RO205-3859) 
VERSION NUMBER: 
2 
IND NUMBER: 
N/A 
EUDRACT NUMBER: 
N/A 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
PLAN PREPARED BY: 
, Ph.D. 
DATE FINAL: 
21 Jun 2019 
DATE AMENDED:  
Version1.0:  21 Feb 2016 
 
 
 
 
 
 
 


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TABLE OF CONTENTS 
1. 
BACKGROUND ............................................................................................ 4 
2. 
STUDY DESIGN ........................................................................................... 6 
2.1 
Protocol Synopsis .................................................................... 7 
2.2 
Outcome Measures ................................................................. 8 
2.3 
Determination of Sample Size ................................................. 8 
2.4 
Analysis Timing ....................................................................... 9 
3. 
STUDY CONDUCT ....................................................................................... 9 
3.1 
Randomization Issues ............................................................. 9 
3.2 
Data Monitoring (STEERING COMMITTEE) ........................... 9 
4. 
STATISTICAL METHODS ............................................................................ 9 
4.1 
Analysis Populations ............................................................. 10 
4.1.1 
Per Protocol Population ......................................................... 10 
4.1.2 
Safety Population .................................................................. 10 
4.2 
Analysis of Study Conduct ..................................................... 10 
4.3 
Efficacy Analysis .................................................................... 11 
4.3.1 
Primary Efficacy Endpoint ...................................................... 11 
4.3.2 
Secondary Efficacy Endpoints ............................................... 12 
4.3.3 
Sensitivity Analyses ............................................................... 12 
4.3.4 
Subgroup Analyses ............................................................... 12 
4.4 
Safety Analyses ..................................................................... 13 
4.4.1 
Exposure of Study Medication ............................................... 14 
4.4.2 
Adverse Events ..................................................................... 14 
4.4.3 
Laboratory Data ..................................................................... 14 
4.4.4 
Vital Signs .............................................................................. 14 
4.5 
Missing Data .......................................................................... 14 
4.6 
Interim Analyses .................................................................... 14 
4.7 
References ............................................................................ 22 
 


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LIST OF TABLES 
Table 2 
Example Table Format for Outlining Analysis Timings .................. 9 
 
 
LIST OF APPENDICES 
Appendix 1 
 Protocol Synopsis ...................................................................... 16 
Appendix 2 
 Schedule of Assessments .......................................................... 20 
Appendix 3 
 Statistical Analysis Method ........................................................ 21 


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1. 
BACKGROUND 
Chronic refractory anemia and long-term use of blood transfusions pose a tremendous 
clinical and economic burden to the management of MDS patients. Thus, treatment 
options aimed at maintaining transfusion independence or delaying transfusion 
dependence play an important role in the management of low-risk early disease.  
Of the currently available therapeutic options, Erythropoiesis-stimulating agents (ESAs) 
alone or in combination with GCSF appear to fulfill this goal in a significant proportion of 
MDS patients. In contrast to the application of these growth factors to treat the side effects 
of chemotherapy in other cancers, their use in MDS 
appears to serve  
a therapeutic role since ineffective hematopoiesis, and specifically defective 
erythropoiesis, constitute the basic pathology in MDS. By promoting survival and 
differentiation ESAs overcome excessive apoptosis of erythroid progenitors and, hence, 
are therapeutic in alleviating the basic pathology of these disorders. 
Recombinant erythropoietin (EPO) can correct anaemia in about 20% of MDS when used 
alone and 40% when combined with recombinant human granulocyte colony-stimulating 
factor (G-CSF), and the response rate to EPO + G-CSF is higher than that of symptomatic 
treatment (Casadevall et al., 2004; Economopoulos et al., 1999; Hellstrom-Lindberg et al., 
2003; Remacha et al., 1999) Major prognostic factors for a favourable response to EPO ± 
G-CSF are low endogenous serum EPO levels (<200 or 500 U/l) and relatively low 
transfusion requirement. In patients with a serum EPO level below 500 U/l, response rates 
to EPO + G-CSF reach 60%(Casadevall et al., 2004; Hellstrom-Lindberg et al., 2003). 
Result from prospective randomized phase III trial by the Eastern Cooperative Oncology 
Group (E1996) confirm earlier studies by demonstrating the efficacy of adding G-CSF to 
EPO and higher EPO dose for enhancing erythroid responses in MDS(Greenberg et al., 
2009). Mo yo et al.(Moyo, Lefebvre, & Duh, 2007) also suggest increasing EPO dose may 
have a greater impact on erythroid responses than addition of G/GM-CSF.Three ESAs 
have been used in MDS, epoetin-α and darbepoetin-α in the USA, and in addition epoetin-
β outside of the USA. Several studies have proven the efficacy of these ESAs in eliciting 
erythroid 
response 
in 
low/int-1 
MDS 
patients 
(Mundle, 
2006).  
A pre-therapy endogenous serum erythropoietin (sEPO) level of less than 500 mU/ml and 
transfusion requirement of less than two units/month appear to predict the best response 
to ESA therapy, particularly in low/int-1 disease. As reviewed previously, with the use of 
these criteria for patient selection and that of the standardized response evaluation criteria 
recommended by the International Working Group in MDS, erythroid response rates have 
significantly improved to nearly 60–65% from approximately 20% in the past with their 
earlier use in unselected all-comer MDS patients evaluated for response with variable 
criteria(Mundle, 2006). The responses to ESA alone, or in combination with granulocyte 
colony-stimulating factor (GCSF), appear to be remarkably durable with a median of 23 
months in the absence of transfusions(Jadersten, Montgomery, Dybedal, Porwit-
MacDonald, & Hellstrom-Lindberg, 2005). The responses are observed both in 
transfusion-dependent patients in terms of transfusion avoidance and Hb improvement, 
as well as in transfusion-independent patients in terms of Hb improvement. 


