Early and Low Dose Deferasirox (3.5 mg/kg FCT) to Suppress NTBI and LPI as Early Intervention to Prevent Tissue Iron Overload in Lower Risk MDS
Phase: PHASE2
Conditions: Myelodysplastic Syndromes
Sponsor: Fondazione Italiana Sindromi Mielodisplastiche-ETS

 
FISM_ IRON-MDS, version n.2.1, date 22.04.2020. 
 
1
 
 
 
Clinical Protocol 
 
Title: Early and low dose Deferasirox (3.5 mg/kg FCT) to 
suppress NTBI and LPI as early intervention to prevent 
tissue iron overload in lower risk MDS. 
IRON – MDS 
ID Study: FISM_IRON – MDS 
EudraCT number: 2018-003542-17 
 
INVESTIGATOR SPONSOR 
Fondazione Italiana Sindromi Mielodisplastiche -ETS (FISiM-ETS) 
 
COORDINATING INVESTIGATOR/S 
 
 
 
Dr. Emanuele Angelucci, Genova, Italia 
 
WRITING COMMITTEE AND SCIENTIFIC 
SUPPORT 
Dr Mario Capasso, Napoli, Italia 
Prof Matteo Della Porta, Milano, Italia 
Dr. Gianluca Forni, Genova, Italia 
Prof Domenico Girelli, Verona, Italia 
Dr Ester Oliva, Reggio Calabria, Italia 
Dr Federica Pilo, Cagliari, Italia 
Prof. Valeria Santini, Firenze, Italia  
 
 
Version and date of Protocol: Version 2.1, April 22, 2020 
 
 
CONFIDENTIALITY STATEMENT 
The information contained in this document is the property of Fondazione Italiana Sindromi 
Mielodisplastiche-ETS (FISiM-ETS) and therefore is provided to you in confidence for review by you, 
your staff, an applicable Ethics Committee/Institutional Review and regulatory authorities. It is 
understood that the information will not be disclosed to others without prior written approval from the 
Fondazione Italiana Sindromi Mielodisplastiche ETS  (FISiM-ETS), except to the extent necessary 
to obtain informed consent from those persons to whom the medication may be administered.  

 
FISM_ IRON-MDS, version n.2.1, date 22.04.2020. 
 
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1. RESPONSIBILITIES 
 
1.1. Sponsor and data owner. 
 : Fondazione Italiana Sindromi Mielodisplastiche-ETS (FISiM-ETS), Via De’ Poeti, 
1/7 - 40124 Bologna, Italy  
: +39 349 6754617 
Email: segreteria@fismonlus.it  
 
1.2. Coordinating Investigator(s) 
 : Emanuele Angelucci, Ematologia, Ospedale Policlinico San Martino, Largo 
Rosanna Benzi 10, 16132 Genova, Italy 
 :+39 010 5553651 Fax: +30 010 5556789 
 
Email: emanuele.angelucci@hsanmartino.it, emnang@tin.it  
 
1.3. Writing Committee 
 : Mario Capasso, Dipartimento di Medicina molecolare e Biotecnologie 
mediche,Università degli studi di Napoli Federico II, Via Pansini 5, 80131 Napoli, Italy 
 : +39 081-3737889 
 
 
 
Email: mario.capasso@unina.it 
 
 : Matteo Della Porta, Ematologia, Istituto Humanitas, Via Manzoni 56, 20089 - 
Rozzano, Milano, Italy  
 : +39 02 82247668 
 
 
Email: matteo.della_porta@hunimed.eu   
 
 : Gianluca Forni, S.S.D. Microcitemia, anemie congenite e dismetabolismo del ferro, 
Ospedali Galliera, Mura delle cappuccine 14, 16128 Genova  
 : +39 010 5634557 
 
 
Email: gianluca.forni@galliera.it 
 
 : Domenico Girelli, Dipartimento di Medicina, Università degli studi di Verona, 
Piazzale L. A. Scuro, 10, 37134 Verona, Italy 
 :+39  0458124791 
 
