Conditions: Low and Int 1-risk Myelodysplastic Syndrome
Keywords: myelodysplastic syndrome MDS myelodysplasia blood disorder cytopenias low blood counts progressive bone marrow failure adult ICL570 deferasirox erythropoietin erythropoiesis NF-kB pathway hematopoiesis.
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 28
Healthy volunteers: no

Brief summary:
The primary purpose of this trial was is to assess the effect of treatment with deferasirox combined with erythropoietin vs. erythropoietin alone on erythropoiesis in patients with low- and int-1-risk myelodysplastic syndrome. The addition of deferasirox to erythropoietin can lead to a potential synergism with the reduction of reactive oxygen species, through both the NF-kB pathway and the control of free toxic iron. This may create a better environment in the bone marrow for a better response with erythropoietin.

This study was designed to test in a prospective way the combination of deferasirox with erythropoietin in terms of their effect on hematopoiesis.

Detailed description:
This study did not meet the original enrollment objective of 60 patients and was terminated without extending enrollment past original planned LPFV of 31-Oct-2016.

Arms:
arm 1: Patients will receive erythropoietin 40,000 units/week. If after 4 weeks erythroid improvement is inadequate, dose will be escalated to 60,000 units/week. If after 12 weeks of treatment, erythroid improvement in inadequate, patients will be switched to the combination arm. At any time when erythroid response is achieved, erythropoietin treatment will be stopped until end of study. arm 2: Patients will receive deferasirox dispersible tablet (DT) 10 mg/kg/day or deferasirox film-coated tablet (FCT) 7 mg/kg/day in combination with erythropoietin 40,000 units/week. If after 4 weeks erythroid improvement is inadequate, erythropoietin dose will be escalated to 60,000 units/week. If after 12 weeks of treatment, erythroid improvement in inadequate, patients will be discontinued from the study. At any time when erythroid response is achieved, erythropoietin treatment will be stopped until end of study. Patients will continue deferasirox treatment.

Interventions: intervention 1: Deferasirox DFX, DT intervention 2: Erythropoietin alpha intervention 3: Deferasirox DFX, FCT
Intervention descriptions: intervention 1: provided as dispersible tablets for oral use in 125 and 250, 500 mg intervention 2: None intervention 3: provided as film-coated tablet for oral use in 90, 180, 360 mg strengths

Protocol document:
Prot_000.pdf: 
Clinical Development 
Deferasirox (ICL670) 
Clinical Trial Protocol CICL670A2421 / NCT01868477 
An open-label, phase II, randomized, pilot study to assess 
the effect in term of erythroid improvement of deferasirox 
combined with erythropoietin compared to erythropoietin 
alone in patients with low- and int-1-risk myelodysplastic 
syndrome 
Authors 
 
Document type 
Amended Protocol Version 
EUDRACT number 
2013-000981-12 
Version number 
03 (Clean) 
Development phase 
II 
Document status 
Final 
Release date 
06-Aug-2015
Property of Novartis 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 


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Table of contents 
Table of contents .................................................................................................................. 2 
List of figures ....................................................................................................................... 6 
List of tables ........................................................................................................................ 6 
List of abbreviations ............................................................................................................ 7 
Glossary of terms ................................................................................................................. 9 
Amendment 3..................................................................................................................... 10 
Summary of previous amendments ................................................................................... 16 
Protocol summary .............................................................................................................. 35 
1 
Background ........................................................................................................................ 38 
1.1 
Overview of disease pathogenesis, epidemiology and current treatment .............. 38 
1.2 
Introduction to investigational treatment(s) and other study treatment(s) ............. 41 
1.2.1 
Overview of Deferasirox (ICL670) ....................................................... 41 
1.2.2 
Overview of EPO .................................................................................. 44 
2 
Rationale ............................................................................................................................ 45 
2.1 
Study rationale and purpose ................................................................................... 45 
2.2 
Rationale for the study design ................................................................................ 46 
2.3 
Rationale for dose and regimen selection .............................................................. 47 
2.4 
Rationale for choice of combination drugs ............................................................ 48 
3 
Objectives and endpoints ................................................................................................... 48 
4 
Study design ...................................................................................................................... 51 
4.1 
Description of study design .................................................................................... 51 
4.2 
Definition of end of the study ................................................................................ 56 
4.3 
Early study termination .......................................................................................... 56 
5 
Population .......................................................................................................................... 56 
5.1 
Patient population .................................................................................................. 56 
5.2 
Inclusion criteria .................................................................................................... 57 
5.3 
Exclusion criteria ................................................................................................... 58 
6 
Treatment ........................................................................................................................... 59 
6.1 
Study treatment ...................................................................................................... 59 
6.1.1 
Dosing regimen ..................................................................................... 59 
6.1.2 
Ancillary treatments .............................................................................. 63 
6.1.3 
Guidelines for continuation of treatment ............................................... 63 
6.1.4 
Treatment duration ................................................................................ 63 
6.2 
Dose escalation guidelines ..................................................................................... 64 
6.3 
Dose modifications ................................................................................................ 64 


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6.3.1 
Dose modification and dose delay ........................................................ 64 
6.3.2 
Treatment interruption and treatment discontinuation .......................... 67 
6.3.3 
Follow-up for toxicities ......................................................................... 67 
6.3.4 
Anticipated risks and safety concerns of the study drug ....................... 68 
6.4 
Concomitant medications ...................................................................................... 68 
6.4.1 
Permitted concomitant therapy .............................................................. 68 
6.4.2 
Permitted concomitant therapy requiring caution and/or action ............ 68 
6.4.3 
Prohibited concomitant therapy ............................................................. 69 
6.5 
Patient numbering, treatment assignment or randomization ................................. 69 
6.5.1 
Patient numbering ................................................................................. 69 
6.5.2 
Treatment assignment or randomization ............................................... 69 
6.5.3 
Treatment blinding ................................................................................ 69 
6.6 
Study drug preparation and dispensation ............................................................... 70 
6.6.1 
Study drug packaging and labeling ....................................................... 70 
6.6.2 
Drug supply and storage ........................................................................ 70 
6.6.3 
Study drug compliance and accountability ........................................... 70 
6.6.4 
Disposal and destruction ........................................................................ 71 
7 
Visit schedule and assessments ......................................................................................... 71 
7.1 
Study flow and visit schedule ................................................................................ 71 
7.1.1 
Screening ............................................................................................... 75 
7.1.2 
Treatment period ................................................................................... 76 
7.1.3 
End of Treatment Visit including study completion and premature 
withdrawal ............................................................................................. 76 
7.1.4 
Follow up period ................................................................................... 77 
7.2 
Assessment types ....................................................................................................... 77 
7.2.1 
Efficacy assessments ............................................................................. 77 
7.2.2 
Safety and tolerability assessments ....................................................... 78 
 
 
7.2.4 
Other assessments .................................................................................. 82 
8 
Safety monitoring and reporting ........................................................................................ 82 
8.1 
Adverse events ....................................................................................................... 82 
8.1.1 
Definitions and reporting ...................................................................... 82 
8.1.2 
Laboratory test abnormalities ................................................................ 83 
8.1.3 
Adverse events of special interest ......................................................... 83 
8.2 
Serious adverse events ........................................................................................... 84 
8.2.1 
Definitions ............................................................................................. 84 


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8.2.2 
Reporting ............................................................................................... 84 
8.3 
Emergency unblinding of treatment assignment ................................................... 85 
8.4 
Pregnancies ............................................................................................................ 85 
8.5 
Warnings and precautions ...................................................................................... 85 
8.6 
Data Monitoring Committee .................................................................................. 85 
8.7 
Steering Committee ............................................................................................... 86 
9 
Data collection and management ....................................................................................... 86 
9.1 
Data confidentiality ............................................................................................... 86 
9.2 
Site monitoring ...................................................................................................... 86 
9.3 
Data collection ....................................................................................................... 87 
9.4 
Database management and quality control ............................................................ 87 
10 Statistical methods and data analysis ................................................................................. 88 
10.1 
Analysis sets .......................................................................................................... 88 
10.1.1 
Full Analysis Set ................................................................................... 88 
10.1.2 
Safety Set............................................................................................... 88 
10.1.3 
Per Protocol Set ..................................................................................... 88 
10.2 
Patient demographics/other baseline characteristics ............................................. 88 
10.3 
Treatments (study treatment, concomitant therapies, compliance) ........................ 89 
10.4 
Primary objective ................................................................................................... 89 
10.4.1 
Variable ................................................................................................. 89 
10.4.2 
Statistical hypothesis, model, and method of analysis .......................... 89 
10.5 
Secondary objectives ............................................................................................. 89 
10.5.1 
To assess the effect of treatment with DFX+EPO and EPO alone 
on hematological response within 24 weeks of treatment .................... 89 
10.5.2 
To assess the effect of treatment on erythropoiesis within 24 weeks 
in patients who were non-responder to EPO alone after 12 weeks 
and switched to DFX+EPO ................................................................... 91 
10.5.3 
To assess time to erythroid response in patients treated with 
DFX+EPO and patients treated with EPO alone .................................. 91 
10.5.4 
To assess the effect of treatment with EPO alone on erythropoiesis 
after 24 weeks of treatment ................................................................... 91 
10.5.5 
To estimate time to erythroid response in patients who were non- 
responder to EPO alone after 12 weeks and switched to DFX+EPO ...91 
10.5.6 
To estimate time to hematological response in patients treated with 
DFX+EPO and EPO alone within 24 weeks ......................................... 92 
10.5.7 
To estimate duration of erythroid response among responders 
treated with EPO alone .......................................................................... 92 


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10.5.8 
To estimate duration of erythroid response among responders 
treated with DFX+EPO ......................................................................... 93 
10.5.9 
To assess iron parameters in patients randomized to EPO alone, 
DFX+EPO and in patients randomized to EPO alone and switched 
to DFX+EPO after 12 weeks ................................................................. 93 
10.5.10 
To assess Hb parameters in patients in patients randomized to EPO 
alone, DFX+EPO and in patients randomized to EPO alone and 
switched to DFX+EPO after 12 weeks .................................................. 93 
10.5.11 
Safety objectives ................................................................................... 93 
10.5.12 
Resource utilization ............................................................................... 95 
10.5.13 
Patient-reported outcomes ..................................................................... 95 
 
 
10.7 
Interim analysis ...................................................................................................... 95 
10.8 
Sample size calculation .......................................................................................... 96 
10.9 
Power for analysis of key secondary variables ...................................................... 96 
11 Ethical considerations and administrative procedures ....................................................... 96 
11.1 
Regulatory and ethical compliance ........................................................................ 96 
11.2 
Responsibilities of the investigator and IRB/IEC/REB .......................................... 96 
11.3 
Informed consent procedures ................................................................................. 96 
11.4 
Discontinuation of the study .................................................................................. 97 
11.5 
Publication of study protocol and results ............................................................... 97 
11.6 
Study documentation, record keeping and retention of documents ....................... 97 
11.7 
Confidentiality of study documents and patient records ....................................... 98 
11.8 
Audits and inspections ........................................................................................... 98 
11.9 
Financial disclosures .............................................................................................. 98 
12 Protocol adherence ............................................................................................................. 98 
12.1 
Amendments to the protocol .................................................................................. 99 
13 References (available upon request) ................................................................................ 100 
14 Appendices ...................................................................................................................... 105 
14.1 
Appendix 1: WHO classification of primary MDS ............................................. 105 
14.2 
Appendix 2: Modified International Working Group response criteria for 
hematologic improvement ................................................................................... 106 
14.3 
Appendix 3: Erythropoietin Treatment and Monitoring Guidelines for MDS 
patients ................................................................................................................. 107 
14.4 
Appendix 4: Microscopic Urine Panel ................................................................. 109 


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List of figures 
Figure 4-1 
Study Design ......................................................................................... 53 
 
 
List of tables 
Table 1-1 
FAB classification of MDS ................................................................... 38 
Table 3-1 
Objectives and related endpoints .......................................................... 49 
Table 4-1 
EPO Dosing ........................................................................................... 55 
Table 6-1 
Dose and treatment schedule ................................................................. 59 
Table 6-2 
Dosing table for 10 mg/kg/day for deferasirox DT (Exjade®) .............. 61 
Table 6-3 
Dosing table for 5 mg/kg/day for deferasirox DT (Exjade®) ................ 61 
Table 6-4 
Dosing table for 7 mg/kg/day for deferasirox FCT ............................... 62 
Table 6-5 
Dosing table for 3.5 mg/kg/day for deferasirox FCT ............................ 62 
Table 7-1 
Visit evaluation schedule ....................................................................... 72 
Table 7-2 
Clinical laboratory parameters collection plan...................................... 79 
 
 
Table 10-1 
Criteria for hematological response and hematologic improvement .... 90 
Table 14-1 
WHO classification of primary MDS .................................................. 105 
Table 14-2 
Modified International Working Group response criteria for 
hematologic improvement ................................................................... 106 
Table 14-3 
Baseline testing and eligibility criteria for MDS ................................. 107 
Table 14-4 
Initial dosing of EPO for MDS ............................................................ 107 
Table 14-5 
Adjusting EPO dosing for MDS .......................................................... 107 
Table 14-6 
Recommended monitoring .................................................................. 108 
Table 14-7 
Microscopic Urine Panel ..................................................................... 109 


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List of abbreviations 
 
AE 
Adverse Event 
ALT 
Alanine aminotransferase/glutamic pyruvic transaminase/GPT 
AML 
Acute Myeloid Leukemia 
ANC 
Absolute neutrophil count 
Anti-HBs 
Hepatitis B Surface Antibody 
Anti-HCV 
Hepatitis C Antibody 
AST 
Aspartate aminotransferase/glutamic oxaloacetic transaminase/GOT 
ATG 
Antithymocyte globulin 
b.i.d. 
bis in diem/twice a day 
CMML 
Chronic myelomonocytic Leukemia 
CrCl 
Creatinine Clearance 
CRF 
Case Report/Record Form; the term CRF can be applied to either EDC or Paper 
CRO 
Contract Research Organization 
CSR 
Clinical study report 
CSR addendum 
An addendum to Clinical Study Report (CSR) that captures all the additional information that 
is not included in the CSR 
DFO 
Deferoxamine 
DFX 
Deferasirox 
DLT 
Dose Limiting Toxicity 
DS&E 
Drug Safety and Epidemiology 
DT 
Dispersible Tablet 
ECG 
Electrocardiogram 
EOT 
End of study treatment 
EPO 
Erythropoietin 
FAB 
French-American-British Cooperative Group 
FAS 
Full Analysis Set 
FCT 
Film-Coated Tablet 
G-CSF 
Granulocyte colony stimulating factor 
 
 
GF 
Growth factor 
GM-CSF 
Granulocyte macrophage colony stimulating factor 
Hb 
Hemoglobin 
HBsAg 
Hepatitis B surface Antigen 
HCV 
Hepatitis C 
HGF 
Hematopoietic growth factor 
HIV 
human immunodeficiency virus 
i.v. 
Intravenous(ly) 
IB 
Investigator Brochure 
ICH 
International Conference on Harmonization 
ICT 
Iron chelation therapy 
IEC 
Independent Ethics Committee 
 
 
 
 
 
 
Int-1 (risk) 
Intermediate-1 (risk) 
 


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IO 
Iron Overload 
IPSS 
International Prognostic Scoring System 
IRB 
Institutional Review Board 
ITT 
Intention To Treat 
IWG 
International Working Group 
IWR 
Interactive Web Response System 
LIC 
Liver Iron Concentration 
LPI 
Labile plasma iron 
MAP 
Master Analysis Plan documents project standards in the statistical methods which will be 
used within the individual clinical trial RAP documentation 
MDS 
Myelodysplastic syndromes 
MPD 
Myeloproliferative disease 
MRI 
Magnetic Resonance Imaging 
MTD 
Maximum Tolerated Dose 
NF-kB 
nuclear factor 'kappa-light-chain-enhancer' of activated B-cells 
o.d. 
Omne in die/once a day 
OS 
Overall survival 
p.o. 
per os/by mouth/orally 
PCR 
Polymerase Chain Reaction 
PHI 
Protected Health Information 
PI 
Prescribing Information 
PP 
Per Protocol 
PS 
Performance Status 
RA 
Refractory Anemia 
RAEB 
Refractory Anemia with Excess of blasts 
RAEB-T 
RAEB in transformation 
RAP 
The Report and Analysis Plan (RAP) is a regulatory document which provides evidence of 
preplanned analyses 
RARS 
Refractory Anemia with Ringed sideroblasts 
RBC 
Red blood cell 
RCMD 
Refractory Cytopenia with multilineage Dysplasia 
REB 
Research Ethics Board 
ROS 
Reactive Oxygen Species 
s.c. 
Subcutaneous(ly) 
SAE 
Serious Adverse Event 
SEC 
Study Evaluation Completion 
SF 
Serum Ferritin 
SJS 
Stevens-Johnson Syndrome 
SOP 
Standard Operating Procedure 
 
 
TfR 
Transferrin Receptor 
TIBC 
Total Iron Binding Capacity 
 
 
TSAT 
Transferrin Saturation 
ULN 
Upper limit of normal 
WHO 
World Health Organization 
 


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Glossary of terms 
Assessment 
A procedure used to generate data required by the study 
Control drug 
A study treatment used as a comparator to reduce assessment bias, preserve blinding 
of investigational drug, assess internal study validity, and/or evaluate comparative 
effects of the investigational drug 
Cycles 
Number and timing or recommended repetitions of therapy are usually expressed as 
number of days (e.g.: q28 days) 
Dose level 
The dose of drug given to the patient (total daily or weekly etc.) 
Enrollment 
Point/time of patient entry into the study; the point at which informed consent must be 
obtained (i.e. prior to starting any of the procedures described in the protocol) 
Investigational drug 
The study treatment whose properties are being tested in the study; this definition is 
consistent with US CFR 21 Section 312.3 and is synonymous with “investigational new 
drug.” 
Investigational 
treatment 
Drug whose properties are being tested in the study as well as their associated placebo 
and active treatment controls (when applicable). This also includes approved drugs 
used outside of their indication/approved dosage, or that are tested in a fixed 
combination. Investigational treatment generally does not include other study 
treatments administered as concomitant background therapy required or allowed by the 
protocol when used in within approved indication/dosage 
Medication number 
A unique identifier on the label of each study treatment package which is linked to one 
of the treatment groups of a study 
Other study treatment 
Any drug administered to the patient as part of the required study procedures that was 
not included in the investigational treatment 
Patient Number 
A unique identifying number assigned to each patient/subject/healthy volunteer who 
enrolls in the study 
Period 
A subdivision of the study timeline; divides stages into smaller functional segments 
such as screening, baseline, titration, washout, etc. 
Premature patient 
withdrawal 
Point/time when the patient exits from the study prior to the planned completion of all 
study treatment administration and/or assessments; at this time all study treatment 
administration is discontinued and no further assessments are planned, unless the 
patient will be followed for progression and/or survival 
Randomization number 
A unique treatment identification code assigned to each randomized patient, 
corresponding to a specific treatment arm assignment 
Stage related to study 
timeline 
A major subdivision of the study timeline; begins and ends with major study milestones 
such as enrollment, randomization, completion of treatment, etc. 
Stop study participation 
Point/time at which the patient came in for a final evaluation visit or when study 
treatment was discontinued whichever is later 
Study treatment 
Includes any drug or combination of drugs in any study arm administered to the patient 
(subject) as part of the required study procedures, including placebo and active drug 
run-ins. 
In specific examples, it is important to judge investigational treatment component 
relationship relative to a study treatment combination; study treatment in this case 
refers to the investigational and non-investigational treatments in combination. 
Study treatment 
discontinuation 
Point/time when patient permanently stops taking study treatment for any reason; may 
or may not also be the point/time of premature patient withdrawal 
Supportive treatment 
Refers to any treatment required by the exposure to a study treatment, e.g. 
premedication of vitamin supplementation and corticosteroid for pemetrexed disodium. 
Treatment group 
A treatment group defines the dose and regimen or the combination, and may consist 
of 1 or more cohorts. Cohorts are not expanded, new cohorts are enrolled. 
Variable 
Identifier used in the data analysis; derived directly or indirectly from data collected 
using specified assessments at specified timepoints 


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Amendment 3 
The purpose of protocol amendment 3 is to allow the use of deferasirox film-coated tablets as 
detailed below, to modify the inclusion criteria of Serum Ferritin related to transfusional iron 
and to allow for the same Creatinine Clearance limits in all eligible patients. 
At the time of writing this protocol amendment, 11 patients out of 60 planned patients have 
been randomized in the study and 21 patients failed screening. Due to the early status of the 
study, there is no anticipated impact of this amendment on the study outcome. 
 
Amendment rationale 
• Addition of Deferasirox film-coated tablet (DFX FCT) as optional study medication 
Introducing the new deferasirox film-coated tablet (FCT) as optional study medication in this 
clinical trial will make it easier for patients to administer DFX with improved palatability. 
The FCT can be taken on an empty stomach or after a light meal, while the deferasirox 
dispersible tablet (DT) (Exjade®) has to be taken on an empty stomach, at least 30 minutes 
before a meal. 
In the USA, the deferasirox FCT is commercially available under the trade name Jadenu® 
since March 2015. The FCT is planned to become available in different countries globally 
before end of 2016. 
The film-coated tablet (FCT) contains the same active substance and is strength-adjusted to 
achieve comparable exposure to the currently approved dispersible tablet (DT). Thus the two 
formulations are not expected to have an impact on primary endpoint and statistical analysis 
for combination data of deferasirox with EPO in the present study. 
Study sites will be allowed to offer the new formulation for deferasirox FCT as study 
medication if local regulations permit. 
In order to minimize potential dosing errors, patients who are ongoing and receive DFX DT 
will continue with the DT. It is not permitted to change the deferasirox formulation during 
treatment. 
In conclusion, offering patients deferasirox FCT is expected to support easier drug 
administration and protocol compliance. 
• Change the inclusion criterion of lower limit of Creatinine Clearance to add: 
Patients with creatinine clearance between 40 and less than 60 mL/min, who do not 
present with additional risk factors that may impair renal function, may be eligible 
at the discretion of the investigator. 
Deferasirox is registered in more than 120 countries globally. Prescribing information in 
many of these countries allows for treatment of patients presenting with a CrCl of 40-60 
mL/min with caution and close monitoring. As of protocol amendment 2 study eligibility 
criteria allows including patients according to the local prescribing information. 
Allowing for a the lower limit of CrCl to > 40 mL/min within the setting of a controlled 
clinical trial for the patient population in this study is supported by an analysis of pooled data 
of MDS and non-MDS patients with iron overload treated with DFX from 5 different studies. 
The data from 1798 patients were included in the pooled analysis. It was concluded that DFX 


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at recommended doses may be used in patients with CrCl of 40 - 60 mL/min with close 
monitoring (Schmid 2009). 
In this study DFX at the dose of 10 mg/kg (DT) or 7 mg/kg (FCT) is combined with EPO 
treatment. There is no evidence that the EPO i.v. alone has an impact on renal safety (Eprex® 
i.v. injection, Product Information, 2012). The drug has been used in patients with chronic 
renal failure. Therefore no overlapping renal toxicity is expected. 
Patient monitoring and visit schedule in this study are in line with recommendations for 
monitoring of patients with renal function parameter of CrCl between 40 and less than 60 
mL/min. 
In conclusion, using the same CrCl limit across the study population will allow for collecting 
additional renal safety data in this MDS patient population with DFX at the dose of 10 
mg/kg/day in combination with EPO in a controlled setting. 
• Change the inclusion criterion of upper limit of Serum Ferritin from 1,000 ng/mL to 
1,500 ng/mL (Values within 10% difference above 1500 ng/mL or 10% difference 
below 300 ng/mL may be accepted at discretion of the investigator if the patient 
represents the investigational population. However a notification to the study team is 
required.) 
Presently, no data suggests that serum ferritin (SF) levels of 1000 - 1500 ng/mL would change 
the probability of hematologic response and would impact the homogeneity of the MDS study 
population. 
Public data indicate a high prevalence of red blood cells transfusions 6 month prior to MDS 
diagnosis based on Hb levels < 10 g/dL in these elderly patients (Kelaidi 2010). 
There is also an increasing understanding of the ineffective erythropoiesis and non- 
transfusional iron overload in MDS patients (Fertrin 2014) which explains observed increased 
SF levels in IPSS lower risk MDS patients at diagnosis even without blood transfusion 
dependence (Gattermann 2005). Even though patients must not be transfusion dependent in 
the present study, they may have received up to 10 RBC transfusions. This transfusional iron 
together with non-transfusional iron accumulation leads to frequently observed SF levels > 
1000 ng/mL in the study population. 
The label of DFX allows chelation at SF > 1000 ng/mL. Clinical practice guidelines for 
treatment of IPSS lower risk MDS patients recommend initiation of supportive care with iron 
chelation at SF levels > 1000 ng/mL - 2500 ng/mL or if the patient received > 20-50 Units of 
packed red blood cells (Gattermann 2008). 
In conclusion, the increase of the upper limit of SF for eligibility of this study continues to be 
in accordance with current clinical practice and corresponds with the target MDS patient 
population. 


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Changes to the protocol 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions. 
Changes to cover page 
• Exjade© was deleted. 
• Name of new statistician was added to the ‘Authors’. 
Changes to list of abbreviations 
• DT for ‘Dispersible tablet’ was added. 
• FCT for ‘Film-Coated tablet’ was added. 
• q.d. for ‘quaque die/ daily/ once daily was deleted. 
Changes to protocol summary 
• Inclusion criteria: 
• Term ‘units’ was deleted from history of transfusions < 10 RBC. 
• SF upper limit was extended from 1,000 ng/mL to 1,500 ng/mL. 
• Investigational and reference therapy: 
• Dispersible tablet (DT) was added to Deferasirox 10 mg/kg/day. 
• Deferasirox film-coated tablet (FCT) 7 mg/kg/day was added. 
• Term ‘EPO’ was added to both strengths of Erythropoietin alpha. 
Changes  to Section 1.1 Overview of disease pathogenesis, epidemiology and current 
treatment 
• Year was corrected in one article reference (Chan 2008). 
Changes to Section 1.2.1 Overview of Deferasirox (ICL670) 
• Clarification was added on formulation of deferasirox dispersible tablet (DFX DT). 
• Term ‘DT’ was added throughout the paragraph where applicable. 
• Information was added on Deferasirox film-coated tablet (DFX FCT) formulation. 
Changes to Section 1.2.1.2 Clinical experience 
• Clarification was added that DFX is not approved to treat anemic patients without 
transfusional iron overload. 
Changes to Section 2.1 Study rationale and purpose 
• Year was corrected in one article reference (Chan 2008). 
Changes to Section 2.3 Rationale for dose and regimen selection 
• Term ‘DT’ was added to Deferasirox 10 mg/kg/day. 
• Information was added on the dose of DFX FCT formulation which is established at 7 
mg/kg/day. 
Changes to Section 4.1 Description of study design 
• ‘ICL670, Exjade® 10 mg/kg/day’ was deleted 


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• Information was added that the dose of DFX DT will be 10 mg/kg/day and the dose of 
DFX FCT will be 7 mg/kg/day. At the time when DFX FCT study drug becomes available 
at a study site, all new patients who are randomized to combination therapy will receive 
the DFX FCT. Patients who are ongoing and receive DFX DT will continue with the DT. 
It is not permitted to change formulation during treatment. 
• Term ‘DT’ was added to Deferasirox 10 mg/kg/day in the ‘Treatment phase’ paragraph. 
• Term ‘q.d.’ was deleted from DFX DT 10 mg/kg/day in the ‘Treatment phase’ paragraph. 
• Information was added on DFX FCT 7 mg/kg/day p.o. in the ‘Treatment phase’ paragraph. 
• Information was added in the ‘Treatment phase’ paragraph that at the time when DFX 
FCT study drug becomes available at a study site, all new patients who are randomized to 
combination therapy will receive the DFX FCT. Patients who are ongoing and receive 
DFX DT will continue with the DT. It is not permitted to change formulation during 
treatment. 
• Clarification was added on RBC transfusion and dependence in the ‘Treatment phase’ 
paragraph. 
Changes to Figure 4-1 Study Design 
• Term ‘DT’ was added to Deferasirox 10 mg/kg/day. 
• DFX FCT 7 mg/kg/day was added to the figure. 
Changes to Table 4-1 EPO Dosing 
• Term ‘DT’ was added to Deferasirox 10 mg/kg/day in the header and footnote of the table. 
• Information was added on DFX FCT 7 mg/kg/day in the header and footnote of the table. 
Changes to Section 5.2 Inclusion criteria 
• Inclusion criterion 6 was changed. Term ‘units’ was deleted. Clarification was added on 
RBC transfusion and dependence. 
• Inclusion criterion 10 was changed. Information was added that patients with creatinine 
clearance between 40 and less than 60 mL/min, who do not present with additional risk 
factors that may impair renal function, may be eligible at the discretion of the investigator. 
• Inclusion criterion 14 was changed. Upper limit of SF was changed from 1,000 ng/mL to 
1,500 ng/mL (Values within 10% difference above 1500 ng/mL or 10% difference below 
300 ng/mL may be accepted at discretion of the investigator if the patient represents the 
investigational population. However a notification to the study team is required.) 


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Changes to Section 6.1 Study treatment 
• Term ‘DT’ was added to Deferasirox. 
• Information was added on DFX FCT 7 mg/kg/day film-coated tablet. 
• Information was added that at the time when DFX FCT study drug becomes available at a 
study site, all new patients who are randomized to combination therapy will receive the 
DFX FCT. Patients who are ongoing and receive DFX DT will continue with the DT. It is 
not permitted to change formulation during treatment. 
Changes to Section 6.1.1 Dosing regimen 
• Term ‘DT’ was added to Deferasirox throughout the ‘Deferasirox DT (10 mg/kg/day, 
Exjade®)’ paragraph. 
• An example was added to explain the calculation of daily dose for DFX DT. 
• New paragraph was added on ‘Deferasirox FCT (7 mg/kg/day)’ to explain the dosing 
regimen. An example was also added to explain the calculation of daily dose for DFX 
FCT. 
Changes to Table 6-1 Dose and treatment schedule 
• Term ‘DT’ was added to Deferasirox. 
• Term ‘q.d.’ was changed to ‘once daily’. 
• Information was added on DFX FCT 7 mg/kg/day film-coated tablet. 
Changes to Table 6-2 Dosing table for 10 mg/kg/day for deferasirox DT (Exjade®) 
• Terms ‘DT’ and ‘Exjade®’ were added to the title. 
Addition of Table 6-3 Dosing table for 5 mg/kg/day for deferasirox DT (Exjade®) 
• Dosing table was added for deferasirox DT 5 mg/kg/day. 
Addition of Table 6-4 Dosing table for 7 mg/kg/day for deferasirox FCT 
• Dosing table was added for deferasirox FCT 7 mg/kg/day. 
Addition of Table 6-5 Dosing table for 3.5 mg/kg/day for deferasirox FCT 
• Dosing table was added for deferasirox FCT 3.5 mg/kg/day. 
Changes to Section 6.3.1 Dose modification and dose delay 
• Term ‘DT’ was added to DFX throughout the section. 
• Information was added on DFX FCT standard dose and dose adjustments. 
Changes to Section 6.3.1.1 Change in patient’s weight 
• Reference was added on DFX FCT Dosing Table. 
• Clarification was added on reference for DFX DT dosing table. 
Changes to Section 6.3.1.2 Elevations in serum creatinine 
• Term ‘DFX DT’ was added throughout the section. 
• Information was added on DFX FCT dose reduction, re-initiation and re-escalation. 
Changes to Section 6.3.1.3.1 Stevens-Johnson syndrome (SJS) 
• Term ‘Exjade’ was replaced by ‘DFX’. 


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Changes to Section 6.3.1.3.2 Skin Rash other than SJS 
• Term ‘DFX DT’ was added throughout the section. 
• Information was added on DFX FCT dose management. 
Changes to Section 6.3.1.4 Increased liver enzyme levels 
• Term ‘DT’ was added to DFX. 
• Information was added on DFX FCT dose re-initiation and escalation. 
Changes to Section 6.3.1.6 Dose modification criteria for auditory (decreased hearing) 
and ocular (lens opacities) disturbances 
• Term ‘DFX DT’ was added. 
• Information was added on DFX FCT dose reduction. 
Changes to Section 7.1.2 Treatment period 
• Term ‘DT’ was added to DFX. 
• Term ‘q.d.’ was deleted from DFX DT. 
• DFX FCT was added. 
Changes to Table 7-2 Clinical laboratory parameters collection plan 
• Information was added that the whole Microscopic Panel is listed in Table 14-7. 
Addition of Table 14-7 Microscopic Urine Panel 
• Table was added for Microscopic Urine parameters in Appendix 14.4. 
 
IRB/IEC 
A  copy  of  this  amended  protocol  will  be  sent  to  the  Institutional  Review  Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. In addition, if the changes herein affect the Informed Consent, sites are 
required to update and submit for approval a revised Informed Consent that takes into account 
the changes described in this amended protocol. 


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Summary of previous amendments 
 
Amendment 2 
At the time of writing this protocol amendment, 5 patients out of 60 planned patients have 
been randomized in the study and 6 patient failed screening. Due to the early status of the 
study, there is no anticipated impact of this amendment on the study outcome. 
 
Amendment rationale 
• Change the inclusion criterion of upper limit of documented diagnosis of MDS 
disease from < 2 years to < 3 years 
This protocol was updated to change upper limit of documented diagnosis of MDS disease 
from < 2 years to < 3 years. 
This inclusion criterion was modified to address a common reason for pre-screening failure 
observed among lower risk MDS patients that are being considered for the study. Patients 
were prohibited from entering the trial solely, because they have just passed the 2 year 
boundary. Although this boundary was introduced based on expert advice to ensure a 
homogenous MDS study population, there is no data to suggest that lower risk MDS patients 
with a limited need for supportive treatment over 3 years instead of 2 years represent a 
different disease population. 
Many patients are asymptomatic at MDS diagnosis and blood cytopenias or other problems 
are identified as part of a routine blood count. Those lower risk MDS patients may be 
managed in watch and wait approach for quite some time before requiring active supportive 
treatment, including ESA, according to MDS treatment guidelines (Malcovati 2013). 
In addition, the subgroup of IPSS low risk MDS patients have a median OS of 5,7 years; in 
Intermediate-1 (Int-1) risk group the median OS is 3,6 years. Therefore extending the upper 
boundary is adequate and will now allow lower risk MDS patients who develop a limited need 
for supportive treatment 2-3 years after diagnosis and matching the entry criteria to participate 
in the study. 
• Change the inclusion criterion of lower limit of creatinine clearance from ≥ 60 
mL/min to above the concentration limit in locally approved prescribing information 
This protocol was updated to change lower limit of creatinine clearance (CrCl) ≥ 60 mL/min 
CrCl above the concentration limit in locally approved prescribing information (PI). 
The median age at diagnosis for MDS patients is 70-75 years (Vardiman 2009). The age- 
related reduction in CrCl is accompanied by a reduction in the daily urinary creatinine 
excretion due to reduced muscle mass. In addition a gender related difference is known with 
lower CrCl in women. Thus in aged women a CrCl of 60ml/min may represent a lower limit 
of normal. 
Lowering the limit of CrCl to > 40 mL/min if supported by the PI is supported by an analysis 
of pooled data of MDS and non-MDS patients with iron overload from 5 different studies that 
was presented at ASH 2009. The data from 1798 patients that were included in the analysis 
showed that MDS patients were more likely to present with a baseline CrCl < 60mL/min. 


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However patients with a baseline CrCl < 60mL/min did not have a greater decline in renal 
function over 13 months study period than those with baseline > 60mL/min. It was concluded 
that DFX may be used in patients with CrCl of 40-60 mL/min with close monitoring (Schmid 
2009). 
Based on this analysis, in the majority of prescribing information globally a contraindication 
to DFX is for patients with a CrCl of < 40 mL/min for countries where this is in accordance 
with the local PI of DFX. In a global monitored clinical trial setting including patients with 
CrCl of ≥ 40 mL/min will generate additional safety information in this patient sub-group. 
• Include patients with stable steroid treatment for other chronic medical conditions 
than adrenal failure is allowed 
This protocol was updated to clarify that patients receiving steroids or immunosuppressive 
therapy for the improvement of hematological parameters must not be enrolled in the study; 
however patients on steroid treatment for other chronic medical conditions  than  adrenal 
failure may be enrolled if the condition and treatment was stable or improving over at least 2 
months prior to screening. 
This update was added to address the fact that the incidence and prevalence of chronic 
inflammatory diseases like Rheumatoid arthritis increases with age, with a peak in the sixth 
decade of life (Symmons 2002). In an Australian study it was found that arthritis is the most 
common prevalent comorbidity among cancer patients across all ages (43.8%) (Caughey 
2008). Chronic inflammatory diseases are among the common comorbidities of an elderly 
population such as MDS patients. Oral corticosteroids represent a standard of care treatment 
(Woodworth 2013). This condition is acceptable at study entry if likely to be stable 
throughout the 24 weeks study period. 
• Exclude patients with hepatic impairment fulfilling criteria of Child-Pugh Class B or 
C 
This protocol was updated to exclude patients with hepatic impairment fulfilling criteria of 
Child-Pugh Class B or C. 
Exjade should not be used in patients with hepatic impairments fulfilling Child-Pugh Class C. 
MDS patients presenting with hepatic impairment fulfilling Child-Pugh Class C are excluded. 
It is recommended to reduce the initial standard dose of 20 mg/kg by 50% in case of Child- 
Pugh Class B hepatic impairment. Since this study investigates if the addition of 10 mg/kg 
DFX to standard of care with EPO is superior to EPO alone further initial reduction is not 
allowed. As a consequence MDS patients presenting with hepatic impairment fulfilling Child- 
Pugh Class B are excluded. 
• Guidance on treating patients with Stevens-Johnson syndrome 
Dose modification guidelines to skin disorders were updated to provide guidance on treating 
patients with Stevens-Johnson syndrome. It is now clarified that the adverse event Stevens- 
Johnson syndrome requires immediate permanent discontinuation of deferasirox and the 
management of patients according to standard clinical practice. 