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It is evident that complete transfusion independence is achieved in 30–50% of patients, 
with a noticeable decrease in the mean number of PRBC units required to maintain Hb in 
others. 
To date, no treatment-related side effects have been noted with ESA therapy and 
treatment with ESAs appears to be well-tolerated. In fact, the only largest randomized 
placebo-controlled trial with ESA in MDS conducted thus far showed that the patients 
treated with EPO as a single agent had numerically lower rates of adverse events (32%) 
compared with those on placebo (43%) (Italian Cooperative Study Group for rHuEpo in 
Myelodysplastic et al., 1998). Furthermore, encouragingly, no treatment-related episodes 
of thrombosis or seizures were reported in this trial or even after long-term administration 
of EPO to MDS patients in another large, single-arm trial (Terpos et al., 2002). The 
noticeable absence of therapy-related thrombotic events with EPO treatment of MDS in 
several clinical trials so far is indeed distinguished from even the minimum acceptable risk 
of thrombotic complications of ESAs when used in chemotherapy-induced anemia as 
listed in the drug prescribing information for epoetin-α or darbepoetin-α. Thus, treatment 
of MDS with ESA in general seems to be well tolerated with significant clinical benefits in 
MDS. 
ESA use in MDS is widespread; recent estimates suggest that 60% of MDS patients 
received ESAs(Sekeres et al., 2008). The last update of the 2011 National Comprehensive 
Cancer Network guidelines(Greenberg et al., 2011) acknowledges the fact that anemia is 
a major issue in MDS patients to be addressed even more carefully than in the past with 
parallel statements by the Italian Society of Hematology (Alessandrino et al., 2002), the 
United Kingdom (UK) MDS Guidelines Group(Bowen et al., 2003), Nordic MDS Group 
(Guideline by NMDS group), and the Thai MDS study group (Guideline by The Thai 
Society of Hematology).As improvements in hemoglobin are usually noted 6–8 weeks 
after initiation of an adequate dose of ESA, a minimum 8-week therapeutic trial was 
considered to be indicated. Moreover, it should be noted that ESA doses found to impact 
the anemia of MDS are substantially higher than those used in chronic renal 
insufficiency(Oliva et al., 2010). The addition of granulocyte colony-stimulating factor (G-
CSF), thought to synergize with ESA in producing an erythropoietic effect in MDS patients, 
is suggested for patients who do not manifest a response to ESA (Hellstrom-Lindberg et 
al., 2003; Jadersten et al., 2008). 
The relative durable clinical benefits and lack of adverse effects on survival or rate of 
leukemic transformation may uniquely position ESAs as the eminent therapeutic choice. 
Importantly, the subset of MDS patients benefiting from ESA therapy is now well defined 
as the low-/int-1-risk group with sEPO of less than 500 mU/ml and a PRBC transfusion 
need of less than two units/month. From a benefit–risk perspective, the positive long-term 
outcomes demonstrated with ESAs in a specified group of MDS patients have yet to be 
shown with other therapies. ESAs thus remain a treatment of choice for low-/int-1 MDS 
patients when considered against the significant risks and estimated high costs associated 
with complicated chronic blood transfusions. 
However, the majority of clinical studies of ESAs in MDS patients use EPO-alpha. Few 
data have been published for EPO-beta. This prospective study aim to provide evaluate 
the additional effectiveness and safety profile of Recormon® (EPO-beta) for treatment of 
symptomatic anemia associated with MDS patients for all epoetin formulations review by 
Thai FDA. 