Fax: 
+39 0458027473 
Email: domenico.girelli@univr it  
 
 : Federica Pilo, Ematologia. Ospedale Oncologico A. Businco, Azienda Ospedaliera 
Brotzu, via Edward Jenner sn, 09121 Cagliari  
 : +39 339 6879269 
 
Email: pilofederica@gmail.com 
 
 : Ester Oliva, U.O.C. di Ematologia, Grande Ospedale Metropolitano"Bianchi-
Melacrino-Morelli", Viale Europa,89133 Reggio Calabria (RC), Italy : +39 
0965.591791 
 
Fax: 
+39 0965.349513 
 
Email: estheroliva@hotmail.com 
 
 : Valeria Santini, S.O.D. Ematologia, Azienda Ospedaliero Universitaria Careggi, 
Largo Brambilla 3, 50134 Firenze, Italy : +39 055 7947476  
Fax: 
+39 055 
412098 
Email: valeria.santini@unifi.it 
 
1.4. Biological Studies Coordinator 
 : Federica Pilo, Ematologia. Ospedale Oncologico A. Businco, Azienda Ospedaliera 
Brotzu, via Edward Jenner sn, 09121 Cagliari 
 : +39 339 6879269 
 
 
Email: pilofederica@gmail.com 

 
FISM_ IRON-MDS, version n.2.1, date 22.04.2020. 
 
3
 
 
 
1.5. Pharmacovigilance 
 : Ufficio Farmacovigilanza, Uffici Studi FIL, Fondazione Italiana Linfomi Onlus, c/o 
Uffici PACTO, Spalto Marengo 44, 15121 Alessandria 
 : +39.0131.033156 Fax: +39 0131 263455 
  
Email: drugvigilance@filinf.it  
 
 
1.6. Start up 
 : Sandra Mossuto FISiM ETS  Via De’ Poeti, 1/7 - 40124 Bologna, Italy  
 : +39 3496754617   
Email: segreteria@fismonlus.it  
 
1.7. Study Coordinator 
 : Sandra Mossuto FISiM ETS  Via De’ Poeti, 1/7 - 40124 Bologna, Italy  
 : +39 3496754617  
 
Email: segreteria@fismonlus.it 
 
1.8. Coordinating Statistician 
 : Mario Capasso, Dipartimento di Medicina Molecolare e Biotecnologie Mediche, 
Università degli Studi di Napoli Federico II, Via Pansini 5, 80131 Napoli, Italy 
 : +39 081-3737889 
 
 
Email: mario.capasso@unina.it 
 
 

 
FISM_ IRON-MDS, version n.2.1, date 22.04.2020. 
 