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• Guidance on concomitant administration of deferasirox with CYP1A2 substrates 
that have a narrow therapeutic index and the concomitant use of bile acid 
sequestrates 
Guidance was added regarding the concomitant administration of DFX with CYP1A2 
substrates that have a narrow therapeutic index and the concomitant use of bile acid 
sequestrates in alignment with the Exjade prescribing information. 
Bile acid sequestrates belong to the class of lipid lowering drugs. The bile acid resins are 
highly positively charged molecules that bind to the negatively charged bile acids in the 
intestine and are not absorbed. They have the potential to bind to vitamins, hormones or 
medications such as DFX in the intestine and result in sub-therapeutic serum levels. As the 
standard dose of DFX in this study is already low, the risk of reaching sub-therapeutic levels 
is considerable if co-administered with bile acid sequestrates. 
• Introduction of Per Protocol set, grouping for safety analyses and supportive 
analyses 
• Introduce the per protocol (PP) set for analyzing the primary and secondary objectives 
using the PP set in addition to Full Analysis Set (FAS) population and clarify the 
grouping for the safety analyses. 
• Clarify secondary objectives related to hematological response, iron parameters and 
Hb parameters and adding supportive analyses to secondary end-points. 
• Revision of analysis sets of primary and secondary objectives 
Primary objective: 
• Analysis of primary objective of erythroid response within 12 weeks of treatment will be 
performed also at PP set in addition to FAS population. 
Secondary objectives: 
• All secondary efficacy endpoints will be analyzed on the FAS and PP set. This change has 
been made to be able to determine the biological effect of adding DFX to the standard 
treatment with respect to different outcome parameters and the fact that the major 
deviations which can impact the parameters related efficacy analysis should be avoided by 
using the PP set. 
Secondary objectives related to hematological response: 
• All patients will be evaluated according to the change in hematological parameters Hb, 
neutrophil count, and platelet count. Patients fulfilling the IWG 2006 pre-treatment 
criteria at baseline and the on- treatment criteria for parameter increase are defined as 
responders. Patient with increasing Hb or cell counts but not fulfilling IWG 2006 pre- 
treatment criteria at baseline will be evaluated separately. 
• Analysis of the secondary objective on hematological response and on time to 
hematological response of patients randomized to EPO and remaining in the EPO 
throughout 24 weeks is added. Patients fulfilling the IWG 2006 pre-treatment criteria 
at baseline and the on- treatment criteria for parameter increase are defined as 
responders. Patient with increasing Hb or cell counts but not fulfilling IWG 2006 pre- 
treatment criteria at baseline will be evaluated separately. 


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• Table included for criteria of hematologic improvement and hematological response. 
Secondary objective on iron parameters: 
• Analysis by 24 weeks will be performed on patients remaining in EPO arm 
throughout 24 weeks, remaining in EPO+DFX arm throughout 24 weeks and patients 
who switched from EPO to EPO+DFX after 12 weeks is added. 
Secondary objective on Hb parameters: 
• Analysis by 24 weeks will be performed on patients remaining in EPO arm 
throughout 24 weeks, remaining in EPO+DFX arm throughout 24 weeks, and patients 
who switched from EPO to EPO+DFX after 12 weeks is added. 
 
Changes to the protocol 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions. 
Changes to list of abbreviations 
• CrCl for ‘Creatinine Clearance’ was added. 
• FAS for ‘Full Analysis Set’ was added. 
• Int-1 (risk) for ‘Intermediate-1 (risk)’ was added. 
• ITT for ‘Intention To Treat’ was added. 
• PI for ‘Prescribing Information’ was added. 
• PP for ‘Per Protocol’ was added. 
• SJS for ‘Stevens-Johnson Syndrome’ was added. 
Changes to protocol summary 
• Inclusion criteria: 
• Time since diagnosis of MDS disease was extended from ≥ 3 months and < 2 years to 
≥ 3 months and < 3 years. 
• Exclusion criteria: 
• Clarification was provided that stable steroid treatment for adrenal failure or other 
chronic medical conditions are allowed during the study. 
• Clarification was provided that B12 and folate deficient patients with or without 
clinical symptoms must not be enrolled in the study. 
Changes to Section 1.1 Overview of disease pathogenesis, epidemiology and current 
treatment 
• Terms ‘erythropoietin’ and ‘deferasirox’ were abbreviated to simplify the text. 
Changes to Section 1.2.1 Overview of deferasirox 
• Information on deferasirox was updated and descripted text on deferasirox simplified. 
• Term ‘deferasirox’ was abbreviated to simplify the text. 


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Changes to Section 1.2.1.1 Non-clinical experience 
• Descriptive text on non-clinical experience of deferasirox was simplified. 
• Reference to the current Investigators’ Brochure was added. 
• Term ‘deferasirox’ was abbreviated to simplify the text. 
Changes to Section 1.2.1.2 Clinical experience 
• Number of patients treated with deferasirox in clinical trials and exposure information 
with commercial deferasirox was updated according to most current information. 
• Term ‘deferasirox’ was abbreviated to simplify the text. 
Changes to Section 1.2.2 Overview of EPO 
• Term ‘erythropoietin’ was abbreviated to simplify the text. 
• Further information on the risk and benefit of EPO in MDS patients was added. 
Changes to Section 2 Rationale 
• Term ‘deferasirox’ was abbreviated to simplify the text. 
Changes to Table 3-1 Objectives and related endpoints 
• Term ‘deferasirox’ was abbreviated to simplify the text. 
• Wording ‘deferasirox combined with EPO’ was simplified to ‘DFX+EPO’. 
• Secondary objective and endpoint on hematologic improvement changed to hematological 
response and patients treated with EPO alone within 24 weeks of treatment were added. 
• Secondary endpoint on time to erythroid response in patients who were non-responder to 
EPO alone within 12 weeks and switched to DFX+EPO was specified to be measured 
from week 13 to week 24. 
• Secondary objective on time to hematologic improvement response changed to 
hematological response and patients treated with EPO alone within 24 weeks of treatment 
were added. 
• Secondary endpoint on duration of erythroid response among responders treated with EPO 
alone was specified to be measured within the whole 24 weeks period. 
• Secondary endpoint on duration of erythroid response among responders treated with 
DFX+EPO was specified to be measured among patients randomized to EPO+DFX up to 
week 24 and for patients switched from EPO to DFX+EPO from week 13 to week 24. 
• Secondary objective and endpoint on assessment of iron parameters was changed to be 
measured by change in SF from baseline to every visit instead of monthly throughout the 
study and the patients to be considered changed to patients randomized to EPO alone, 
EPO+DFX and in patients randomized to EPO and switched to EPO+DFX after 12 weeks. 
• Secondary objective and endpoint on assessment of Hb parameters was changed to be 
measured by change in Hb from baseline to every visit instead of monthly throughout the 
study and the patients to be considered changed to patients randomized to EPO alone, 
EPO+DFX and in patients randomized to EPO and switched to EPO+DFX after 12 weeks. 
• Supportive analyses on hematologic improvement for patients who do not satisfy the IWG 
2006 pre-treatment criteria were added. 


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• Supportive analyses on total hematological response were added. 
• Supportive analyses on time to hematologic improvement for patients who do not satisfy 
the IWG 2006 pre-treatment criteria were added. 
• Supportive analyses on time to total hematological response were added. 
Changes to Section 4.1 Description of study design 
• Term ‘deferasirox’ was abbreviated to simplify the text. 
• Clarification was added that no RBC transfusions are allowed after randomization. 
• Information was added that RBC transfusion dependence is defined as ≥2 U RBC /month 
during the past 3 month. 
Changes to Section 4.2 Definition of end of the study 
• Definition of end of the study was modified to provide clarification that the study will end 
when the last patient will have either withdrawn from the study or completed the study, 
whichever occurs earlier. 
Changes to Section 5.2 Inclusion criteria 
• Inclusion criterion 3 was changed. Upper limit of documented diagnosis of MDS disease < 
2 years was changed to < 3 years. 
• Inclusion criterion 5 was changed. Redundant information was deleted that patients who 
require RBC transfusions must not be enrolled in the study and that patients must be 
withdrawn from the study anytime when transfusion as rescue therapy is needed. 
Information was added that Hb values within 5% difference above 10g/dL or 5% 
difference below 8 g/dL mL may be accepted at discretion of the investigator if the patient 
represents the investigational population. However a notification to the study team is 
required. 
• Inclusion criterion 6 was specified. Information was added that patients who are RBC 
transfusion dependent must not be enrolled in the study and that patients must be 
withdrawn from the study anytime when transfusion as rescue therapy is needed. 
Information was added that RBC transfusion dependence is defined as ≥2 U RBC /month 
during the past 3 month. 
• Inclusion criterion 9 was specified. Information was added such that the mean value of 
serum creatinine of Screening Visit 1 and 2 will be used for eligibility criterion. 
• Inclusion criterion 10 was changed. Lower limit of CrCl ≥ 60 mL/min was changed to 
above the limit in locally approved PI to allow for a lower limit of ≥ 40 mL/min in the 
respective countries. 
• Inclusion criterion 14 was specified. Information was added that SF values within 10% 
difference above 1000 ng/mL or 10% difference below 300 ng/mL may be accepted at 
discretion of the investigator if the patient represents the investigational population. 
However a notification to the study team is required. 


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Changes to Section 5.3 Exclusion criteria 
• Term ‘deferasirox’ was abbreviated to simplify the text. 
• Exclusion criterion 3 was specified. Information was added that also stable steroid 
treatment for other chronic medical conditions than adrenal failure is allowed. 
• Exclusion criterion 4 was specified. Information was added that B12 and folate deficient 
patients with or without clinical symptoms must not enter the study. 
• Exclusion criterion 10 was modified. Information was added that patients with hepatic 
impairment fulfilling criteria of Child-Pugh Class B or C must not enter the study. 
• Exclusion criterion 12 was modified. Redundant information was deleted that patients 
with B12 and folate deficiencies must not enter the study. 
• Exclusion criterion 15 was modified to align with the effective contraception wording as 
per Exjade prescribing information and Novartis pregnancy guidelines. 
Changes to Section 6.1 Study treatment 
• Terms ‘erythropoietin’ and ‘deferasirox’ were abbreviated to simplify the text. 
Changes to Section 6.1.1 Dose regimen 
• Terms ‘erythropoietin’ and ‘deferasirox’ were abbreviated to simplify the text. 
• Information was added that EPO must be self-administered via the subcutaneous route by 
the patient or competent personal and that the patient will be instructed by the investigator 
to take the study drug as prescribed. 
• Treatment instructions were modified to clarify that treatment ‘will’ be done as described 
in the text instead of ‘should’ be done as described. 
Changes to Section 6.1.2 Ancillary treatments 
• Information was added so that steroid treatment for chronic medical conditions is allowed, 
if stable or improving over at least 2 months prior to screening. 
• Clarification was added that no RBC transfusions are allowed after randomization and 
patients who are RBC transfusion dependent must not be enrolled in the study. 
Changes to Section 6.1.4 Treatment duration 
• Clarification was provided that the primary objective will be assessed ‘by’ 12 weeks of 
treatment instead of ‘at’ 12 weeks of treatment. 
• Clarification was provided that patients who showed Hb increase ≥ 1 g/dL ‘by’ week 12 
will be assessed for full hematological response instead of patients who showed Hb 
increase ≥ 1 g/dL ‘at’ week 12. 
• Clarification was provided that patients with ≥ 50% decrement from maximum response 
levels in granulocytes or platelet or reduction in Hb level by ≥1.5 g/dL or patient requiring 
blood transfusion at any time will be discontinued from the study. 
Changes to Section 6.3.1 Dose modification and dose delay 
• Clarification was provided that the dose of DFX must not be escalated above 10 
mg/kg/day. 


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Changes to Section 6.3.1.1 Change is patient’s weight 
• Information was added so that the dose of study drug will also be recalculated if the 
change in body weight exceeds 10% of the weight compared to the last dose adjustment 
due to change in patient’s body weight. 
Changes to Section 6.3.1.2 Elevations in serum creatinine 
• Information was added so that serum creatinine should be monitored during the study as 
stated in the visit evaluation schedule Table 7-1. 
• Information on dose reduction due to serum creatinine increase was specified so that the 
dose of deferasirox will be reduced to 5 mg/kg/day until serum creatinine returns to below 
the age adjusted ULN. 
• Information was added so that it is recommended to check fluid balance and ensure 
adequate hydration of the patient. 
• Information was added to state that that standard dose of deferasirox is 10 mg/kg/day. 
• Guidance was added regarding treatment discontinuation and caution based on CrCl. 
Changes to Section 6.3.1.3 Skin disorders 
• This section was separated into two sub-sections in order to differentiate between Stevens- 
Johnson syndrome (Section 6.3.1.3.1) and Skin Rash other than Stevens- Johnson 
syndrome (Section 6.3.1.3.2). 
• Information was added to state that if Stevens-Johnson syndrome is suspected, study 
treatment must be immediately discontinued and not be reintroduced. Patients should be 
treated according to standard clinical practice. 
Changes to Section 6.3.1.4 Increased liver enzyme levels 
• Term ‘deferasirox’ was abbreviated to simplify the text. 
• Clarification was provided as to how deferasirox dose should be re-initiated once the 
cause of the liver function test abnormalities has been identified or after a return to normal 
levels. 
Addition of Section 6.3.1.5 Hepatic Impairment 
• Section was added to provide guidance to treatment dose modifications for patients with 
moderate hepatic impairment (Child-Pugh B). 
Changes to Section 6.3.1.6 Dose modification criteria for auditory and ocular 
disturbances 
• Term ‘deferasirox’ was abbreviated to simplify the text. 
• Information was added that if disturbances occur during study, dose reduction to 5mg/kg/d 
or interruption may be considered. 
Changes to Section 6.3.1.7 Dose modification criteria for hypersensitivity reactions 
• Term ‘deferasirox’ was abbreviated to simplify the text. 
Changes to Section 6.3.1.8 Dose modification criteria for cytopenias 
• Term ‘deferasirox’ was abbreviated to simplify the text. 


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Changes to Section 6.3.4 Anticipated risks and safety concern of the study drug 
• Terms ‘erythropoietin’ and ‘deferasirox’ were abbreviated to simplify the text. 
Changes to Section 6.4.1 Permitted concomitant therapy 
• Term ‘deferasirox’ was abbreviated to simplify the text. 
• Descriptive text was simplified to explain that the investigator must instruct the patient to 
notify the study site about any new medications and that any medications and significant 
non-drug therapies must be listed on the respective eCRF. 
Changes to Section 6.4.2 Permitted concomitant therapy requiring caution and/or action 
• Term ‘deferasirox’ was abbreviated to simplify the text. 
• Information was added that concomitant administration of DFX with CYP1A2 substrates 
that have a narrow therapeutic index is not recommended. 
• Information was added that when deferasirox and theophylline are used concomitantly, 
monitoring of theophylline concentration and theophylline dose reduction should be 
considered. 
• Information was added that the concomitant use of bile acid sequestrates (e.g. 
cholestyramine, colesevelan, colestipol) decreases deferasirox systemic exposure. 
• Redundant information was deleted that the investigator must instruct the patient to notify 
the study site about any new medications and that any medications and significant non- 
drug therapies must be listed on the respective eCRF. 
Changes to Section 6.6.1 Study drug packaging and labeling 
• Term ‘erythropoietin’ and ‘deferasirox’ were abbreviated to simplify the text. 
Changes to Section 6.6.4 Disposal and destruction 
• Information was added to ensure that all unused study drug supply must be destroyed. 
Changes to Section 7.1.1 Screening 
• Information was added to make mention of the fact that the two Screening Visits must be 
at least 14 days apart. 
Changes to Section 7.1.3.1 Criteria for premature patient withdrawal 
• Information was added as the MHRA (UK HA) recently issued grounds for non- 
acceptance on Novartis protocols regarding the current template guidance. This section 
was updated to comply with the MHRA approved text. 
• Additional reasons for premature patient withdrawal were added. 
Changes to Section 7.2.1 Efficacy assessments 
• Term ‘deferasirox’ was abbreviated to simplify the text. 
• Typo was corrected that the efficacy parameter Hb will be assessed bi-weekly in the first 
month of treatment instead of bi-weekly in the first week of treatment 
• Information was added that change in hematological parameters will be assessed for all 
subjects on study regardless if a patient meets the required precondition as defined by 
IWG 2006. 


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Changes to Section 7.2.2.2 Vital signs 
• Information was added that the pulse will be measured after at least 5min rest by full 
minute assessment. 
Changes to Section 7.2.2.4 Laboratory evaluations 
• Information was added to specify microscopic panel for urinalysis and additional tests. 
Changes to Section 7.2.2.4.1 Hematology 
• Information was modified to clarify that hematology samples ‘must’ be sent instead of 
‘should’ be sent to the central laboratory. 
Changes to Section 7.2.2.4.2 Clinical chemistry 
• Term ‘deferasirox’ was abbreviated to simplify the text. 
Changes to Section 7.2.2.4.3 Urinanalysis 
• Information was added to specify that a fresh urine sample will be collected to assess 
eligibility. 
Changes to Section 7.2.2.5.1 Electrocardiogram (ECG) 
• Information was added to clarify that patients with significant cardiac abnormalities may 
only be enrolled if endorsed by Novartis. 
Changes to Section 8.4 Pregnancies 
• Information was deleted to confirm that pregnancy outcomes must be collected for the 
female partners of any males who took study treatment in this study and that consent to 
report information regarding these pregnancy outcomes should be obtained from the 
mother, as it was inadvertently added in the original protocol. 
Changes to Section 10 Statistical methods and data analysis 
• Terms ‘erythropoietin’ and ‘deferasirox’ were abbreviated to simplify the text. 
Changes to Section 10.1.1 Full Analysis Set 
• Information of treatment arms, EPO or EPO+DFX, was added to specify FAS. 
Changes to Section 10.1.2 Safety Set 
• Information was added to clarify that the safety set includes all randomized patients who 
received at least one dose of study medication, i.e. either EPO or EPO+DFX, and with at 
least one post-baseline safety assessment (e.g. lab, vital signs, AEs) and the statement that 
a subject did not experience an adverse event can currently be regarded as a valid safety 
assessment. 
Changes to Section 10.1.3 Per Protocol Set 
• Section was added to define PP set, as the definition was inadvertently missed in the 
original protocol. 
Changes to Section 10.3 Treatments (study treatment, concomitant therapies, 
compliance) 
• Information was modified to clarify that planned and actual dose will be summarized. 


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Changes to Section 10.4 Primary objective 
• Term ‘deferasirox’ was abbreviated to simplify the text. 
Changes to Section 10.4.2 Primary objective – statistical hypothesis, model, and method 
of analysis 
• Information was added stating that analysis of primary objective will be performed also at 
PP set in addition to FAS population. 
Changes to Section 10.5.1 Secondary objectives – To assess the effect of treatment with 
DFX+EPO and EPO alone on hematological response within 24 weeks of treatment 
• Information was added that this analysis includes patients who were randomized to EPO 
and EPO+DFX and remained in their respective treatment arms. 
• Information was added to specify the definition of hematological response according to 
modified IWG 2006 criteria. 
• Information was added stating that patients not meeting IWG 2006 pre-treatment 
conditions for neutrophil and/or platelet response according to modified IWG criteria, 
proportion of patients achieving hematologic improvement, summary statistics on the 
parameters related to hematologic improvement and change from baseline will be assessed 
and described as supportive analysis. 
• Information was added stating that the proportion of patients achieving a hematological 
response within 24 weeks of treatment with DFX combined with EPO and EPO alone will 
be calculated along with 95% Clopper-Pearson confidence interval. 
• Information was added stating that the analysis of this secondary objective will be 
performed also at PP set in addition to FAS population. 
• Table 10-1 included for criteria of hematological response and hematologic improvement. 
Changes to Section 10.5.2 Secondary objectives – To assess the effect of treatment on 
erythropoiesis after 24 weeks in patients that were non-responder to EPO alone after 12 
weeks and switched to DFX+EPO 
• Information was added stating that the proportion of erythroid responders between week 
13 and 24 will be reported along with its 95% Clopper-Pearson confidence interval. 
• Information was added stating that the analysis of this secondary objective will be 
performed also at PP set in addition to FAS population. 
Changes to Section 10.5.3 Secondary objectives – To assess time to erythroid response in 
patients treated with DFX+EPO and patients treated with EPO alone 
• Information was added stating that the analysis will include patients who were randomized 
to EPO and EPO+DFX and remained in their respective treatment arms. 
• Definition of erythroid response was added. 
• Information was added to clarify that event of erythroid response can occur between week 
1 to week 24. 
• Information was added stating that the analysis of this secondary objective will be 
performed also at PP set in addition to FAS population. 


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Changes to Section 10.5.4 Secondary objectives – To assess the effect of treatment with 
EPO alone on erythropoiesis after 24 weeks of treatment 
• Information was modified to clarify that the event of erythroid response can occur 
between week 1 to week 24. 
• Information was added stating that the proportion of erythroid responders who starts with 
EPO alone and are not switched to combination therapy will be reported along with the 
corresponding 95% Clopper-Pearson confidence interval. 
• Information was added stating that the analysis of this secondary objective will be 
performed also at PP set in addition to FAS population. 
Changes to Section 10.5.5 Secondary objectives – To estimate time to erythroid response 
in patients who were non-responder to EPO alone after 12 weeks and switched to 
DFX+EPO 
• Definition of erythroid response was added. 
• Information was modified to clarify that the event of erythroid response can occur 
between week 13 to week 24 instead of week 12 to week 24. 
• Information was added stating that the analysis of this secondary objective will be 
performed also at PP set in addition to FAS population. 
Changes to Section 10.5.6 Secondary objectives – To estimate time to hematological 
response in patients treated with DFX+EPO and EPO alone within 24 weeks 
• Incorrect information was deleted stating that the analysis includes only patients on 
combination who switched to DFX after 12 weeks. 
• Information on patients remaining in EPO arm and EPO+DFX was added. 
• Definition of hematological response and hematologic improvement was added. 
• Information on descriptive statistics on time to neutrophil and platelet improvement for 
patients who did not satisfy pre-treatment IWG criteria along with summary on total time 
to hematological response for patients remaining in the EPO+DFX arm and EPO alone 
arm was added as supportive analysis. 
• Information was added stating that the analysis of this secondary objective will be 
performed also at PP set in addition to FAS population. 
Changes to Section 10.5.7 Secondary objectives – To estimate duration of erythroid 
response among responders treated with EPO alone 
• Information was added stating that the analysis of this secondary objective will be 
performed also at PP set in addition to FAS population. 
Changes to Section 10.5.8 Secondary objectives – To estimate duration of erythroid 
response among responders treated with DFX+EPO 
• Information was added to clarify that the analysis will include patients treated with DFX 
combined with EPO at baseline and patients who switch to DFX+EPO from EPO arm 
after 12 weeks. 
• Information was added stating that the duration of response will be evaluated within the 
whole 24 week period for patients randomized to EPO+DFX and within week 13-24 for 


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patients randomized to EPO at baseline and switched to combination therapy after 12 
weeks. 
• Information was added stating that the analysis of this secondary objective will be 
performed also at PP set in addition to FAS population. 
Changes to Section 10.5.9 Secondary objectives – To assess iron parameters in patients 
randomized to EPO alone, DFX+EPO and in patients randomized to EPO alone and 
switched to DFX+EPO after 12 weeks 
• Information was added to clarify that the analysis will include patients randomized to 
either EPO or DFX+EPO at baseline as well as patients who are non-responders to 
erythroid at week 12 in the EPO group switched to combination therapy. 
• Information was added stating that the analysis of this secondary objective will be 
performed also at PP set in addition to FAS population. 
Changes to Section 10.5.10 Secondary objectives – To assess Hb parameters in patients 
randomized to EPO alone, DFX+EPO and in patients randomized to EPO alone and 
switched to DFX+EPO after 12 weeks 
• Information was added to clarify that the analysis will include patients randomized either 
to EPO or DFX+EPO at baseline as well as patients who are non-responders to erythroid 
at week 12 in the EPO group switched to combination therapy. 
• Information was added stating that the analysis of this secondary objective will be 
performed also at PP set in addition to FAS population. 
Changes to Section 10.5.11.1 Analysis set and grouping for the analyses 
• Information was added to clarify how the reporting for safety analyses will be done before 
and after cross-over based on the different treatment groups. 
 
 
 
 
 
 
 
 
 
 
 
 
IRB/IEC 
A  copy  of  this  amended  protocol  will  be  sent  to  the  Institutional  Review  Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. In addition, if the changes herein affect the Informed Consent, sites are 
required to update and submit for approval a revised Informed Consent that takes into account 
the changes described in this amended protocol. 


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Amendment 1 
 
Amendment rationale 
The main purpose of the amendment is to: 
• Change inclusion criteria of lower hemoglobin (Hb) threshold value of > 6 g/dl to ≥ 8 
g/dL 
• Clarify that patients with PS > 2 must not be enrolled in the study 
• Clarify that patients with need of transfusion must not be enrolled in the study and they 
must be withdrawn from the study anytime when transfusion as rescue therapy is needed 
• Delete prophylactic hydrocortisone to prevent transfusion reaction from the list of allowed 
concurrent therapy 
• Standardize term for trial design from exploratory to pilot 
 
 
 
Change inclusion criteria of lower Hb threshold value of > 6 g/dl to ≥ 8 g/dL 
This protocol was updated to change inclusion criteria of lower hemoglobin (Hb) threshold 
value of > 6 g/dl to ≥ 8 g/dL. 
In the “Erythropoietin Treatment and Monitoring Guideline” published by David Mc Culloch 
in 2010, erythropoietin is indicated in patients with anemia caused by MDS with Hb value 
less than 10 g/dL. Treatment and eligibility criteria for this trial are aligned with those 
guidelines. 
Because of the wide variability of transfusional practices across different countries and to ensure 
the safety of patients a lower threshold of 6 g/dL was added as inclusion criteria in the initial 
protocol. This criterion does not interfere with the physician judgment on what is best for the 
patient and when the physician prescribes transfusion to a patient that patient will not qualify for 
this study according to the inclusion and exclusion criteria. 
However, some Health Authorities required that the decision of transfusing patients when 
they have low levels of Hb should not be left to the discretion of investigators therefore, we 
changed inclusion criteria of lower Hb threshold value of > 6 g/dl to ≥ 8 g/dL, a threshold 
below which blood transfusion is indicated in most countries. 
Clarify that patients with PS > 2 must not be enrolled in the study 
Exclusion criteria are amended to clarify that patients with PS > 2 must not be enrolled in the 
study. 
The protocol excludes patients with serious medical condition or any other unstable medical 
comorbidity that would put the patient at unacceptable risk during study treatment. Although 
this criteria and other exclusion criteria largely prevent the participation of patients with a 
PS > 2, this exclusion criteria was amended to explicitly exclude patients with a PS > 2 from 
the study to further improve patients safety and to prevent inclusion of patients with PS of 3 
as they should be transfused or not be enrolled in this trial. 


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Clarify that patients with need of transfusion must not be enrolled in the study and they 
must be withdrawn from the study anytime when transfusion as rescue therapy is 
needed 
To ensure patients safety, explicit guidance is provided for patients who have an acute or 
foreseeable need of transfusion due to symptomatic anemia, as they must not be enrolled in 
the study and they must be withdrawn from the study anytime when transfusion as rescue 
therapy is needed. 
Delete prophylactic hydrocortisone to prevent transfusion reaction from the list of 
allowed concurrent therapy 
Prophylactic hydrocortisone to prevent transfusion reaction was deleted from the list of 
conditions where prophylactic hydrocortisone is allowed concurrent therapy. This minimizes 
the risk of confusion because transfusion is not allowed in this study. Standardize term for 
trial design from exploratory to pilot 
In the initial protocol, both terms, pilot and exploratory study were used, which led to 
confusion regarding the need of sample size calculation. In the protocol amendment the terms 
for the trial design are standardized from exploratory to pilot. A pilot sample size is based on 
the pragmatics of recruitment and the necessities for examining feasibility. This is what is 
being followed in the study where 60 patients are enrolled based on site capabilities. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Changes to the protocol 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions. 
Changes to list of abbreviations 
• PS for ‘Performance Status’ was added. 
 
 
 
 
 
 
Changes to protocol summary 
• Inclusion Criteria: Lower limit of Hb was changed from > 6 g/dL to ≥ 8 g/dL. 
• Exclusion Criteria: Prophylactic hydrocortisone to prevent transfusion reaction was 
deleted from the list of conditions where prophylactic hydrocortisone is allowed 
concurrent therapy. 
 
 
Changes to Section 1.1 Overview of disease pathogenesis, epidemiology and current 
treatment 
Information on recent authorization of lenalidomide in Europe for the treatment of patients 
with transfusion-dependent anemia resulting from low- or int-1-risk MDS associated with 
isolated 5q deletion was included. 
 
 
 
Changes to Section 1.2.1 Overview of deferasirox 
Descriptive text on deferasirox was simplified. 
Changes to Section 1.2.1.2 Clinical Experience 
Information was removed that detailed information regarding the correlation of toxicities and 
pK parameters is provided in the current [Investigators’ Brochure]. 
Changes to Section 2.1 Study rationale and purpose 
 
Changes to Section 2.2 Rationale for the study design 
Statement concerning study design was altered from exploratory to pilot. 
Changes to Section 2.4 Rationale for choice of combination drugs 
Statement concerning study design was altered from exploratory to pilot. 


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Changes to Table 3-1 Objectives and related endpoints 
 
Changes to Section 4.1 Description of Study Design 
Information was added that patients who require RBC transfusions must not be enrolled in the 
study and that patients must be withdrawn from the study anytime when transfusion as rescue 
therapy is needed. 
Changes to Section 5.2 Inclusion Criteria 
Inclusion Criteria 5 was changed. Lower Hb threshold value of > 6 g/dl was changed to ≥ 8 
g/dL. Information was added that patients who require RBC transfusions must not be enrolled 
in the study and that patients must be withdrawn from the study anytime when transfusion as 
rescue therapy is needed. 
Prophylactic hydrocortisone to prevent transfusion reaction was deleted from the list of 
conditions where prophylactic hydrocortisone is allowed concurrent therapy. 
Changes to Section 5.3 Exclusion Criteria 
Prophylactic hydrocortisone to prevent transfusion reaction was deleted from the list of 
conditions where prophylactic hydrocortisone is allowed concurrent therapy. 
Exclusion Criteria 7 was amended to clarify that patients with PS > 2 must not be enrolled in 
the study. 
Changes to Section 6.1 Study Treatment 
Instruction how to prepare deferasirox study medication was changed to add that deferasirox 
can be dispensed in fruit juice. 
Changes to Section 6.1.2 Ancillary Treatment 
Prophylactic hydrocortisone to prevent transfusion reaction was deleted from the list of 
conditions where prophylactic hydrocortisone is allowed concurrent therapy. 
Information was included that patients who require RBC transfusions must not be enrolled in 
the study and that patients must be withdrawn from the study anytime when transfusion as 
rescue therapy is needed. 
Changes to Section 6.1.3 Guidelines for continuation of treatment 
Statement concerning adjustments was altered to refer to reductions. 
Changes to Section 6.3.1 Dose modification and dose delay 
Statement concerning adjustments was altered to refer to reductions. 
Changes to Section 6.3.1.5 Dose modification criteria for auditory (decreased hearing) 
and ocular (lens opacities) disturbances 
Auditory and ocular Section was amended due to 6 months duration of the study. 


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Changes to Section 6.4.2 Permitted concomitant therapy requiring caution and/or action 
Any other iron chelation therapy was deleted as permitted concomitant therapy requiring 
caution and/or action. Transfusions as non-drug therapy that should be listed on the 
Concomitant medications/Significant non-drug therapies after start of study drug eCRF was 
deleted. 
Changes to Section 6.5.2 Treatment assignment or randomization 
Statement was deleted, that randomization numbers are linked to medication numbers and 
medication packs. 
Changes to Table 7-1 Visit Schedule 
IWR was deleted at visits 7, 9, 10, 11, 12. 
Unit of height (cm) and weight (kg) was provided. 
Changes to Section 7.1.3.1 Criteria for premature patient withdrawal 
Transfusion was deleted as reason that patients may be withdrawn from the study. 
Information  was  added  that  patients  must  be  withdrawn  from  the  study  anytime  when 
transfusion as rescue therapy is needed. 
Changes to Section 7.2.2.4.5 Hepatitis Viral tests 
‘Qualitative w/confirmation’ was removed in order to be consistent with Table 7-2. 
 
 
 
 
Changes to Section 10.5.4 To assess the effect of treatment with EPO alone on 
erythropoiesis after 24 weeks of treatment 
Reference to EPO guidelines was deleted. 
 
 
Changes to Section 10.8 Sample size calculation 
Statement  concerning  study  design  was  altered  from  exploratory  to  pilot.  Additional 
information on sample size justification in pilot studies was provided. 
Changes to Section 13 References 
Reference regarding sample size justification in pilot studies was added. 


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IRB/IEC 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. In addition, if the changes herein affect the Informed Consent, sites are 
required to update and submit for approval a revised Informed Consent that takes into account 
the changes described in this amended protocol. 


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Protocol summary: 
Protocol number 
CICL670A2421 
Title 
An open-label, phase II, randomized, pilot study to assess the effect in term of erythroid 
improvement of deferasirox combined with erythropoietin compared to erythropoietin 
alone in patients with low- and int-1-risk myelodysplastic syndrome 
Brief title 
Combination study of deferasirox and erythropoietin in patients with low- and int-1-risk 
myelodysplastic syndrome 
Sponsor and 
Clinical Phase 
Novartis 
Phase II 
Investigation type 
Drug 
Study type 
Interventional 
Purpose and 
rationale 
The primary purpose is to assess the effect of treatment with deferasirox combined with 
erythropoietin vs. erythropoietin alone on erythropoiesis in patients with low- and int-1- 
risk myelodysplastic syndrome. 
The addition of deferasirox to erythropoietin could lead to a potential synergism with the 
reduction of reactive oxygen species, through both the NF-kB pathway and the control 
of free toxic iron. This may create a better environment in the bone marrow for a better 
response with erythropoietin. 
This study is designed to test in a prospective way the combination of deferasirox with 
erythropoietin in terms of their effect on hematopoiesis. 
Primary Objective(s) 
and Key Secondary 
Objective 
To assess the effect of treatment with deferasirox combined with erythropoietin vs. 
erythropoietin alone on erythropoiesis after 12 weeks of treatment defined by 
hemoglobin levels. 
Secondary 
Objectives 
To assess the effect of treatment with deferasirox combined with erythropoietin and 
erythropoietin alone on hematological response within 24 weeks of treatment in patients 
randomized to combination therapy at baseline defined by hemoglobin, platelets and 
neutrophil levels. 
To assess the effect of treatment on erythropoiesis after 24 weeks in patients that were 
non-responder to erythropoietin alone after 12 weeks and switched to combination of 
deferasirox combined with erythropoietin defined by hemoglobin levels. 
To assess the effect of treatment with erythropoietin alone on erythropoiesis after 24 
weeks of treatment defined by hemoglobin levels. 
To assess time to erythroid response in patients treated with deferasirox combined with 
erythropoietin and patients treated with erythropoietin alone. 
To estimate time to erythroid response in patients who were non-responder to 
erythropoietin alone after 12 weeks and switched to combination of deferasirox 
combined with erythropoietin. 
To estimate time to hematological response in patients treated with deferasirox 
combined with erythropoietin and erythropoietin alone in 24 weeks. 
To estimate duration of erythroid response among responders treated with deferasirox 
combined with erythropoietin or erythropoietin alone. 
To evaluate tolerability and safety of the combination by incidence of adverse events 
(AEs) overall and by severity, and serious adverse events (SAEs). 