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2. 
STUDY DESIGN 
This is a phase IV, prospective, multi-centre, open label study to assess the efficacy of 
Recormon® 
for 
treating 
anemic 
patients 
with 
low/intermediate-1 
risk 
MDS,  
in approximately 120 adult patients. The primary efficacy endpoint is a proportion of 
patients achieving erythroid response at week 12 according to IWG 2006 definition 
(Cheson et al., 2006). The trial will be conducted at approximately 7 centres nationwide. 
All potential study patients must provide signed written informed consent approved by the 
relevant independent Ethics Committee before undergoing any study-specific procedures. 
Results of the screening assessments must be available and patients must meet all 
eligibility criteria prior to enrolment into the study. The study design is shown in Figure 1. 
 
Figure 1 
Study Scheme 
 
The study consists of a 2-week screening period, a 12-week treatment phase and  
end-of-study visit (see figure 1). After screening, eligible patients will be treated with 
epoetin beta (Recormon®) as recommended in the approved label and international 
guidelines for the use of epoetin in MDS patients, Recormon® dosage will be adjusted on 
the basis of erythroid response. 
During screening period, serum level of endogenous erythropoietin will be assessed,  
as well as liver and kidney function. Bone marrow morphology analysis and karyotyping 
are also performed during screening if they have not been assessed in the 6 months prior 
to participation in the study. Complete blood count test is performed during screening 
period and at every patient’s visit until the end of study visit. The result should be available 
prior to dosing of Recormon®. 
The patient’s erythroid response will be assessed at week 4 and every 4 weeks thereafter, 
until end-of-study visit. Patients who achieve Hb level ≥ 12 g/dL will stop treatment, while 
patients with Hb level ˂ 12 g/dL will continue treatment for the total of 12 weeks. 
Concurrent G-CSF can be administered upon physician discretion. 


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TABLE 1:  Schedule of Assessments  
 
Screening 
treatment phase 
End-of-
Study 
visit* 
Visit 
S1 
V1 
V2 
V3 
V4 
F 
Week 
-2 
0 
4 
8 
12 
15a 
Visit window ±  (week) 
 
 
1 
1 
1 
1 
Informed consent b 
X 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
Physical 
examination/vital signs 
X 
X 
X 
X 
X 
X 
CBCc 
X 
X 
X 
X 
X 
X 
Liver function test d 
X 
X 
X 
X 
X 
X 
Creatinine 
X 
X 
X 
X 
X 
X 
Serum EPO 
X 
 
 
 
 
 
Serum Ferritin 
X 
 
 
 
 
X 
Serum pregnancy e 
X 
 
 
 
 
 
Record of RBC 
Transfusion  
X 
X 
X 
X 
X 
X 
Concomitant treatment 
X 
X 
X 
X 
X 
X 
Adverse event 
 
X 
X 
X 
X 
X 
Drug dispensing f 
 
X 
X 
X 
 
 
a In case of early discontinuation, end-of-study for safety follow up must be undertaken 4 weeks 
after the last study drug administration  (unless the reason for early withdrawal is withdrawal of 
consent) 
b Written informed consent is required before performing any study-specific tests or procedures. 
Signing of the Informed Consent Form can occur outside the 14-day screening period.  
c Parameters will include haemoglobin (Hb), red blood cell count (RBC), white blood cell count 
(WBC) and differentials, and platelet count  
d Liver function test includes alanine aminotransferase (ALT/SGPT), aspartate aminotransferase 
(AST/SGOT) 
e  All women of childbearing potential (including those who have had a tubal ligation) will have a 
serum pregnancy test at screening. Patients who are amenorrheic for at least 12 months are not 
considered of childbearing potential. 
f  If haemoglobin level reaches ≥ 12 g/dL at any time, Recormon® should be discontinued until Hb 
levels are  10 g/dL. 
2.1 
PROTOCOL SYNOPSIS 
The Protocol Synopsis is in Appendix 1.  For additional details, see the Schedule of 
Assessments in Table 1 