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2. TABLE OF CONTENTS 
1. 
RESPONSIBILITIES ............................................................................................................... 2 
2. 
TABLE OF CONTENTS .......................................................................................................... 4 
3. 
INVESTIGATOR AGREEMENT .............................................................................................. 7 
4. 
SYNOPSIS .............................................................................................................................. 8 
5. 
LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS ................................................. 13 
6. 
STUDY FLOW CHART ......................................................................................................... 15 
7. 
INTRODUCTION. AIM OF THE STUDY ............................................................................... 16 
8. 
BACKGROUND .................................................................................................................... 16 
8.1. 
DISEASE BACKGROUND .................................................................................................................... 16 
8.2. 
MECHANISM OF IRON ACCUMULATION AND CELLULAR IRON DAMAGE................................................... 17 
8.3. 
CURRENT THERAPIES FOR IRON OVERLOAD IN LOWER RISK MDS ....................................................... 19 
8.4. 
STUDY DRUG (MECHANISM OF ACTION, ABSORPTION, DISTRIBUTION, METABOLISM AND EXCRETION) . 19 
8.5. 
COMPLETE AND ON-GOING CLINICAL EXPERIENCES WITH STUDY DRUG ................................................ 21 
9. 
STUDY RATIONALE ............................................................................................................ 21 
10. 
STUDY OBJECTIVES ....................................................................................................... 22 
10.1. 
PRIMARY OBJECTIVE......................................................................................................................... 22 
10.2. 
SECONDARY OBJECTIVES ................................................................................................................. 22 
10.3. 
EXPLORATORY ................................................................................................................................. 22 
11. 
STUDY DESIGN ............................................................................................................... 22 
11.1. 
OVERVIEW OF STUDY DESIGN ............................................................................................................ 22 
11.2. 
NUMBER OF PATIENTS ...................................................................................................................... 23 
11.3. 
DURATION OF THE STUDY .................................................................................................................. 23 
12. 
STUDY POPULATION ...................................................................................................... 23 
12.1. 
INCLUSION CRITERIA ......................................................................................................................... 23 
12.2. 
EXCLUSION CRITERIA ........................................................................................................................ 23 
13. 
PATIENTS ENROLLMENT ............................................................................................... 24 
13.1. 
INFORMED CONSENT ......................................................................................................................... 24 
13.2. 
PATIENT REGISTRATION AND DATA COLLECTION ................................................................................ 25 
14. 
TREATMENT .................................................................................................................... 25 
14.1. 
DRUG 1: DEFERASIROX FCT ............................................................................................................ 25 
14.1.1. 
Supplier(s) ............................................................................................................................. 25 
14.1.2. 
Preparation and administration .............................................................................................. 25 
14.1.3. 
Receipt of study drug ............................................................................................................. 25 
14.1.4. 
Storage and handling ............................................................................................................ 25 
14.1.5. 
Unused study drug supplies .................................................................................................. 25 
14.2. 
TREATMENT SCHEDULE AND DESIGN.................................................................................................. 25 
14.2.1. 
Single arm (DFX-FCT 3.5 mg/kg/day) ................................................................................... 25 
14.3. 
PREMEDICATION ............................................................................................................................... 26 
14.4. 
PROPHYLACTIC MEASURES ............................................................................................................... 26 
14.4.1. 
Prevention of infections ......................................................................................................... 26 
14.4.2. 
Patients HBV positive ............................................................................................................ 26 
14.4.3. 
Patients HCV positive ............................................................................................................ 26 
14.4.4. 
Patients HIV positive ............................................................................................................. 26 
14.4.5. 
Contraception ........................................................................................................................ 26 
14.5. 
EXCLUDED/ADMITTED CONCOMITANT MEDICATION. ............................................................................ 26 
14.6. 
TOXICITY .......................................................................................................................................... 27 
14.6.1. 
Hematological and non hematological toxicity ...................................................................... 27 