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To assess iron parameters in patients randomized to erythropoietin alone, deferasirox 
combined with erythropoietin and in patients randomized to erythropoietin and switched 
to deferasirox combined with erythropoietin after 12 weeks by change in serum ferritin 
from baseline to every visit throughout the study. 
To assess hemoglobin parameters in patients randomized to erythropoietin alone, 
deferasirox combined with erythropoietin and in patients randomized to erythropoietin 
and switched to deferasirox combined with erythropoietin after 12 weeks by change in 
hemoglobin from baseline to every visit throughout the study. 
Study design 
This is an open-label, phase II, randomized, multi-center, pilot study in patients with 
low- and int-1-risk myelodysplastic syndrome. 60 Patients will be randomly assigned to 
deferasirox plus erythropoietin or to erythropoietin alone in a 1:1 ratio. The study 
treatment duration is 24 weeks. 
Population 
Adult patients with low- and int-1-risk myelodysplastic syndrome. 
60 patients will be randomized to receive either deferasirox plus erythropoietin or 
erythropoietin alone. 
Inclusion criteria 
● Patients with low- and Int-1-risk myelodysplastic syndrome 
● Documented diagnosis of the following: 
● Myelodysplastic syndrome lasting ≥ 3 months and < 3 years 
● Disease must not be secondary to treatment with radiotherapy, chemotherapy, 
and/or immunotherapy for malignant or autoimmune diseases 
● A hemoglobin < 10 g/dL and ≥ 8 g/dL 
● History of transfusions < 10 RBC 
● 300 ng/mL < serum ferritin < 1,500 ng/mL 
● Endogenous erythropoietin levels < 500 units/L 
Exclusion criteria 
● Patients with MDS with isolated del(5q) 
● Patients who had received prior EPO treatment or other recombinant growth factors 
regardless of the outcome (Patient who had received prior EPO treatment or other 
recombinant growth factors for less than 4 weeks and not within 3 months before 
screening without a documented response are allowed) 
● Patients receiving steroids or immunosuppressive therapy for the improvement of 
hematological parameters (stable steroid treatment for adrenal failure or chronic 
medical conditions, and intermittent dexamethasone as antiemetics are allowed) 
● B12 and folate deficient patients with and without clinical symptoms (patients could 
be rescreened after successful therapy of B12 and folate deficiency) 
● Uncontrolled seizures or uncontrolled hypertension 
Investigational and 
reference therapy 
Deferasirox dispersible tablet (DT) 10 mg/kg/day or Deferasirox film-coated tablet (FCT) 
7 mg/kg/day 
Erythropoietin alpha (EPO) 40,000 units/week 
Erythropoietin alpha (EPO) 60,000 units/week 
Efficacy assessments 
Hemoglobin levels will be assessed bi-weekly in the first month of treatment and then at 
every visit to assess erythroid response, time to erythroid response and duration of 
erythroid response 
Hemoglobin levels, neutrophils and platelets will be assessed bi-weekly in the first 
month of treatment and then at every visit to assess hematologic improvement and time 
to hematologic improvement 


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Safety assessments 
Continuous monitoring of Adverse Events (AEs) and serious AEs (SAEs) after patient 
signs informed consent and 30 days after discontinuation of treatment 
Ocular and audiometry examination at Screening Visit 1 
ECG at Screening Visit 1 
Monitoring of chemistry values at Screening Visits 1 and 2, weekly in the first month of 
treatment and then monthly throughout the study 
Monitoring of hematology values at Screening Visits 1 and 2, biweekly during first 
month of treatment and then monthly during the study 
Liver enzymes (AST/SGOT and ALT/SGPT), direct/indirect/total bilirubin, alkaline 
phosphatase at Screening Visits 1 and 2, weekly during the first month of treatment and 
then monthly during the study 
Serum creatinine at Screening Visits 1 and 2, weekly during the first month of treatment 
and then monthly during the study 
Proteinuria (urinary protein/creatinine ratio) at Screening Visits 1 and 2, weekly during 
the first month of treatment and then monthly during the study 
Other assessments 
 
 
 
Data analysis 
The primary variable is the difference in proportion of patients achieving an erythroid 
response after 12 weeks of treatment between the two arms according to a criterion 
based on modified IWG 2006 (increase in Hb from baseline ≥ 1.5 g/dL). Difference in 
proportions between treatment groups with its 95% Agresti-Caffo (Agresti & Caffo 2000) 
confidence interval will be provided. Erythroid response proportion will be also 
summarized by treatment group with its 95% Clopper-Pearson confidence intervals. 
Analysis will be performed on full analysis set and per protocol set. 
Key words 
myelodysplastic syndrome, deferasirox, erythropoietin 


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1 
Background 
1.1 
Overview of disease pathogenesis, epidemiology and current 
treatment 
 
Overview 
The myelodysplastic syndromes (MDS) include a diverse group of acquired disorders of 
hematopoeisis, collectively characterized by bone marrow failure (ie, inadequate production 
of healthy, mature blood cells) and a tendency for clonal evolution, including progression to 
acute myeloid leukemia (AML, defined by ≥ 20% blast cells in the marrow) (Steensma 2006). 
The incidence rate of MDS in the USA for 2001–2003 was 3.3/100,000, and the overall 3- 
year survival for MDS was 45% (Rollison 2008). The incidence increases with age, and the 
median age at diagnosis is 70–75 years. Men have a significantly higher incidence rate than 
women (4.5 vs. 2.7 per 100,000/year) (Vardiman 2009). 
Signs and symptoms of MDS relate to hematopoietic failure, manifesting in anemia, 
thrombocytopenia or leukopenia. The anemia is often severe, leading to regular transfusion 
and reduced quality of life. 
 
Classification 
The French-American-British Cooperative Group (FAB) originally classified MDS into 5 
different types (Bennett 1982) (Table 1-1). However, the World Health Organization (WHO) 
has revised this classification and now identifies 8 different disorders. Both organizations 
distinguish the different forms of MDS based on bone marrow and peripheral smear findings, 
i.e. the percent of myeloblasts in the bone marrow and peripheral blood, the type and degree 
of dysplasia, and the presence of ringed sideroblasts (Appendix 1). 
 
Table 1-1 
FAB classification of MDS 
 
MDS Subtype 
Peripheral blasts 
(%) 
Bone marrow 
blasts (%) 
Auer Rods 
Ringed Sideroblasts 
> 15% 
Monocyte 
> 1000 
RA 
≤ 1 
< 5 
No 
No 
No 
RARS 
≤ 1 
< 5 
No 
Yes 
No 
RAEB 
< 5 
5-20 
No 
± 
No 
RAEB-T 
≤ 5 
20-30 
± 
± 
± 
CMML 
< 5 
5-20 
No 
± 
Yes 
RA 
Refractory Anemia 
RARS 
Refractory Anemia with Ringed Sideroblasts 
RAEB 
Refractory Anemia with Excess of Blasts 
RAEB-T 
RAEB in Transformation 
CMML 
Chronic Myelomonocytic Leukemia 
 
In this study the classification of MDS patients will be  done  according  to  the  FAB 
(Table 1-1). This is done in consistency with previous trials that studied the addition of 
granulocyte colony stimulating factor (G-CSF) to erythropoietin (EPO) and others that 
established some prognostic factors of response to EPO. Therefore the results of this study in 


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terms of response to the combination of deferasirox (DFX) and EPO and the multivariate 
analysis could be compared to those historical results (Hellström-Lindberg 1998). 
 
Treatment 
The majority of patients with MDS have macrocytic anemia with or without additional 
cytopenias present at time of diagnosis. In principle, the treatment is based upon the severity 
of the symptoms and may comprise chemotherapy and bone marrow transplantation, as well 
as supportive care. The supportive care can include growth factors: erythropoietin (EPO), 
granulocyte colony stimulating factor (G-CSF), and granulocyte macrophage colony 
stimulating factor (GM-CSF), immune modulators, antithymocyte globulin (ATG) and 
lenalidomide (Revlimid®) to reduce the need for transfusions, antibiotic therapy and 
hemotransfusions. 
Allogeneic bone marrow transplantation currently offers the only potentially curative 
treatment for MDS, but less than 15% of patients with MDS are eligible for this treatment due 
to age, co-morbid conditions, or resistant high-risk disease. Aggressive polychemotherapy as 
established for AML can induce remissions in younger high risk patients, but cure is rarely 
achieved. 
Azacitidine and decitabine as novel drugs for the treatment of MDS showed promising results 
(Silverman 2002, Kantarjian 2006, Fenaux 2009). Since these drugs are cytotoxic as well as 
DNA-demethylating, and can therefore lead to the typical side effects of cytostatic 
chemotherapy, they are especially used for high-risk patients. 
Lenalidomide, a new drug and derivative of thalidomide, was recently licensed in the USA for 
the treatment of low and intermediate risk-1 (int-1) MDS with a deletion of chromosome 5q. 
It is especially effective in patients with deletion of chromosome 5q as sole abnormality (5q 
minus syndrome) (List 2006). Recently lenalidomide/Revlimid® has also been authorised in 
Europe for the treatment of patients with transfusion-dependent anemia resulting from low or 
int-1MDS associated with isolated 5q deletion. 
Treatment goals for patients with lower risk MDS primarily involve managing anemia and 
cytopenias. Supportive therapy with EPO and G-CSF has improved the quality of life of 
selected patients. Standard supportive therapy consists of blood transfusions and treatment of 
complications. While specific therapies and the use of growth factors may alleviate 
transfusion requirements in some patients, 60-80% of patients do not respond and require 
ongoing platelet and red blood cell (RBC) transfusions due to impaired hematopoiesis. 
Erythropoietic stimulating agents reduce transfusion requirements in 15-20% of MDS patients 
who receive epoetin alpha equivalent doses of 40,000-80,000 units weekly (Hellström- 
Lindberg 1995). Other more recent studies have confirmed the results and found a response to 
EPO ranged from a maximum of 68% to a minimum of 19% (Santini 2011). 
Greenberg et al. showed that erythroid responders had significantly improved survival 
compared to non-responders (median 5.5 vs. 2.3 years, P = 0.004). In addition, they showed 
that the combination of EPO with G-CSF was synergistic for a proportion of patients who 
either did not respond initially to EPO or whose response was transient. Higher doses of EPO 
further enhanced the erythroid responses in a proportion of patients who initially failed to 
respond to treatment (Greenberg 2009). 


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Red blood cell (RBC) transfusions remain the mainstay of treatment for MDS, it is estimated 
that approximately 40% of MDS patients receive regular RBC transfusions with the 
transfusion frequency increasing in the higher-risk disease (Bennett 2008). 
Since hematological remissions and cure of MDS are rarely achieved, at least without 
intensive chemotherapy and/or transplantation, less stringent responses have also to be 
objectively classified, if treatment strategies for MDS are assessed. These less stringent 
criteria are summarized as “hematologic improvement”. Standardized response criteria have 
been put forward in 2000 and an update has been proposed in 2006 (Cheson 2000; Cheson 
2006). The Modified International Working Group (IWG) response criteria for hematologic 
improvement are defined for erythroid response as Hb increase and reduction of transfusions, 
for platelet response and neutrophil response (Appendix 2, Cheson 2006). 
 
Iron overload in MDS 
In many patients iron overload is an inevitable consequence of this transfusion therapy since 
every unit of transfused blood contains approximately 200 to 250 mg of iron and natural iron 
losses equal only 1 mg per day (Schafer 1981). Furthermore, iron overload is already present 
in many MDS patients even before the start of the transfusion regimen. The intestinal iron 
intake is stimulated due to anemia and/or ineffective erythropoiesis. Liver dysfunction, 
cirrhosis and endocrinopathies have been described in multi-transfused MDS patients (even 
with a short-term duration of transfusion), where even mild liver function abnormalities have 
been associated with marked hepatic IO and portal fibrosis on biopsy (Schafer 1981, Jaeger 
1992). IO may impact survival in MDS, which is especially relevant for low-risk patients. A 
recent retrospective analysis of 467 MDS patients demonstrated that cardiac failure and liver 
cirrhosis constituted 51% and 8% respectively of the non-leukemic causes of death (Malcovati 
2005). Use of deferoxamine (DFO) in iron-overload MDS patients has been reported to 
improve organ dysfunction (Jensen 2003, Schafer 1985), and even improve cytopenias 
(Jensen 1996). The use of DFX will be discussed in Section 1.2 and Section 2.1. 
Reactive oxygen species (ROS) and serum ferritin levels are both considered to be important 
biological factors in the pathogenesis of MDS. Data has shown that iron chelation therapy in 
MDS patients can reverse this intracellular ROS accumulation (Chan 2008). There is  a 
positive correlation between ROS levels and serum ferritin levels, and a negative correlation 
between ROS levels and hemoglobin levels. There is a negative relationship between serum 
hemoglobin and ferritin levels. The results indicated that iron accumulation or severe anemia 
could contribute to oxidative stress in MDS patients. Therefore iron chelation therapy may be 
suitable for the management of MDS (Saigo 2011). 
 
 
 
 
 
 
 
 


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1.2 
Introduction to investigational treatment(s) and other study 
treatment(s) 
 
1.2.1 
Overview of Deferasirox (ICL670) 
Deferasirox (DFX) (company research code: ICL670) is an orally active chelator that is 
highly selective for iron (III). It is a tridentate ligand that binds iron with high affinity in a 2:1 
ratio. Two molecules of DFX form a complete complex with Fe3+. 


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The high potency of DFX in mobilizing tissue iron and promoting iron excretion was 
demonstrated both in vitro and in vivo model systems (Nick 2003). DFX is eliminated from 
the body by hepatic glucuronidation and biliary excretion. 
The formulation of marketed DFX (Exjade®) is a dispersible tablet (DT). DFX DT was first 
approved for the treatment of chronic iron overload due to blood transfusions (transfusional 
hemosiderosis) in adults and pediatric patients aged 2 years and older in the United States in 
November 2005 and is currently approved for this indication in more than 100 countries, 
including the European Union, Switzerland and Japan. DFX DT has also been approved in 
more than 60 countries for the treatment of chronic iron overload in patients with non- 
transfusion dependent thalassemia aged 10 years and older. 
DFX DT is formulated as a dispersible tablet for oral suspension which facilitates 
administration of the appropriate quantity of drug substance to both pediatric and adult 
patients. DFX DT is supplied as 125 mg, 250 mg and 500 mg tablets which can be dispersed 
in water, orange juice or apple juice. Bioavailability studies indicate that absorption is highly 
variable when DFX DT is taken together with food. Therefore, it is recommended that DFX 
DT is taken on an empty stomach, at least 30 minutes prior to food intake. 
Because of the chronic nature of chelation therapy and the importance of patient compliance, 
an improved DFX formulation for oral administration was developed. The film-coated tablet 
(FCT) to be used in this study contains the same active substance and is strength-adjusted to 
achieve comparable exposure to the DT. DFX FCT is available in three dose strengths (90 mg, 
180 mg and 360 mg) and is dosed based on body weight. DFX FCT should be swallowed 
whole with some water on an empty stomach or after a light meal. For patients who are unable 
to swallow whole tablets, the FCT may be crushed and administered by sprinkling the full 
dose onto soft food, e.g. yogurt or apple sauce (pureed apple). The dose should be 
immediately and completely consumed, and not stored for future use. 
 
1.2.1.1 
Non-clinical experience 
Preclinical studies revealed that DFX did not affect fertility and it is neither teratogenic nor 
carcinogenic. Detailed information on preclinical evaluation of DFX is provided in the current 
[Investigators’ Brochure]. 
In addition to serum ferritin levels also reactive oxygen species (ROS) are considered to be an 
important biological factor in the pathogenesis of MDS. DFX iron chelation therapy may be 
suitable for the reduction of ROS as iron accumulation or severe anemia could contribute to 
oxidative stress in MDS patients, because there is a positive correlation between ROS levels 
and serum ferritin levels, and a negative correlation between ROS levels and hemoglobin 
levels (Saigo 2011). 
In vitro studies have also shown that DFX is active in attenuating the intracellular levels of 
NF-kB, an apoptotic pathway of malignant cells. Moreover, agents that inhibit NF-kB are 
expected to have anticancer and antioxidant properties (Sarkar 2008). 


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1.2.1.2 
Clinical experience 
 
Clinical studies have shown 
DFX to effectively chelate iron in patients with transfusional iron overload as demonstrated 
by decreases in LIC, SF and cardiac iron (MRI T2*) in patients with various underlying 
anemia (Nick 2003, Cappellini 2006, Vichinsky 2007, Porter 2008, Pennell 2010). 
Anecdotal case reports and clinical trials suggest that MDS patients can show improvement in 
hematopoietic function if they receive iron chelation therapy with DFX. In an ad hoc analysis, 
erythroid response rate during DFX treatment was 22% in 341 MDS patients included in the 
EPIC trial, a study evaluating the efficacy and safety of DFX in patients diagnosed with 
transfusion dependent iron overload (Cappellini 2010, Gattermann 2010). 
DFX has demonstrated acceptable safety and tolerability in adult and pediatric patients with 
transfusional iron overload (Piga 2006, Cappellini 2006, Vichinsky 2007). The most frequent 
reactions reported during chronic treatment with DFX in adult and pediatric patients included 
gastrointestinal disturbances in about 26% of patients (mainly nausea, vomiting, diarrhea, or 
abdominal pain), and skin rash in approximately 7% of patients. These reactions are dose- 
dependent, mostly mild to moderate, generally transient and mostly resolve even if treatment 
is continued. 
Mild, non-progressive increases in serum creatinine, mostly within the normal range, occurred 
in approximately 36% of patients. These were dose-dependent, often resolved spontaneously 
and some were alleviated by reducing the dose. Rare cases of acute renal failure, mostly 
serum creatinine increases ≥ 2 x ULN have been reported following the prescription use of 
DFX; these were usually reversible after treatment interruption. 
Elevations of liver transaminases were reported as an adverse reaction in approximately 2% of 
patients. These were not dose dependent and most of these patients had elevated levels prior 
to receiving DFX due to a high background incidence of chronic viral hepatitis and of liver 
damage secondary to chronic iron overload. Elevations of transaminases > 10 x ULN, 
suggestive of hepatitis, were uncommon (0.3%). There have been post-marketing reports of 
hepatic failure, mostly in patients with severe baseline liver disease. 
In a 1-year, randomized, double-blind, placebo-controlled study in patients with non- 
transfusion-dependent thalassemia syndromes and iron overload, diarrhea (9.1%), rash (9.1%), 
and nausea (7.3%) were the most frequent study drug-related adverse events reported by 
patients receiving 10 mg/kg/day of DFX. Abnormal serum creatinine and creatinine clearance 
values were reported in 5.5% and 1.8%, respectively, of patients receiving 10 mg/kg/day of 
DFX. Elevations of liver transaminases greater than 2 times the baseline and 5 times the upper 
limit of normal were reported in 1.8% of patients treated with 10 mg/kg/day of DFX. 
There have been occasional post-marketing reports of leukocytoclastic vasculitis, urticaria, 
alopecia and hypersensitivity reactions (including anaphylaxis and angioedema). 
There have been post-marketing reports (both spontaneous and from clinical trials) of 
cytopenias including neutropenia, thrombocytopenia, and aggravated anemia in patients 
treated with DFX. Most of these patients had pre-existing hematological disorders that are 


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frequently associated with bone marrow failure. The relationship of these episodes to 
treatment with DFX is uncertain. 
As with other iron chelator therapies, high frequency hearing loss and lenticular opacities 
(early cataracts) have been uncommonly observed in patients treated with DFX. 
The risk of toxicity of DFX may be increased when inappropriately high doses are prescribed 
to patients with a low iron burden or with SF levels that are only slightly elevated. Patients 
with MDS and “other anemias” had slightly more AEs than patients with β-thalassemia, with 
the most notable differences for gastrointestinal disorders, general disorders, musculoskeletal 
disorders, respiratory disorders and metabolism disorders. 
As expected, patients with MDS exhibited more cytopenias (i.e., neutropenia and 
thrombocytopenia) compared to patients with β-thalassemia. Although the frequencies of 
infections were comparable between the disease categories, infections in MDS patients were 
more severe (e.g., pneumonia) as a result of their advanced age and related cardiovascular co- 
morbidities. Gastrointestinal AEs were more frequent in patients with MDS with diarrhea 
reported most frequently. The incidence of hemorrhagic gastrointestinal AEs was low across 
the disease categories but more frequent in MDS. The frequency of hepatobiliary AEs was 
also higher in “other anemias” and MDS than in β-thalassemia. However, the number of 
hepatic AEs was generally low across the disease categories without any cases of hepatic 
failure. 
Across the 3 disease categories, the AEs of increased blood creatinine and urine protein/urine 
creatinine ratio were comparable, but there were more cases of reported renal failure in 
patients with MDS and “other anemias". 
In summary, DFX is a once-daily oral iron chelator that has been approved for treating 
transfusional iron overload, with demonstrated efficacy in the reduction or maintenance of 
body iron stores, and an acceptable safety profile. DFX is not approved to treat anemic 
patients without transfusional iron overload. 
 
1.2.2 
Overview of EPO 
The process of erythropoiesis in the bone marrow takes 14–17 days and is highly dependent 
on a number of hemopoietic growth factors. Erythropoietin (EPO) alone, or in combination 
with other colony-stimulating factors (CSFs), has therefore been investigated as a potential 
approach to correct the anemia associated with MDS. Although it is not approved in MDS, the 
guidelines for treatment of MDS patients, e.g. NCCN Guidelines, recommend the use of EPO 
in lower risk MDS patients with symptomatic anemia and endogenous EPO levels ≤ 500 
mU/mL. 
In the EPO treatment and monitoring guideline published by David Mc Culloch in 2010, EPO 
is also indicated in patients with anemia caused by MDS (Appendix 3). 
Treatment with EPO as monotherapy may induce erythroid responses in 16–30% of patients 
with low-risk MDS (Hellström-Lindberg 2005). One placebo-controlled randomized study 
demonstrated an overall positive effect in the EPO-treated cohort, however, at the subgroup 
level, only patients with FAB RA, and patients without transfusion need showed a significant 
response  to  treatment  (Italian  Cooperative  Study  Group  for  rHuEpo  in  Myelodysplastic 


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Syndromes 1998). Several smaller phase II studies have indicated that patients with low pre- 
treatment serum EPO levels (<150–200 U/L) are particularly likely to benefit (Hellström- 
Lindberg 2005). 
A meta-analysis of 205 patients from 17 studies revealed an overall response rate of 16%, and 
showed that patients with no transfusion requirement and MDS other than RARS were more 
likely to benefit from treatment than other patient types (Hellström-Lindberg 1995). There is 
no consistent information as to the optimal duration of treatment necessary to assess a 
response to treatment. While the majority of studies have treated patients for 12–16 weeks, a 
few trials have reported that additional responses may be observed if treatment is pursued for 
as long as 6 months (Terpos 2002). The effect of the new long-acting darbepoetin-alfa has 
been assessed in some recent trials, and it has been found to be at least as effective as EPO 
(Mannone 2006, Stasi 2005). 
Therapy with EPO increases the risk for thrombo-embolic events, including deep-vein 
thrombosis, pulmonary emboli, stroke and myocardial infarction. Other adverse events linked 
to EPO therapy are hypertension, flu-like symptoms, arthalgia and dermatological reactions. 
 
2 
Rationale 
2.1 
Study rationale and purpose 
Treatment goals for patients with lower risk MDS primarily involve managing anemia and 
cytopenias. While specific therapies and the use of growth factors stimulating erythropoiesis 
may alleviate transfusion requirements in some patients, 60-80% of patients do not respond 
and require ongoing platelet and red blood cell (RBC) transfusions. There is currently an 
unmet medical need for this large group of patients who fail on treatment with EPO. 
Anecdotal case reports and clinical trials suggest that MDS patients can show improvement in 
hematopoietic function if they receive iron chelation therapy with DFX. In an ad hoc analysis, 
erythroid response rate during DFX treatment was 22% in 341 MDS patients included in the 
EPIC trial, a study evaluating the efficacy and safety of DFX in patients diagnosed with 
transfusion dependent iron overload (Cappellini 2010, Gattermann 2010). This effect of DFX 
on the hematopoiesis is being studied among others in TELESTO, a double-blind, randomized 
study, to prospectively assess the efficacy and safety of iron chelation therapy with DFX 
compared to placebo in patients with low- and int-1-risk MDS and transfusional iron overload. 
However, TELESTO patients are selected based on their iron overload status regardless of 
their history of, or current treatment with EPO. 
Reactive oxygen species (ROS) and serum ferritin levels are both considered to be important 
biological factors in the pathogenesis of MDS. Chan et al. establish that intracellular reactive 
oxygen species (ROS) arederegulated in BM lymphocytes and CD34+ cells in MDS. CD34+ 
intracellular ROS was strongly correlated with serum ferritin concentration for patients with 
higher-risk MDS and iron overload. Data from the same group also indicate that iron 
chelation therapy in this patient population can reverse this intracellular ROS accumulation 
(Chan 2008). Saigo et al. evaluated the levels of ROS in 40 patients with MDS (5 patients 
with RA, 32 with RA with multilineage dysplasia, 1 with RAEB-I, 2 with RAEB-II). The 
group demonstrated that there is a positive correlation between ROS levels and serum ferritin 


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levels, and a negative correlation between ROS levels and hemoglobin levels. There is a 
negative relationship between serum hemoglobin and ferritin levels. The results indicated that 
iron accumulation or severe anemia could contribute to oxidative stress in MDS patients. 
Therefore iron chelation therapy may be suitable for the management of MDS (Saigo 2011). 
Labile plasma iron (LPI), a non-transferrin-bound component of plasma iron detected in iron 
overload disorders is a potential source of cellular iron accumulation and ensuing oxidative 
damage. DFX has shown the ability to suppress LPI (Zanninelli 2009). 
 
 
 
 
 
 
 
Agents that inhibit NF-kB are expected to have anticancer and antioxidant properties (Sarkar 
2008). In vitro, DFX was shown to decrease NF-kB activity in samples showing high basal 
activity (Messa et al 2010). In lower risk MDS patients NF-kB was shown to be low and is 
therefore not measured in this study. 
In summary, the addition of DFX to EPO could lead to a potential synergism with the 
reduction of reactive oxygen species, through both the NF-kB pathway and the control of free 
toxic iron; this may create a better environment in the bone marrow for a better response with 
EPO. 
This study is designed to test in a prospective way the synergism of the combination of DFX 
with EPO in term of their effect on hematopoiesis in lower-risk MDS patients. 
 
2.2 
Rationale for the study design 
This is an open-label, phase II, randomized, pilot study. 
Although, DFX and EPO have been administered concomitantly in some studies (EPIC, US22) 
this was not part of the study design and the combination was not analyzed. In addition, there 
are no published studies of the combination of EPO and iron chelation agents, in particular 
DFX. However, there are different separate scientific elements (see Section 2.1) that lead to a 
strong hypothesis on the potential synergism of both drugs. Hence, this study is designed as 
pilot. 
Although EPO is not approved in MDS, it is the standard of care in terms of improving the 
hematological parameters in these anemic patients before implementing regular blood 
transfusion and it is recommended in guidelines for treatment of MDS (Greenberg 2011, 
Rizzo 2008, Santini 2010). Consequently, patients treated with EPO alone are the control arm. 
The assessment of the primary and some secondary endpoints depends mainly on a laboratory 
parameter (hemoglobin) that is independent from the investigator’s judgment or the patient’s 
perception. Thus, an open label design will not create major bias for the study. 


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The MDS patients included in this study will be classified according to the FAB into 5 
different MDS types (Table 1-1). This is done to be consistent with previous trials in MDS 
patients that studied the addition of G-CSF to EPO and others that established some 
prognostic factors of response to EPO. Therefore the results of this study in terms of response 
to the combination of DFX and EPO and the multivariate analysis could be compared to those 
historical results (Hellström-Lindberg 1998). 
The timelines for assessing the primary and some secondary endpoints have been chosen 
based on the guidelines of treatment with EPO. The assessments in those guidelines are 
mainly conducted at 4, and 12 weeks of treatment (Appendix 3). 
The same schema is followed in this study: EPO dose changes are considered at 4 and 12 
weeks according to the EPO guidelines. The primary endpoint (erythroid response according 
to IWG criteria: Hb increase from baseline ≥ 1.5 g/dL) is assessed at 12 weeks. The primary 
objective of this study will allow understanding if the addition of DFX can increase number of 
responders to EPO. 
Patients who do not respond to 12-week-EPO treatment will be switched to the combination 
for another period of 12 weeks. The analysis of those patients after the cross-over to the 
combination will allow understanding if the addition of DFX to EPO is efficacious in patients 
who are already non-responders to EPO. 
In summary, the open label, randomized design and the schedule of assessment are 
appropriate for this study and are according to the current standards of care. 
 
2.3 
Rationale for dose and regimen selection 
EPO treatment is used in MDS patients early after the diagnosis to induce erythroid response 
and alleviate the symptoms of anemia. At this stage, iron overload is not expected to be high. 
In addition, the mechanism by which DFX might be efficacious in this setting is related to the 
depletion of toxic free iron and possibly to the inhibition of NF-kB in the malignant cells. 
High doses of DFX are not required to achieve these objectives. Therefore, the dose of DFX 
DT is established at 10 mg/kg/day and the dose of DFX FCT is established at 7 mg/kg/day. 
The current practice for the use of EPO is so variable and differs among countries and even 
among physicians. Therefore the dose of EPO in this study is chosen based on the guidelines 
(ASH-ASCO) published by David McCulloch in 2010. According to that, the starting dose in 
this study is 40,000 units/week. If increase in Hb is < 1g/dL and total Hb is < 12 g/dL after 4 
weeks, the dose should be increased to 60,000 units/week. If increase in Hb is ≥ 1 g/dL and 
total Hb is < 12 g/dL, patients should continue the current EPO dose. If Hb increase is ≥ 1 
g/dL and total Hb is ≥ 12 g/dL, the patients should hold EPO treatment. 
Dose change after 12 weeks of study treatment will also be performed according to the EPO 
guidelines (Appendix 3). If Hb increase is ≥ 1 g/dL and total Hb is < 12 g/dL, patients should 
continue the current EPO dose. If Hb increase is ≥ 1 g/dL and total Hb is ≥ 12 g/dL, the 
patients should hold EPO dose (Table 4-1). According to the EPO guidelines, if after 12 
weeks of treatment with EPO, Hb increase is < 1 g/dL and total Hb < 12 g/dL, the patient 
should discontinue EPO as the patient is not responding. In this study, those patients who do 
not respond to 12-week-EPO treatment will not be discontinued, but they will be switched to 
the combination for another period of 12 weeks. 


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As the EPO guidelines only provide guidance for EPO use: EPO dosing, dose adjustments and 
dose discontinuation, and do not specify any criteria for the evaluation of erythroid response 
in MDS patients, in this study, the assessment of the erythroid response at 12 weeks is 
performed based on the IWG-2006 criteria (Appendix 2), which is more widely recognized 
and used to assess hematologic improvement in anemic patients. An increase in Hb of 1.5 
g/dL or more is required for a response. For the assessment of erythroid response, only the 
hemoglobin component is used and not the reduction of RBC transfusions. As the study 
population in this trial consists only of patients with low- and Int-1-risk MDS, which receive 
only few or no transfusions, these patients would otherwise wrongly counted as responders. 
 
2.4 
Rationale for choice of combination drugs 
Anecdotal case reports and clinical trials suggest that MDS patients can show improvement in 
hematopoietic function if they receive iron chelation therapy with DFX. In an ad hoc analysis, 
erythroid response rate during DFX treatment was 22% in 341 MDS patients included in the 
EPIC trial. This effect of DFX on the hematopoiesis is being studied among others in 
TELESTO, a prospective randomized study. However, TELESTO patients are selected based 
on their iron overload status regardless of their history of, or current treatment with EPO. This 
is the first pilot study to assess the effect in term of erythroid improvement of DFX combined 
with EPO in patients with low- and int-1-risk MDS. 
Serum ferritin levels and also reactive oxygen species (ROS) are both considered to be an 
important biological factor in the pathogenesis of MDS. DFX iron chelation therapy may be 
suitable for the reduction of ROS as iron accumulation or severe anemia could contribute to 
oxidative stress in MDS patients (Saigo 2011). 
 
 
 
 
 
 
 
Moreover, agents that inhibit NF-kB are expected to have anticancer and antioxidant 
properties (Sarkar 2008). In vitro studies have also shown that DFX is active in attenuating 
the intracellular levels of NF-kB, an apoptotic pathway of malignant cells. 
The addition of DFX to EPO could harness a potential synergism with the reduction of 
reactive oxygen species; this may create a better environment in the bone marrow for a better 
response with EPO. 
This study is designed to test in a prospective way the combination of DFX with EPO in term 
of their effect on hematopoiesis in lower-risk MDS patients. 
 