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2.2 
OUTCOME MEASURES 
2.2.1 
Efficacy Outcome Measures 
The efficacy outcome measures as hematologic improvement (HI) for this study are as 
follows: 
 
The cumulative proportion of patients achieving hematologic improvement on 
erythroid response (HI-E) at week 12 according to IWG 2006 (Cheson et al., 2006) 
definition as  
 
Hb increase by ı 1.5 g/dL or 
 
Reduction of units of RBC transfusions by an absolute number of at least 4 
RBC transfusions/8 weeks compared with the pre-treatment transfusion 
number in the previous 8 weeks. Only RBC transfusions given for a Hb of  
İ9.0 g/dL pre-treatment will count in the RBC transfusion response evaluation 
 
Proportion of  patients with hematologic improvement onplatelet response (HI-P)  
o Absolute increase of ≥ 30 x 109/L for patients starting with > 20 x 109/L 
platelets. Or  
o Absolute increase to Increase to > 20 x 109/L for patients starting with  < 
20 x 109/L and by at least > 100% 
 
Proportion of patients with hematologic improvement on neutrophil response (HI-
N) (At least 100% increase and an absolute increase > 0.5 x 109/L) 
 
2.2.2 
Safety Outcome Measures 
The safety outcome measures for this study are as follows: 
 
Tolerability and safety of Recormon (Incidence, nature, and severity of adverse 
events) 
Safety assessments will include AEs, SAEs, routine safety laboratory tests, vital signs 
measurements, and recording of concomitant medications. All clinical AEs and SAEs as 
well as laboratory abnormalities will be recorded and graded according to the NCI-CTCAE 
version 4.0. 
Patients will undergo an end- safety assessment 4 weeks after the last Recormon 
administration or after early withdrawal (unless the reason for early withdrawal is 
withdrawal of consent) 
 
2.3 
DETERMINATION OF SAMPLE SIZE 
Sample size based on a 5% significance level and the 80% power with 10% drop out 
resulting of 100 patients in total. 
 
Efficacy: Assuming a 10% withdrawal rate, 100 patients will be enrolled such that 
we expect 90 patients will not withdraw and will remain evaluable.  To give an 
estimate of the precision of this study in terms of estimating the proportion of 
patients with erythroid response, then with 90 evaluable patients in this study, if 
the observed proportion of patients with erythroid response in the study were 0.25, 


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then the half width of the 95% confidence interval for this proportion would be 0.089 
(i.e. the 95% confidence interval would be 0.161 to 0.339). 
 
Safety: Assuming more than 90% of target patients will be administered, so  we 
expect 100 patients will not withdraw and will remain evaluable.  With 100 
evaluable patients in this study, the sample size is sufficient to have at least 92% 
probability of observing a particular adverse event in at least one patient in this 
study, if the true proportion of patients in the target population as a whole who 
experience this event is 0.0274 i.e. approximately 1 in every 37 patients. 
2.4 
ANALYSIS TIMING 
There will be 2 analysis timing defined for the study analyses: one interim and final 
analysis. The interim and final analysis are planned, when first 30 and 120 enrolled 
patients have completed their 12-week treatment, respectively.  
Table 2 
Example Table Format for Outlining Analysis Timings 
Analysis 
Timing of 
Analysis 
Percent 
Information 
Adjusted 
Two-Sided 
Alpha Level 
Cumulative 
Two-Sided 
Alpha Level 
Power 
(%) 
First interim 
30 patients 
25% 
0.0155 
0.031 
80 
Final 
100 patients 
100% 
0.025 
0.05 
80 
 
3. 
STUDY CONDUCT 
3.1 
RANDOMIZATION ISSUES 
This is an open-label non randomized single-arm study. 
3.2 
DATA MONITORING (STEERING COMMITTEE) 
NA 
4. 
STATISTICAL METHODS 
Descriptive statistic would be performed using t-test and pair t-test for independent or 
dependent continuous variables to test significant, while chi-square or ANOVA would 
perform to test difference between nominal two group variables or more than 2 groups 
with continuous variables respectively. Univariate and multivariate logistic regression 
would be performed in accordance with ANCOVA in order to controlled confounding 
variable factors to realize adjusted mean. 
All descriptive statistic would be presented as 95% confidence interval or mean and 
standard deviation (SD). 