 
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14.7. 
(DRUG) DOSE MODIFICATION ............................................................................................................. 27 
14.8. 
TOXICITIES MANAGEMENT ................................................................................................................. 27 
14.9. 
RESCUE MEDICATION ....................................................................................................................... 27 
14.10. 
BENEFIT/RISK ASSESSMENT ............................................................................................................. 27 
15. 
REMOVAL OF SUBJECTS FROM TREATMENT AND/OR STUDY ................................. 28 
15.1. 
DISCONTINUATION FROM STUDY TREATMENT ..................................................................................... 28 
15.2. 
WITHDRAWAL OF CONSENT .............................................................................................................. 28 
15.3. 
PATIENTS LOST TO FOLLOW UP ........................................................................................................ 29 
15.4. 
PREMATURE TERMINATION OF THE STUDY .......................................................................................... 29 
16. 
STUDY PROCEDURES TIMEPOINTS ............................................................................. 29 
16.1. 
SCREENING PERIOD (WITHIN 3 WEEKS PRIOR TO STUDY CYCLE 1 DAY 1) ............................................ 29 
16.2. 
TREATMENT ..................................................................................................................................... 30 
16.3. 
EOT PHASE ..................................................................................................................................... 30 
16.4. 
EARLY WITHDRAWN (DISCONTINUATION FROM STUDY TREATMENT) ..................................................... 30 
16.5. 
INVESTIGATIONS TESTS ..................................................................................................................... 30 
16.6. 
SCHEDULE OF ASSESSMENTS ............................................................................................................ 31 
16.7. 
SCHEDULE OF BLOOD SAMPLES ASSESSMENTS FOR EXPERIMENTAL BIOLOGICAL STUDY ..................... 33 
17. 
EFFICACY MEASUREMENTS AND PARAMETERS ....................................................... 34 
17.1. 
EFFICACY MEASUREMENT ................................................................................................................. 34 
17.2. 
EFFICACY PARAMETERS.................................................................................................................... 34 
17.2.1. 
Primary endpoints .................................................................................................................. 34 
17.2.2. 
Secondary objective and endpoints....................................................................................... 34 
18. 
SAFETY MONITORING AND REPORTING ..................................................................... 36 
18.1. 
ADVERSE EVENTS ............................................................................................................................ 36 
18.2. 
SERIOUS ADVERSE EVENTS .............................................................................................................. 37 
18.2.1 Definitions .................................................................................................................................... 37 
18.2.2 Reporting...................................................................................................................................... 37 
19. 
PREGNANCIES ................................................................................................................ 38 
20. 
STATISTICAL CONSIDERATIONS .................................................................................. 39 
20.1. 
STUDY DESIGN ................................................................................................................................. 39 
20.2. 
SAMPLE SIZE CALCULATION .............................................................................................................. 39 
20.3. 
STATISTICAL METHOD AND DATA ANALYSES. ..................................................................................... 40 
21. 
INDEPENDENT DATA SAFETY MONITORING COMMITTEE (DMSC) ........................... 42 
22. 
GOOD CLINICAL PRACTICE, QUALITY CONTROL AND QUALITY ASSURANCE ...... 42 
22.1. 
MONITORING, AUDITS AND INSPECTIONS ........................................................................................... 42 
22.2. 
INVESTIGATOR(S) RESPONSIBILITIES .................................................................................................. 42 
23. 
ETHICAL AND REGULATORY STANDARDS ................................................................. 43 
23.1. 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE REVIEW APPROVAL ...................... 43 
23.2. 
PROTOCOL AMENDMENTS APPROVAL ............................................................................................... 44 
24. 
ADMINISTRATIVE PROCEDURES .................................................................................. 44 
24.1. 
CURRICULUM VITAE .......................................................................................................................... 44 
24.2. 
CONFIDENTIALITY AGREEMENT .......................................................................................................... 44 
24.3. 
RECORD RETENTION IN INVESTIGATING CENTERS. .............................................................................. 44 
24.4. 
OWNERSHIP OF DATA AND USE OF THE STUDY RESULTS. .................................................................... 44 
24.5. 
AUTHORSHIP .................................................................................................................................... 44 
24.6. 
INSURANCE COVERAGE ..................................................................................................................... 45 
24.7. 
PROTOCOL AMENDMENTS PROCEDURES ............................................................................................ 45 
25. 
DATA HANDLING AND RECORD KEEPING ................................................................... 45 
25.1. 
DATA/DOCUMENTS ........................................................................................................................... 45 

 
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25.2. 
DATA MANAGEMENT......................................................................................................................... 45 
25.3. 
RETENTION OF RECORDS .................................................................................................................. 46 
26. 
PRIVACY OF PERSONAL DATA ..................................................................................... 46 
27. 
REFERENCES .................................................................................................................. 47 
28. 
APPENDICES ................................................................................................................... 53 
28.1. 
APPENDIX A: ECOG PERFORMANCE STATUS ................................................................................ 53 
28.2. 
APPENDIX B: COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS   (CTCAE) ....................... 54 
28.3. 
APPENDIX C: QUESTIONNAIRE-QOL .............................................................................................. 55 
28.4. 
APPENDIX D: QUESTIONNAIRE- CIRS ............................................................................................ 56 
28.5. 
APPENDIX E: IPSS AND REVISED IPSS ......................................................................................... 57 
28.6. 
APPENDIX F: EASL CRITERIA FOR CHRONIC HEPATITIS EASL 2017 CLINICAL PRACTICE ............... 58 
28.7. 
APPENDIX G: TRANSFERRIN SATURATION CALCULATION ................................................................. 59 
28.8. 
APPENDIX H: SAMPLING, CONSERVATION AND SHIPMENT MODALITY FOR CENTRALIZED TESTS .......... 60 
28.9. 
APPENDIX I: IMAGE ACQUISITION GUIDELINES FOR LIVER/SPLEEN/PANCREAS MRI ............................ 61 
 
 
 

 
FISM_ IRON-MDS, version n.2.1, date 22.04.2020. 
 