3 
Objectives and endpoints 
Objectives and related endpoints are described in Table 3-1 below. 


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Table 3-1 
Objectives and related endpoints 
 
 
Objective 
Endpoint 
Analysis 
 
Primary 
Refer to Section 10.4 
To assess the effect of treatment with DFX+EPO vs. EPO 
alone on erythropoiesis after 12 weeks of treatment 
 
Secondary 
To assess the effect of treatment with DFX+EPO and EPO 
alone on hematological response within 24 weeks of 
treatment 
To assess the effect of treatment on erythropoiesis within 24 
weeks in patients that were non-responder to EPO alone 
within 12 weeks and switched to DFX+EPO 
 
To assess the effect of treatment with EPO alone on 
erythropoiesis after 24 weeks of treatment 
 
To assess time to erythroid response in patients treated with 
DFX+EPO and patients treated with EPO alone 
 
To estimate time to erythroid response in patients who were 
non-responder to EPO alone after 12 weeks and switched to 
DFX+EPO 
 
To estimate time to hematological response in patients 
treated with DFX+EPO and EPO alone within 24 weeks 
 
 
To estimate duration of erythroid response among 
responders treated with EPO alone 
Difference in proportion of patients achieving an erythroid response within 12 
weeks of treatment between the two arms according to modified IWG 2006 
criteria (increase in Hb ≥ 1.5 g/dL) 
 
Proportion of patients achieving a hematological response within 24 weeks of 
treatment with DFX+EPO and EPO alone (increase in Hb, improvement of 
neutropenia and thrombocytopenia) according to modified IWG 2006 criteria 
Proportion of patients achieving an erythroid response according to modified 
IWG 2006 criteria (increase in Hb ≥ 1.5 g/dL) within 24 weeks in patients 
which were non-responder to EPO alone within 12 weeks and switched to 
DFX+EPO 
Proportion of patients achieving an erythroid response within 24 weeks of 
treatment with EPO alone (increase in Hb ≥ 1.5 g/dL) according to modified 
IWG 2006 criteria 
Time to erythroid response is defined as the time from date of start of 
treatment to the date of event defined as the first documented response 
according to modified IWG 2006 criteria (increase in Hb ≥ 1.5 g/dL) 
Time to erythroid response is defined as the time from date of switch (start of 
treatment with the combination) to the date of event , i.e. from week 13 to 
week 24, defined as the first documented response according to modified IWG 
2006 criteria (increase in Hb ≥ 1.5 g/dL) 
Time to hematological response is defined as the time from date of start of 
treatment to the date of event defined as the first documented response 
(increase in Hb, improvement of neutropenia and thrombocytopenia) 
according to modified IWG 2006 criteria 
Duration of erythroid response is defined as the time from onset of the first 
response to progression/relapse (decrease in Hb ≥ 1.5 g/dL from Hb value at 
response) among responders treated with EPO alone within the whole 24 
weeks period 
 
 
 
 
 
Refer to Section 10.5.1 
 
 
Refer to Section 10.5.2 
 
 
 
Refer to Section 10.5.4 
 
 
Refer to Section 10.5.3 
 
 
Refer to Section 10.5.5 
 
 
 
Refer to Section 10.5.6 
 
 
 
Refer to Section 10.5.7 
 


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Objective 
Endpoint 
Analysis 
To estimate duration of erythroid response among 
responders treated with DFX+EPO 
Duration of erythroid response is defined as the time from onset of the first 
response to progression/relapse (decrease in Hb ≥ 1.5 g/dL from Hb value at 
response) among patients randomized to EPO+DFX up to week 24 and for 
patients switched from EPO to DFX+EPO from week 13 to week 24 
Refer to Section 10.5.8 
To evaluate tolerability and safety of the combination 
Incidence of adverse events (AEs) overall and by severity, and serious 
adverse events (SAEs). 
Refer to Section 10.5.11 
To assess iron parameters in patients randomized to EPO 
alone, DFX+EPO and in patients randomized to EPO alone 
and switched to DFX+EPO after 12 weeks 
To assess Hb parameters in patients randomized to EPO 
alone, DFX+EPO and in patients randomized to EPO alone 
and switched to DFX+EPO after 12 weeks 
Supportive 
To assess the effect of treatment with DFX+EPO and EPO 
alone on hematologic improvement within 24 weeks of 
treatment 
To assess the effect of treatment with DFX+EPO and EPO 
alone on total hematological response within 24 weeks of 
treatment 
 
 
To estimate time to hematologic improvement in patients 
treated with DFX+EPO and EPO alone within 24 weeks 
 
To estimate time to total hematological response in patients 
treated with DFX+EPO and EPO alone within 24 weeks 
 
 
 
Change in SF from baseline to every visit in patients throughout in the 
combination arm, throughout in the EPO arm and switched from EPO arm to 
EPO+DFX after 12 weeks 
Change in Hb from baseline to every visit in patients throughout in the 
combination arm, throughout in the EPO arm and switched from EPO arm to 
DFX+EPO after 12 weeks 
 
Proportion of patients achieving a hematologic improvement (improvement of 
neutropenia and thrombocytopenia) within 24 weeks of treatment with 
DFX+EPO and EPO alone 
Proportion of patients achieving a hematological response (increase in Hb, 
improvement of neutropenia and thrombocytopenia) according to modified 
IWG 2006 criteria and patients achieving a hematologic improvement 
(improvement of neutropenia and thrombocytopenia) within 24 weeks of 
treatment with DFX+EPO and EPO alone 
Time to hematologic improvement is defined as the time from date of start of 
treatment to the date of event defined as the first documented hematologic 
improvement (improvement of neutropenia and thrombocytopenia) 
Time to total hematological response is defined as the time from date of start 
of treatment to the date of event defined as the first documented hematologic 
improvement (improvement of neutropenia and thrombocytopenia) or 
hematological response (increase in Hb, improvement of neutropenia and 
thrombocytopenia) according to modified IWG 2006 criteria 
Refer to Section 10.5.9 
 
 
Refer to Section 10.5.10 
 
 
 
Refer to Section 10.5.1 
 
 
Refer to Section 10.5.1 
 
 
 
 
Refer to Section 10.5.6 
 
 
Refer to Section 10.5.6 
 
 
 
 


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4 
Study design 
4.1 
Description of study design 
This is an open-label, phase II, randomized, multi-center, pilot study to assess the efficacy in 
term of erythroid improvement of DFX combined with EPO compared to EPO alone in 
patients with low- and int-1-risk MDS. 
Patients will be randomly assigned to DFX plus EPO 40,000 units/week or  to  EPO 
40,000 units/week alone in a 1:1 ratio. The dose of DFX DT will be 10 mg/kg/day and the 
dose of DFX FCT will be 7 mg/kg/day. At the time when DFX FCT study drug becomes 
available at a study site, all new patients who are randomized to combination therapy will 
receive the DFX FCT. Patients who are ongoing and receive DFX DT will continue with the 
DT. It is not permitted to change formulation during treatment. EPO dose changes after 4 and 
12 weeks of study treatment will also be performed in both arms according to the EPO 
guidelines. 
If after 4 weeks, increase in Hb is < 1g/dL and total Hb is < 12 g/dL, the EPO dose will be 
increased to 60,000 units/week. If increase in Hb is ≥ 1 g/dL and total Hb is < 12 g/dL, 
patients will continue the current EPO dose. If Hb increase is ≥ 1 g/dL and total Hb is ≥ 12 
g/dL, the patients will hold EPO treatment until end of study (Table 4-1). 
If after 12 weeks of treatment with EPO alone, Hb increase is < 1 g/dL and total Hb is < 12 
g/dL, the patient will switch to the combination therapy with EPO and DFX. If increase in Hb 
is ≥ 1 g/dL and total Hb is < 12 g/dL, patients will continue the current EPO dose. If Hb 
increase is ≥ 1 g/dL and total Hb is ≥ 12 g/dL, the patients will hold EPO treatment until end 
of study (Table 4-1). 
If after 12 weeks of treatment with EPO in combination with DFX, Hb increase is < 1 g/dL 
and total Hb is < 12 g/dL, the patient will be discontinued from the study. If increase in Hb is 
≥ 1 g/dL and total Hb is < 12 g/dL, patients will continue the current EPO dose plus DFX. If 
Hb increase is ≥ 1 g/dL and total Hb is ≥ 12 g/dL, the patients will hold EPO dose and receive 
treatment with DFX alone. 
As the EPO guidelines only provide guidance for EPO use (EPO dosing, dose adjustments 
and dose discontinuation) and do not specify any criteria for the evaluation of erythroid 
response in MDS patients, in this study, the primary objective erythroid response will be 
assessed according to IWG criteria (Hb increase ≥ 1.5 g/dL) at 12 weeks of treatment. At any 
time, if Hb ≥ 12 g/dL, EPO will be stopped until the end of study. Patients treated with the 
combination therapy will stop EPO if Hb ≥ 12 g/dL and continue on DFX. 
At 24 weeks, patients initially assigned to the combination therapy who showed Hb increase 
≥ 1 g/dL at week 12 will be assessed for full hematological response according IWG criteria 
(Erythroid response: Hb increase from baseline ≥ 1.5 g/dL; Neutrophil response: increase 
from baseline of ≥ 100% and > 0.5 x 109/L; Platelet response: increase from baseline of ≥ 30 
x 109/L). 


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Patients initially treated with EPO alone and switched to the combination therapy with EPO 
and DFX after 12 weeks will be assessed for erythroid response at study end after 24 weeks of 
study treatment. 


 
 
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Figure 4-1 
Study Design 
 
 


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Pre-treatment phase (Screening) 
At Screening Visit (Visit 1) the investigator or his/her designee will assign a unique number 
to patients being considered for the study. 
Prior to performing any study-related procedures or assessments, the patient must provide 
written consent to participation in this study. A screening period (up to 28 days) will be used 
to assess patient eligibility. Two Screening Visits will be required because key safety 
parameters need to be performed twice before the first dose administration (Table 7-1). 
This study will use an Interactive Web Response (IWR) technology for randomization. Once 
the patient provides a signed informed consent form and eligibility is confirmed (all 
inclusion/exclusion criteria have been verified) the investigator and/or his designee can 
register the patient using the IWR. 
 
Treatment phase 
Patients will be randomized in a 1:1 ratio at Visit 3 to receive either DFX plus EPO or EPO 
alone. Study treatment is defined as DFX DT 10 mg/kg/day p.o. or DFX FCT 7 mg/kg/day p.o. 
plus EPO 40,000 units/week s.c. once weekly or EPO 40,000 units/week once weekly s.c.. 
The study treatment duration is 24 weeks. After randomization, patient visits will occur 
weekly during the first month because key safety assessments need to be performed weekly in 
the first month of treatment and then every 4 weeks thereafter until week 24. In case of a dose 
increase of EPO to 60,000 units/week after 4 weeks of treatment, an additional visit needs to 
be performed after 2 weeks of dose increase (Visit 8). 
At the time when DFX FCT study drug becomes available at a study site, all new patients who 
are randomized to combination therapy will receive the DFX FCT. Patients who are ongoing 
and receive DFX DT will continue with the DT. It is not permitted to change formulation 
during treatment.Patients will have their first dose of study treatment at Visit 3. 
EPO dose adjustments are allowed in both arms according to the EPO guidelines 
(Appendix 3). After 4 weeks, if increase in Hb is < 1g/dL and total Hb is < 12 g/dL, the dose 
will be increased to 60,000 units/week. If increase in Hb is ≥ 1 g/dL and total Hb is < 12 g/dL, 
patients will continue the current EPO dose. If Hb increase is ≥ 1 g/dL and total Hb is ≥ 12 
g/dL, the patients will hold EPO treatment until end of study (Table 4-1). 
If after 12 weeks of treatment with EPO alone, Hb increase is < 1 g/dL and total Hb is < 
12 g/dL, the patient will switch to the combination therapy with EPO and DFX. If increase in 
Hb is ≥ 1 g/dL and total Hb is < 12 g/dL, patients will continue the current EPO dose; if Hb 
increase ≥ 1 g/dL and total Hb ≥ 12 g/dL, the patients will hold EPO treatment until end of 
study (Table 4-1). 
If after 12 weeks of treatment with EPO in combination with DFX, Hb increase is < 1 g/dL 
and total Hb is < 12 g/dL, the patient will be discontinued from the study. If increase in Hb 
is ≥ 1 g/dL and total Hb is < 12 g/dL, patients will continue the current EPO dose plus DFX. 
If Hb increase is ≥ 1 g/dL and total Hb is ≥ 12 g/dL, the patients will hold EPO dose and 
receive treatment with DFX alone (Table 4-1). 


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Table 4-1 
EPO Dosing 
 
 
Initial Treatment 
EPO 40,000 units/week 
EPO 40,000 units/week + DFX DT 10 mg/kg 
day or DFX FCT 7 mg/kg day 
 
 
Week 4 
Hemoglobin status 
Action 
Hb increased < 1 g/dL from baseline 
and Hb < 12 g/dL 
Hb increase is ≥ 1 g/dL 
and Hb < 12 g/dL 
Hb increase is ≥ 1 g/dL 
and Hb ≥ 12 g/dL 
Increase EPO to 60,000 units/week * 
Continue EPO 40,000 units/week * 
Hold EPO treatment * 
Week 12 
Hemoglobin status 
Action 
Hb increased < 1 g/dL from baseline 
and Hb < 12 g/dL 
 
 
 
Hb increase is ≥ 1 g/dL 
and Hb < 12 g/dL 
Hb increase is ≥ 1 g/dL 
and Hb ≥ 12 g/dL 
If patient is in the combination arm: 
Discontinue from the study 
or 
If patient is in the EPO monotherapy arm: 
Switch to the combination EPO + DFX 
Continue current EPO dose * 
Hold EPO treatment * 
* Patients in combination arm will continue DFX DT 10 mg/kg/day or DFX FCT 7 mg/kg/day treatment 
 
The primary objective (erythroid response according to IWG criteria: Hb increase ≥ 1.5 g/dL) 
will be assessed at 12 weeks of treatment. At any time, if Hb ≥ 12 g/dL, EPO will be stopped 
until the end of study. 
At 24 weeks, patients initially assigned to the combination therapy who showed Hb increase 
≥ 1 g/dL at week 12 will be assessed for full hematological response according IWG criteria 
(Erythroid response: Hb increase from baseline ≥ 1.5 g/dL; Neutrophil response: increase 
from baseline of ≥ 100% and > 0.5 x 109/L; Platelet response: increase from baseline of ≥ 30 
x 109/L).Patients initially treated with EPO alone and switched to the combination therapy 
with EPO and DFX after 12 weeks will be assessed for erythroid response according to IWG 
criteria after 24 weeks. 
No RBC transfusions are allowed after randomization, as transfusions would affect the 
endpoints of the trial. Patients who are RBC transfusion dependent must not be enrolled in the 
study. RBC transfusion dependence is defined as more than 2 units RBC /4 weeks at any time 
during the last 12 week period prior to study entry (Gale 2011). Patients must be withdrawn 
from the study anytime when transfusion as rescue therapy is needed. 
Safety assessments are routinely performed including collection of AEs, SAEs, vital signs, 
physical examination, ECG, hematological and biochemistry assessments. 
Patients will continue therapy until disease progression or intolerable toxicity, patient decision 
or death, after 12 weeks of combination treatment without response or after 24 weeks 
treatment duration at which point an End of Treatment (EOT) Visit will be performed and the 
End of Treatment CRF page will be completed. 


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30 day follow-up 
Patients who discontinue study drug before completing the study should be scheduled for a 
visit as soon as possible, at which time all of the assessments listed for the final visit will be 
performed. At a minimum, all patients who discontinue study treatment, including those who 
refuse to return for a final visit, will be contacted for safety evaluations during the 30 days 
following the last dose of study drug. 
All patients must be followed for AEs and SAEs for 30 days after the last dose of study 
treatment. 
 
4.2 
Definition of end of the study 
The study will end when the last patient will have either withdrawn (including follow-up 
period of 30 days) from the study or completed the study (24 weeks + follow up period of 30 
days) from the start of treatment (EPO or EPO+DFX), whichever occurs earlier. 
 
4.3 
Early study termination 
The study can be terminated at any time for any reason by Novartis. Should this be necessary, 
the patient should be seen as soon as possible and the same assessments should be performed 
as described in Section 7.1.3 for a prematurely withdrawn patient. The investigator may be 
informed of additional procedures to be followed in order to ensure that adequate 
consideration is given to the protection of the patient’s interests. The investigator will be 
responsible for informing IRBs and/or ECs of the early termination of the trial. 
Patients who discontinue the study regardless of the reason should have end of study 
treatment evaluations (Table 7-1 and Table 7-2) on the day of study drug discontinuation or 
within 2 weeks of study drug discontinuation. The investigator or his/her designee will 
complete the End of Treatment CRF indicating the date and reason for discontinuing the study 
drug. Additional details are provided in Table 7-1 and Table 7-2. 
 
5 
Population 
5.1 
Patient population 
The patient population consists of 60 MDS patients. The investigator or designee must ensure 
that only patients who meet all the following inclusion and none of the exclusion criteria are 
offered treatment in the study. All inclusion/exclusion criteria have to be met at the two 
Screening Visits. 


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5.2 
Inclusion criteria 
Patients eligible for inclusion in this study have to meet all of the following criteria: 
1. Written informed consent must be obtained prior to any screening procedures 
2. Males and females aged 18 years or more 
3. Documented diagnosis of the following: 
• MDS lasting ≥ 3 months and < 3 years 
• Disease must not be secondary to treatment with radiotherapy, chemotherapy, and/or 
immunotherapy for malignant or autoimmune diseases 
4. Patients with low- and Int-1-risk MDS 
5. A hemoglobin < 10 g/dL and ≥ 8 g/dL (Values within 5% difference above 10g/dL or 5% 
difference below 8 g/dL may be accepted at discretion of the investigator if the patient 
represents the investigational population. However a notification to the study team is 
required.) 
6. History of < 10 RBC transfusions in total and must not be RBC transfusion dependent (A 
patient is regarded RBC dependent per protocol if the patient received more than 2U 
RBC/4 weeks at any time during the last 12 week period prior to study entry). Patients 
must be withdrawn from the study anytime when a RBC transfusion as rescue therapy is 
clinically indicated. 
7. ANC ≥ 500/mm^3 (myeloid growth factor support independent) 
8. Platelet count ≥ 30,000/mm^3 (platelet transfusion independent) 
9. Serum creatinine ≤ 1.5 times upper limit of normal (ULN) (mean value of Screening Visit 
1 and 2 will be used for eligibility criteria) 
10. Creatinine clearance above the concentration limit in locally approved PI. Patients with 
creatinine clearance between 40 and less than 60 mL/min, who do not present with 
additional risk factors that may impair renal function, may be eligible at the discretion of 
the investigator 
11. AST and ALT ≤ 2.0 times ULN 
12. Serum total bilirubin < 3.0 mg/dL 
13. FE/TIBC (TSAT) ≥ 20% 
14. 300 ng/mL < SF < 1,500 ng/mL (Values within 10% difference above 1500 ng/mL or 10% 
difference below 300 ng/mL may be accepted at discretion of the investigator if the patient 
represents the investigational population. However a notification to the study team is 
required.) 
15. Endogenous EPO levels < 500 units/L 
ALLOWED PRIOR CONCURRENT THERAPY: 
• Concurrent steroids for adrenal failure, hormones for non-cancer-related conditions (e.g., 
insulin for diabetes), or intermittent dexamethasone as an antiemetic 
• More than 8 weeks since prior cytotoxic chemotherapeutic agents or experimental agents 
(agents that are not commercially available) for the treatment of MDS 


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5.3 
Exclusion criteria 
Patients eligible for this study must not meet any of the following criteria: 
1. Patients with MDS with isolated del(5q) 
2. Patients who had received prior EPO treatment or other recombinant growth factors 
regardless of the outcome (Patient who had received prior EPO treatment or other 
recombinant growth factors for less than 4 weeks and not within 3 months before 
screening without a documented response are allowed) 
3. Patients receiving steroids or immunosuppressive therapy for the improvement of 
hematological parameters (stable steroid treatment for adrenal failure or other chronic 
medical conditions, and intermittent dexamethasone as antiemetics are allowed). 
4. B12 and folate deficient patients with or without clinical symptoms (patients could be 
rescreened after successful therapy of B12 and folate deficiency) 
5. Uncontrolled seizures or uncontrolled hypertension 
6. History of other malignancy (except basal cell or squamous cell skin carcinoma or 
carcinoma in situ of the cervix or breast) unless the patient has been confirmed disease- 
free for ≥ 3 years 
7. Serious medical condition or any other unstable medical comorbidity, or patients with 
PS > 2, or psychiatric illness that would preclude informed consent or put the patient at 
unacceptable risk during study treatment 
8. Thromboembolic events within the past 3 years 
9. Known allergic reaction to epoetin alfa or human serum albumin 
10. Clinical or laboratory evidence of active Hepatitis B or Hepatitis C (HBsAg in the absence 
of HBsAb OR HCV Ab positive with HCV RNA positive) or hepatic impairment fulfilling 
criteria of Child-Pugh Class B or C 
11. Known HIV-1 seropositivity 
12. Clinically significant anemia resulting from iron deficiencies, autoimmune or hereditary 
hemolysis, or gastrointestinal bleeding 
13. Active bleeding 
14. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female 
after conception and until the termination of gestation, confirmed by a positive hCG 
laboratory test. 
15. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception 
during dosing and for 28 days of study medication. Highly effective contraception 
methods include: 
• Total abstinence (when this is in line with the preferred and usual lifestyle of the 
subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception 
• Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy) or tubal ligation at least six weeks before taking study treatment. In 
case of oophorectomy alone, only when the reproductive status of the woman has 
been confirmed by follow up hormone level assessment 


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• Male partner sterilization (at least 6 months prior to screening). For female subjects 
on the study the vasectomized male partner should be the sole partner for that subject. 
• Combination of a+b: 
a. Placement of an intrauterine device (IUD) or intrauterine system (IUS) 
b. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository 
Please note that DFX may reduce the efficacy of hormonal contraception thus it is 
recommended to use alternative methods of contraception as described above. 
 
6 
Treatment 
6.1 
Study treatment 
The investigational study drugs used in this trial are deferasirox (DFX DT) (Exjade®) 
provided as dispersible tablets for oral use, or deferasirox (DFX FCT) provided as film-coated 
tablet for oral use and erythropoietin alpha (EPO) for s.c. injection. The investigational 
treatment is DFX plus EPO or EPO alone. 
At the time when DFX FCT study drug becomes available at a study site, all new patients who 
are randomized to combination therapy will receive the DFX FCT. Patients who are ongoing 
and receive DFX DT will continue with the DT. It is not permitted to change formulation 
during treatment. 
 
6.1.1 
Dosing regimen 
 
Table 6-1 
Dose and treatment schedule 
Pharmaceutical form and route 
 
 
Frequency 
Study treatments 
of administration 
Dose 
and/or Regimen 
 
Deferasirox (DFX, DT) 
tablets for dispersion 
10 mg/kg/day 
once daily 
Deferasirox (DFX, FCT) 
film-coated tablets 
7 mg/kg/day 
once daily 
Erythropoietin alpha (EPO) 
solution for subcutaneous injection 
40,000 units/week 
60,000 units/week 
once weekly 
once weekly 
 
Having completed the screening period, patients will be randomized to DFX plus EPO or 
EPO alone. Patients will be assigned to one of the two arms in a ratio of 1:1. 
Patients will be instructed to take the assigned amount of drug and will be obliged to return all 
unused study medication at their next visit. Study medication returned by the patient will be 
counted and unused study medication will be recorded by the investigator/pharmacist 
involved in the study. 
Drug accountability will be noted by the field monitor during site visits and at the completion 
of the trial. 


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Deferasirox DT (10 mg/kg/day, Exjade®) 
If patients will commence study treatment with once daily DFX dispersible tablet at 10 mg/kg, 
the patient’s daily dose will be rounded to the nearest whole tablet according to the available 
strengths of DFX DT tablets (125mg, 250 mg and 500 mg). The appropriate daily dose will be 
calculated by the investigator based on the patient’s actual body weight. 
An example illustrating this approach is provided here below: 
• For a patient whose body weight is 66 kg, and whose planned DFX DT dose is 
10 mg/kg/day, the calculated DFX DT daily dose would be 660 mg. So taking into 
account the available strengths of 125, 250 and 500 mg DFX DT tablets, the patient 
should receive the closest daily dose of 625 mg which can be easily constituted by taking 
1 x 125 mg and 1 x 500 mg DFX DT tablets = 2 tablets. 
The dose per body weight including tablet strength to  be  prescribed  is  described  in 
Table 6-2. The investigator should instruct the patient to take the study drug as prescribed. All 
doses planned and prescribed to the patient and all dose changes including reasons for change 
during the study must be recorded in the eCRF. For dose adjustments please see Table 6-3 and 
Section 6.3.1. 
During the regular study visits the investigator or pharmacist will administer to the patient an 
appropriate number of DFX DT tablets from a choice of 125 mg, 250 mg and 500 mg 
strengths, based on the patient’s calculated dose. The number of tablets of each strength (125 
mg, 250 mg and 500 mg) dispensed will be recorded in the Study Drug Dosing Log. All DFX 
DT medication (used and unused blister) returned by the patient will be counted and the sum 
entered in the study drug dosing log by the investigator or pharmacist at the study site. 
Each time the DFX DT study drug is dispensed to the patient, the investigator will provide 
detailed instructions on how to prepare and administer the dose. 
Study medication DFX DT must be taken once daily on an empty stomach at least 30 minutes 
before food preferably at the same time every day. The tablets are dispersed by stirring in a 
glass of water or apple or orange juice (100 to 200 mL) until a fine suspension is obtained. 
After the suspension has been swallowed, any residue must be re-suspended in a small 
volume of water or juice and swallowed. The tablets must not be chewed or swallowed whole. 
Dispersion in carbonated drinks or milk is not recommended due to foaming and slow 
dispersion, respectively. 


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Table 6-2 
Dosing table for 10 mg/kg/day for deferasirox DT (Exjade®) 
 
Pt Weight in Kg 
Closest Dose 
125 mg 
250 mg 
500 mg 
35-43 
375 
3 
44-56 
500 
1 
57-68 
625 
1 
1 
69-81 
750 
1 
1 
82-93 
875 
3 
1 
94-106 
1000 
2 
107-118 
1125 
1 
2 
119-131 
1250 
1 
2 
132 
1375 
3 
2 
> 132 
1375 
3 
2 
Table 6-3 
Dosing table for 5 mg/kg/day for deferasirox DT (Exjade®) 
Pt Weight in Kg 
Closest Dose 
125 mg 
250 mg 
500 mg 
20-37.5 
125 
1 
0 
0 
37.6-62.5 
250 
0 
1 
0 
62.6-87.5 
375 
3 
0 
0 
87.6-112.5 
500 
0 
0 
1 
112.6-137.5 
625 
1 
0 
1 
 
Deferasirox FCT (7 mg/kg/day) 
If patients will commence study treatment with once daily DFX film-coated tablet at 7 mg/kg, 
the patient’s daily dose will be rounded to the nearest whole tablet according to the available 
strengths of DFX FCT (90 mg, 180 mg and 360 mg). The appropriate daily dose will be 
calculated by the investigator based on the patient’s actual body weight. 
An example illustrating this approach is provided here below: 
• For a patient whose body weight is 60 kg, and whose planned DFX FCT dose is 7 
mg/kg/day, the calculated DFX FCT daily dose would be 420 mg. So taking into account 
the available strengths of 90, 180 and 360 mg DFX FCT tablets, the patient should receive 
the closest daily dose of 450 mg which can be constituted by taking 1 x 360 mg and 1 x 90 
mg DFX FCT tablets = 2 tablets. 
The dose per body weight including tablet strength to  be  prescribed  is  described  in 
Table 6-4. The investigator should instruct the patient to take the study drug as prescribed. All 
doses planned and prescribed to the patient and all dose changes including reasons for change 
during the study must be recorded in the eCRF. For dose adjustments please see Table 6-5 and 
Section 6.3.1. 
During the regular study visits the investigator or pharmacist will administer to the patient an 
appropriate number of DFX FCT from a choice of 90 mg, 180 mg and 360 mg strengths, 
based on the patient’s calculated dose. The number of tablets of each strength (90 mg, 180 mg 
and 360 mg) dispensed will be recorded in the Study Drug Dosing Log. All DFX FCT 


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medication (used and unused bottle) returned by the patient will be counted and the sum 
entered in the study drug dosing log by the investigator or pharmacist at the study site. 
Each time the DFX FCT study drug is dispensed to the patient, the investigator will provide 
detailed instructions on how to prepare and administer the dose. 
DFX FCT should be swallowed whole with some water on an empty stomach or after a light 
meal. For patients who are unable to swallow whole tablets, the FCT may be crushed and 
administered by sprinkling the full dose onto soft food, e.g. yogurt or apple sauce (pureed 
apple). The dose should be immediately and completely consumed, and not stored for future 
use. 
 
Table 6-4 
Dosing table for 7 mg/kg/day for deferasirox FCT 
 
Pt Weight in Kg 
Closest Dose 
90 mg 
180 mg 
360 mg 
20 - 32 
180 
0 
1 
0 
33 - 44 
270 
1 
1 
0 
45 - 57 
360 
0 
0 
1 
58 - 70 
450 
1 
0 
1 
71 - 83 
540 
0 
1 
1 
84 - 96 
630 
1 
1 
1 
97 - 109 
720 
0 
0 
2 
110 - 122 
810 
1 
0 
2 
123 - 134 
900 
0 
1 
2 
135 - 147 
990 
1 
1 
2 
 
Table 6-5 
Dosing table for 3.5 mg/kg/day for deferasirox FCT 
 
Pt Weight in Kg 
Closest Dose 
90 mg 
180 mg 
360 mg 
20-38 
90 
1 
0 
0 
39-64 
180 
0 
1 
0 
65-89 
270 
1 
1 
0 
90-115 
360 
0 
0 
1 
116-141 
450 
1 
0 
1 
 
Erythropoietin alpha 
Patients will commence study treatment with EPO at 40,000 units once weekly. EPO will be 
provided as available in the respective country. The EPO must be self-administered via the 
subcutaneous route by the patient or competent personal. The patient will be instructed by the 
investigator to take the study drug as prescribed. All doses planned and prescribed to the 
patient and all dose changes including reasons for change during the study must be recorded 
in the eCRF. 
During the regular study visits the investigator or pharmacist will administer to the patient an 
appropriate number of vials or prefilled syringes, respectively, depending on the local 
availability. The number of vials or prefilled syringes of each strength dispensed will be 
recorded in the Study Drug Dosing Log. All EPO medication (used and unused) returned by 
the patient will be counted and the sum entered in the study drug dosing log by the 
investigator or pharmacist at the study site. 


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The initial dose is 40,000 units given subcutaneously once a week. If increase in Hb is < 
1 g/dL and total Hb is < 12 g/dL after 4 weeks, the dose will be increased to 60,000 
units/week. If increase in Hb is ≥ 1 g/dL and total Hb is < 12 g/dL, patients will continue the 
current EPO dose. If Hb increase is ≥ 1 g/dL and total Hb is ≥ 12 g/dL, the patients will hold 
EPO dose (Table 4-1). 
If after 12 weeks of treatment with EPO, Hb increase is < 1 g/dL and total Hb < 12 g/dL, the 
patient will discontinue EPO as the patient is not responding. These patients who do not 
respond to 12-week-EPO treatment will be switched to the combination for another period of 
12 weeks. If Hb increase is ≥ 1 g/dL and total Hb is < 12 g/dL, patients will continue the 
current EPO dose. If Hb increase is ≥ 1 g/dL and total Hb is ≥ 12 g/dL, the patients will hold 
EPO dose (Table 4-1). 
Instruction how to self-administer subcutaneous injections should be provided by the study 
personal. 
 
6.1.2 
Ancillary treatments 
Any additional therapy aimed to treat anemia and cytopenias during this trial (i.e. recombinant 
growth factors, steroids or immunosuppressive therapy for the improvement of hematological 
parameters) is not allowed, except study medication. Steroid treatment for chronic medical 
conditions is allowed if stable or improving over at least 2 months prior to screening. No RBC 
transfusions are allowed after randomization. Patients who are RBC transfusion dependent 
must not be enrolled in the study. Patients must be withdrawn from the study anytime when 
transfusion as rescue therapy is needed. 
No other iron chelation therapy is allowed while patients are receiving study treatment in this 
trial. 
 
6.1.3 
Guidelines for continuation of treatment 
For patients who are unable to tolerate the protocol-specified dosing schedule, dose reductions 
are permitted in order to keep the patient on study drug. These changes must be recorded on 
the dosage administration record eCRF. 
The majority of dose reductions are covered in Section 6.3.1. For all cases where a dose 
adjustment is considered necessary but is not covered in the following sections, the 
investigator will send a written request to Novartis. The request must justify the dose change 
and provide all the supportive clinical and laboratory information for complete evaluation by 
Novartis. Any dose adjustment for reasons not included in this section needs to be authorized 
by Novartis. A written reply will be promptly sent back to the investigator by Novartis. 
 
6.1.4 
Treatment duration 
The whole treatment period will last 24 week. The primary objective (erythroid response 
according to IWG criteria: Hb increase ≥ 1.5 g/dL) will be assessed by 12 weeks of treatment. 
At any time, if Hb ≥ 12, EPO will be stopped until the end of study. These patients will be 
considered as responders. 


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By 24 weeks, patients initially assigned to the combination therapy who showed Hb increase 
≥ 1 g/dL by week 12 will be assessed for full hematological response according IWG criteria 
(Erythroid response: Hb increase from baseline ≥ 1.5 g/dL; Neutrophil response: increase 
from baseline of ≥ 100% and > 0.5 x 109/L; Platelet response: increase from baseline of ≥ 30 
x 109/L). 
If after 12 weeks of treatment with EPO alone, Hb increase is < 1 g/dL and total Hb is < 12 
g/dL, the patient will switch to the combination therapy with EPO and DFX for the remaining 
12 weeks and will be assessed for erythroid response by 24 weeks. If after 12 weeks of 
treatment with EPO in combination with DFX, Hb increase is < 1 g/dL and total Hb is < 
12 g/dL, the patient will be discontinued from the study. 
Subjects need to be discontinued from the study if at least one of the following occurs: 
• ≥ 50% decrement from maximum response levels in granulocytes or platelets 
• Reduction of Hb level ≥ 1.5 g/dL compared to best response 
• Patient requiring blood transfusion at any time 
 
6.2 
Dose escalation guidelines 
Not applicable. 
 
6.3 
Dose modifications 
 
6.3.1 
Dose modification and dose delay 
For patients who do not tolerate the protocol-specified dosing schedule, dose reductions are 
permitted in order to allow the patient to continue the study treatment. The following 
guidelines need to be applied: 
During the study, the dose of DFX DT must not be escalated above 10 mg/kg/day or the dose 
of DFX FCT above 7 mg/kg/day. The standard dose of DFX DT 10 mg/kg/day or DFX FCT 7 
mg/kg/day may be reduced as part of the management of side effects. No dose changes based 
on efficacy parameters are permitted. Dose adjustments in increments of 5 or 10 mg/kg for 
DFX DT and of 3.5 or 7 mg/kg for DFX FCT may be made as part of adverse events 
management. 
These changes must be recorded on the Dosage Administration Record CRF. 
The majority of dose adjustments are covered in the Section 6.3.1 below. For cases where an 
exceptional dose adjustment (i.e., an adjustment not covered in the following sections) is 
considered necessary, the investigator will send a written request to Novartis. The request 
must justify the dose change and provide all the supportive clinical and laboratory information 
for complete evaluation by Novartis. Any exceptional dose adjustment needs to be authorized 
by Novartis. A written reply will be sent back to the investigator by Novartis within 5 
working days. 


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6.3.1.1 
Change in patient’s weight 
The dose of study drug will only be recalculated using Dosing Table 6-2 and Table 6-3 (DFX 
DT), and Table 6-4 and Table 6-5 (DFX FCT) during the study if the change (increase or 
decrease) in body weight exceeds 10% of the weight compared to the Randomization Visit or 
the last dose adjustment due to change in patient’s body weight. 
 
6.3.1.2 
Elevations in serum creatinine 
Serum creatinine should be monitored during the study as stated in the visit evaluation 
schedule Table 7-1. 
During the treatment period, patients who develop an increase in serum creatinine ≥ 33% 
above their baseline value (average of visit 1 and 2) resulting in a serum creatinine above the 
upper limit of normal (ULN), on two consecutive occasions, the dose of the study drug will be 
reduced to 5 mg/kg/day for DFX DT and 3.5 mg/kg/day for DFX FCT until serum creatinine 
returns to below the age adjusted ULN. 
It is recommended to check fluid balance and ensure adequate hydration of the patient. 
In case of a single increase in serum creatinine, the assessment will be repeated in 2 weeks. 
If after a dose reduction, a progressive increase in serum creatinine beyond the age adjusted 
ULN is observed, a treatment interruption is recommended. 
After an interruption, if serum creatinine falls below the age appropriate ULN range on two 
consecutive visits, it is recommended to resume DFX DT therapy at 5 mg/kg/day or DFX 
FCT therapy at 3.5 mg/kg/day, and after 1 month, if the serum creatinine increase does not 
recur, study medication can be re-escalated to the standard dose of DFX DT at 10 mg/kg/day 
or DFX FCT at 7 mg/kg/day. 
Caution should especially be used in patients with CrCl between 40 and less than 60 mL/min, 
particularly in cases where there are additional risk factors that may impair renal function 
such as concomitant medications, dehydration, or severe infections. 
DFX therapy must be discontinued in case serum creatinine >2 times the age-appropriate 
upper limit or if CrCl <40 mL/min. 
If after dose reduction, a progressive increase in serum creatinine is observed, Novartis must 
be contacted. 
 
6.3.1.3 
Skin disorders 
 
6.3.1.3.1 Stevens-Johnson syndrome (SJS) 
Severe skin reactions, including Stevens-Johnson syndrome (SJS), have been reported during 
DFX therapy. 
If Stevens Johnson syndrome is suspected, study treatment must be immediately discontinued 
and not be reintroduced. 


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6.3.1.3.2 Skin Rash other than SJS 
For skin rash of mild/moderate severity (defined as those causing minimal symptoms which 
require no or minimal supportive treatment), study drug should be continued without dose 
adjustment. The skin rash may resolve spontaneously without further intervention. 
If the rash persists for >1 week or becomes more severe, hold study drug. After the rash 
resolves, resume study drug at 50% of patient’s dose. If the rash does not recur, increase dose 
back to 10 mg/kg/day for DFX DT or 7 mg/kg/day for DXF FCT after 2 weeks. 
For a severe rash (distressing symptoms requiring discontinuation and/or systemic steroids), 
discontinue treatment until resolution of rash. Once the rash has resolved, resume at 50% of 
patient’s dose. If necessary, a brief course of oral steroids may be given concurrently with 
resumption of study drug. If the rash does not recur, increase to initial dose of 10 mg/kg/day 
for DFX DT or 7 mg/kg/day for DFX FCT. 
If the rash recurs, study drug may be discontinued if the investigator believes that it is in the 
best interest of the patient. 
Novartis may be contacted by the investigator to discuss dosing options if the investigator 
desires. 
 
6.3.1.4 
Increased liver enzyme levels 
If there is a persistent and progressive increase in serum transaminase levels that cannot be 
attributed to other causes, DFX should be interrupted. Once the cause of the liver function test 
abnormalities has been identified or after a return to normal levels, cautious re-initiation of 
DFX DT treatment at 5 mg/kg/day dose followed by dose escalation up to 10 mg/kg/day or re- 
initiation of DFX FCT treatment at 3.5 mg/kg/day dose followed by dose escalation up to 7 
mg/kg/day may be considered. In cases of a second rise in serum transaminase levels, the 
investigator should contact Novartis. 
 
6.3.1.5 
Hepatic Impairment 
Patients with hepatic impairment fulfilling criteria of Child-Pugh Class B or C are not allowed 
to enter the study. 
In patients developing moderate hepatic impairment (Child-Pugh Class B) during study, study 
treatment will be interrupted and the patient will be discontinued from study. 
 
6.3.1.6 
Dose modification criteria for auditory (decreased hearing) and ocular 
(lens opacities) disturbances 
Auditory (decreased hearing) and ocular (lens opacities) disturbances have been reported with 
DFX treatment. Auditory and ophthalmic testing (including fundoscopy) is recommended 
before the start of DFX treatment. If disturbances occur during study, dose reduction of DFX 
DT to 5 mg/kg/day or DFX FCT to 3.5 mg/kg/day or interruption may be considered. 


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6.3.1.7 
Dose modification criteria for hypersensitivity reactions 
Cases of serious hypersensitivity reactions (such as anaphylaxis and angioedema) have been 
reported in patients receiving DFX, with the onset of the reaction occurring in the majority of 
cases within the first month of treatment. If reactions are severe, DFX should be discontinued 
and appropriate medical intervention instituted. 
 
6.3.1.8 
Dose modification criteria for cytopenias 
There have been post-marketing reports (both spontaneous and from clinical trials) of 
cytopenias in patients treated with DFX. Most of these patients had  pre-existing 
hematological disorders that are frequently associated with bone marrow failure. The 
relationship of these episodes to treatment with DFX is uncertain. In line with the standard 
clinical management of such hematological disorders, blood counts should be monitored 
regularly. Dose interruption of treatment with DFX should be considered in patients who 
develop unexplained cytopenia. Reintroduction of therapy with DFX may be considered, once 
the cause of the cytopenia has been identified. 
 