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Demographic and baseline characteristics of efficacy and safety variable (primary and 
secondary endpoints) including exploratory endpoint will be summarized as table and 
above criteria for statistical significant would be used. 
 All demographic baseline summaries will base on intent-to-treat (ITT)  population. Safety 
endpoint analysis will be presented as grade 3, 4, overall survival and adverse events 
4.1 
ANALYSIS POPULATIONS 
The efficacy analysis will be performed based on the intent-to-treat (ITT) population 
defined as all enrolled patients who receive at least one dose of study medication.  
The Safety population will include all patients who receive at least one dose of study 
medication. 
4.1.1 
Intention to treat Population 
The efficacy analysis will be performed based on the intent-to-treat (ITT) population 
defined as all enrolled patients who receive at least one dose of study medication. 
4.1.2 
Safety Population 
The Safety population will include all patients who receive at least one dose of study 
medication. 
4.2 
ANALYSIS OF STUDY CONDUCT 
All baseline and demographic characteristics will be summarized for the ITT and safety 
populations for overall. Included will be age, gender, height, weight, hematologic 
laboratory values, and concomitant disease history. Pregnancy test results (serum test) 
will be summarized for women of child-bearing potential for the safety population; and 
blood pressure level will also be summarized as safety population. 
Notes: 
 
Age will be calculated as the integer ((Date of Consent – Date of Birth) / 365.25). 
Only year of birth is collected. Day and month will be replaced with the 1st of the 
month and year (January) respectively. Age will be presented/summarized as a 
whole number. Derived age will be used in all summaries. 
 
Blood pressure categories were classified by JCN8 criteria (James et al., 2014) 
(percentages and number of patients are derived from the overall efficacy 
population) will be used as the cut off points for the blood pressure categories 
 
For patients aged > 60 years who had systolic blood pressure (SBP) < 150 
mmHg and diastolic blood pressure (DBP) <90 mmHg was considered no 
hypertension. 
 
For patients aged < 60 years who had SBP <140 mmHg and DBP <90 
mmHg was considered no hypertension. 
 
For patients regardless of aged who had either diabetes or chronic kidney 
disease (CKD), SBP < 140 mmHg and DBP <90 mmHg was considered no 
hypertension. 


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 
Medical history will be coded according to the latest version of Medical Dictionary 
for Regulatory Activities (MedDRA).  
 
Table. 3 Demographic data  
Characteristics 
Number (Percentage) 
Mean± SD/ Median (min-max)* 
Age  
 
Gender ( Female) 
 
Proportion 
of 
patients 
who 
have 
concomitant disease (HT, DM, CKD if 
any) 
 
Proportion of patients who required 
transfusion** 
 
RBC unit required for transfusion 
 
Hematologic laboratory 
 
 Hb (g/dL) 
 
 Platelet (106 /µL) 
 
 Neutrophil (106 /µL) 
 
 WBC  
 
*where applicable 
** at least 1 units prior study entry would be counted 
 
4.3 
EFFICACY ANALYSIS 
Primary endpoint will be percentage of patients who achieved response based on 
response criteria according to IWG2006 at week 12 
Secondary endpoint will be percentage of events that occurred based on NCI-CTCAE 
version 4.0. 
 
4.3.1 
Primary Efficacy Endpoint 
Primary efficacy endpoint would be percentage of patients who achieved response based 
on response criteria according to IWG2006 which were  
 
An increasing of Hb of ≥1.5 g/dL at week 12.  
Statistical significant of base line and treatment at week 12 as adjusted mean would be 
performed using multivariate logistic regression. Covariate variables such as age, gender, 
hypertension categories would be controlled as confounding factors using ANCOVA. 


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Pairwise dependent t-test using continuous variables (percentage of response patients) 
would be performed to test statistical significant at type I error of 0.05. 
 
Analysis will be based on pool data, stratified by centers were not pre-specified and would 
not be included in primary analysis.  
 
4.3.2 
Secondary Efficacy Endpoints 
Secondary efficacy endpoints include platelet and neutrophil response at week 12, 
defined by the following IWG 2006 criteria and will analyzed for the PP population.  
 
% patients with platelet response (pre-treatment < 100×109/L) at week 12 defined 
by IWG 2006 as following; 
 Absolute increase of ≥ 30 x 109/L for patients starting with > 20 x 109/L platelets or  
Increase from < 20 x 109/L to > 20 x 109/L and by at least 100%. 
 