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3. INVESTIGATOR AGREEMENT 
 
I have read this protocol and agree that it contains all necessary details for carrying out this study. I 
will conduct the study as outlined herein and will complete the study within the time designated. 
I will provide copies of the protocol and all pertinent information to all individuals responsible to me 
who assist in the conduct of this study. I will discuss this material with them to ensure that they are 
fully informed regarding the study drug and the conduct of the study. 
 
______________________________________________ 
Investigator’s Signature 
Date 
 
_  
Name of Investigator (Typed or Printed) 
 
______________________________________________ 
Institution, Address* 
 
______________________________________________ 
Phone Number* 
 
Investigator-Sponsor Signature* 
Date 
(where required) 
_______________________________________________ 
Name of Coordinating Investigator (Typed or Printed) 
 
________________________________________________ 
Institution 
 
 
 
* If the address or phone number of the investigator changes during the course of the study, 
written notification will be provided by the investigator to the sponsor and will not require protocol 
amendment(s). 
 
 
 
 
 
 

 
FISM_ IRON-MDS, version n.2.1, date 22.04.2020. 
 
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4. SYNOPSIS 
Study ID 
FISM_IRON – MDS 
Eudract N° 
2018-003542-17 
Title of the study 
Early and low dose Deferasirox (3.5 mg/kg FCT) to suppress NTBI 
and LPI as early intervention to prevent tissue iron overload in lower 
risk MDS. 
Phase of the study 
II 
Investigational 
product 
DEFERASIROX FCT 
Protocol version 
2 
Centers 
About 12 Italian Hematology centers 
 
Objective 
Endpoint 
Primary Objective and 
endpoints 
Balance iron burden in one-year 
treatment 
in 
early 
phase 
of 
transfusion requirement by low 
dose 
(3.5 
mg/kg) 
DFX-FCT 
(prevention of iron overload) as 
demonstrated by hepatic iron 
concentration. 
 
Change of hepatic iron from the 
baseline according to baseline 
hepatic iron level: 
For patients with baseline  LIC ≤ 5 
mg/g dry weight (dw) ± 1.5 mg/g 
dw. 
For patients with baseline LIC >5 
mg/g dw ±20% as demonstrated 
by R2- MRI (test performed in a 
1.5 tesla 
MRI machine 
and 
analyzed following R2 method –
Baseline versus EOS.  
 
The 
corresponding 
secondary 
efficacy 
variable 
will 
be 
the 
absolute change in hepatic iron 
concentration 
EOS 
versus 
baseline. 
 
Secondary Objectives 
Objectives 
Secondary Endpoints 
Descriptive-
observational objective  
 
Definition 
of 
iron 
overload 
(including serological markers and 
MRI definition of iron loading in 
liver, tissue reactive iron species 
and oxidative stress in MDS at 
beginning of transfusional history.  
Absolute values of serum ferritin, 
transferrin saturation, NTBI, LPI, 
liver MRI and oxidative stress at 
baseline.  
 
Efficacy 
Absolute change in hepatic iron 
concentration 
EOS 
versus 
baseline. 
 
 
On year evolution of iron overload 
serologic markers  
 
Absolute and relative changes in 
serum 
ferritin 
and 
transferrin 
saturation from baseline to every 
visit during the whole treatment 
period. 

 
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9
 
Presence 
and 
quantitative 
evolution of toxic serum iron forms 
(iron 
tissue 
reactive 
species) 
under low dose DFX therapy.  
 
Proportion of patients with NTBI > 
normal values and/or LPI > normal 
values at end of study vs baseline. 
Changes in NTBI and LPI from 
baseline to every visit during the 
whole treatment period. 
 