6.3.2 
Treatment interruption and treatment discontinuation 
Patients who permanently discontinue study drug before completing the study should be 
scheduled for a visit as soon as possible, at which time all of the assessments listed for the 
final visit will be performed. The Study Treatment Completion eCRF should be completed, 
documenting the date and reason for stopping randomized study treatment. Any safety finding 
that leads to discontinuation of study drug should be captured on the AE eCRF. 
All patients who discontinue study drug, including those who refuse to return for a final visit, 
will be contacted by the investigational site for safety evaluations during the 30 days 
following the last dose of study drug. 
Patients who discontinue study drug should be considered withdrawn from the study after the 
final visit assessments are performed or when it is clear that the patient will not return for 
these assessments. 
All patients must be followed for AEs and SAEs for 30 days after the last dose of study 
treatment. Patients lost to follow up should be recorded as such on the eCRF. For patients who 
are lost to follow-up, the investigator should show “due diligence” by documenting in the 
source documents steps taken to contact the patient, e.g., dates of telephone calls, registered 
letters, etc. 
 
6.3.3 
Follow-up for toxicities 
Patients whose treatment is interrupted or permanently discontinued due to an AE or 
abnormal laboratory value must be followed at least once a week for 4 weeks, and 
subsequently at 4-week intervals, until resolution or stabilization of the event, whichever 
comes first. 


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6.3.4 
Anticipated risks and safety concerns of the study drug 
Appropriate eligibility criteria and specific DLT definitions, as well as specific dose 
modification and stopping rules are included in this protocol. Preclinical toxicity and/or 
clinical data can be found in the DFX Investigator’s Brochure and Summary of Product 
Characteristics of EPO. 
 
6.4 
Concomitant medications 
 
6.4.1 
Permitted concomitant therapy 
The concomitant administration of DFX and vitamin C has not been formally studied. Doses 
of vitamin C up to 200 mg/d have not been associated with adverse consequences. 
Any investigational drug other than study medication is NOT permitted during the study. 
The investigator must instruct the patient to notify the study site about any new medications 
(including over-the-counter products) he/she takes after the start of the study drug. All 
medications (other than study drug) and significant non-drug therapies (including physical 
therapy and herbal / natural) administered after the patient starts treatment with study drug 
must be listed on the Concomitant medications/Significant non-drug therapies after start of 
study drug eCRF. 
 
6.4.2 
Permitted concomitant therapy requiring caution and/or action 
• Aluminium containing antacid therapies should be avoided because they may bind to DFX. 
• The concomitant use of DFX with potent UGT inducers (e.g. rifampicin, phenytoin, 
phenobarbital, ritonavir) may result in a decrease in DFX efficacy. 
Caution must be exercised in patients who are taking study drug in combination with the 
following drugs: 
• Concomitant administration of DFX with drugs that have known ulcerogenic potential, 
such as NSAIDs, corticosteroids, or oral bisphosphonates, and use of DFX in patients 
receiving anticoagulants may increase the risk of gastrointestinal irritation 
• DFX, as a weak CYP3A4 inducer, may potentially decrease serum levels of substances 
metabolised through CYP3A4 (e.g. cyclosporin, simvastatin, hormonal contraceptive 
agents) 
• DFX  is  a  moderate  inhibitor  of  CYP2C8  and  therefore  it  may  increase  serum 
concentrations of substances metabolised through CYP2C8 (e.g repaglinide, paclitaxel) 
• DFX can potentially increase the exposure of the concomitantly administered CYP1A2 
substrates that have a narrow therapeutic index (e.g. theophylline, clozapine, tizanidine). 
Therefore the concomitant administration is not recommended. When deferasirox and 
theophylline are used concomitantly, monitoring of theophylline concentration and 
theophylline dose reduction should be considered. 
• The concomitant use of bile acid sequestrants (e.g. cholestyramine, colesevelan, colestipol) 
decreases deferasirox systemic exposure. 


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6.4.3 
Prohibited concomitant therapy 
Concomitant iron therapy is not allowed during the study. 
Any investigational drug other than study medication is NOT permitted during the study. 
 
6.5 
Patient numbering, treatment assignment or randomization 
 
6.5.1 
Patient numbering 
Each patient is identified in the study by a Patient Number, that is assigned when the patient is 
first enrolled for screening and is retained as the primary identifier for the patient throughout 
his/her entire participation in the trial. The Patient Number consists of 
 
 
so that each patient is numbered uniquely across the entire database. 
Upon signing the informed consent form, the patient is assigned to the next sequential Patient 
Number. 
The investigator or designated staff will contact the IWR and provide the requested 
identifying information for the patient to register them into the IWR. Once assigned, the 
Patient Number must not be reused for any other patient and the Patient Number for that 
individual must not be changed, even if the patient is re-screened. If the patient fails to be 
randomized or start treatment for any reason, the reason will be entered into the Screening 
Log. 
IWR must be notified within 2 days that the patient was not randomized. 
 
6.5.2 
Treatment assignment or randomization 
Patients will be assigned to one of the 2 treatment arms (Section 4.1 and Section 6.1) in a ratio 
of 1:1. 
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from patients and investigator staff. A patient 
randomization list will be produced by the Interactive Web Response Technology (IWR) 
provider using a validated system that automates the random assignment of patient numbers to 
randomization numbers. These randomization numbers are linked to the different treatment 
arms. 
Prior to dosing, all patients who fulfill all inclusion/exclusion criteria will be randomized via 
IWR to one of the treatment arms. The investigator or his/her delegate will log on to the IWR 
and confirm that the patient fulfills all the inclusion/exclusion criteria. 
 
6.5.3 
Treatment blinding 
This is an open-label study and therefore patients, investigators, study site staff and study field 
monitors are not blinded to the study treatment. 


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6.6 
Study drug preparation and dispensation 
The investigator or responsible site personnel must instruct the patient or caregiver to take the 
study drugs as per protocol. Study drug(s) will be dispensed to the patient by authorized site 
personnel only. All dosages prescribed to the patient and all dose changes during the study 
must be recorded on the Dosage Administration Record CRF. 
 
6.6.1 
Study drug packaging and labeling 
DFX and EPO can be provided as local commercial material or global clinical supply where 
appropriate and as per local regulations. Global clinical supply will be provided as open 
supply, and will be packed and labeled under the responsibility of 
 
. Study treatment labels will be available in the local language and comply with 
the legal requirements of each country. They will include storage conditions for the 
medication but no information about the patient. 
If DFX and/or EPO are sourced and labeled in-country, the locally approved form and 
packaging of DFX and/or EPO will be used. 
As per Novartis procedures, investigational treatment will only be shipped directly to the 
investigational sites. 
DFX and/or EPO in different formulations and strengths can be used once they are approved. 
Refer to the latest [Investigator Brochure for DFX] or local product information for dosing 
instructions and storage conditions. 
 
6.6.2 
Drug supply and storage 
Study treatments must be received by designated personnel at the study site, handled and 
stored safely and properly, and kept in a secured location to which only the investigator and 
designated site personnel have access. Upon receipt, the study treatment should be stored 
according to the instructions specified on the drug labels. 
 
6.6.3 
Study drug compliance and accountability 
 
6.6.3.1 
Study drug compliance 
Compliance will be assessed by the investigator and/or study personnel at each patient visit 
and information provided by the patient and/or caregiver will be captured in the Drug 
Accountability Form. This information must be captured in the source document at each 
patient visit. 
 
6.6.3.2 
Study drug accountability 
The investigator or designee must maintain an accurate record of the shipment and dispensing 
of study treatment in a drug accountability log. Drug accountability will be noted by the field 
monitor during site visits and at the completion of the study. Patients will be asked to return 
all unused study treatment and packaging on a regular basis, at the end of the study or at the 
time of study treatment discontinuation. 


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At study close-out, and, as appropriate during the course of the study, the investigator will 
return all used and unused study treatment, packaging, drug labels, and a copy of the 
completed drug accountability log to the Novartis monitor or to the Novartis address provided 
in the investigator folder at each site. 
 
6.6.3.3 
Handling of other study treatment 
Not applicable. 
 
6.6.4 
Disposal and destruction 
All unused study drug supply must be destroyed. The study drug supply can be destroyed at 
the local Novartis facility, Drug Supply group or third party, as appropriate. Study drug 
supply may only be destroyed at the site if permitted by local regulations and authorized by 
Novartis in a prior agreement. 
 
7 
Visit schedule and assessments 
7.1 
Study flow and visit schedule 
Following registering in IWR for screening, patient eligibility will be checked once all 
screening procedures are completed. The eligibility check will be embedded in the IWR 
system. Details guidelines to be followed can be found in the IWR manual. 
Table 7-1 lists all of the assessments and indicates with an “X”, the visits when they are 
performed. All data obtained from these assessments must be supported in the patient’s source 
documentation. Assessments such as laboratory data will be transferred to the database 
electronically. The table indicates which data are entered into the database (D) or remain in 
source documents only (S) (column category). 


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Table 7-1 
Visit evaluation schedule 
 
Category 
Protocol Section 
Screening 1 
Screening 2 
Treatment Period 
Follow-up 
period 
Randomization 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Cycle 6 
End of study 
treatment 
(EOT) 
30-day 
Safety Follow-up 
Study 
evaluation 
completion 
Visit 
1 
2 
3 
4 
5 
6 
7 
83 
9 
10 
11 
12 
777 
501 
778 
Week 
-4 to -1 
1 
2 
3 
4 
5 
7 
9 
13 
17 
21 
25 
Obtain Informed Consent 
D 
7.1.1.3 
X 
Inclusion/exclusion criteria 
D 
7.1.1.3 
X 
X 
Demography 
D 
7.1.1.3 
X 
IWR 
D 
6.5.2 
X 
X 
X 
Medical history 
D 
7.1.1.3 
X 
Physical examination 
S 
7.2.2.1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height (cm) 
D 
7.2.2.3 
X 
Weight (kg) 
D 
7.2.2.3 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs 1 
D 
7.2.2.2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Transfusion/RBC History 
D 
7.1.1 
X 
FAB classification 
D 
7.1.1.3 
X 
ECG 
D 
7.2.2.5.1 
X 
Ocular Exam 2 
D 
7.1.1.3 
X 
Audiometry 2 
D 
7.1.1.3 
X 
Laboratory Assessments 
7.2.2.4 
Hematology 
D 
7.2.2.4.1 
X 
X 
X 
X 
X 
X3 
X 
X 
X 
X 
X 
Biochemistry 
D 
7.2.2.4.2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Category 
Protocol Section 
Screening 1 
Screening 2 
Treatment Period 
Follow-up 
period 
Randomization 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Cycle 6 
End of study 
treatment 
(EOT) 
30-day 
Safety Follow-up 
Study 
evaluation 
completion 
Visit 
1 
2 
3 
4 
5 
6 
7 
83 
9 
10 
11 
12 
777 
501 
778 
Week 
-4 to -1 
1 
2 
3 
4 
5 
7 
9 
13 
17 
21 
25 
Hepatitis Viral 
D 
7.2.2.4.5 
X 
Serum Ferritin 4 
D 
7.2.2.4.2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
FE/TIBC (TSAT) 
D 
7.2.2.4.2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Endogenous EPO 
D 
7.2.2.4.2 
X 
B12 
D 
7.2.2.4.2 
X 
Folate 
D 
7.2.2.4.2 
X 
Serum Creatinine 5 
D 
7.2.2.4.2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ALT/AST 
D 
7.2.2.4.2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Direct/Indirect/Total bilirubin 
D 
7.2.2.4.2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Alkaline phosphatase 
D 
7.2.2.4.2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Creatinine Clearance 6 
D 
7.2.2.4.2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine dipstick 7 
D 
7.2.2.4.3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Microscopic urine 7 
D 
7.2.2.4.3 
Only if medically indicated in case of positive dipstick 
Urinary protein/creatinine 
ratio 
D 
7.2.2.4.3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum pregnancy test 8 
D 
7.2.2.4.4 
X 
X 
Urinary pregnancy test 8 
D 
7.2.2.4.4 
X 
X 
X 
X 
X 
X 
Blood pressure self- 
monitoring1 
S 
----------------------------------------------------continuous---------------------------------------------------- 


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Category 
Protocol Section 
Screening 1 
Screening 2 
Treatment Period 
Follow-up 
period 
Randomization 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Cycle 6 
End of study 
treatment 
(EOT) 
30-day 
Safety Follow-up 
Study 
evaluation 
completion 
Visit 
1 
2 
3 
4 
5 
6 
7 
83 
9 
10 
11 
12 
777 
501 
778 
Week 
-4 to -1 
1 
2 
3 
4 
5 
7 
9 
13 
17 
21 
25 
Concomitant medication 
D 
6.4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 10 
D 
8.1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Drug Dispensing 
D 
6.6.3 
X 
X 
X 
X 
X 
X 
Drug Accountability DFX 
D 
6.6.3 
X 
X 
X 
X 
X 
X 
Drug Accountability EPO 
S 
6.6.3 
X 
X 
X 
X 
X 
X 
Study Evaluation completion 
(SEC) 
D 
X 
1 Blood pressure has to be measured before each dose of EPO. EPO needs to be hold if BP >160/80. 
2 Ocular and Audiometry examinations must be performed at screening, should a patient have evidence at the Screening Visit that the examination(s) were performed 6 
months prior to screening then the examination(s) do not need to be repeated. The examination(s) can be performed at any time at the investigators discretion if 
symptomatically/clinically indicated. 
3 Visit 8 has to be performed only if EPO dose was increased at Visit 7. Then hematology parameters have to be assessed at Visit 8. 
4 Serum ferritin: Two samples at screening done at least 14 days apart. The serum ferritin samples should be obtained in the absence of known infection. 
5 Serum creatinine will be measured at Screening Visit 1 and Screening Visit 2 and the mean value will be used for eligibility criteria. Serum creatinine will also be 
measured weekly between the Randomization Visit and Week 4 visit. 
6 Creatinine clearances will be calculated by the central laboratory at every visit. 
7 Microscopic analysis will be performed only in case of positive dipstick. Dipsticks will be supplied by the central lab. 
8 Required for Females only. 
 
 
10 Adverse events must be followed up for 30 days after the last dose of study treatment. 


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7.1.1 
Screening 
Prior to commencement of the screening examination, the patient must have given full 
informed consent and have completed the study Informed Consent form. Once this has been 
signed and dated by the patient then the investigator can take the patient through the study 
inclusion and exclusion criteria to make sure that the patient is fully eligible to participate. 
The full list of assessments to be performed during the screening period (week -4 to week -1) 
is detailed in Table 7-1 and Table 7-2. Two Screening Visits that are at least 14 days apart are 
needed to perform key safety parameters prior to first dose administration as specified in the 
label. 
Re-screening is permissible on a case by case basis. Please contact Novartis for guidance and 
see Section 7.1.1.2 to get information on how to process screen failures. 
 
7.1.1.1 
Eligibility screening 
Patient eligibility will be confirmed by the site monitor during the second monitoring visit. 
 
7.1.1.2 
Information to be collected on screening failures 
Patients who sign an informed consent but fail to be started on treatment for any reason will 
be considered a screen failure. The reason for not being started on treatment will be entered on 
the Screening Log and each patient`s demographic information will be on the Demography 
CRF. 
If the patient fails to be randomized, the IWR must be notified within 2 days of the screen fail 
that the patient was not randomized. 
 
7.1.1.3 
Patient demographics and other baseline characteristics 
At Visits 1 and/or 2, data will be collected on patient characteristics including demographic 
information (age, sex, ethnicity, etc.) and other background or relevant medical  history/ 
current medical condition, transfusion history, disease history, MDS classification by FAB, 
serum pregnancy test and vital signs. 
To determine eligibility to be enrolled into the study, patients will also undergo assessments 
as per the inclusion and exclusion criteria which include hematology and biochemistry 
evaluations, hepatitis viral evaluation, serum ferritin and transferrin saturation, endogeneous 
EPO, B12, folate, serum creatinine, creatinine clearance, ALT/AST, direct/indirect/total 
bilirubin, alkaline phosphatase, a known history of HIV positive test result (ELISA or 
Western blot) which is documented in the source documents, active Hepatitis B and/or C, 
serum pregnancy test and urinalysis. 
Other assessments include ocular exam, audiometry and ECG. 


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7.1.2 
Treatment period 
Having completed the screening period, patients are enrolled and randomized to receive either 
DFX plus EPO or EPO alone. Study treatment is defined as DFX DT 10 mg/kg/day p.o. or 
DFX FCT 7 mg/kg/day p.o. plus EPO 40,000 units/week s.c. once weekly or EPO 40,000 
units/week once weekly s.c.. EPO dose changes are allowed in both arms according to the 
EPO guidelines (Appendix 3). For details on study design and dose adjustments, see Section 
4.1. The study treatment duration is 24 weeks. After randomization, patient visits will occur 
weekly during the first month because key safety assessments need to be performed weekly in 
the first month of treatment and then every 4 weeks thereafter until week 24. In case of a dose 
increase of EPO after 4 weeks of treatment, an additional visit needs to be performed after 2 
weeks of dose increase. 
For details of assessments, see Table 7-1 and Table 7-2. 
 
7.1.3 
End of Treatment Visit including study completion and premature 
withdrawal 
At the time patients discontinue study treatment, a visit should be scheduled as soon as 
possible, at which time all of the assessments listed for the End of Treatment (EOT) Visit will 
be performed. An End of Treatment CRF page must be completed, giving the date and reason 
for stopping the study treatment. 
At a minimum, all patients who discontinue study treatment, including those who refuse to 
return for a final visit, will be contacted for safety evaluations during the 30 days following 
the last dose of study treatment. 
Patients who discontinue study treatment should be considered withdrawn from the study after 
the final visit assessments are performed or when it is clear that the patient will not return for 
these assessments. 
If a study withdrawal occurs, or if the patient fails to return for visits, the investigator must 
determine the primary reason for a patient’s premature withdrawal from the study and record 
this information on the End of Treatment CRF page. 
The Investigator must contact the IWR to register the subject’s discontinuation. 
For criteria for premature withdrawal see Section 7.1.3.1. 
7.1.3.1 
Criteria for premature patient withdrawal 
Patients may voluntarily withdraw from the study or be dropped from it at the discretion of 
the investigator at any time. 
Premature patient withdrawal refers to the point/time when the patient exits from the study 
prior to the planned completion of all study treatment administration and/or assessments; at 
this time, all study drug treatment is discontinued and no further assessments are planned. 
Patients who become pregnant, withdrew consent, or died must be withdrawn from the study. 
Patients may be withdrawn from the study if any of the following occur: 


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• Unwillingness to comply with procedures as outlined in the study protocol, including 
unwillingness to comply with the prescribed study treatment 
• Discovery of failure of randomization 
• Discovery of patient ineligibility 
• Intake of prohibited medications 
• Adverse event(s) 
• Abnormal lab value(s) 
• Unsatisfactory therapeutic effect 
• Protocol violation 
• Lost to follow-up 
• Administrative problems 
Patients must be withdrawn from the study anytime when transfusion as rescue therapy is 
needed to ensure that all medically indicated transfusion requirements are covered, regardless 
of participation in the study. 
 
7.1.4 
Follow up period 
All patients must have safety evaluations for 30 days after the last dose of study treatment. 
Patients lost to follow up should be recorded as such on the CRF. For patients who are lost to 
follow-up, the investigator should show "due diligence" by documenting in the source 
documents steps taken to contact the patient, e.g., dates of telephone calls, registered letters, 
etc. 
 
7.2 
Assessment types 
 
7.2.1 
Efficacy assessments 
To  assess  the  effect  of  treatment  with  DFX  combined  with  EPO  vs.  EPO  alone  on 
erythropoiesis after 12 weeks of treatment is the primary objective of this study. 
Secondary objectives are to assess the effect of treatment with EPO alone on erythropoiesis 
after 24 weeks of treatment and to assess the effect of treatment on erythropoiesis after 24 
weeks in patients that were non-responder to EPO alone after 12 weeks and switched to 
combination of DFX combined with EPO. 
Further secondary objectives are to assess time to erythroid response and duration of erythroid 
response in the different treatment arms. 
The efficacy parameter Hb will be assessed bi-weekly in the first month of treatment and then 
at every visit. Erythroid response is defined as increase in Hb ≥ 1.5 g/dL according to 
modified IWG 2006 criteria (Appendix 2). 
The efficacy variable will be the difference in Hb from baseline vs. every month throughout 
the study. 
To assess the effect of treatment with DFX combined with EPO on hematologic improvement 
within 24 weeks of treatment in patients randomized to combination therapy at baseline is one 


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of the secondary objectives of this study. The efficacy parameters Hb, neutrophils and 
platelets will be assessed bi-weekly in the first week of treatment and then at every visit. 
Hematological response is defined as increase in Hb, improvement of neutropenia and 
thrombocytopenia according to modified IWG 2006 criteria (Appendix 2). Change in 
hematological parameters will be assessed for all subjects on study regardless if a patient 
meets the required precondition as defined by IWG 2006. 
Another secondary objective is to assess time to hematologic improvement in this treatment 
arm. 
 
7.2.2 
Safety and tolerability assessments 
Safety will be monitored by hematology, blood chemistry values, regular measurement of 
vital signs as detailed in Table 7-1 and Table 7-2, as well as collection of the adverse events at 
every visit. For details on AE collection and reporting, see Section 8. 
During EPO treatment, blood pressure will be self-measured before each dose of EPO. All 
patients will enter the results in the patient diary. Patient diaries will not be collected by the 
sponsor. 
 
7.2.2.1 
Physical examination 
A physical examination will be performed at Screening Visit 1, Randomization Visit and all 
subsequent visits except of Visit 8 which has to be performed only if EPO dose was increased 
at Visit 7. The physical examination at the Randomization Visit will serve as the Baseline 
physical examination for the entire study. The exam will entail an examination of general 
appearance, skin, neck (including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, 
back, lymph nodes, extremities and nervous system. 
Information about the physical examination must be present in the source documentation at 
the study site. 
All subjects will have standing height measured at the Screening Visit(s). This height 
measurement must be captured in the eCRF. Body weight will be recorded in all patients at 
screening, then at every clinic visit and captured in the eCRF. Weight should be measured 
while the patient is wearing ordinary clothing without shoes. 
Significant findings that are present prior to the signing of informed consent must be included 
in the Relevant Medical History/Current Medical Conditions page on the patient’s CRF. 
Significant new findings that begin or worsen after informed consent which meet the 
definition of an Adverse Event must be recorded on the Adverse Event page of the patient’s 
CRF. 
 
7.2.2.2 
Vital signs 
Vital signs include blood pressure and pulse measurements and will be measured at all study 
visits except of Visit 8 which has to be performed only if EPO dose was increased at Visit 7. 
After the patient has been sitting for five minutes, with back supported and both feet placed 
on the floor, systolic and diastolic blood pressure will be measured three times using an 
automated validated device, e.g. OMRON, with an appropriately sized cuff. The repeat sitting 


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measurements will be made at 1 - 2 minute intervals and the mean of the three measurements 
will be used. In case the cuff sizes available are not large enough for the patient’s arm 
circumference, a sphygmomanometer with an appropriately sized cuff may be used. The pulse 
will be measured after at least 5min rest as described above by full minute assessment. 
 
7.2.2.3 
Height and weight 
Height in centimeters (cm) and body weight (to the nearest 0.1 kilogram (kg) in indoor 
clothing, but without shoes) will be measured at the Screening Visit 1. 
Weight will be measured at Screening Visit 1, Randomization Visit 3, Visit 7, 9, 10, 11, 12 
and 777 (EOT). 
 
7.2.2.4 
Laboratory evaluations 
 
Table 7-2 
Clinical laboratory parameters collection plan 
 
Test Category 
Test Name 
Hematology 
Hemoglobin, hematocrit, white blood cell (WBC) count with differential, platelet count, red 
blood cell (RBC) count, mean corpuscular volume (MCV), ANC and reticulocyte count 
Chemistry 
Albumin, Alkaline phosphatase, ALT (SGPT), AST (SGOT), Bicarbonate, Calcium, Chloride, 
Creatinine, glucose, inorganic phosphorus, potassium; sodium, C-reactive protein; Creatine 
kinase, Direct Bilirubin, Indirect Bilirubin, Total Bilirubin, Total Cholesterol, LDL, HDL, Total 
Protein, Triglycerides, Blood Urea Nitrogen (BUN) or Urea, Uric Acid, gamma-glutamyl 
transpeptidase (GGT) 
Urinalysis 
Macroscopic Panel (Dipstick) (Bilirubin, Blood, Glucose, Ketones, Leukocytes esterase, pH, 
Protein, Specific Gravity); 
Microscopic Panel (examples: Bacteria, Epithelial cells, Amorphous crystals, Calcium 
Oxalate crystals, Uric acid crystals, Granular casts, Waxy casts, RBC casts, Casts hyaline ) 
See complete list of Microscopic Panel in Table 14-7 . 
Hepatitis markers 
HBsAg, Anti-HCV, HCV PCR (Quantitative), Anti-HBs 
Additional tests 
Serum ferritin, Endogenous EPO, B12, folate, iron, UIBC, TIBC, FE/TIBC (TSAT), creatinine 
clearance, urinary protein /creatinine ratio, serum pregnancy test, urinary pregnancy test 
A central laboratory will be used for analysis of all specimens collected, except urinary 
Dipstick analysis and urinary pregnancy tests will be performed by the local lab. 
Details on the collections, shipment of samples and reporting of results by the central 
laboratory are provided to investigators in the [Laboratory Manual]. 
 
7.2.2.4.1 Hematology 
Hematology samples will be collected at Screening Visits 1 and 2, Visit 3, 5, 7, 8, 9 and then 
at 4 week intervals, thereafter, as described in the [Laboratory Manual]. Safety laboratory 
parameters monitored during the study will include Hb, hematocrit, white blood cell (WBC) 
count with differential, platelet count, red blood cell (RBC) count, mean corpuscular volume 
(MCV), ANC and reticulocyte count. All hematology samples must be sent to the central 
laboratory. 


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7.2.2.4.2 Clinical chemistry 
Clinical chemistry samples will be collected at Screening Visits 1 and 2, at Randomization 
Visit 3 and weekly for the first four weeks of study drug administration at Visits 4, 5, 6, at 
Visit 7 and then at 4 week intervals, thereafter, as described in the [Laboratory Manual]. 
Parameters to be measured will include: albumin, alkaline phosphatase, ALT/SGPT, 
AST/SGOT, bicarbonate, calcium, chloride, creatinine, glucose, inorganic phosphorus, 
potassium, sodium, C-reactive protein, creatine kinase, direct bilirubin, indirect bilirubin, total 
bilirubin, total cholesterol, LDL, HDL, total protein, triglycerides, blood urea nitrogen (BUN) 
or urea, uric acid, gamma-glutamyl transpeptidase (GGT). 
In accordance with the DFX label, serum creatinine, creatinine clearance,  alkaline 
phosphatase, ALT/SGPT, AST/SGOT, direct bilirubin, indirect bilirubin, total bilirubin must 
be assessed in duplicate before the initiation of therapy to establish a reliable pre-treatment 
baseline. 
In addition, serum creatinine, alkaline phosphatase, ALT/SGPT, AST/SGOT, direct bilirubin, 
indirect bilirubin, total bilirubin will be measured weekly for the first four weeks of study 
drug administration at Visits 4, 5, 6. 
Creatinine clearance will be estimated using the Cockcroft-Gault equation. This estimate will 
be provided each time serum creatinine is collected. 
Serum ferritin test will also be performed at Screening Visits 1 and 2 to assess the eligibility 
of the patient. The baseline serum ferritin value is defined as the average of the two 
measurements obtained during the screening period. Serum ferritin testing will also be 
performed monthly starting at Randomization Visit 3. 
Endogenous EPO will be assessed at Screening Visit 1 to assess the eligibility of the patient. 
Fe/TIBC (TSAT), B12 and Folate will be performed at Screening Visit 1 to assess eligibility 
to EPO treatment. Fe/TIBC (TSAT) will be additionally assessed at therapy initiation at Visit 
3 and then monthly. 
 
7.2.2.4.3 Urinalysis 
Urinalysis samples will be collected at Screening Visits 1 and 2, Randomization Visit 3 and 
every week during the first four weeks and then every four weeks thereafter. A midstream, 
second voided morning urine sample will be obtained. Specific gravity, pH, blood, glucose, 
protein, bilirubin, ketones, and leukocyte esterase will be assessed. Microscopic analysis will 
be performed only in case of positive dipstick. Dipsticks will be supplied by the central lab. 
At Screening Visits 1 and 2, a fresh urine sample (at least 15 ml) will be collected and sent to 
the central laboratory for urinary protein/creatinine ratio to assess the eligibility of the patient. 
In addition, urine samples for urinary protein/creatinine ratios will be collected at 
Randomization Visit 3 and every week during the first four weeks and then every four weeks 
thereafter, as described in the [Laboratory Manual]. First morning void samples must not be 
used for this analysis. Significant proteinuria is indicated by a urinary protein/creatinine 
ratio > 0.1 mg/mg. 


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For patients who develop proteinuria or a worsening of pre-existing proteinuria (assessed by a 
dipstick) at any visit, urine samples must be collected and urine protein assessed by the central 
laboratory. 
 
7.2.2.4.4 Pregnancy and assessments of fertility 
All female patients capable of becoming pregnant will have a pregnancy test (serum β-HCG) 
at Screening Visits 2 and at EOT Visit. The results of the test must be available prior to 
initiating treatment with any study medication. Serum pregnancy test is recommended within 
48 hours prior first study drug administration. If not possible, a urine pregnancy test must also 
be done at Visit 3 prior to first study drug administration. Positive pregnancy tests will 
exclude a patient from participating in this trial. 
During the treatment period, local urinary pregnancy testing will be performed monthly in all 
female patients capable of becoming pregnant. See Section 8.4 for procedures to report 
pregnancy. 
Pregnancy must be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the local Novartis Clinical Safety & Epidemiology Department. Pregnancy 
follow-up must be recorded on the same form and must include an assessment of the possible 
relationship to the Novartis study drug of any pregnancy outcome. Any SAE experienced 
during pregnancy must be reported on the SAE Report Form. 
 
7.2.2.4.5 Hepatitis Viral tests 
Hepatitis Viral testing consists of the following items: Hepatitis B Surface Antibody (Anti- 
HBs), Hepatitis C Antibody (Anti-HCV), Hepatitis B surface Antigen (HBsAg), HCV PCR 
(Quantitative). Hepatitis Viral testing will be conducted at Screening Visit 1 to assess trial 
eligibility. 
 
7.2.2.5 
Cardiac assessments 
 
7.2.2.5.1 Electrocardiogram (ECG) 
A standard 12 lead ECG will be performed at Screening. Interpretation of the tracing must be 
made by a qualified physician and documented on the ECG CRF page. Each ECG tracing 
should be labeled with the study number, patient initials (where regulations permit), patient 
number, date, and kept in the source documents at the study site. Clinically significant 
abnormalities present when the patient signed informed consent should be reported on the 
Medical History CRF page. Clinically significant findings must be discussed with Novartis 
prior to enrolling the patient in the study. Patients with significant cardiac abnormalities may 
only be enrolled if endorsed by Novartis. New or worsened clinically significant findings 
occurring after informed consent must be recorded on the Adverse Events CRF page. 
 
 
 
 
 
 
 


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7.2.4 
Other assessments 
No additional tests will be performed on patients entered into this study. 
 
8 
Safety monitoring and reporting 
8.1 
Adverse events 
 
8.1.1 
Definitions and reporting 
An adverse event is defined as the appearance of (or worsening of any pre-existing) 
undesirable sign(s), symptom(s), or medical condition(s) that occur after patient’s signed 
informed consent has been obtained. 
Abnormal laboratory values or test results occurring after informed consent constitute adverse 
events only if they induce clinical signs or symptoms, are considered clinically significant, 
require therapy (e.g., hematological abnormality that requires transfusion or hematological 
stem cell support), or require changes in study medication(s). 
Except for screening failures, adverse events that begin or worsen after informed consent 
should be recorded in the Adverse Events CRF. Conditions that were already present at the 
time of informed consent should be recorded in the Relevant Medical History/Current 
Medical Conditions CRF of the patient’s CRF. Adverse event monitoring should be continued 
for at least 30 days (or 5 half-lives, whichever is longer) following the last dose of study 
treatment. Adverse events (including lab abnormalities that constitute AEs) should be 
described using a diagnosis whenever possible, rather than individual underlying signs and 
symptoms. When a clear diagnosis cannot be identified, each sign or symptom should be 
reported as a separate Adverse Event. 
Severity of adverse events will be assessed as mild, moderate, or severe. Information about 
deaths will be collected though an EOT form. 
The occurrence of adverse events should be sought by non-directive questioning of the patient 
(subject) during the screening process after signing informed consent and at each visit during 
the study. Adverse events also may be detected when they are volunteered by the patient 
(subject) during the screening process or between visits, or through physical examination, 
laboratory test, or other assessments. As far as possible, each adverse event should be 
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1. The severity grade (mild moderate, or severe) 
2. Its duration (Start and end dates or Ongoing at End of Study) 
3. Its relationship to the study treatment (Reasonable possibility that AE is related: No, Yes) 
4. Action taken with respect to study or investigational treatment (none, dose adjusted, 
temporarily interrupted, permanently discontinued, unknown, not applicable) 
5. Whether medication or therapy was given (no concomitant medication/non-drug therapy, 
concomitant medication/non-drug therapy) 
6. Whether it is serious, where a serious adverse event (SAE) is defined as in Section 8.2.1 
All adverse events should be treated appropriately. If a concomitant medication or non-drug 
therapy is given, this action should be recorded on the Adverse Event CRF. 
Once an adverse event is detected, it should be followed until its resolution or until it is 
judged to be permanent, and assessment should be made at each visit (or more frequently, if 
necessary) of any changes in severity, the suspected relationship to the study treatment, the 
interventions required to treat it, and the outcome. 
 
8.1.2 
Laboratory test abnormalities 
 
8.1.2.1 
Definitions and reporting 
Laboratory abnormalities that constitute an Adverse event in their own right (are considered 
clinically significant, induce clinical signs or symptoms, require concomitant therapy or 
require changes in study treatment), should be recorded on the Adverse Events CRF. 
Whenever possible, a diagnosis, rather than a symptom should be provided (e.g. anemia 
instead of low hemoglobin). Laboratory abnormalities that meet the criteria for Adverse 
Events should be followed until they have returned to normal or an adequate explanation of 
the abnormality is found. When an abnormal laboratory or test result corresponds to a 
sign/symptom of an already reported adverse event, it is not necessary to separately record the 
lab/test result as an additional event. 
Laboratory abnormalities, that do not meet the definition of an adverse event, should not be 
reported as adverse events. A severe event does not automatically indicate a SAE unless it 
meets the definition of serious as defined below and/or as per investigator’s discretion. A dose 
hold for the lab abnormality may be required by the protocol in which case the lab 
abnormality would still, by definition, be an adverse event and must be reported as such. 
 
8.1.3 
Adverse events of special interest 
See Section 6.3.1.1 through Section 6.3.1.7. 


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8.2 
Serious adverse events 
 
8.2.1 
Definitions 
Serious adverse event (SAE) is defined as one of the following: 
• Is fatal or life-threatening 
• Results in persistent or significant disability/incapacity 
• Constitutes a congenital anomaly/birth defect 
• Is medically significant, i.e., defined as an event that jeopardizes the patient or may 
require medical or surgical intervention to prevent one of the outcomes listed above 
• Requires inpatient hospitalization or prolongation of existing hospitalization, 
• Note that hospitalizations for the following reasons should not be reported as serious 
adverse events: 
• Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 
• Elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent 
• Social reasons and respite care in the absence of any deterioration in the patient’s 
general condition 
• Note that treatment on an emergency outpatient basis that does not result in hospital 
admission and involves an event not fulfilling any of the definitions of a SAE given above 
is not a serious adverse event 
 
8.2.2 
Reporting 
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the 
patient has provided informed consent and until at least 30 days after the patient has stopped 
study treatment must be reported to Novartis within 24 hours of learning of its occurrence. 
Any SAEs experienced after this 30 days period should only be reported to Novartis if the 
investigator suspects a causal relationship to the study treatment. Recurrent episodes, 
complications, or progression of the initial SAE must be reported as follow-up to the original 
episode within 24 hours of the investigator receiving the follow-up information. An SAE 
occurring at a different time interval or otherwise considered completely unrelated to a 
previously reported one should be reported separately as a new event. 
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 
thorough report. The investigator must assess and record the relationship of each SAE to each 
specific study treatment (if there is more than one study treatment), complete the SAE Report 
Form in English, and send the completed, signed form by fax within 24 hours to the oncology 
Novartis Drug Safety and Epidemiology (DS&E) department. 
The telephone and telefax number of the contact persons in the local department of Drug 
Safety and Epidemiology (DS&E), specific to the site, are listed in the investigator folder 


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provided to each site. The original copy of the SAE Report Form and the fax confirmation 
sheet must be kept with the case report form documentation at the study site. 
Follow-up information is sent to the same contact(s) to which the original SAE Report Form 
was sent, using a new SAE Report Form stating that this is a follow-up to the previously 
reported SAE and giving the date of the original report. Each re-occurrence, complication, or 
progression of the original event should be reported as a follow-up to that event regardless of 
when it occurs. The follow-up information should describe whether the event has resolved or 
continues, if and how it was treated, whether the blind was broken or not, and whether the 
patient continued or withdrew from study participation. 
If the SAE is not previously documented in the [Investigator’s Brochure] or Package Insert 
(new occurrence) and is thought to be related to the Novartis study treatment, an oncology 
Novartis Drug Safety and Epidemiology (DS&E) department associate may urgently require 
further information from the investigator for Health Authority reporting. Novartis may need to 
issue an Investigator Notification (IN), to inform all investigators involved in any study with 
the same drug that this SAE has been reported. Suspected Unexpected Serious Adverse 
Reactions (SUSARs) will be collected and reported to the competent authorities and relevant 
ethics committees in accordance with Directive 2001/20/EC or as per national regulatory 
requirements in participating countries. 
 