 
% patients with neutrophil response (pre-treatment < 1.0 x 109/L) at week 12 
defined by IWG 2006 as following; 
 At least 100% increase and an absolute increase > 0.5 x 109/L 
 
The percentages of patient who achieve the above hematologic responses at week 12, 
according to the IWG 2006 criteria will be presented in summary tables.   
The secondary efficacy endpoint would be presented as percentage of patients who 
achieved above platelet or neutrophil response criteria  
Statistical significant by type I error (α) level would be 0.05. statistical significant difference 
would be tested using dependent pair t-test in which covariate, e.g., age, gender, 
hypertension categories was controlled by ANCOVA method.  
Table. 4 Hematologic improvement (HI) 
Response  
Number  
Percentage 
Hematologic responses  
 
 
Platelet response  
 
 
Neutrophil response  
 
 
 
4.3.3 
Sensitivity Analyses 
N/A 
4.3.4 
Subgroup Analyses 
Not currently planned  


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4.4 
SAFETY ANALYSES 
Safety analysis would be performed by collecting samples for laboratory test by study 
site’s local laboratory for analysis prior to Recormon® administration and at the end of 
study. Any adverse events which considered related or non-related must be reported as 
descriptive statistics (frequencies versus total patients) categorized by major organ 
functions. The following variables would be analyzed for safety endpoints at the end of 
study period comparing with baseline. 
 
Hematologic laboratories;  CBC, WBC and differentials and platelet count, ferritin 
level 
 
Liver function: serum creatinine alanine aminotransferase (ALT/SGPT) and 
aspartate aminotransferase (AST/SGOT) in all patients. 
 
Kidney function : creatinine level  
 
Cardiovascular disease : blood pressure level  
 
Changes in concomitant medication (if any) 
All safety data would be reported based on organ function both total adverse event (AE) 
and serious adverse event (SAE). 
Table. 5  Adverse event and serious adverse events by sites of organ (HI) 
Organ site of adverse event 
AEs 
 
SAEs 
 
no. 
% 
no. 
% 
Blood and lymphatic system disorders 
 
 
 
 
Gastrointestinal disorders 
 
 
 
 
Vascular disorders 
 
 
 
 
Infections and infestations 
 
 
 
 
Psychiatric disorders 
 
 
 
 
Skin and subcutaneous tissue disorders 
 
 
 
 
Eye disorders 
 
 
 
 
Cardiac disorders 
 
 
 
 
 
 
 
 
 


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Table. 6 Changes in laboratory values  
Laboratory 
Screening 
(Mean±SD) 
Week 12 
(Mean±SD) 
P-values 
Hematologic : CBC, WBC, 
Neutrophil, Platelet, Hb 
 
 
 
Liver : SGOT, SGPT  
 
 
 
Kidney ; creatinine  
 
 
 
Etc. 
 
 
 
*pair t-test : p<0.05 considered significant, CBC = completed blood count, WBC= white 
blood cell, Hb= Hemoglobin level, SGOT=Serum glutamic oxaloacetic transaminase, 
SGPT=serum glutamic-pyruvic transaminase. 
Descriptive statistic would be applied for safety analysis. All safety variables would be 
tested  for significant level using type I error of 5% (α level =0.05). Pair t-test would be 
performed to test significant with all above safety variables. Chi-square test or Fisher’s 
exact would be performed for frequency tables (if any), where appropriate statistical 
assumption based on statistical test applied. 
4.5 
MISSING DATA 
All key efficacy and safety variables of missing data would be verified with study site; and 
in case that data verification was available, double verification with central CRO and study 
site coordinators would accomplished. In case of no variables could be achieved, missing 
data would be treated by imputing method using bootstrap technique. 
4.6 
INTERIM ANALYSES 
- The interim analysis was planned once thirtieth patients finished study at week 12; and  
patients deposition diagram based on screening, dosage adjustment and responses 
would be also demonstrated. (Figure.2) The interim efficacy for primary or secondary 
endpoint including safety analysis would be performed based on analysis methodology in 
section 4.3.1 and statistical assumption in table 2.  