Verify if regular suppression of the 
“free 
iron 
forms” 
prevent 
accumulation of tissue iron.  
Relationship between NTBI and 
LPI with serum ferritin and liver 
and pancreas iron overload (MRI) 
at end of study versus baseline  
 
Evaluate the overall safety of 
deferasirox FCT formulation in 
patients with lower risk MDS at the 
beginning of their transfusional 
history  
 
Overall safety, as measured by 
frequency and severity of reported 
AEs and SAEs and changes in 
laboratory values from baseline: 
serum 
creatinine, 
creatinine 
clearance ALT, AST, complete 
blood count (platelets, RBC and 
WBC) and total direct and indirect 
bilirubin).  
 
Leukemic 
transformation 
(including progression to leukemia 
or higher rIPSS scores) 
 
Proportion of patients with a 
disease progression (progression 
defined as a transition into a 
higher MDS risk group based on 
revised 
IPSS 
scoring 
or 
progression to AML) 
Time to progression (defined as 
above) 
or 
to 
leukemia 
transformation. 
 
Hemopoietic response 
Percentage 
of 
patients 
with 
hematologic improvements in term 
of erythroid response following 
IWG 2006 criteria.  
 
Time 
to 
reach 
transfusion 
dependence defined as > 2 PRBC 
units/months for 3 months for 
patients with pre-transfusional Hb 
< 9.0 g/dl (or <10 g/dl for patients 
with cardiac disease) or a total 
number of PRBC units received = 
20 from baseline. 
 
Absolute reticulocytes count from 
baseline to every visit during the 
whole treatment period. 
 
Absolute values and evolution of 
serum 
transferrin 
receptor, 
GDF11, 
GDF15 
and 
erythroferrone from baseline to 
every visit during the whole 
treatment period. 
 
Evaluation of transfusional ratio: 
number of units received in a 

 
FISM_ IRON-MDS, version n.2.1, date 22.04.2020. 
 
10 
predetermined period/ mean pre-
transfusional Hb level. Compared 
with other studies on general 
population 
(study 
and 
FISiM 
registry). 
Patients 
receiving 
concurrent 
rHuEpo 
and 
other 
disease 
modifying agents will not be 
considered 
for 
hemopoietic 
response. 
 
Costs analysis 
Cost and outcome with low dose in 
early 
chelation 
vs. 
chelation 
treatment in MDS patients with 
transfusional iron overload in 
accordance with either local or 
international guidelines 
 
Exploratory 
Study 
of 
biological 
cellular 
damage by iron toxicity before and 
during treatment     
 
MDA values during the study and 
relationship to NTBI and LPI 
values 
Study design 
• 
This is an open-label, single arm, phase II, study designed to look 
whether early intervention with low dose DFX improves clinical 
outcome of patients with MDS. 
• 
Efficacy of early - low dose DFX FCT to prevent iron accumulation 
regularly suppressing reactive oxygen species.  
• 
Safety of early low dose DFX FCT.  
• 
Exploratory: possibility to guide chelation therapy by NTBI/LPI. 
• 
One arm  
• 
Fixed dose 
• 
Blinding:  Open  
• 
Structure: Single Group  
• 
Randomized:  Non-randomized 
• 
A standard pre-transfusion Hemoglobin level will be indicated (Hb 
threshold for transfusion Hb 9 g/dl or 10 g/dl for patients with 
cardiac disease) to be maintained during the study year. Pre 
transfusion hemoglobin level and transfusions date and 
frequencies will be recorded. A transfusional ratio will be 
determined: number of units received in a predetermined period/ 
mean pre-transfusion Hb level 
Duration of the study 
Enrolment 1 year. Per protocol treatment: 1 year. Total duration 2 years 
Number of patients 
60 (50 + 10 for 20% drop out rate) 
Population 
Adult MDS patients (≥18 years). Very low, low and intermediate risk 
group by revised-IPSS. Regularly transfused patients with low PRBC 
transfusion burden (less than 2 units/months for 3 consecutive months) 
at beginning of their transfusion story (total number of PRBC units 
received 5-20). Patients should not meet the published criteria for 
transfusion dependency (2 PRBC units /month for three consecutive 
months). 
Inclusion criteria 
Study population:  
• 
Diagnosis: Adult Myelodysplastic Syndrome (≥18 years). 
• 
Revised IPSS: very low. low – intermediate. 