8.3 
Emergency unblinding of treatment assignment 
Not applicable, this is an open-label treatment study. 
 
8.4 
Pregnancies 
To ensure patient safety, each pregnancy occurring while the patient is on study treatment 
must be reported to Novartis within 24 hours of learning of its occurrence. The pregnancy 
should be followed up to determine outcome, including spontaneous or voluntary termination, 
details of the birth, and the presence or absence of any birth defects, congenital abnormalities, 
or maternal and/or newborn complications. 
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the oncology Novartis Drug Safety and Epidemiology Department (DS&E). 
Pregnancy follow-up should be recorded on the same form and should include an assessment 
of the possible relationship to the study treatment any pregnancy outcome. Any SAE 
experienced during pregnancy must be reported on the SAE Report Form. 
 
8.5 
Warnings and precautions 
No evidence available at the time of the approval of this study protocol indicated that special 
warnings or precautions were appropriate, other than those noted in the provided Investigator 
Brochure. Additional safety information collected between IB updates will be communicated 
in the form of Investigator Notifications. This information will be included in the patient 
informed consent and should be discussed with the patient during the study as needed. 
 
8.6 
Data Monitoring Committee 
Not applicable. 


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8.7 
Steering Committee 
Not applicable. 
 
9 
Data collection and management 
9.1 
Data confidentiality 
Information about study subjects will be kept confidential and managed under the applicable 
laws and regulations. Those regulations require a signed subject authorization informing the 
subject of the following: 
• What protected health information (PHI) will be collected from subjects in this study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• The rights of a research subject to revoke their authorization for use of their PHI. 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization. For subjects that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect follow-up safety information (e.g. has the 
subject experienced any new or worsened AEs) at the end of their scheduled study period. 
The data collection system for this study uses built-in security features to encrypt all data for 
transmission in both directions, preventing unauthorized access to confidential participant 
information. Access to the system will be controlled by a sequence of individually assigned 
user identification codes and passwords, made available only to authorized personnel who 
have completed prerequisite training. 
 
9.2 
Site monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, Novartis 
personnel (or designated CRO) will review the protocol and CRFs with the investigators and 
their staff. During the study, the field monitor will visit the site regularly to check the 
completeness of patient records, the accuracy of entries on the CRFs, the adherence to the 
protocol to Good Clinical Practice, the progress of enrollment, and to ensure that study 
treatment is being stored, dispensed, and accounted for according to specifications. Key study 
personnel must be available to assist the field monitor during these visits. 
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information recorded on CRFs must be traceable to source documents in the 
patient's file. The investigator must also keep the original signed informed consent form (a 
signed copy is given to the patient). 
The investigator must give the monitor access to all relevant source documents to confirm 
their consistency with the CRF entries. Novartis monitoring standards require full verification 
for  the  presence  of  informed  consent,  adherence  to  the  inclusion/exclusion  criteria  and 


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documentation of SAEs. Additional checks of the consistency of the source data with the 
CRFs are performed according to the study-specific monitoring plan. 
 
9.3 
Data collection 
For studies using Electronic Data Capture (EDC), the designated investigator staff will enter 
the data required by the protocol into the Electronic Case Report Forms (eCRF). The eCRFs 
have been built using fully validated secure web-enabled software that conforms to 21 CFR 
Part 11 requirements, Investigator site staff will not be given access to the EDC system until 
they have been trained. Automatic validation programs check for data discrepancies in the 
eCRFs and, allow modification or verification of the entered data by the investigator staff. 
The Principal Investigator is responsible for assuring that the data entered into eCRF is 
complete, accurate, and that entry and updates are performed in a timely manner. 
 
9.4 
Database management and quality control 
For studies using eCRFs, Novartis personnel (or designated CRO) will review the data entered 
by investigational staff for completeness and accuracy. Electronic data queries stating the 
nature of the problem and requesting clarification will be created for discrepancies  and 
missing values and sent to the investigational site via the EDC system. Designated 
investigator site staff are required to respond promptly to queries and to make any necessary 
changes to the data. 
Concomitant treatments and prior medications entered into the database will be coded using 
the WHO Drug Reference List, which employs the Anatomical Therapeutic Chemical 
classification system. Medical history/current medical conditions and adverse events will be 
coded using the Medical dictionary for regulatory activities (MedDRA) terminology. 
Samples and/or data will be processed centrally and the results will be sent electronically to 
Novartis (or a designated CRO). 
Randomization codes and data about all study treatments dispensed to the patient will be 
tracked using an Interactive Response Technology. The system will be supplied by a 
vendor(s), who will also manage the database. The data will be sent electronically to Novartis 
personnel (or designated CRO). 
At the conclusion of the study, the occurrence of any emergency code breaks will be 
determined after return of all code break reports and unused drug supplies to Novartis 
personnel (or designated CRO). The occurrence of any protocol violations will be determined. 
After these actions have been completed and the data has been verified to be complete and 
accurate, the database will be declared locked. Authorization is required prior to making any 
database changes to locked data, by joint written agreement between the Global Head of 
Biostatistics and Data Management and the Global Head of Clinical Development. 
For EDC studies, after database lock, the investigator will receive a CD-ROM or paper copies 
of the patient data for archiving at the investigational site. 


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10 
Statistical methods and data analysis 
This is an open-label, phase II, randomized, pilot study to assess the efficacy in term of 
erythroid improvement of DFX combined with EPO compared to EPO alone in patients with 
low- or int-1-risk myelodysplastic syndrome. 
The data will be analyzed by Novartis and/or a designated CRO. 
Continuous variables will be summarized by number of patients, mean, standard deviation, 
minimum, 25th-percentile, median, 75th percentile and maximum. Categorical variables will be 
summarized by absolute and relative frequencies. 
In addition to the statistical methods outlined below, further details and any additional, 
exploratory analyses that may be performed will be described in the Report and Analysis Plan 
(RAP). 
 
10.1 
Analysis sets 
 
10.1.1 
Full Analysis Set 
The Full Analysis Set (FAS) comprises all patients to whom study treatment has  been 
assigned by randomization (EPO or EPO+DFX). According to the intent to treat principle, 
patients will be analyzed according to the treatment they have been assigned to during the 
randomization procedure. 
 
10.1.2 
Safety Set 
The Safety Set includes all randomized patients who received at least one dose of study 
medication, i.e. either EPO or EPO+DFX, and with at least one post-baseline safety 
assessment (e.g. lab, vital signs, AEs) and the statement that a subject did not experience an 
AE can currently be regarded as a valid safety assessment. 
 
10.1.3 
Per Protocol Set 
The per protocol (PP) set consists of all patients from the Full Analysis Set without any major 
protocol deviation, who have been randomized, are evaluable for efficacy (has both baseline 
and at least one post-baseline value for Hb) and who received at least one dose of assigned 
study medication. 
However, if a patient discontinued for adverse event or died before the minimum exposure 
requirement could be met, or before he/she could become evaluable for efficacy, the patient 
will still be included in the PP set. 
 
10.2 
Patient demographics/other baseline characteristics 
Demographic and other baseline data and disease characteristics will be summarized 
descriptively by treatment group for the FAS. 


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10.3 
Treatments (study treatment, concomitant therapies, compliance) 
Duration of study drug exposure for EPO and DFX as well as DFX planned dose (mg/kg/day), 
DFX actual dose (mg/day) and EPO planned and actual dose (units/week) will be summarized. 
Frequency tables for dose adjustments and related reason will be provided for DFX and EPO 
by treatment group as well as number of dose interruptions. Any dose adjustments and 
reasons will be listed. 
Descriptive statistics will be provided for frequency of patients switching at 12 weeks to other 
treatment regimen, as per EPO guidelines. 
DFX compliance based on prescribed amount of study medication versus amount of 
medication taken based on dispensed and returned amount of study medication will be 
summarized. 
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will also be provided. Analysis will be done on safety set. 
 
10.4 
Primary objective 
The primary objective is to assess the effect of treatment with DFX combined with EPO vs. 
EPO alone on erythropoiesis. 
 
10.4.1 
Variable 
The primary variable is the difference in proportion of patients achieving an erythroid 
response after 12 weeks of treatment between the two arms according to a criterion based on 
modified IWG 2006 (increase in Hb from baseline ≥ 1.5 g/dL). 
Patients meeting the criterion at any time within the first 12 weeks period will be considered 
as erythroid responders. 
 
10.4.2 
Statistical hypothesis, model, and method of analysis 
A patient is defined as an erythroid responder if the criterion of Hb increase from baseline ≥ 
1.5 g/dL is met at any time within the first 12 weeks period. Baseline is defined as the last 
available Hb value available within windows of 4 weeks prior to or on treatment start date. No 
imputation will be performed for missing laboratory data. 
Difference in proportions between treatment groups with its 95% Agresti-Caffo (Agresti-
Caffo 2000) confidence interval will be provided. Erythroid response proportion will be also 
summarized by treatment group with its 95% Clopper-Pearson confidence intervals. 
Analysis will be performed on FAS and PP set. 
 
10.5 
Secondary objectives 
 
10.5.1 
To assess the effect of treatment with DFX+EPO and EPO alone on 
hematological response within 24 weeks of treatment 
This analysis includes patients who were randomized to EPO and EPO+DFX and remained in 
their respective treatment arms. 


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Hematological response will be assessed on this subset of patients and hematological 
responder is defined as patient meeting at least one of the following modified IWG 2006 
criteria: 
Hematological response: 
• Hb increase from baseline ≥ 1.5 g/dL and Hb < 11 g/dL at baseline (All patients on study 
per inclusion criterion 5, section 5.2) 
• Neutrophil response: Neutrophil increase from baseline of ≥ 100% and increase > 
0.5 x 109/L and neutrophils < 1.0 × 109/L at baseline 
• Platelet response: Platelet increase from baseline of ≥ 30 x 109/L and platelets < 100 × 
109/L at baseline 
Patients who met at least one of the 3 conditions of hematological response at any time 
between first day of treatment and week 24 will be considered as responders. 
Supportive analyses (proportion of patients, descriptive statistics on the related parameters, 
change from baseline) will also be provided for patients who do not satisfy the IWG 2006 pre- 
treatment conditions for neutrophil and/or platelet response (i.e., these patients have baseline 
neutrophils ≥ 1.0 × 109/L and baseline platelets ≥ 100 × 109/L) but show hematologic 
improvement with respect to neutrophils (increase from baseline > 0.5 × 109/L) and platelets 
(increase from baseline ≥ 30 × 109/L). 
Proportion of patients achieving a hematological response within 24 weeks of treatment with 
DFX combined with EPO and EPO alone will be calculated along with 95% Clopper-Pearson 
confidence interval. Descriptive statistics will be provided for hematological response, as well 
as for all improvement of myeloid cell lineages (erythrocytes, neutrophils and platelets). 
Analysis will be performed on FAS and PP set. 
 
Table 10-1          Criteria for hematological response and hematologic improvement 
 
Pre-treatment conditions 
Post-baseline 
Response 
Hematological response: 
Hb < 11 g/dL at baseline 
Hb increase from baseline by 
Erythroid 
If a patient fulfills at least 
≥ 1.5 g/dL 
response 
erythroid or platelet or neutrophil 
response as well as it’s 
corresponding pre-treatment 
condition 
Platelet < 100 ×109/L at 
baseline 
Neutrophil < 1.0 × 109/L at 
baseline 
Increase from baseline ≥ 30 × 
109/L 
Increase from baseline > 
100% and increase from 
Platelet 
response 
Neutrophil 
response 
baseline > 0.5 × 109/L 
Hematologic improvement: 
If a patient fulfills at least platelet 
or neutrophil improvement 
response without it’s 
corresponding pre-treatment 
condition 
Platelet ≥ 100 ×109/L at 
baseline 
Neutrophil ≥ 1.0 × 109/L at 
baseline 
Increase from baseline ≥ 30 × 
109/L 
Increase from baseline > 0.5 
× 109/L 
Platelet 
improvement 
Neutrophil 
improvement 


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10.5.2 
To assess the effect of treatment on erythropoiesis within 24 weeks in 
patients who were non-responder to EPO alone after 12 weeks and 
switched to DFX+EPO 
Patients who are non-responders to erythroid at week 12 in the EPO group will have to switch 
to combination therapy, if they continue to participate in the study. 
Patients meeting the criterion (Hb increase from baseline ≥ 1.5 g/dL) at any time between 
week 12 and week 24 will be considered as erythroid responders. 
Proportion of erythroid responders between week 13 and 24 will be reported along with its 
95% Clopper-Pearson confidence interval. Descriptive statistics will be provided for erythroid 
response. Analysis will be performed on FAS and PP set. 
 
10.5.3 
To assess time to erythroid response in patients treated with 
DFX+EPO and patients treated with EPO alone 
This analysis will include patients who were randomized to EPO and EPO+DFX and 
remained in their respective treatment arms. Descriptive statistics will be provided for 
erythroid responder patients (achieved Hb increase ≥ 1.5 g/dL from baseline) for time to 
response (days), defined as the time from date of start of treatment to the date of event defined 
as the first documented erythroid response between week 1 to week 24. Analysis will be 
performed on FAS and PP set for both treatment groups. 
 
10.5.4 
To assess the effect of treatment with EPO alone on erythropoiesis 
after 24 weeks of treatment 
This analysis includes patients who started with the EPO alone and are not switched to 
combination therapy. 
Patients meeting the criterion (Hb increase from baseline ≥ 1.5 g/dL) at any time between 
week 1 and week 24 will be considered as erythroid responders. 
Proportion of erythroid responders who starts with EPO alone and are not switched to 
combination therapy will be reported along with its 95% Clopper-Pearson confidence interval. 
Descriptive statistics will be provided for erythroid response. Analysis will be performed on 
FAS and PP set. 
 
10.5.5 
To estimate time to erythroid response in patients who were non- 
responder to EPO alone after 12 weeks and switched to DFX+EPO 
Descriptive statistics will be provided for erythroid responder patients (achieved Hb increase 
≥ 1.5 g/dL from baseline) for time to response (days), defined as the time from date of switch 
to combination to the date of event defined as the first documented erythroid response within 
the period between week 13 and week 24. Analysis will be performed on FAS and PP set. 


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10.5.6 
To estimate time to hematological response in patients treated with 
DFX+EPO and EPO alone within 24 weeks 
This analysis includes patients who started with combination therapy and EPO alone and 
remained in their respective treatment arms. 
Descriptive statistics will be provided for responder patients for time to response (days), 
defined as the time from date of start of treatment to the date of event defined as the first 
documented hematological response (increase in Hb, improvement of neutropenia and 
thrombocytopenia) up to week 24. 
Hematological response will be assessed on this subset of patients and hematological response 
is defined for patients meeting at least one of the following modified IWG 2006 criteria: 
• Hb increase from baseline ≥ 1.5 g/dL and Hb < 11 g/dL at baseline (all patients on study 
per inclusion criterion 5, Section 5.2). 
• Neutrophil response: increase from baseline of ≥ 100% and increase > 0.5 x 109/L and < 
1.0 × 109/L at baseline. 
• Platelet response: increase from baseline of ≥ 30 x 109/L and < 100 × 109/L at baseline. 
Patients who met at least one of the 3 conditions of hematological response at any time 
between first day of treatment and week 24 will be considered as responders. 
Analysis will be performed on FAS and PP set. 
Further descriptive statistics on time to neutrophil and platelet improvement for patients who 
did not satisfied pre-treatment IWG criteria but show hematologic improvement according to 
modified IWG response criteria: 
• Neutrophil improvement: increase from baseline > 0.5 × 109/L 
• Platelet improvement: increase from baseline of ≥ 30 × 109/L 
will be  provided  along  with  summary  on  total  time  to  hematological  response 
(Section 10.5.1). Such analysis will be done for patients remaining in the EPO+DFX arm and 
EPO alone arm. 
 
10.5.7 
To estimate duration of erythroid response among responders treated 
with EPO alone 
Descriptive statistics will be provided for responder patients for rate of relapse (decrease in 
Hb ≥ 1.5 g/dL from value at response) as well as for duration of response (days) defined as the 
time from onset of the first response to relapse. Duration of response will be evaluated within 
the whole 24 weeks period. Analysis will be performed on FAS and PP set. 


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10.5.8 
To estimate duration of erythroid response among responders treated 
with DFX+EPO 
This analysis will include patients treated with DFX combined with EPO at baseline and 
patients who switch to DFX+EPO from EPO arm after 12 weeks. Descriptive statistics will be 
provided for responder patients for rate of relapse (decrease in Hb ≥ 1.5 g/dL from value at 
response) as well as for duration of response (days) defined as the time from onset of the first 
response to relapse. Duration of response will be evaluated within the whole 24 weeks period 
for patients randomized to EPO+DFX and within week 13-24 for patients randomized to EPO 
at baseline and switched to combination therapy after 12 weeks. Analysis will be performed 
on FAS and PP set. 
 
10.5.9 
To assess iron parameters in patients randomized to EPO alone, 
DFX+EPO and in patients randomized to EPO alone and switched to 
DFX+EPO after 12 weeks 
This analysis will include patients randomized either to EPO or DFX+EPO at baseline as well 
as patients who are non-responders to erythroid at week 12 in the EPO group switched to 
combination therapy. The time-course of serum ferritin and its absolute/relative changes from 
baseline will be summarized by descriptive statistics by visit and erythroid response. Data will 
be summarized on FAS and PP set. 
Note: Patients randomized to EPO and not switching after 12 weeks to EPO+DFX, will 
consist of only responders. 
 
10.5.10 To assess Hb parameters in patients in patients randomized to EPO 
alone, DFX+EPO and in patients randomized to EPO alone and 
switched to DFX+EPO after 12 weeks 
This analysis will include patients randomized either to EPO or DFX+EPO at baseline as well 
as patients who are non-responders to erythroid at week 12 in the EPO group switched to 
combination therapy. The time-course of Hb and its absolute/relative changes from baseline 
will be summarized by descriptive statistics by visit and erythroid response. Data will be 
summarized on FAS and PP set. 
Note: Patients randomized to EPO and not switching after 12 weeks to EPO+DFX, will 
consist of only responders. 
 
10.5.11 Safety objectives 
Analysis will be done on safety set. 
 
10.5.11.1 Analysis set and grouping for the analyses 
The overall study period will be divided into three mutually exclusive segments: 


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1. pre-treatment period: from day of patient’s informed consent to the day before first dose 
of study medication 
2. on-treatment period: from day of first dose of study medication to 30 days after last dose 
of study medication 
3. post-treatment period: starting at day 30+1 after last dose of study medication. 
The reporting of AEs and AEs of special interest will be reported in the following periods 
based on the treatment received as follows: 
• For patients receiving EPO during the first 12 weeks and for those continuing with EPO 
after 12 weeks (no switching to EPO+DFX arm), the safety data will be reported based on 
the corresponding treatment group: EPO. The safety data will be reported in period 1-12 
weeks, 13-24 weeks and 1-24 weeks. 
• For patients receiving EPO+DFX from week 1 and continuing with EPO+DFX after 12 
weeks or with DFX alone after 12 weeks, the safety data will be reported based on the 
corresponding treatment EPO+DFX. The safety data will be reported in period 1-12 weeks 
and 1-24 weeks. 
• For patients receiving EPO alone and switched to EPO+DFX after 12 weeks of treatment, 
the safety data will be reported only in period 13-24 weeks. 
 
10.5.11.2 Adverse events (AEs) 
Summary tables for adverse events (AEs) will include only AEs that started or worsened 
during the on-treatment period, the treatment-emergent AEs. However, all safety data 
(including those from the pre and post-treatment periods) will be listed and those collected 
during the pre-treatment and post-treatment period are to be flagged. 
The incidence of treatment-emergent adverse events (new or worsening from baseline) will be 
summarized by system organ class and or preferred term, severity (mild/moderate/severe), 
type of adverse event, relation to study treatment by treatment group. 
Deaths reportable as SAEs and non-fatal serious adverse events will be listed by patients and 
tabulated by type of adverse event and treatment group. 
 
10.5.11.3 Laboratory abnormalities 
All laboratory values will be converted into SI units and the severity grade calculated using 
the low/normal/high classifications based on laboratory normal ranges and for selected 
parameters by notable/extended ranges. 
The following summaries will be generated separately for hematology, biochemistry and 
urinary laboratory tests: 


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• shift tables using normal/notable/extended ranges to compare baseline to the worst on- 
treatment value 
• listing of all laboratory data with values flagged to show the corresponding 
normal/notable/extended ranges. 
For each hematology/iron metabolism parameter, observed values (and changes from baseline) 
will be summarized by descriptive statistics (n, mean, standard deviation, minimum, lower 
quartile, median, upper quartile and maximum). 
Creatinine clearance will be estimated using the Cockcroft-Gault equation will be displayed 
using relative change from baseline by categories. 
 
10.5.11.4 Other safety data 
Data from electrocardiogram, vital signs, ocular and auditory examination will be listed, 
summarized and flagged as appropriate by treatment group. 
Any  significant  findings  after  start  of  study  will  be  documented  as  adverse  events  and 
reported as such. 
 
10.5.12 Resource utilization 
Not applicable. 
 
10.5.13 Patient-reported outcomes 
Not applicable. 
 
 
10.7 
Interim analysis 
Not applicable. 


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10.8 
Sample size calculation 
This is a pilot study which plans to enroll approximately 60 patients considering site 
capabilities. The sample size in a pilot study is based on the pragmatics of recruitment and the 
necessities of examining feasibility (Leon et al, 2011). Hence no formal sample size 
calculation based on primary endpoint assumptions is performed. 
However to give an idea regarding primary endpoint analysis, for a given number of 60 
patients, under scenarios, where considering a minimal detectable differences of 20%, 30% 
and 40% assuming a reference response rate of 40% at 5% level of significance gives a 95% 
Agresti-Caffo confidence interval of (-0.04, 0.44), (0.068, 0.53) and (0.18, 0.62). 
 
10.9 
Power for analysis of key secondary variables 
Not applicable. 
 
11 
Ethical considerations and administrative procedures 
11.1 
Regulatory and ethical compliance 
This clinical study was designed, shall be implemented and reported in accordance with the 
ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC and US Code of Federal Regulations 
Title 21), and with the ethical principles laid down in the Declaration of Helsinki. 
 
11.2 
Responsibilities of the investigator and IRB/IEC/REB 
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly constituted Institutional Review Board/Independent Ethics Committee/Research 
Ethics Board (IRB/IEC/REB) before study start. Prior to study start, the investigator is 
required to sign a protocol signature page confirming his/her agreement to conduct the study 
in accordance with these documents and all of the instructions and procedures found in this 
protocol and to give access to all relevant data and records to Novartis monitors, auditors, 
Novartis Clinical Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs/REBs and regulatory authorities as required. 
 
11.3 
Informed consent procedures 
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC/REB-approved informed consent or, if incapable of 
doing so, after such consent has been provided by a legally acceptable representative of the 
patient. In cases where the patient’s representative gives consent, the patient should be 
informed about the study to the extent possible given his/her understanding. If the patient is 
capable of doing so, he/she should indicate assent by personally signing and dating the written 
informed consent document or a separate assent form. 
Informed consent must be obtained before conducting any study-specific procedures (i.e. all 
of the procedures described in the protocol). The process of obtaining informed consent 


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should be documented in the patient source documents. The date when a subject’s Informed 
Consent was actually obtained will be captured in their CRFs. 
Novartis will provide to investigators, in a separate document, a proposed informed consent 
form (ICF) that is considered appropriate for this study and complies with the ICH GCP 
guideline and regulatory requirements. Any changes to this ICF suggested by the investigator 
must be agreed to by Novartis before submission to the IRB/IEC/REB, and a copy of the 
approved version must be provided to the Novartis monitor after IRB/IEC/REB approval. 
Women of child bearing potential should be informed that taking the study medication may 
involve unknown risks to the fetus if pregnancy were to occur during the study and agree that 
in order to participate in the study they must adhere to the contraception requirement for the 
duration of the study. If there is any question that the patient will not reliably comply, they 
should not be entered in the study. 
 
11.4 
Discontinuation of the study 
Novartis reserves the right to discontinue this study under the conditions specified in the 
clinical study agreement. Specific conditions for terminating the study are outlined in Section 
4.3. 
 
11.5 
Publication of study protocol and results 
Novartis assures that the key design elements of this protocol will be posted in a publicly 
accessible database such as clinicaltrials.gov. In addition, upon study completion and 
finalization of the study report the results of this study will be either submitted for publication 
and/or posted in a publicly accessible database of clinical study results. 
 
11.6 
Study documentation, record keeping and retention of 
documents 
Each participating site will maintain appropriate medical and research records for this trial, in 
compliance with Section 4.9 of the ICH E6 GCP, and regulatory and institutional 
requirements for the protection of confidentiality of subjects. As part of participating in a 
Novartis-sponsored study, each site will permit authorized representatives of the sponsor(s) 
and regulatory agencies to examine (and when required by applicable law, to copy) clinical 
records for the purposes of quality assurance reviews, audits and evaluation of the study 
safety and progress. 
Source data are all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. 
Examples of these original documents and data records include, but are not limited to, hospital 
records, clinical and office charts, laboratory notes, memoranda, subjects’ diaries or 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies or transcriptions certified after verification as being accurate and complete, 
microfiches, photographic negatives, microfilm or magnetic media, x-rays, and subject files 
and records kept at the pharmacy, at the laboratories, and medico-technical departments 
involved in the clinical trial. 


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Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site Principal Investigator. The study case report form (CRF) is the primary data collection 
instrument for the study. The investigator should ensure the accuracy, completeness, legibility, 
and timeliness of the data reported in the CRFs and all other required reports. Data reported 
on the CRF, that are derived from source documents, should be consistent with the source 
documents or the discrepancies should be explained. All data requested on the CRF must be 
recorded. Any missing data must be explained. Any change or correction to a paper CRF 
should be dated, initialed, and explained (if necessary) and should not obscure the original 
entry. For electronic CRFs an audit trail will be maintained by the system. The investigator 
should retain records of the changes and corrections to paper CRFs. 
The investigator/institution should maintain the trial documents as specified in Essential 
Documents for the Conduct of a Clinical Trial (ICH E6 Section 8) and as required by 
applicable regulations and/or guidelines. The investigator/institution should take measures to 
prevent accidental or premature destruction of these documents. 
Essential documents (written and electronic) should be retained for a period of not less than 
fifteen (15) years from the completion of the Clinical Trial unless Sponsor provides written 
permission to dispose of them or, requires their retention for an additional period of time 
because of applicable laws, regulations and/or guidelines. 
 
11.7 
Confidentiality of study documents and patient records 
The investigator must ensure anonymity of the patients; patients must not be identified by 
names in any documents submitted to Novartis. Signed informed consent forms and patient 
enrollment log must be kept strictly confidential to enable patient identification at the site. 
 
11.8 
Audits and inspections 
Source data/documents must be available to inspections by Novartis or designee or Health 
Authorities. 
 
11.9 
Financial disclosures 
Financial disclosures should be provided by study personnel who are directly involved in the 
treatment or evaluation of patients at the site - prior to study start. 
 
12 
Protocol adherence 
Investigators ascertain they will apply due diligence to avoid protocol deviations. Under no 
circumstances should the investigator contact Novartis or its agents, if any, monitoring the 
study to request approval of a protocol deviation, as no authorized deviations are permitted. If 
the investigator feels a protocol deviation would improve the conduct of the study this must 
be considered a protocol amendment, and unless such an amendment is agreed upon by 
Novartis and approved by the IRB/IEC/REB it cannot be implemented. All significant 
protocol deviations will be recorded and reported in the CSR. 


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12.1 
Amendments to the protocol 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, Health Authorities where required, and the IRB/IEC/REB. 
Only amendments that are required for patient safety may be implemented prior to 
IRB/IEC/REB approval. Notwithstanding the need for approval of formal protocol 
amendments, the investigator is expected to take any immediate action required for the safety 
of any patient included in this study, even if this action represents a deviation from the 
protocol. In such cases, Novartis should be notified of this action and the IRB/IEC at the study 
site should be informed according to local regulations (e.g. UK requires the notification of 
urgent safety measures within 3 days) but not later than 10 working days. 


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13 
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transfusion-dependent myelodysplastic syndromes: Results from the large 1-year EPIC study. 
Leuk Res; 34:1143-50. 
Greenberg PL, Sun Z, Miller KB, et al (2009). 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; 114:2393-400. 
Greenberg PL, Attar E, Bennett JM, et al (2011). NCCN Clinical Practice Guidelines in 
Oncology: myelodysplastic syndromes. J Natl Compr Canc Netw; 2011 9:30-56. 
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meta-analysis of 205 patients from 17 studies. Br J Haematol; 89:67-71. 
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the use of L1 for oral iron chelation. Drugs of Today; 28(Suppl A): 143-47. 
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haemopoiesis in MDS patients with transfusional iron overload. Br J Haematol; 94:288-299. 
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and transfusional iron overload prior to and during iron chelation with desferrioxamine: a 
study in adult patients with acquired anemias. Blood; 101:91-96. 
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myelodysplastic syndromes: results of a phase III randomized study. Cancer; 106:1794-803. 
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myelodysplastic syndromes in France: data from 907 patients in a one-week cross-sectional 
study by the Groupe Francophone des Myelodysplasies. Haematologica; 95(6):892- 
9.Kilpatrick LE, Sun S, Ki H, et al (2010). Regulation of TNF-induced oxygen radical 
production in human neutrophils: role of δ-PKC. J Leukoc Biol; 87:153–164. 
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human serum. Br J Haematol; 64:277–81. 
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with chromosome 5q deletion. N Engl J Med; 355:1456-65. 


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Malcovati L (2007). Impact of transfusion dependency and secondary iron overload on the 
survival of patients with myelodysplastic syndromes. Leuk Res; 31:S2–S6. 
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in myelodysplastic syndromes classified according to WHO criteria: a basis for clinical 
decision making. J Clin Oncol; 23:7594-7603. 
Malcovati L, Hellström-Lindberg E, Bowen D, et al (2013). Diagnosis and treatment of 
primary myelodysplastic syndromes in adults: recommendations from the European 
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Mannone L, Gardin C, Quarre MC, et al (2006). High-dose darbepoetin alpha in the treatment 
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133:513-9. 
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95:1308-16. 
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in dysplastic erythropoiesis in myelodysplastic syndrome. Eur J Haematol; 79(1):8-16. 
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and interleukin-1 beta in myelodysplastic syndromes responsive to recombinant 
erythropoietin. Haematologica; 79:265. 
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verus deferoxamine for the treatment of transfusional iron overload in sickle cell disease. 
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advances in understanding the pathogenesis, risk factors, comorbidities and risk–benefit of 
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Chem; 394:231-8. 


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14 
Appendices 
14.1 
Appendix 1: WHO classification of primary MDS 
 
Table 14-1 
WHO classification of primary MDS 
 
 
Category 
Peripheral blood 
Bone marrow 
 
 
Refractory cytopenia with unilineage dysplasia (RCUD) 
RA 
Anemia 
Blasts <5% 
Blasts <1% 
unilineage erythroid dysplasia 
(in ≥10% of cells) 
RN 
Neutropenia 
Blasts <5% 
Blasts <1% 
unilineage granulocytic dysplasia 
RT 
Thrombocytopenia 
Blasts <5% 
Blasts <1% 
unilineage megakaryocytic dysplasia 
 
 
RARS 
Anemia 
Blasts <5% 
No Blasts 
ringed sideroblasts ≥15% 
unilineage erythroid dysplasia 
RCMD 
Cytopenia(s) 
multilineage dysplasia ± ring sideroblasts 
Blasts <1% 
Blasts <5% 
no Auer rods 
no Auer rods 
 
 
RAEB-I 
Cytopenia(s) 
unilineage or multilineage dysplasia 
Blasts <5% 
Blasts 5%–9% 
no Auer rods 
no Auer rods 
 
 
RAEB-II 
Cytopenia(s) 
unilineage or multilineage dysplasia 
Blasts 5%–19% 
Blasts 10%–19% 
± Auer rods 
± Auer rods 
 
 
MDS del (5q) 
Anemia 
del(5q) deletion 
Blasts <1% 
Blasts <5% 
hypolobated megakaryocytes 
Childhood MDS, including refractory 
cytopenia of childhood (RCC) 
pancytopenia 
<5% marrow blasts for RCC, 
hypocellular marrow 
MDS–U 
Cytopenias 
does not fit any other category 
Blasts ≤1% 
dysplasia or MDS-associated karyotype 
no Auer rods 
Blasts <5% 
no Auer rods 


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14.2 
Appendix 2: Modified International Working Group response 
criteria for hematologic improvement 
 
Table 14-2 
Modified International Working Group response criteria for 
hematologic improvement 
 
Category 
Pretreatment 
Modified IWG Response Criteria (≥ 8 weeks) 
Erythroid response 
Hb < 11 g/dL 
Hb increase by ≥ 1.5 g/dL 
Reduction of ≥ 4 RBC transfusions/8 weeks versus pretreatment 
requirements in previous 8 weeks; only RBC transfusions given for 
a pretreatment Hb of ≤ 9.0 g/dL count 
Platelet response 
< 100 x 109/L 
increase of ≥ 30 x 109/L (starting with > 20 x 109/L) 
Increase from < 20 x 109/L to > 20 x 109/L by ≥100% 
Neutrophil response 
< 1.0 x 109/L 
increase of ≥ 100% and > 0.5 x 109/L 
Progression/ relapse after hematological 
improvement 
 
See Cheson 2006. 
≥ 1 of the following: 
≥ 50% decrement from maximum response levels in granulocytes 
or platelets; reduction in Hb by ≥1.5 g/dL; transfusion dependence 
 


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14.3 
Appendix 3: Erythropoietin Treatment and Monitoring Guidelines 
for MDS patients 
 
Table 14-3 
Baseline testing and eligibility criteria for MDS 
 
 
Required baseline tests 
EPO eligibility criteria (CMS) 
Hemoglobin 
Fe/TIBC (TSAT) 
Ferritin 
B12 
Folate 
Pretreatment Hb < 10 g/dL 
TSAT ≥ 20% 
B12 and folate not deficient 
Life expectancy > 3 months 
Symptomatic anemia (fatigue, SOB) 
Diagnosis confirmed by cytology or physician 
Marrow blast count is < 5% 
 
Note: Hemoglobin must be done within 1 week prior to EPO treatment 
 
 
Table 14-4 
Initial dosing of EPO for MDS 
 
 
Initial dose 
 
EPO 40,000 units SQ once weekly for 4 weeks 
The starting dose in low weight patients with stable anemia - and always in case of reduced renal function - 
should be lower: 30,000 units weekly 
 
Note: Check blood pressure prior to each dose 
 
 
Table 14-5 
Adjusting EPO dosing for MDS 
 
 
Week 
Hemoglobin status 
Action 
Week 4 
Hb increased < 1 g/dL from 
baseline and Hb < 12 g/dL 
Hb increase is ≥ 1 g/dL 
and Hb < 12 g/dL 
Hb increase is ≥ 1 g/dL 
and Hb > 12 g/dL 
 
 
Week 12 
Hb increased < 1 g/dL from 
baseline 
and Hb < 12 g/dL 
Or transfusion requirement has 
not decreased by 50% resulting 
in a rate of 2 units per month or 
less for treatment to continue. 
Hb increase is ≥ 1 g/dL 
and Hb < 12 g/dL 
Hb increase is ≥ 1 g/dL 
and Hb > 12 g/dL 
Increase EPO to 60,000 units once weekly for 4 weeks 
Continue current EPO dose 
Hold EPO dose 
Check CBC weekly until Hb is <12 g/dL. When Hb is 
<12 g/dL resume EPO at reduced dose (decrease dose 
50%). Continue to check CBC weekly. 
Discontinue EPO, the patient is not responding 
 
 
 
 
 
Continue current EPO dose 
Hold EPO dose 
Check CBC weekly until Hb is < 12 g/dL. When Hb is < 
12 g/dL resume EPO at reduced dose (decrease dose 
50%). Continue to check CBC weekly. 
Maintenance 
(beyond week 12) 
MDS: target Hb level 10–12 g/dL 
During maintenance, in case Hb > 12 g/dL, decrease 
the weekly dose every 8 weeks (recommended 
schedule: 60-40-30-20-15-10- 5,000 units/week). 
Median maintenance dose is 30,000 units (range is 
5,000–60,000 units/week). 
 