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Figure 2 
patients deposition diagram 
 
An interim analysis would base on early stopping rule by Simon two stages(Cornelia 
& Meinhard, 2011), (Appendix 3)  


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Appendix 1  
Protocol Synopsis 
PROTOCOL SYNOPSIS 
TITLE: 
A prospective open-label study of the effectiveness of epoetin 
beta for treating anemic patients with low/intermediate-1-risk 
myelodysplastic syndrome (MDS)  
PROTOCOL NUMBER: 
ML29005 
VERSION NUMBER: 
1 
EUDRACT NUMBER: 
To be determined 
IND NUMBER: 
To be determined 
TEST PRODUCT: 
epoetin beta (RO205-3859) 
PHASE: 
IV 
INDICATION: 
Treatment of symptomatic anemia associated with 
Myelodysplastic Syndromes (MDS)   
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
Objectives 
 
Primary Objectives 
To assess the safety profile of Recormon for treating anemic patients with low/intermediate 1 
risk MDS  
 
Secondary Objectives 
To assess the efficacy of Recormon for treating anemic patients with low/intermediate 1 risk 
MDS  
 
Study Design 
The study consists of a 2-week baseline phase, a 12-week treatment phase and end-of-study visit 
(see figure). After screening, eligible patients will be treated with epoetin beta (Recormon®). As 
recommended in the approved label and international guidelines for the use of epoetin in MDS 
patients, Recormon dosage will be adjusted on the basis of erythroid response (see 
Investigational Medicinal Products part). 
At baseline, serum levels of endogenous erythropoietin are assessed, as well as liver and kidney 
function. Bone marrow morphology analysis and karyotyping are also performed at baseline if 
they have not been assessed in the 6 months prior to participation in the study. Complete blood 
count is performed at baseline and every 4 weeks until the end of the 12-week period. 
 
The patient’s erythroid response will be assessed at week 4 and every 4 weeks thereafter, until 
end-of-study visit. Patients who achieve Hb level ≥12 g/dl will stop treatment, while patients with 


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Hb level 12 g/dl will continue treatment for the total of 12 weeks. Concurrent G-CSF can be 
administered upon physician discretion. 
Patients can withdraw from the study at any time in case of: (a) severe adverse reaction or 
severe intercurrent illness; (b) a request by the patient or by the investigator; and (c) evolution 
into high-risk MDS or overt leukemia.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Number of Patients 
120 patients expected to be enrolled. 
 


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Target Population 
Adult anemic MDS patients (≥18 years old) in the low and intermediate 1 risk group according 
tothe International Prognostic Scoring System (IPSS). 
 
Inclusion Criteria 
• 
Written informed consent 
• 
Adult patients ( ≥ 18 years old) 
• 
Low and intermediate-1 risk MDS (having IPSS risk score  1) confirmed with bone marrow 
morphology analysis and karyotyping within 6 months prior to participation in the study 
• 
No previous treatment with hematopoietic growth factors within 3 months prior to study 
entry 
• 
Symptomatic anemia (Hb < 10 g/dl) 
• 
Serum Erythropoietin  500 mU/ml   
• 
Require no red blood cell transfusion or dependent on  2 units/month 
• 
Clinically stable for at least one month prior to entry into the study 
 
Exclusion Criteria 
• 
Contraindications to Recormon treatment, Hypersensitivity to the active substance or any of 
the excipients 
• 
Poorly controlled hypertension 
• 
History of Acute myeloid leukemia (AML) or high risk for AML 
• 
Pregnancy or breast-feeding 
• 
Women of childbearing potential without effective contraception 
• 
High likelihood of early withdrawal or interruption of the study 
• 
Administration of another investigational drug within 1 month before screening or planned 
during the study period 
 
Procedures (summary) 
 
Enrolment 
All potential study patients must provide signed written informed consent before undergoing any 
study specific procedure. 
Women of childbearing potential had to agree to use two reliable forms of contraception 
simultaneously or to practice complete sexual abstinence. 
Baseline (Day -14 to Day 1) 
Patients will undergo the following assessments within 14 days prior to enrolment into the study, 
unless the procedure/assessment has already been conducted during this time period as part of 
the patient’s routine clinical care: 
• 
Demographics, medical history, and concomitant medications 
• 
General physical examination, height, weight, measurement of vital signs (including blood 
pressure, pulse, and body temperature) 
• 
Laboratory examination: Hemoglobin (Hb), Serum erythropoietin (EPO), Liver function 
tests (LFTs), Creatinine, Serum Ferritin, and Complete blood count (CBC) 
• 
Transfusion need 
12-week treatment phase 
Patients will see the doctor every 4 weeks until 12 weeks. At each visit the patients will undergo 
the following examinations: 