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Table 14-6 
Recommended monitoring 
 
 
Test(s) 
Frequency 
Action 
 
Blood pressure 
Before each dose of EPO 
hold EPO if BP >160/80 
 
CBC 
Every 2 weeks until stable (at therapy initiation and 
-- 
after any dose change of EPO 20% or more) 
Then monthly 
FE/TIBC 
Ferritin 
At 1 month (at therapy initiation and after oral iron 
-- 
dose change or after IV ferritin) 
Then at 3 months 
Then every 3 months 
 
Stool occult blood 
Consider testing if iron stores low in spite of iron 
-- 
supplementation 
Reticulocyte count 
Vitamin B12 
Folate, 
Haptoglobin 
Consider testing if patient is not responding to therapy 
-- 
as expected 
 


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14.4 
Appendix 4: Microscopic Urine Panel 
 
Table 14-7 
Microscopic Urine Panel 
 
 
Test name 
Test name 
 
Calcium Carbonate Crystals 
Leucine Crystals 
 
Fatty Casts 
Mixed Casts 
 
Tryosine Crystals 
Monosodium Urate Crystals 
 
Acid Urate Crystals 
Urinalysis RBC 
 
Ammonium Biurate Crystals 
RBC Casts 
 
Ammonium Oxalate 
Renal Tubular Cells 
 
Amorphorus Crystals 
Sulfa Crystals 
 
Amorphorus Phosphate Crystals 
Transitional Epithelial Cells 
 
Amorphorus Urate Crystals 
Triple Phosphate Crystals 
 
Bacteria 
Uric Acid Crystals 
 
Bacterial Casts 
Waxy Casts 
 
Bilirubin Crystals 
Urinalysis WBC 
 
Calcium Oxalate Crystals 
WBC Casts 
 
Calcium Phosphate Crystals 
Hippuric Acid Crystals 
 
Cholesterol Crystals 
Starch Granules 
 
Cystine Crystals 
Trichomonas 
 
Epithelial Casts 
Yeast 
 
Epithelial Cells 
Creatinine Urine 
 
Fat Bodies 
Protein total 
 
Granular Casts 
Urine Protein/Creatinine Ratio 
Hyaline Casts 

SAP_001.pdf: 
Clinical Development
ICL670 (Deferasirox)
CICL670A2421 / NCT01868477
An open-label, phase II, randomized, pilot study to assess the effect 
in term of erythroid improvement of deferasirox combined with 
erythropoietin compared to erythropoietin alone in patients with 
low- and int-1-risk myelodysplastic syndrome
RAP Module 3 – Detailed Statistical Methodology
Author:
 
Document type:
RAP Documentation
Document status:
Final 5.0 (Amendment 4)
Release date:
12 June 2017
Number of pages:
43
Property of Novartis
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


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Table of contents
Table of contents .................................................................................................................3
List of tables ........................................................................................................................5
List of Abbreviations...........................................................................................................6
1
Introduction .........................................................................................................................7
1.1
Document content....................................................................................................7
7
2
Clinical Study Report Section 9.7 - Statistical methods planned in the protocol and 
determination of sample size...............................................................................................8
2.1
CSR Section 9.7.1 – Statistical and analytical plans ...............................................8
2.2
Data included in the analyses ..................................................................................8
2.3
Analysis sets ............................................................................................................8
2.4
Protocol Deviations .................................................................................................8
2.5
Statistical methods and data analysis.......................................................................9
2.6
Patient disposition, background and demographic characteristics ..........................9
2.6.1
Patient disposition...................................................................................9
2.6.2
Background and demographic characteristics.......................................10
2.6.3
Medical History.....................................................................................11
2.7
Study treatment......................................................................................................11
2.7.1
Exposure to study treatment..................................................................12
2.7.2
Dose exposure .......................................................................................13
2.7.3
Dose reductions and interruptions.........................................................14
2.8
Concomitant medication........................................................................................15
2.9
Efficacy evaluation ................................................................................................15
2.9.1
Primary objective ..................................................................................15
2.9.2
Secondary objectives.............................................................................16
2.10
Safety evaluation ...................................................................................................18
2.10.1
Analysis set and grouping for the analyses...........................................18
2.10.2
Adverse events (AEs)............................................................................19
2.10.3
Laboratory data .....................................................................................20
2.10.4
Vital signs, weight and body mass index..............................................23
2.10.5
Other safety data ...................................................................................24
2.11
CSR Section 9.7.2: Sample size and power considerations...................................24
3
Clinical Study Report – Appendix 16.1.7 Randomization scheme and codes ..................26
3.1
Randomization scheme and codes.........................................................................26
3.2
Treatment assignment or randomization ...............................................................26


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3.3
Treatment blinding.................................................................................................26
4
Clinical Study Report – Appendix 16.1.9 Documentation of statistical methods.............27
4.1
Appendix 16.1.9 – Documentation of statistical methods.....................................27
4.2
Definitions .............................................................................................................29
4.2.1
Study drug and study treatment.............................................................29
4.2.2
Date of first administration of study treatment .....................................29
4.2.3
Date of last administration of study drug..............................................29
4.2.4
Study start date......................................................................................29
4.2.5
End of treatment....................................................................................29
4.2.6
Definition of End of study.....................................................................29
4.2.7
Study Day definition .............................................................................30
4.2.8
Treatment period ...................................................................................30
4.2.9
Baseline.................................................................................................30
4.2.10
Calculation of change............................................................................30
4.2.11
Visit Windows.......................................................................................31
4.3
Data handling conventions ....................................................................................32
4.4
Protocol deviations ................................................................................................34
4.5
Other rules .............................................................................................................40
4.6
Number of decimals...............................................................................................40
5
References .........................................................................................................................41
6
SAS procedure used for inferential analysis .....................................................................42
6.1
Clopper-Pearson (Exact) CI for response rate .......................................................42
6.2
Agresti-Caffo CI for difference in proportions......................................................42


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List of tables
Document History – Changes compared to previous version of RAP module 3. ......................2
Table 2-1
EPO Dosing...........................................................................................12
Table 2-2
Criteria for hematological response and hematologic improvement ....17
Table 2-4
Criteria for clinically notable and extended laboratory ranges .............21
Table 4-1
Visit windows........................................................................................31
Table 4-2
AE/Treatment Date Abbreviations........................................................32
Table 4-3
Imputation algorithm.............................................................................33
Table 4-4
Relationship and Imputation Legend ....................................................33
Table 4-5
Example Scenarios................................................................................33
Table 4-6
CSR Reportable Protocol Deviation Categories ...................................34
Table 4-7 
Protocol Deviations List........................................................................35


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List of Abbreviations
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALT
Alanine aminotransferase/glutamic pyruvic transaminase/GPT
AST
Aspartate aminotransferase/glutamic oxaloacetic transaminase/GOT
BMI
Body Mass Index
CRF
Case Report Form
CSR
Clinical Study Report
CTCAE
Common Terminology Criteria for Adverse Events v3.0
CTT
Clinical Trial Team
CV
Coefficient of Variation
DFX
Deferasirox
DT
Dispersible Tablet
ECG
electrocardiogram
eCRF
electronic Case Report Form
EOS
End of Study Evaluation Completion
EOT
End of Study Treatment
EPO
Erythropoietin 
FAB
French-American-British Cooperative Group
FAS
Full Analysis Set
FCT
Film-Coated Tablet
g/dL
grams per deciLiter
Hb
hemoglobin
IWG
International Working Group
IWR
Interactive Web Response Technology
MDS
Myelodysplastic syndromes
MedDRA
Medical Dictionary for Regulatory Activities
mg
milligrams
mg/m2
milligrams / meter squared
mg/kg/day
milligrams / meter squared / day
NCI-CTCAE
National Cancer Institute’s Common Terminology Criteria for Adverse Events
p.o.
per os/by mouth/orally
PD
Protocol Deviation
PP
Per Protocol
PT
Preferred Term
RAP
Report analysis plan
s.c
Subcutaneous(ly)
SAE
Serious Adverse Event
SOC
System Organ Class


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TEAE
treatment-emergent Adverse Event
ULN
Upper limit of normal
WHO
World Health Organization
1
Introduction
1.1
Document content 
This Report and Analysis Plan (RAP) module describes the planned statistical methods for all 
efficacy and safety analyses for phase II study CICL670A2421 which is an open-label, phase 
II, randomized, pilot study to assess the effect in term of erythroid improvement of 
deferasirox (DFX) combined with erythropoietin (EPO) compared to EPO alone in patients 
with low- and int-1-risk myelodysplastic syndrome (MDS).
It is structured as:

A draft of Section 9.7 (Statistical methods planned in the protocol and determination of
sample size)

A draft of Appendix 16.1.7 and 16.1.9 (Documentation of statistical methods) of the CSR.
It is written in future tense. It will be reviewed and updated (including conversion to past 
tense) for entry into the clinical study report after the analysis has taken place.
The shells for the in-text tables and figures, post-text tables, figures and listings, and the table 
of contents will be in Module 7. Programming specifications, including derivations and 
imputation dates will be given in Module 8.


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2
Clinical Study Report Section 9.7 - Statistical methods 
planned in the protocol and determination of sample size
2.1
CSR Section 9.7.1 – Statistical and analytical plans
All data will be analyzed by 
, and reviewed by Novartis, according to the data 
template analysis section 10 of the study protocol which is available in Appendix 16.1.1 of the 
CSR.  Important information is given in the following sections and details are provided, as 
applicable, in Appendices 16.1.7 and 16.1.9 of the CSR template. Analysis data sets and 
statistical outputs will be produced using the most recent SAS® Version, and stored in 
.
2.2
Data included in the analyses
Data will be collected on patients aged ≥ 18 years or older with low- and-int-1-risk MDS, 
randomized in 1:1 ratio to DFX+EPO or EPO alone. If after 12 weeks of treatment with EPO 
alone, Hb increase is < 1 g/dL and total Hb is < 12 g/dL, the patient will switch to 
combination therapy of EPO and DFX. The study treatment duration is 24 weeks.  
As per the current protocol, no interim analysis is planned. All interim (if required) and final 
CSRs will have a documented medical review by
 
.
2.3
Analysis sets 
The analysis will consider the following populations: 
Full Analysis Set: The Full Analysis Set (FAS) comprises all patients to whom study 
treatment has been assigned by randomization (EPO or EPO+DFX). According to the intent to 
treat principle, patients will be analyzed according to the treatment they have been assigned to 
during the randomization procedure.
Safety Set: The Safety Set includes all randomized patients who received at least one dose of 
study medication, i.e. either EPO or EPO+DFX, and with at least one post-baseline safety 
assessment (e.g. lab, vital signs, AEs) and the statement that a subject did not experience an 
AE can currently be regarded as a valid safety assessment.
2.4
Protocol Deviations 
The number and percentage of patients with any relevant CSR reportable protocol deviations 
(PDs) will be tabulated. All relevant CSR reportable PDs will be also listed. PD criteria are 
specified in the Validation Analysis Plan Module 3 “Protocol Deviations” document.
ICH E3 defines the categories into which most CSR reportable PDs will fall:

Eligibility: Subject entered study even though they did not satisfy the entry criteria.

Withdrawal: Subject developed study/treatment withdrawal criteria during the study but 
was not withdrawn.

Study drug: Subject received the wrong treatment or incorrect dose.


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
Concomitant medication: Subject took an excluded concomitant medication.

Others: Important deviations which do not align with one of the above categories and 
which might jeopardize the safety or rights of the subject or which may impact the 
scientific value of the trial.
Refer to section 4.4. with regard to describing actions against protocol violations.
2.5
Statistical methods and data analysis 
Categorical parameters
Categorical (qualitative) data (e.g., gender, race, etc) will be presented as frequencies and 
percentages. A missing category for categorical data will be presented where applicable. 
Unless otherwise noted, percentages will be based on the number of patients in the relevant 
population or subgroup as the denominator. Categorical variables will be summarized by 
absolute and relative frequencies where applicable.
Continuous parameters
Continuous (quantitative) data (e.g., age, body weight, etc.) will be summarized by number of 
patients, mean, standard deviation, median, minimum, and maximum. The lower and upper 
quartiles may also be used under special circumstances.
2.6
Patient disposition, background and demographic 
characteristics
All analyses described in this section will be conducted using the FAS.
2.6.1
Patient disposition
This analysis will provide the number and percentage of patients who:
1. Have been randomized (Treated/ Untreated),
2. Have completed the study (patient who completes treatment duration as per protocol as 
per the EOT [777] page of CRF and also completes the follow up phase as per protocol in 
the EOS [778] page of CRF),
The number (%) of patient by reason of study treatment discontinuation will be provided for 
those patients who have discontinued the study treatment. Similarly, this will be performed 
for study discontinuation. Protocol deviations will be summarized and listed.
The study will end when the last patient will have either withdrawn (including follow-up of 
30 days) from the study or completed the study (24 weeks + follow up period of 30 days) 
from the start of treatment (EPO or EPO+DFX), whichever occurs earlier.
Listings will be provided for screen failure patients (with reasons for screen failure). Screen 
failures are patients who have been screened (patients who have signed ICF) and who failed 
to be randomized and treated for any reason (i.e. failing to meet inclusion or exclusion criteria 
or any other screening procedure).


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2.6.2
Background and demographic characteristics
The FAS will be used for all baseline and demographic summaries and listings.
Basic demographic data
Demographic data (gender, predominant race, ethnicity, age, height, weight, BMI) and other 
baseline data (baseline serum ferritin, EPO levels at screening, baseline Hb) will be 
summarized descriptively and listed. 
While being analyzed as continuous variables, age, baseline serum ferritin, baseline Hb, EPO 
levels at screening will also be reported using categories. 
Age (years) category will consider the following categories: <65 and ≥65.
EPO levels at screening will consider the following categories:  0 - < 20, 20 - < 50, 50 - < 200, 
200 - < 500 and >= 500.
BMI (kg/ m2) will be calculated as weight [kg] / (height2 [m2]). 
History of disease
The French-American-British Cooperative Group (FAB) classification at screening will be 
tabulated and listed. 
The FAB originally classified MDS into 5 different types (see protocol Table 1-1). However, 
the World Health Organization (WHO) has revised this classification and now identifies 8 
different orders (see protocol Appendix 1).
The FAB classifications for subjects with MDS to be considered in this study are: 

Refractory Anemia (RA), 

Refractory Anemia with Ringed Sideroblasts (RARS) and

Refractory Anemia with Excess of Blasts (RAEB). 
The information can be obtained from the HIS panel of the CRF. 
History of blood transfusion
History of blood transfusions (number of prior transfusions, time since last transfusion) will 
be summarized and listed. Time since last transfusion is the time interval from the last blood 
transfusion to start of study), ie.,
Time since last transfusion (years) = (Screening 1 visit date – Date of last transfusion received
+1) / 365.25.
Time since diagnosis of MDS
Time since diagnosis of MDS as obtained from the CND panel (Relevant medical 
history/current medical conditions) of the CRF with MDS being the active problem will be 


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summarized and listed. Time since diagnosis of MDS is the time interval between the date of 
diagnosis of MDS to start of study, i.e.,
Time since diagnosis of MDS (years) = (Screening 1 visit date – Date of diagnosis of MDS+1) 
/ 365.25.
Other baseline characteristics
Childbearing potential and serum pregnancy test results will be listed. Overall interpretation 
in audiometric test (normal or clinically significant or insignificant abnormality), overall 
interpretation in ocular exam (normal or clinically significant or insignificant abnormality),
and clinically significant abnormality in electrocardiogram (ECG) (yes or no), will be 
summarized and listed.
Baseline summary for serum ferritin will be provided. Baseline categories (described in RAP 
M7) will be provided for serum creatinine, creatinine clearance, ALT and AST. 
2.6.3
Medical History
The FAS will be used for all medical history and current medical conditions including cancer-
related conditions and symptoms, which will be summarized and listed. Separate summaries 
will be presented for current and historical medical conditions. The summaries will be 
presented by primary system organ class (SOC) and preferred term (PT) based on latest 
available Medical Dictionary for Regulatory Activities (MedDRA) dictionary version at time 
of database lock.  The MedDRA version used for reporting the study will be specified as a 
footnote in the related tables/listings.
2.7
Study treatment 
The investigational study drugs used in this trial are deferasirox (DFX DT) provided as 
dispersible tablet or deferasirox (DFX FCT) provided as film-coated tablet for oral use and 
erythropoietin alpha (EPO) for subcutaneous injection. 
The study treatment is DFX + EPO or EPO alone.
At the time when DFX FCT study drug becomes available at a study site, all new patients who
are randomized to combination therapy will receive the DFX FCT. Patients who are ongoing
and receive DFX DT will continue with the DT. It is not permitted to change formulation 
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Table 2-1
EPO Dosing
Initial Treatment
EPO 40,000 units/week
EPO 40,000 units/week + DFX DT 10 mg/kg
day or DFX FCT 7 mg/kg day
Week 4
Hemoglobin status
Action
Hb increased < 1 g/dL from baseline 
and Hb < 12 g/dL
Increase EPO to 60,000 units/week *
Hb increase is ≥ 1 g/dL
and Hb < 12 g/dL
Continue EPO 40,000 units/week *
Hb increase is ≥ 1 g/dL
and Hb ≥ 12 g/dL
Hold EPO treatment *
Week 12
Hemoglobin status
Action
Hb increased < 1 g/dL from baseline
and Hb < 12 g/dL
If patient is in the combination arm:
Discontinue from the study
or
If patient is in the EPO monotherapy arm:
Switch to the combination EPO + DFX
Hb increase is ≥ 1 g/dL
and Hb < 12 g/dL
Hb increase is ≥ 1 g/dL
and Hb ≥ 12 g/dL
Hold EPO treatment *
* Patients in combination arm will continue DFX DT 10 mg/kg/day or DFX FCT 7 mg/kg/day treatment
2.7.1
Exposure to study treatment
For all analysis described in this section, the Safety Set will be used.
Duration of exposure
The duration of exposure to study drug is defined as the time interval from first (non-zero) 
dose of study drug administration to last study drug administration date (i.e. last known study 
drug administration date), and it will be calculated using the following formula:
Duration of exposure (days) = [(last date of exposure to the study drug) – (date of first 
administration of the study drug) + 1 day], where:

‘Date of first administration of the study drug’ is defined as the first date when a non-zero 
dose of study treatment is administered. For the sake of simplicity, the date of first 
administration of study treatment is referred to start date of study treatment.

‘Last date of exposure to the study drug’ is the date of last administration of this study 
treatment which is defined as the last date when a non-zero dose of study treatment is 
administered. This date will also be referred as last date of study treatment.  
The duration of exposure includes the periods of temporary study drug interruption. 


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For patients who did not take any study drug, the duration of exposure is defined as zero. 
The duration of exposure excluding the temporary study drug interruption will also be 
computed, only time interval where the drug was known to be taken will be considered. It will 
be computed using the following formula:
Duration of exposure excluding temporary study drug interruption (days) = Duration of 
exposure (days) – number of days during this time interval where the actual dose was zero.
Both the duration of exposure and duration of exposure excluding interruptions will be 
summarized as continuous variables and by days as <28, 28 to <56, 56 to <84, 84 to <140, 
140 to <164 and ≥ 164. 
Percentage of exposure
The percentage
of
exposure is defined as
100×(duration of exposure excluding 
interruptions)/(duration of exposure).
It will be summarized as a continuous variable and by the following categories as <20%, 20%
to <40%, 40% to <60%, 60% to <80% and 80% to ≤100%.
2.7.2
Dose exposure
For all analysis described in this section, the Safety Set will be used.
The dose exposure will be provided for both DFX and EPO in the following way:

*For patients randomized to EPO and those who do not switch to combination after 12 
weeks: Duration of exposure to EPO for 24 weeks.

For patients randomized to EPO+DFX: Duration of exposure to EPO for 24 weeks (with 
suitable exposure categories described in RAP M7) and duration of exposure to DFX DT 
or DFX FCT for 24 weeks (duration unit expressed as number of days with suitable 
exposure categories described in RAP M7).

For patients randomized to EPO and switched to combination after 12 weeks: Duration of 
exposure to EPO for 24 weeks and duration of exposure to DFX DT or DFX FCT for 12 
weeks (week 13 to week 24).
Note: Patients randomized to EPO and switched to combination after 12 weeks, will not be 
counted in *. The patient population as described in * will be exclusively those patients who 
were randomized to EPO and remained in the EPO arm for 24 weeks.
2.7.2.1
Deferasirox
Exposure to DFX DT or DFX FCT will be summarized descriptively using the following 
parameters: average planned daily dose (mg/kg/day) and average actual daily dose 
(mg/kg/day).
The actual daily dose is calculated in the following way:
Actual daily dose per kg of weight (mg/kg/day) = actual daily dose (mg/day) / last 
available weight prior to the dose administration (kg)


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The cumulative dose is calculated in the following way which is used later to calculate 
average actual dose.
Cumulative dose (mg/kg) = sum of all (actual daily dose Z (mg/kg/day) × duration of dose 
Z administration (days)); where Z is the specific dose level considered, e.g. 10 mg/kg/day
for DFX DT or 7 mg/kg/day for DFX FCT.
The following formulae will be used to compute the average daily planned and the average 
actual daily doses.
1. Average planned dose (mg/kg/day) = sum of all (planned dose (mg/kg/day) × 
corresponding planned dose exposure) / overall drug exposure (days),
where the planned dose is the dose reported in the CRF page for a given time interval.
2. Average actual dose (mg/kg/day) = Cumulative dose (mg/kg) / overall drug exposure
(days).
2.7.2.2
Erythropoietin
Similarly, the exposure to EPO will be summarized in the following way: 
Cumulative dose (units/week) = sum of all (actual weekly dose Z (units/week) × duration 
of dose Z administration (week)); where Z is the specific dose level considered, e.g. 
40,000 units/week.
The following formulae will be used to compute the average weekly planned and the average 
actual weekly doses.
1. Average planned dose (units/week) = sum of all (planned dose Z (units/week) × 
corresponding planned dose Z exposure) / overall drug exposure (weeks),
2. Average actual dose (units/week) = Cumulative dose (unit/week) / overall drug exposure
(weeks).
2.7.3
Dose reductions and interruptions
The number of patients with dose reductions or interruptions, as well as the reasons leading to 
study drug dose reduction or to study drug interruption will be tabulated.
The number of dose interruptions and dose reductions will be tabulated by treatment group. 
Both of dose reduction and dose interruption will be calculated with regards to DFX DT or 
DFX FCT and EPO. Patients randomized to EPO arm or EPO+DFX arm may have an AE 
related to either EPO and/or DFX and thus the drug may be stopped or the dose may be 
reduced till the AE severity reduces.
An interruption is defined as a dose equal to zero on one or more days as reported in the 
CRF. A missing dose will not be considered as zero. A zero dose will not be considered as an 
interruption if it is the last dose administration record for a patient. 
An interruption during consecutive days for the same reason is counted once.


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If an interruption occurs for more than one consecutive day due to different reasons, then it 
will be counted for each reason.
A dose reduction is defined as a decrease in dose from the protocol planned starting dose or a 
decrease from the previous non-zero dose, even if this decrease has been directly preceded by 
an interruption.  If, due to a dosing error, a patient receives higher dose than protocol planned 
starting dose and moves down to the planned starting dose then this is not be counted as a 
reduction. However if they move directly from a higher than planned starting dose down to a 
lower than protocol planned starting dose, then this is counted as a reduction.
A dose increase is defined as an increase in dose from the protocol planned starting dose or 
an increase from the previous non-zero dose, even if this increase has been directly preceded 
by an interruption.
2.8
Concomitant medication 
For all analysis described in this section, the Safety Set will be used.
Concomitant therapy is defined as any interventions (therapeutic treatments, procedures or 
significant non-drug therapies) other than the study treatment administered to a patient 
coinciding with the study treatment period. 
Concomitant or prior medications entered into the database will be coded using the World 
Health Organization (WHO) Drug Dictionary Enhanced (DDE) ATC term according to the 
latest version during the time of analysis of data.
In addition to categorizing medication data by preferred term, drugs are classified according 
to their ATC classification in order to present and compare how they are being utilized.
Concomitant medications and significant non-drug therapies taken concurrently with the study 
drug will be listed and summarized by ATC class, preferred term and treatment arm by means 
of frequency counts and percentages. These summaries will include medications starting on or 
after the start of study treatment or medications starting prior to the start of study treatment 
and continuing after the start of study treatment.
Any prior medications, procedures or significant non-drug therapies starting and ending prior 
to the start date of study treatment will be listed.
2.9
Efficacy evaluation
2.9.1
Primary objective 
The primary objective will be to assess the effect of treatment with DFX+EPO vs. EPO alone 
on erythropoiesis after 12 weeks of treatment. 
2.9.1.1
Variable
The primary variable is the difference in proportion of patients achieving an erythroid 
response after 12 weeks of treatment between the two arms according to modified IWG 2006 
criterion (increase in Hb from baseline ≥ 1.5 g/dL).


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Patients meeting the criterion at any time within the first 12 weeks period will be considered 
erythroid responders.
2.9.1.2
Statistical hypothesis, model, and method of analysis
A patient is defined as an erythroid responder if the criterion of Hb increase from baseline ≥
1.5 g/dL is met at any time within the first 12 weeks period.
Baseline is defined as the last available value within windows of 4 weeks prior to or on 
treatment start date. No imputation will be performed for missing Hb value.
Difference in proportions between treatment groups with its 95% Agresti-Caffo (Agresti-
Caffo 2000) confidence interval will be provided. Erythroid response proportion will be also 
summarized by treatment group with its 95% Clopper-Pearson confidence intervals (Clopper 
and Pearson 1934). Analysis will be performed on FAS.
2.9.2
Secondary objectives 
The following secondary endpoints will be analyzed by treatment arms.
2.9.2.1
To assess the effect of treatment with DFX+EPO and EPO alone on 
hematologic response within 24 weeks of treatment
This analysis includes patients who were randomized to EPO and EPO+DFX and remained in
their respective treatment arms.
Hematological response will be assessed on this subset of patients and hematological 
responder is defined as patient meeting at least one of the following modified IWG 2006 
criteria: 
Hematological response:

Hb increase from baseline ≥ 1.5 g/dL and Hb < 11 g/dL at baseline (All patients on study 
per inclusion criterion 5, cf. study protocol section 5.2).

Neutrophil response: increase from baseline of ≥ 100% and increase > 0.5 x 109 /L and 
neutrophils < 1.0 × 109 /L at baseline.

Platelet response: increase from baseline of ≥ 30 x 109/L and platelets < 100 × 109/L at 
baseline.
Patients who met at least one of the 3 conditions of hematological response at any time 
between first day of treatment and week 12 or 24 will be considered as responders.
Supportive analyses (proportion of patients, descriptive statistics on the related parameters, 
change from baseline) will also be provided for patients who do not satisfy the IWG 2006 pre-
treatment conditions for neutrophil and/or platelet response (i.e., these patients have baseline 
neutrophils ≥ 1.0 × 109/L and baseline platelets ≥ 100 × 109/L) but show hematologic 
improvement with respect to neutrophils (increase from baseline > 0.5 × 109/L) and/or
platelets (increase from baseline ≥ 30 × 109/L).
Proportion of patients achieving a hematological response within 12 weeks and within 24 
weeks of treatment with DFX combined with EPO and EPO alone will be calculated along 
with 95% Clopper-Pearson confidence interval. Descriptive statistics will be provided for 


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hematological improvement response, as well as for all hematological improvement of 
myeloid cell lineages subcomponents (hemoglobin, erythrocytes, neutrophils and platelets). 
Analysis will be performed on FAS.
Hematologic response and improvement within 12 weeks and 24 weeks will be analyzed 
separately.
Table 2-2 summarizes the distinction between response and improvement as being used for 
supportive analyses:
Table 2-2
Criteria for hematological response and hematologic improvement
Pre-treatment 
conditions
Post-baseline
Response
Hematological response:
If a patient fulfills at least
erythroid or platelet or 
neutrophil response as well as 
it’s corresponding pre-
treatment condition
Hb< 
11 
g/dL 
at 
baseline
Hb increase from baseline 
by ≥ 1.5 g/dL
Erythroid response
Platelet < 100 ×109 /L 
at baseline
Increase from baseline ≥ 30 
× 109/L
Platelet response
Neutrophil < 1.0 × 
109/L at baseline
Increase from baseline > 
100% and increase from 
baseline > 0.5 × 109/L
Neutrophil response
Hematologic improvement:
If a patient fulfills at least 
hemoglobin or platelet
or neutrophil improvement
response without it’s 
corresponding pre-treatment 
condition
Hemoglobin < 11 g/dL 
at baseline
Increase from baseline by ≥ 
1 g/dL
Hemoglobin
improvement
Platelet ≥ 100 ×109/L at 
baseline
Increase from baseline ≥ 30 
×109/L
Platelet improvement
Neutrophil ≥ 1.0 × 
109/L at baseline
Increase from baseline > 0.5 
× 109/L
Neutrophil 
improvement
2.9.2.2
To assess the effect of treatment on erythropoiesis within 24 weeks in 
patients who were non-responder to EPO alone after 12 weeks and 
switched to DFX+EPO
Patients who are non-responders to erythroid at week 12 in the EPO group will have to switch 
to combination therapy, if they continue to participate in the study.
Patients meeting the criterion (Hb increase from baseline ≥ 1.5 g/dL) at any time between 
week 12 and week 24 will be considered as erythroid responders.
Proportion of erythroid responders between week 13 and 24 will be reported along with its 95% 
Clopper-Pearson confidence interval. Descriptive statistics will be provided for erythroid 
response. Analysis will be performed on FAS.


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2.9.2.3
To assess the effect of treatment with EPO alone on erythropoiesis 
within 24 weeks of treatment
This analysis includes patients who started with the EPO alone and are not switched to 
combination therapy.
Patients meeting the criterion (Hb increase from baseline ≥ 1.5 g/dL) at any time between 
week 1 and week 24 will be considered as erythroid responders. Proportion of erythroid 
responders who starts with EPO alone and are not switched to combination therapy will be 
reported along with its 95% Clopper-Pearson confidence interval.
Descriptive statistics will be provided for erythroid response. Analysis will be performed on 
FAS.
2.9.2.4
To assess iron parameters in patients randomized to EPO alone,
DFX+EPO and in patients randomized to EPO alone and switched to 
DFX+EPO after 12 weeks
This analysis will include patients randomized either to EPO or DFX+EPO at baseline as well 
as patients who are non-responders to erythroid at week 12 in the EPO group switched to 
combination therapy. The time-course of serum ferritin and its absolute/relative changes from 
baseline will be summarized by descriptive statistics by visit and erythroid response. Data will 
be summarized on FAS.
Note: Patients randomized to EPO and not switching after 12 weeks to EPO+DFX, will
consist of only responders.
2.9.2.5
To assess Hb parameters in patients randomized to EPO alone, 
DFX+EPO and in patients randomized to EPO alone and switched to 
DFX+EPO after 12 weeks
This analysis will include patients randomized either to EPO or DFX+EPO at baseline as well 
as patients who are non-responders to erythroid at week 12 in the EPO group switched to 
combination therapy. The time-course of Hb and its absolute/relative changes from baseline 
will be summarized by descriptive statistics by visit and erythroid response. Data will be 
summarized on FAS. 
Note: Patients randomized to EPO and not switching after 12 weeks to EPO+DFX, will
consist of only responders.
2.10
Safety evaluation
For all safety analyses, the Safety Set will be used. All listings and tables will be presented by 
treatment group.
2.10.1
Analysis set and grouping for the analyses
The overall study period will be divided into three mutually exclusive segments:
1. pre-treatment period: from day of patient’s informed consent to the day before first dose 
of study medication


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2. on-treatment period: from the day of first dose of study medication to 30 days after last 
dose of study medication
3. Post-treatment period: starting at day 31 after last dose of study medication.
If dates are incomplete in a way that clear assignment to pre-, on-, post-treatment period 
cannot be made, then the respective data will be assigned to the on-treatment period.
The assessment of safety will be based mainly on frequency of AEs and on the number of 
laboratory values that fall outside of pre-determined ranges.
The safety summary tables will include on-study assessments (with the exception being the 
prior concomitant medications, laboratory parameters with baseline value taken prior to start 
of study drug). All safety assessments will be listed and those collected outside of the on -
study period will be flagged appropriately.
In all safety listings, a column will be added to provide the true treatment (EPO alone, 
EPO+DFX DT or EPO+DFX FCT, DFX DT or DFX FCT alone, no treatment) at onset of AE 
or at time of any other safety assessment and the original treatment assigned.
2.10.2
Adverse events (AEs)
The reporting of AEs and AEs of special interest will be reported in the following periods
based on the treatment received as follows:

For patients receiving EPO during the first 12 weeks and for those continuing with
EPO after 12 weeks (no switching to EPO+DFX arm), the safety data will be reported
based on the corresponding treatment group: EPO. The safety data will be reported in
period 1-12 weeks, 13-24 weeks and 1-24 weeks.

For patients receiving EPO+DFX DT or EPO+DFX FCT from week 1 and continuing 
with EPO+DFX DT or EPO+DFX FCT after 12 weeks or with DFX DT or DFX FCT
alone after 12 weeks, the safety data will be reported based on the corresponding 
treatment group EPO+DFX. The safety data will be reported in period 1-12 weeks and 
1-24 weeks.

For patients receiving EPO alone and switched to EPO+DFX after 12 weeks of 
treatment, the safety data will be reported only in period 13-24 weeks.
Overall summary will be reported for AEs occurred in period 1-12 weeks of treatments and 1-
24 weeks for patients receiving EPO alone and patients receiving EPO+DFX DT or 
EPO+DFX FCT.
Overall summary, SAE and AEs leading to study drug discontinuation will be reported for in
the corresponding treatment: EPO, DFX DT, DFX FCT, EPO+DFX DT and EPO+DFX FCT.
All AEs will be coded using the latest version of MedDRA at the time of analyzing data using 
the Safety Set. The severities of the AE will be coded as mild/moderate/severe as documented 
in the CRF.
Summary tables for AEs have to include only AEs that started or worsened during the on -
study period, the treatment-emergent AEs, i.e. TEAEs. However, all safety data (including 


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those from the pre and post-study periods) will be listed and those collected during the pre-
study and post-study period will be flagged.
If an AE deteriorates or improves over time, new event will be reported accordingly with new 
severity.
The incidence of treatment-emergent AEs (new or worsening from baseline) will be 
summarized by system organ class and or preferred term, severity (mild/moderate/severe), 
type of AE and relation to study treatment. 
Deaths reportable as SAEs and non-fatal serious AEs will be listed by patients and tabulated 
by type of AE.
Additionally, AEs and SAEs with suspected relationship to study drug, requiring dose 
adjustment, leading to drug interruption/discontinuation, requiring significant additional 
therapy will be specifically tabulated and listed.
AEs of special interest (AESIs) will be listed and summarized by grouped term and preferred 
term as shown in: 
 
. It should be noted that this is a live document and may get updated with time and 
only the latest updated version should be used during the time of analyzing the data.
Also the AESI list to be used should have been updated based on the latest version of the case 
retrieval sheet (CRS) in terms of using the updated MedDRA version for identifying the AEs.
As mentioned above only the most recent version of the AESI list and CRS will be used for 
this study. AEs of special interest (AESIs) will be listed and summarized by group term and 
preferred term.
2.10.2.1 General rules for AE reporting
The number and percentage of patients reporting any AE will be summarized by primary SOC, 
PT overall and by treatment group. The most common AEs reported (xx% in any group for 
each preferred term; xx% depends on the total number of AEs) will be presented in 
descending frequency according to its incidence in EPO and EPO+DFX starting from the 
most common event. 
Additional summaries will be provided by severity and relationship to study treatment. 
If a patient reported more than one AE with the same preferred term, the AE with the greatest 
severity will be presented. If a patient reported more than one AE within the same primary 
system organ class, the patient will be counted only once with the greatest severity at the 
system organ class level, where applicable. 
2.10.3
Laboratory data
All laboratory values will be converted into SI units and the severity grade calculated using 
the low/normal/high classifications based on laboratory normal ranges and for selected 
parameters by notable and extended ranges as available in the deferasirox program standards.


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Note that, Hemoglobin (g/dL) and Serum Ferritin (ng/mL) are the only exceptions which will 
be reported in US-units (if appropriate).
Table 2-4
Criteria for clinically notable and extended laboratory ranges
Parameter
Criteria
Absolute neutrophils
<1.5×109/L (extended range <0.5×109/L)
Platelets
<100×109/L (extended range <50×109/L)
ALT/AST
>5×ULN and >2×baseline value (extended range >10×ULN 
and >2×baseline value)
Serum creatinine
> 33% increase from baseline and >ULN at two consecutive 
measurements at least 7 days apart
Creatinine clearance
<60 mL/min at two consecutive measurements at least 7 days apart 
(extended range <40 mL/min)
Urinary total protein/creatinine ratio
>113.1 mg/mmol at two consecutive measurements at least 7 days 
apart
The frequency of laboratory abnormalities will be displayed by parameter and treatment group. 
Laboratory data will be summarized by presenting summary statistics of raw values at 
baseline and changes from baseline (absolute) to worst post-baseline value and by treatment 
group.
Laboratory data will be summarized by presenting shift tables showing baseline versus most 
extreme post-baseline result by notable range. 
Box plots of absolute value will be provided for selected parameters.
Listings of all laboratory data with values flagged corresponding to normal/notable/extended 
ranges will be provided. The listing of all laboratory values will be provided by planned and 
actual dose along with the columns for treatment arm to which the patient was randomized 
and the treatment arm where the patient belongs at the time of the assessment will be provided.
Hematology:
Box plots on absolute value for Hb, neutrophil and platelets corresponding to each visit will 
be provided.
Absolute change from baseline to worst post-baseline value (the lowest for hematology 
parameters) will be provided for Hb, neutrophil and platelets.
Absolute change from baseline to last available value at the time of EOT will be provided for 
Hb, neutrophil and platelets.
Listings will be provided for Hb, platelets and neutrophils as well.
Only listings will be provided for the parameters: Hematocrit, red blood cell (RBC) count, 
reticulocyte count, mean corpuscular volume (MCV), White blood cell (WBC) count with 
differential.


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Blood chemistry
Absolute change from baseline to worst post-baseline value (the highest for blood chemistry 
parameters except creatinine clearance, which the lowest value is considered to be the worst)
will be provided for serum ferritin, ALT, AST, total bilirubin, serum creatinine, creatinine 
clearance and urinary protein/creatinine ratio.
Absolute change from baseline to last available value at the time of EOT will be provided for 
serum ferritin, ALT, AST, total bilirubin, serum creatinine, creatinine clearance and urinary 
protein/creatinine ratio.
Shift tables from baseline to post-baseline value will be provided for serum ferritin, ALT, 
AST, serum creatinine, creatinine clearance and urinary protein/creatinine ratio in the 
following way:
Serum ferritin - Baseline categories: ≤270 ng/mL, > 270 – 500 ng/mL, > 500 – 1650 
ng/mL, > 1650 ng/mL and Missing; 
Serum ferritin - Post-baseline categories: ≤270 ng/mL, > 270 – 500 ng/mL, > 500 – 1650 
ng/mL, > 1650 ng/mL.
ALT/AST - Baseline categories: ≤ ULN, > ULN - ≤ 5×ULN, > 5×ULN - ≤ 10×ULN, >
10×ULN and Missing; 
ALT/AST - Post-baseline categories: ≤ ULN, > ULN - ≤ 5×ULN, One value > 5×ULN, One 
value > 10×ULN, Two consecutive values measured at least 7 days apart > 5×ULN, Two 
consecutive values measured at least 7 days apart > 10×ULN, > 5×ULN and 2× Baseline 
value, > 10×ULN and 2× Baseline value and Missing.
Serum creatinine - Baseline categories: ≤ULN, >ULN and Missing; 
Serum creatinine - Post-baseline categories: ≤ ULN, One value > ULN, Two values >ULN, 
Two consecutive values measured at least 7 days apart > ULN, Two consecutive values 
measured at least 7 days apart > ULN, both > 33% increase from baseline and Missing-
Urinary protein/creatinine ratio – Baseline categories: ≤ 22.62 mg/mmol, >22.62 - ≤ 113.1
mg/mmol, > 113.1 mg/mmol and Missing; Post-baseline categories: ≤ 113.1 mg/mmol, One 
value > 113.1 mg/mmol, Two values > 113.1 mg/mmol, Two consecutive values measured at 
least 7 days apart > 113.1 mg/mmol and Missing.
Creatinine clearance - Classification I:
Creatinine clearance - Baseline categories: < 40 mL/min, 40 - < 60 mL/min, 60 - < 90 
mL/min, 90 - < 160 mL/min, ≥ 160 mL/min and Missing; 
Creatinine clearance - Post-baseline categories: Two consecutive values measured at least 7 
days apart < 60 mL/min, One value < 60 mL/min, Two consecutive values measured at least 7 
days apart 60 - <90 mL/min, One value 60 - <90 mL/min, two consecutive values measured at 
least 7 days apart 90 - < 160 mL/min, One value 90 - <160 mL/min, ≥ 160 mL/min and 
Missing.
Creatinine clearance - Classification II:


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Creatinine clearance - Baseline categories: < 40 mL/min, 40 - < 60 mL/min, 60 - < 90 
mL/min, 90 - < 160 mL/min, ≥ 160 mL/min and Missing; 
Creatinine clearance - Post-baseline categories: Two consecutive values measured at least 7 
days apart < 40 mL/min, One value < 40 mL/min, Two consecutive values measured at least 7 
days apart 40 - <60 mL/min, One value 40 - <60 mL/min, ≥ 40 mL/min and Missing
Calculation for CrCl:
In the formula below, CrCl denotes creatinine clearance, SCr denotes serum creatinine in 
µmol/L; age in years will be calculated from date of birth and date of the relevant blood 
sample. Weight and height will be the last available measurements at the time of the relevant 
blood sample.
Cockcroft-Gault formula (≥18 years of age), 
CrCl (mL/min) =
Male patients: (140-age)×weight/(815×0.001×SCr)
Female patients: (140-age)×weight×0.85/(815×0.001×SCr) 
Note 1: The recalculated creatinine clearance in derived Lab data and standard UNITCONV 
data:

Parameter names (PARNAM1C) as ‘CRCLSCG’ for Cockcroft-Gault formula.

Preferred (PREUNT1C) and Converted (CNVUNT1C) unit ‘mL/min’ for Cockcroft
Gault formulae.

Zero Precision (CNVPCS1N) for converted values.
Note 2: For Height and Weight, last available values at the time of assessments should be 
used. Current age should be derived at the time of assessments.
Listings will also be provided for serum ferritin, ALT, AST, total bilirubin, serum creatinine, 
creatinine clearance and urinary protein/creatinine ratio.
A listing of all laboratory values will be flagged as appropriate and will be provided along 
with planned and actual dose (EPO and EPO + DFX). Assessment day relative to first dose of 
study drug will be included.
All other blood chemistry parameters apart from the ones mentioned above will only be listed.
For the laboratory result on serum pregnancy: β-HCG and on urine pregnancy, listings will be
provided.
2.10.4
Vital signs, weight and body mass index
Absolute change from baseline to highest and lowest post-baseline for systolic blood pressure, 
diastolic blood pressure, pulse rate and weight will be summarized by treatment group (EPO 
and EPO+DFX), A listing will be provided for systolic blood pressure, diastolic blood 
pressure, pulse rate weight and BMI. Notable systolic blood pressure, diastolic blood pressure, 
pulse rate and weight values will be flagged.
Note: Baseline is defined as the last available value prior to or on the day of first dose of study 
drug.


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The criteria for notably vital signs and weight values is displayed in the table below.
The criteria for clinically notable abnormalities were defined as follows:
Clinically notable elevated values:

Systolic BP: 160 mmHg or increase 20 mmHg from baseline

Diastolic BP: 100 mmHg or increase 15 mmHg from baseline

Weight: Increase from baseline of 7%

Pulse: 100 bpm or increase from baseline of 15 bpm
Clinically notable below normal values:

Systolic BP: 90 mmHg or decrease 20 mmHg from baseline

Diastolic BP: 60 mmHg or decrease 15 mmHg from baseline

Weight: decrease from baseline of 7%

Pulse: 60 bpm or decrease from baseline of 15 bpm
2.10.5
Other safety data
Ocular and auditory examination will be collected at screening, nevertheless the 
examination(s) can be performed at any time if there is a need to be repeated. Data from these 
assessments will be flagged as appropriate and will be listed and summarized by treatment 
group.
2.11
CSR Section 9.7.2: Sample size and power considerations
This is a pilot study that was planned to enroll approximately 60 patients considering site
capabilities. No formal sample size calculation based on primary endpoint assumptions is 
performed.
However to give an idea regarding primary endpoint analysis, for a given number of 60 
patients, under scenarios, where considering a minimal detectable differences of 20%, 30%
and 40% assuming a reference response rate of 40% at 5% level of significance gives a 95% 
Agresti-Caffo confidence interval of (-0.04, 0.44), (0.068, 0.53) and (0.18, 0.62).


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Clinical Development
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Appendix 16.1.7: Randomization scheme and codes
Document type:
Clinical Study Report - Appendix 16.1.7
Property of Novartis
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


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3
Clinical Study Report – Appendix 16.1.7 Randomization 
scheme and codes
This section of the RAP document presents a short account of the randomization procedures.
3.1
Randomization scheme and codes
Each patient will be identified in the study by a Patient Number, that will be assigned when 
the patient will be first enrolled for screening and will be retained as the primary identifier for 
the patient throughout his/her entire participation in the trial. The Patient Number consists of 
the 
 
, so that each patient will be numbered uniquely across 
the entire database.
Upon signing the informed consent form, the patient is assigned to the next sequential Patient 
Number.
The investigator or designated staff will contact the Interactive Web Response Technology 
(IWR) and provide the requested identifying information for the patient to register them into 
the IWR. Once assigned, the Patient Number must not be reused for any other patient and the 
Patient Number for that individual must not be changed, even if the patient is re-screened. If 
the patient fails to be randomized or start treatment for any reason, the reason will be ent ered 
into the Screening Log. 
IWR must be notified within 2 days that the patient was not randomized.
3.2
Treatment assignment or randomization
Patients will be assigned to one of the 2 treatment arms in a ratio of 1:1.
The randomization numbers will be generated using the following procedure to ensure that
treatment assignment is unbiased and concealed from patients and investigator staff. A patient
randomization list will be produced by the IWR provider using a validated system that 
automates the random assignment of patient numbers to randomization numbers. These 
randomization numbers are linked to the different treatment arms, which in turn are linked to 
medication numbers. A separate medication randomization list will be produced by or under 
the responsibility of 
using a validated system that 
automates the random assignment of medication numbers to medication packs containing 
each of the study treatments.
Prior to dosing, all patients who fulfill all inclusion/exclusion criteria will be randomized via
IWR to one of the treatment arms. The investigator or his/her delegate will call or log on to 
the IWR and confirm that the patient fulfills all the inclusion/exclusion criteria.
3.3
Treatment blinding
This is an open-label study and the CTT is unblinded to the study treatment.


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4
Clinical Study Report – Appendix 16.1.9 Documentation of 
statistical methods
This section of the RAP document presents further detail about the statistical methods not 
given in Section 9.7 of the Clinical Study Report (CSR).
4.1
Appendix 16.1.9 – Documentation of statistical methods
The statistical methods used to perform the analyses presented in the clinical study 
report will be described in Section 9.7. Section 16.1.9 will provide further details of 
the statistical methods not already provided in Section 9.7.


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Appendix 16.1.9: Documentation of statistical methods
Document type:
Clinical Study Report - Appendix 16.1.9
Property of Novartis
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


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4.2
Definitions
4.2.1
Study drug and study treatment
Study treatments refers to EPO and EPO+DFX DT or EPO+DFX FCT.
Study drugs are DFX and EPO. 
4.2.2
Date of first administration of study treatment
The date of first administration of study treatment will be derived as the first date when a non-
zero dose of study treatment will be administered. For the sake of simplicity, the date of first 
administration of study treatment is referred to start date of study treatment. Start date of 
study treatment is defined by first non-zero dose administration date of EPO or EPO+DFX
DT or EPO+DFX FCT.  
The date of first administration for EPO and EPO+DFX DT or EPO+DFX FCT will be 
recorded on the corresponding “dosage administration record” (DAR) eCRF page.
4.2.3
Date of last administration of study drug
The date of last administration of study drug is defined as the last date when a non -zero dose 
of study treatment EPO or EPO+DFX DT or EPO+DFX FCT is administered and recorded on 
the DAR of the CRF. The date of last administration of study treatment is referred to end date 
of study treatment or last date of study treatment.
Note: For patients either randomized to EPO+DFX DT or EPO+DFX FCT or for patients who 
switch to EPO+DFX DT or EPO+DFX FCT after 12 weeks, the end date of study treatment 
could be the last date when a non-zero dose of DFX DT or DFX FCT is administered since 
EPO is administered weekly and the patient may have received the EPO 6 days before the last 
non-zero dose of DFX DT or DFX FCT is given.
4.2.4
Study start date
The start date of study should be considered to be the date when the first patient signs the 
informed consent form.
4.2.5
End of treatment 
For a given patient the End of treatment will be defined as the last day when the patients 
received the study drug while still being on study.
4.2.6
Definition of End of study
The study will end when the last patient will have either withdrawn (including follow-up
period of 30 days) from the study or completed the study (24 weeks + follow up period of 30
days) from the start of treatment (EPO or EPO+DFX DT or EPO+DFX FCT), whichever 
occurs earlier.


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4.2.7
Study Day definition
For safety variables and analyses that requires using the safety set, s tudy day will be defined 
as the number of days since the date of first dose of study drug (after randomization or 
enrollment). For a particular date on or after first dose, it will be calculated as:
Study day = Assessment date – Date of first dose of study drug + 1.
Therefore, the date of the first dose of study drug will be Day 1 by definition. 
The day before this day will be defined to be Day -1, i.e., there will be no Day 0. Study days 
before first dose of study drug will be calculated as 
Study day = Assessment date – Date of first dose of study drug.
4.2.8
Treatment period
Having completed the screening period, patients are enrolled and randomized to receive either
DFX DT or DFX FCT plus EPO or EPO alone. Study treatment is defined as DFX DT 10 
mg/kg/day p.o. or DFX FCT 7 mg/kg/day p.o. plus EPO 40,000 units/week s.c. once weekly 
or EPO 40,000 units/week once weekly s.c.. EPO dose changes are allowed in both arms 
according to the EPO guidelines (see Appendix 3 of the CSP). For details on study design and 
dose adjustments, see Section 4.1 of the protocol. The study treatment duration is 24 weeks. 
After randomization, patient visits will occur weekly during the first month because key 
safety assessments need to be performed weekly in the first month of treatment and then every 
4 weeks thereafter until week 24. In case of a dose increase of EPO after 4 weeks of treatment, 
an additional visit needs to be performed after 2 weeks of dose increase. For details of 
assessments, see Table 7-1 and Table 7-2 of the CSP.
4.2.9
Baseline
In general, for safety variables, the baseline value is defined to be the last available value prior 
to or on the day of first dose of study drug. For efficacy variables, the baseline value is 
defined to be the last available value prior to or on the day of randomization. 
This definition does not apply for the following exceptions, where a specific definition was 
used: 

Serum creatinine: baseline value is defined as the mean of visit 1 and 2. 

Serum ferritin: baseline value is defined as the mean of visit 1 and 2.
4.2.10
Calculation of change
Baseline value will be the value collected during the baseline assessment as per the specific 
definition applying to the parameter, e.g. lab value 
Absolute change from baseline will be the absolute difference between value a time point t 
(post-baseline) and value at baseline assessment, it will be calculated as: 

Absolute change from baseline = post-baseline value – baseline value
Relative change from baseline, or Percentage change from baseline, will be calculated as:


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
Relative change from baseline (%) = (absolute change / baseline value) 100
4.2.11
Visit Windows
A year = 365.25 days.
A month = 365.25/12=30.4375 days.
Month 1 = Day (1;45] and then floor(n×30.4375) days±15 days, n=2, 3, 4,… that is Month 2 
= Day (45;75]; Month 3 = Day (75;106]; etc.
For each parameter (i.e., hematologic and erythroid response), time windows will be used to 
identify data to be considered for the specific analysis at a specific time point. If there is more 
than one assessment within the time window, the last available assessment in that time 
window will be used. For all windows after baseline, only values after first dose of study drug 
will be used. Time windows are defined based on date of randomization (=study day 1; Visit 3 
according to VES of protocol). 
The following table shows the time windows for the analyses of responses based on planned 
assessment schedule.
Table 4-1
Visit windows
Planned assessment
Time window
Nominal day for visit
Baseline
Baseline; see definition 4.2.6
Baseline
Visit 3: Date of Randomization
Day 1
Day 1
Visit 4
Day 4 to Day 10*
Day 7
Visit 5
Day 11 to day 17*
Day 14
Visit 6
Day 18 to Day 24*
Day 21
Visit 7
Day 25 to Day 31*
Day 28
Visit 8
Day 35 to Day 49*
Day 42
Visit 9
Day 50 to Day 63*
Day 56
Visit 10
Day 77 to Day 91*
Day 84
Visit 11
Day 105 to Day 119*
Day 112
Visit 12
Day 133 to Day 147*
Day 140
The End of Treatment visit time window is Day 161 to Day 175 with nominal day of visit is 
Day 168 considering Visit 3 as Day 1.
In case of early treatment discontinuation or end of visit 12, the follow up will be 27 -33 days 
from the last date when a non-zero dose of study treatment is administered (Last date of study 
treatment).
Considering, a patient has received EPO only and received a response. This patient will hold 
EPO until study end. However, Follow-up visit for them will be 30 days (+/- 3 days after EOT) 
and not 27-33 days from the last date when a non-zero dose of study treatment is administered.


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4.3
Data handling conventions
Partial dates will be listed as partial dates.  For computing time/duration, the following rules 
will be used to impute partial dates: if the day and month is missing, it will be replaced by 30th
of June (to be used only for prior events, e.g., medical history), if only the day is missing it 
will be replaced by 15th of that month. For dates known to be within the trial period, if this 
imputation makes the date later than trial completion date, then the trial completion date will 
be used; if the imputed date is earlier than the first medication date, then the first medication 
date will be used.  The same rules of assigning AE start and end dates will apply for study 
medication start and end dates for subjects with missing or partial date of or with duplicate 
records of study medication.
Partially or completely missing AE onset dates and concomitant medication dates are imputed 
according to the standard Novartis imputation rules as described in the following:
Date imputation is the creation of a new, complete date from a partial one according to an 
agreed and acceptable algorithm.  Missing date for AE will be handled according to STL 
standard.  
A partial date is simply an incomplete date e.g., 
ddOCT2001
the days are missing from this DDMMMYYYY date
Partial AEs start dates, if left partial, would ultimately mean the following

It would not be possible to place the AE in time.

Therefore the treatment/dosage at the time of the event would be unknown.

Therefore the event could not be reported/summarized appropriately – if at all.
Therefore it is important to perform date imputation to ensure that as many data events are 
represented as correctly as possible. Of course partial and/or missing dates should also be 
caught as edit checks and passed back to the investigator for resolution.
There will be no attempt to impute the following:

Missing AE start dates

AE start dates missing the year

Partial/missing AE end dates
Table 4-2 explains the abbreviations used.
Table 4-2
AE/Treatment Date Abbreviations 
Day
Month
Year
Partial Adverse Event 
Start Date
<not used>
AEM
AEY
Treatment Start Date 
(TRTSTD)
<not used>
TRTM
TRTY


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Table 4-3 describes the possible combinations and their associated imputations. In the light 
grey boxes the upper text indicates the imputation and the lower text the relationship of the 
AE start date to the treatment start date (TRTSTD).
Table 4-3
Imputation algorithm
AEM MISSING
AEM < TRTM
AEM = TRTM
AEM > TRTM
AEY MISSING
NC
Uncertain
NC
Uncertain
NC
Uncertain
NC
Uncertain
AEY < TRTY
( D )
Before TRTSTD
( C )
Before TRTSTD
( C )
Before TRTSTD
( C )
Before TRTSTD
AEY = TRTY
( B )
Uncertain
( C )
Before TRTSTD
( B )
Uncertain
( A )
After TRTSTD
AEY > TRTY
( E )
After TRTSTD
( A )
After TRTSTD
( A )
After TRTSTD
( A )
After TRTSTD
The legend to the above table is shown in Table 4-4.
Table 4-4
Relationship and Imputation Legend
Relationship
Before TRTSTD
Indicates AE start date prior to Treatment Start Date
After TRTSTD
Indicates AE start date after Treatment Start Date
Uncertain
Insufficient to determine the relationship of AE start 
date to Treatment Start Date
Imputation Calculation
NC / Blank
No convention/imputation
( A )
01MONYYYY
( B )
TRTSTD+1
( C )
15MONYYYY
( D )
01JULYYYY
( E )
01JANYYYY
Few examples are shown in Table 4-5.
Table 4-5
Example Scenarios
Partial
AE start date
Treatment
start date
Relationship
Imputation 
Calculation
Imputed Date
12mmyyyy
20OCT2001
Uncertain
NC
<blank>
ddmmm2000
20OCT2001
Before
( D )
01JUL2000
ddmmm2002
20OCT2001
After
( E )
01JAN2002
ddmmm2001
20OCT2001
Uncertain
( B )
21OCT2001
ddSEP2001
20OCT2001
Before
( C )
15SEP2001
ddOCT2001
20OCT2001
Uncertain
( B )
21OCT2001
ddNOV2001
20OCT2001
After
( A )
01NOV2001


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For any continuing events (e.g. AEs, concomitant medication, etc) which needs to be 
summarized for annual reports (or any interim analyses), when a date cut-off date is used an 
indication in the listings will be done to inform that the event is continuing. For patients who 
discontinue the study with ongoing events, the discontinuation date will be used as the 
completion date of the event.
Vital sign, Study Completion, CMP, ECG and laboratory assessment dates will be imputed in 
associating visit date from Visit-based event date imputation (AVIS) (see RAP Module 8).
Any event which has a partial date and requires imputing but has no specific imputation rule
will be described in the RAP Module 8 and the imputed will be as follows:

If the day and month is missing, it will be replaced by 1st of July. If only the day is 
missing it will be replaced by the 1st of that month. Partial dates will remain partial in 
the data listings.

Missing day information for start date of prior chelation therapy or start date of history 
of blood transfusions will be imputed by the 15th of the Month. If the month will be
missing it will be imputed by July.
A missing category for categorical data will be presented where applicable. Unless otherwise 
noted, percentages will be based on the number of patients in the relevant population or 
subgroup.
4.4
Protocol deviations
The complete list of PDs, which is usually described in a Novartis VAP Module 3, is 
described in the following tables:
Table 4-6
CSR Reportable Protocol Deviation Categories
Violation Code
Protocol ID
Description of CSR Reportable Category
Inclusion Criteria
Ixx
Subject enrolled despite selection criteria not being met
Exclusion 
Criteria
Exx
Subject enrolled despite selection criteria not being met
Withdrawal
Dxx
Subject developed withdrawal criteria during the study but was not 
withdrawn
Treatment
Sxx
Subject received the wrong treatment or incorrect dose
Prohibited 
Medication
Mxx
Subject took an excluded concomitant medication
Other
Gxx
For deviations which jeopardize the safety or rights of the individual 
trial subjects, or jeopardize the scientific value of the trial may be 
reported under this category, should it not align with any of the 4 
categories. Protocol deviations captured under this category should be 
reviewed during a PD meeting for CSR- Reportable validity and must be 
reported in CSR if appropriate.


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The table below specifies the actions to be taken if any of the deviations listed in the VAP 
occur:
Table 4-7 Protocol Deviations List
Deviation Code
Protocol Deviation description
Action taken
I01
Patient has not provided consent prior to 
study start
Report as PD, 
include in FAS and Safety Set.
I24
Written informed consent not provided at 
all
Report as PD, 
Exclude from all analyses.
I25
Patient signed incorrect
version of informed consent
Report as PD, 
include in FAS and Safety Set.
I02
Subject is < 18 years or age missing
Report as PD, include in FAS and Safety Set.
I03
Patient does not suffer from MDS
Report as PD, 
include in FAS and Safety Set.
I04
MDS is not lasting ≥ 3
months or < 3 years
Report as PD,
include in FAS and Safety Set.
I05
MDS is secondary to treatment with 
radiotherapy,
chemotherapy, and/or immunotherapy for 
malignant or autoimmune disease
Report as PD, 
include in FAS and Safety Set.
I06
Patient has no low- and Int-1- risk MDS
Report as PD, 
include in FAS and Safety Set.
I07
Hemoglobin is ≥ 10.5 g/dL at Screening 
Visit 1 and/or Screening Visit 2
Report as PD, 
include in FAS and Safety Set.
I08
Hemoglobin is < 7.6 g/dL at Screening 
Visit 1 and/or Screening Visit 2
Report as PD,
include in FAS and Safety Set.
I09
Patient has history of ≥ 10 times RBC 
transfusions in total
Report as PD, 
include in FAS and Safety Set.
I27
Patient has history of ≥ 10 units of RBC 
transfusions in total
Report as PD, 
include in FAS and Safety Set.
I10
ANC < 500/mm^3 at Screening Visit 1 
and/or Screening Visit 2
Report as PD, 
include in FAS and Safety Set.
I11
Platelet count < 30,000/mm^3 at 
Screening Visit 1 and/or Screening Visit 2
Report as PD, 
include in FAS and Safety Set.
I12
Serum creatinine > 1.5 times ULN in 
mean value of measurements at Screening 
Visit 1 and Screening Visit 2
Report as PD, 
include in FAS and Safety Set.
I13
Patients with creatinine clearance < 40 
mL/min.
Report as PD, 
include in FAS and Safety Set.


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I20
Creatinine clearance below the 
concentration limit locally approved PI at 
Screening Visit 1 and/or Screening Visit 2
Report as PD, 
include in FAS and Safety Set.
I14
AST and ALT > 2.0 times ULN at 
Screening Visit 1 and/or Screening Visit 2
Report as PD, 
include in FAS and Safety Set.
I15
Serum total bilirubin ≥ 3.0 mg/dL at 
Screening Visit 1 and/or Screening Visit 2
Report as PD, 
include in FAS and Safety Set.
I16
FE/TIBC (TSAT) < 20% at Screening 
Visit 1
Report as PD,
include in FAS and Safety Set.
I17
SF is ≤ 270 ng/mL at Screening Visit 1 
and/or Screening Visit 2
Report as PD, 
include in FAS and Safety Set.
I18
SF is ≥ 1650 ng/mL at Screening Visit 1 
and/or Screening Visit 2
Report as PD, 
include in FAS and Safety Set.
I19
SF is ≥ 1100 ng/mL at Screening Visit 1 
and/or Screening Visit 2
Report as PD, 
include in FAS and Safety Set.
I21
Endogenous EPO levels ≥ 500 units/L at 
Screening Visit 1
Report as PD, 
include in FAS and Safety Set.
I22
Patient received cytotoxic 
chemotherapeutic agents or experimental 
agents for treatment of MDS within 8 
weeks prior Screening
Report as PD, 
include in FAS and Safety Set.
I23
Patient is transfusion dependent (> 2U 
RBC/4 weeks at any time during the last 
12 weeks period prior to study entry)
Report as PD, 
include in FAS and Safety Set.
I26
Patient is transfusion dependent (≥ 2U 
RBC/month during the past 3 months)
Report as PD, 
include in FAS and Safety Set.
E01
Patient has MDS with isolated del(5q)
Report as PD, 
include in FAS and Safety Set.
E02
Prior EPO treatment or other recombinant 
growth factors with reported outcome, for 
≥ 4 weeks or within 3 month before 
Screening
Report as PD, 
include in FAS and Safety Set.
E03
Patient receiving steroids or 
immunosuppressive therapy for the 
improvement of hematological parameters
Report as PD, 
include in FAS and Safety Set.
E04
B12 or folate deficiency with or without 
clinical symptoms
Report as PD, 
include in FAS and Safety Set.


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E05
Uncontrolled seizures
Report as PD, 
include in FAS and Safety Set.
E06
Uncontrolled hypertension
Report as PD, 
include in FAS and Safety Set.
E07
History of other malignancies and has not 
been confirmed disease free for ≥ 3 years
Report as PD, 
include in FAS and Safety Set.
E08
Significant medical condition interfering 
with the ability to partake in this study
Report as PD, 
include in FAS and Safety Set.
E09
Thromboembolic event within the past 3 
years
Report as a PD, 
include in FAS and Safety Set.
E10
Known allergic reaction to EPO or human 
serum albumin
Report as PD, 
include in FAS and Safety Set.
E11
Clinical or laboratory evidence of active 
Hepatitis B or Hepatitis C (HBsAg in the 
absence of HBsAb OR HCV Ab positive 
with HCV RNA positive)
Report as PD, 
include in FAS and Safety Set.
E12
Patient has known HIV-1 seropositivity
Report as PD, 
include in FAS and Safety Set.
E13
Clinically significant anemia resulting 
from iron deficiencies, autoimmune or 
hereditary hemolysis, or gastrointestinal 
bleeding
Report as PD, 
include in FAS and Safety Set.
E14
Active bleeding
Report as PD, 
include in FAS and Safety Set.
E15
Patient is pregnant or nursing
Report as PD, 
include in FAS and Safety Set.
E16
Female of childbearing potential with 
missing serum HCG test
Report as PD, 
include in FAS and Safety Set.
E17
Patient with child-bearing potential 
without adequate birth control
Report as PD, 
include in FAS and Safety Set.
E19
Hepatic impairment fulfilling criteria of 
Child-Pugh Class B or C
Report as PD, 
include in FAS and Safety Set.
G04
Blood Sample for Hematology not 
collected for analysis at the required visit
Report as PD, 
include in FAS and Safety Set.
S01
Patient not exposed to study medication
Report as PD, 
include in FAS and Safety Set.
S02
Epo dose is not stopped as per protocol 
for more than 1 week but Hb increase is
≥1 g/dL and total Hb ≥ 12 g/dL in
period week 1-24
Report as PD, 
include in FAS and Safety set.


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S19
Epo dose is stopped for more than 1 week 
but Hb increase is not ≥1 g/dL and total 
Hb not ≥ 12 g/dL in period week 1-12
Report as PD, 
include in FAS and Safety Set.
S20
Epo dose is stopped for more than 1 week 
but Hb increase is not ≥1 g/dL and total
Hb not ≥ 12 g/dL in period week 13-24
Reported as PD, 
include in FAS and Safety Set.
S21
Epo dose reduced below assigned dose as 
per protocol for more than 1 week in 
period week 1-12
Report as PD, 
include in FAS and Safety Set.
S22
Epo dose reduced below assigned dose as 
per protocol for more than 1 week in 
period week 13-24
Report as PD, 
include in FAS and Safety Set.
S23
Epo dose increased above assigned dose 
as per protocol for more than 1 week in 
period week 1-12
Report as PD, 
include in FAS and Safety Set.
S24
Epo dose increased above assigned dose 
as per protocol for more than 1 week in 
period week 13-24
Report as PD, include in FAS and Safety Set
S03
Epo dose maintained at 40.000 units/week 
and not increased to 60.000 units/week 
after 4 weeks as per protocol for more 
than 1 week but Hb increase < 1g/dL and 
total Hb < 12 g/dL
Report as PD, 
include in FAS and Safety Set.
S05
Epo dose increased to 60.000 units/week 
and not maintained at 40.000 units/week 
after 4 weeks as per protocol for more 
than 1 week but Hb increase ≥ 1 g/dL and 
total Hb < 12 g/dL
Report as PD, 
include in FAS and Safety Set.
S06
Patient randomized to monotherapy not 
switched to combination therapy as per 
protocol or switch delayed for more than 1 
week after 12 weeks of treatment but Hb 
increase < 1 g/dL and total Hb < 12 g/dL
Report as PD, 
include in FAS and Safety Set.
D12
Patient randomized to combination 
therapy not discontinued after 12 weeks of 
treatment as per protocol or 
discontinuation delayed for more than 1 
week but Hb increase < 1 g/dL and total 
Hb < 12 g/dL
Report as PD, 
include in FAS and Safety Set.
S10
Patient randomized to combination 
therapy stopped DFX treatment for more 
than 1 week in period week 1-12 not as 
per protocol
Report as PD, 
include in FAS and Safety Set.
S25
Patient assigned to combination therapy 
stopped DFX treatment for more than 1 
week in period week 13-24 not as per 
protocol
Reported as PD, 
include in FAS and Safety Set.
M01
Forbidden concomitant medication as per 
Report as PD, 


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protocol
include in FAS and Safety Set.
M02
Patient received iron chelation therapy 
other than the study treatment
Report as PD, 
include in FAS and Safety Set.
D01
Transfusion during the study but not 
withdrawn
Report as PD, 
include in FAS and Safety Set.
D02
Pregnancy during the study, but not 
withdrawn
Report as PD, 
include in FAS and Safety Set.
S11
Patient randomized but received wrong 
study drug
Report as PD, 
include in FAS and Safety Set.
D03
≥50% decrement from maximum response 
levels in granulocytes or platelets but patient 
not withdrawn
Report as PD, 
include in FAS and Safety Set.
D04
Reduction of Hb level ≥1.5g/dL compared to 
best response but patient not withdrawn
Report as PD, 
include in FAS and Safety Set.
D05
Consent withdrawn but patient not 
withdrawn
Report as PD,  
Exclude from all analyses.
S12
Deferasirox dose was not reduced despite 
serum creatinine increase of ≥33% above 
baseline and above ULN at 2 consecutive 
occasions
Report as PD, 
include in FAS and Safety Set.
S13
Deferasirox treatment was not interrupted 
despite severe case of skin rash
Reported as PD, 
include in FAS and Safety Set.
S14
Deferasirox treatment was not interrupted 
despite persistent and progressive increase 
in serum transaminase levels that cannot 
attributed to other causes
Report as PD, 
include in FAS and Safety Set.
S15
Deferasirox treatment was not interrupted 
despite unexplained cytopenia
Report as PD, 
include in FAS and Safety Set.
S16
Deferasirox dose not recalculated 
despite > 10% change in body weight
Report as PD, 
include in FAS and Safety Set.
S17
Deferasirox treatment was not interrupted 
despite severe hypersensitivity reactions
Reported as PD, 
include in FAS and Safety Set.
S18
Deferasirox treatment was not 
permanently discontinued despite 
suspected Stevens Johnson syndrome
Report as PD, 
include in FAS and Safety Set.
G01
Use of local laboratory instead of central 
laboratory
Report as PD, 
include in FAS and Safety Set.
G03
Patient was randomized with missing 
central lab results and/or based on local 
lab results
Reported as PD, 
include in FAS and Safety Set.


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The RAP module 8 will include variables that will flag the missing values at baseline for the 
laboratory parameters or flag corresponding to certain assessments which leads to the 
exclusion of the patient from any analyses. 
4.5
Other rules
Percentages in shift tables cross-tabulating baseline versus post-baseline values will be based 
on all patients with a non-missing post-baseline value in the respective analysis set.
4.6
Number of decimals
Whenever possible, minimum and maximum will be presented to the same precision as the 
raw data. Mean and median will be presented to one more decimal place and standard 
deviation to two more decimal places. 
Unless stated otherwise, no imputation for missing data will be performed.


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5
References
Agresti and Caffo (2000). Simple and Effective Confidence Intervals for Proportions and
Differences of Proportions Result from Adding Two Successes and Two Failures. The 
American Statistican, Vol 54, No. 5.
Cheson BD, Greenberg PL, Bennett JM, et al (2006). Clinical application and proposal for 
modification of the International Working Group (IWG) response criteria in myelodysplasia. 
Blood; 108:419-25.
Clopper, C. J., and Pearson, E. S. (1934), ‘The Use of Confidence or Fiducial Limits 
Illustrated in the Case of the Binomial’, Biometrika 26, 404–413. 


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6
SAS procedure used for inferential analysis
6.1
Clopper-Pearson (Exact) CI for response rate
The 100 × (1 – alpha level) % Pearson-Clopper CI for the proportion of responders (binary
outcome = 1 or “Yes”), for a given treatment group X, is obtained from the following:
PROC FREQ data = dataset;
WHERE group = ‘X’;
TABLE 
binary 
event 
/binomial 
(exact
level='Yes') 
alpha = alpha level;
When there are no responders for treatment group X, SAS does not produce a CI by default.
To obtain a CI in this situation, PROC FREQ is used as specified above except changing
level=”No”. From the results of this modified procedure, the values in percent of the LCL and
UCL of a 0% response rate are calculated as follows:
• LCLLEVEL=”Yes” (%) = 100% - UCLLEVEL=”No” (%)
• UCLLEVEL=”Yes” (%) = 100% - LCLLEVEL=”No” (%)
6.2
Agresti-Caffo CI for difference in proportions
The Agresti-Caffo confidence limits for the risk difference are computed as:
± (	/ × s.e ())
That is: 
 = (+ 1)/( + 2) and  
 = (+ 1)/( + 2)
Column 1
Column 2
Total
Row 1


.
Row 2


.
Total
.
.

The Agresti-Caffo interval adjusts the Wald interval for the risk difference by adding a 
pseudo-observation of each type (success and failure) to each sample. See Agresti and Caffo 
(2000) for more information.


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This CI calculation is available in SAS Version 9.3 using the CL=AC options as follows:
ods select  PdiffCLs; 
ods output PdiffCLs=ciac; 
proc freq data= dataset; 
    tables group*response /riskdiff (CL=AC);
run;