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• 
Assessment of any AEs / SAEs + relevant concomitant medication 
• 
Physicsal examination 
• 
Laboratory examination: Hb, LFT, Creatinine, and CBC 
• 
Transfusion need 
End-of-study visit 
4 weeks after last administration of study drug (week 12) or after early withdrawal (unless the 
reason for early withdrawal is withdrawal of consent), all enrolled patients will undergo the following 
assessments at a post-treatment safety follow-up visit: 
• 
Assessment of any AEs / SAEs 
• 
Physical examinatioin 
• 
Laboratory examination: Hb, LFT, Creatinine, and CBC, Serum Ferritin 
• 
Transfusion need 
• 
Concomitant medication 
 
Study oversight will be assured by a steering committee to guide study conduct, to review the 
results at the end of the study, to approve and sign-off the study report and to prepare and submit 
a publication to a peer-review journal. The steering committee will be made up of investigators and 
Roche representatives and will meet at regular intervals. 
 
Length of Study 
Safety Outcome Measures 
Efficacy Outcome Measures 
The cumulative proportion of patients achieving erythroid response at week 12.  
Erythroid response was defined according to IWG 2006 definition as  
- 
Hb increase by ≥ 1.5 g/dL 
- 
Reduction of units of RBC transfusions by an absolute number of at least 4 RBC 
transfusions/8 weeks compared with the pretreatment transfusion number in the previous 8 
weeks. Only RBC transfusions given for a Hgb of ≤ 9.0 g/dL pretreatment will count in the 
RBC transfusion response evaluation 
 
Investigational Medicinal Products 


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Appendix 2  
Schedule of Assessments 
 
Baseline 
treatment phase 
End-of-
Study 
visit* 
Visit 
S1 
V1 
V2 
V3 
V4 
F 
Week 
-2 
0 
4 
8 
12 
16* 
Visit window ±  (week) 
 
 
1 
1 
1 
1 
Informed consent 
X 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
Physical examination 
X 
X 
X 
X 
X 
X 
CBC 
X 
X 
X 
X 
X 
X 
Liver function test  
X 
X 
X 
X 
X 
X 
Creatinine 
X 
X 
X 
X 
X 
X 
Serum EPO 
X 
 
 
 
 
 
Serum Ferritin 
X 
 
 
 
 
X 
Transfusion needed 
X 
X 
X 
X 
X 
X 
Concomitant treatment 
X 
X 
X 
X 
X 
X 
Adverse event 
 
X 
X 
X 
X 
X 
Drug administration** 
 
X 
X 
X 
X 
 
Treatment adjustment 
 
 
X 
 
 
 


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Appendix 3  
Statistical Analysis Method 
1. The analysis of this study will be conducted using STATA 13 software (STATA CORP); 
and both early stopping rule and hypothesis testing for different will also be 
implemented as followings. 
2. The early stopping rule by simon two stage design for observational study will be 
implemented. An assumption based on sample size calculation (section 2.3) will be 
used as followings,  
 
The response rate of epoetin beta should be more than 25%, whereas the 
response rate of best supportive care would be 7%.  
 
The type I error was 5% with 80% power (type II error) to detect the differences 
A design is indexed by four values  r1/n1  r/n ; and the study would be stopped if there 
were <  r1 responders out of the first n1 participants. The null hypothesis would be 
rejected if there were > r responders out of n participants.  
While R(p) was the probability of concluding that there were no evidence of a treatment 
effects and EN(p)  was the expected sample size 
Type I error = .05, Power        = .8 
H0: p = p0 
H1: p = p1 >=p0, where p0 is .07 and p1 is .25 
The study is stopped if there are <= r1 responders out of the first n1 participants. The 
null hypothesis is rejected if there are >r responders out of n participants 
So, the treatment would be stopped if alternative hypothesis (Ha > 0.25) were rejected. 
The minimax and the optimal design which demonstrates the minimal and optimal 
number of patients to detect the efficacy was used(Cornelia & Meinhard, 2011).  
3. The hypothesis testing of response rate in this study compared to baseline assumption 
which were 0.25 would also performed using chi-square test as followings  
H0: p1 =0.25  
H1: p1 ≠ 0.25 by chi-square test, where α =0.05  
The hypothesis H0 would be rejected if p value by chi square test < 0.05 which 
indicate the response of intervention in this study was different from hypothesis  


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