 
FISM_ IRON-MDS, version n.2.1, date 22.04.2020. 
 
11 
• 
Having received 5-20 packed red blood cell units 
• 
Serum ferritin 300 ng/ml 
• 
Transferrin saturation 60%  
• 
Chelation naïve 
• 
Capability to provide informed consent 
 
Exclusion criteria 
 
• 
Patients aged <18 years old 
• 
Higher risk (revised IPSS) MDS (Intermediate 2, high) 
• 
Cumulative transfusion story of > 20 packed red cell units 
• 
Creatinine Clearance (CrCL):  <60 ml/min. Patients with CrCl of 
40-60ml/min will be included only individually if no other renal risk 
factors are present.  
• 
Serum creatinine >2 x ULN at screening.  If borderline serum 
creatinine will be measured within 7-10 days and the mean value 
will be used for eligibility criteria. 
• 
Significant proteinuria as indicated by a urinary protein/creatinine 
ratio > 0.5 mg/mg in a non-first void urine sample (or alternatively 
in two of three samples obtained for screening). 
• 
ECOG performance status >2. 
• 
Left ventricular ejection fraction < 50% by echocardiography  
• 
A history of repeated hospitalization for congestive heart failure.  
• 
Systemic diseases that would prevent study treatment (e.g. 
uncontrolled hypertension, cardiovascular, renal, hepatic, 
metabolic, etc.) 
• 
Clinical or laboratory evidence of chronic Hepatitis B or Hepatitis 
C (definition of chronic hepatitis follows EASL 2017 criteria).   
• 
History of HIV positive test result (ELISA or Western blot).  
• 
Treatment with systemic investigational drug within 4 weeks or 
topical investigational drug within 7 days of study start. 
• 
ALT or AST over 3 times superior to ULN at screening. 
• 
ANC < 500/ microL  
• 
Platelets transfusion dependency  
• 
Total bilirubin over 1.5 times superior to ULN at screening 
(patients with Gilbert syndrome are allowed to enter the study) 
• 
Diagnosis of Child score C liver cirrhosis.  
• 
Patients participating in another clinical trial other than an 
observational registry study.  
• 
Patients with a history of another malignancy within the past 3 
years, with the exception of basal skin carcinoma or cervical 
carcinoma in situ or completely resected colonic polyps 
carcinoma in situ.  
• 
History of non-compliance to medical regimens, or patients who 
are considered potentially unreliable and/or not cooperative. 
• 
Presence of a surgical or medical condition which might 
significantly alter the absorption, distribution, metabolism or 
excretion of study drug.  
• 
Pregnant, intending-to-become pregnant, or breast-feeding 
patients.  
• 
Women of potential maternity age who do not agree to practice 
effective contraceptive methods for the entire study duration. 
• 
History of drug or alcohol abuse within the 12 months prior to 
enrollment. 

 
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12 
• 
Hypersensitivity to the active substance or to any of the 
excipients. 
• 
Inability to provide a valid informed consent. 
Study treatment and 
response criteria 
DFX FCT 3.5 mg/kg. 
Response criteria: prevention of iron overload as measured by liver iron 
concentration (MRI). 
Assessments 
schedule  
MONTHLY 
Centralized analyses 
TEST 
REQUIRED 
QUANTITY 
NTBI, LPI, Epcidine, MDA 
YES see schedule 
7 
Serum transferrin receptor, 
GDF11 e 15, Erythroferrone. 
YES  see schedule 
5 
NGS 
(molecular 
tumor 
analysis) 
YES see schedule 
2 
MRI liver scan 
YES 
Baseline 
and 
EOS 
2 
Statistical 
considerations 
 
 
 
 
 
 
 
 
 
 
 
Including 50 subjects in the study, we can reach almost 60% power to 
detect small effect size 0.30 (with p-value of 0.05) whereas, we have 
almost 100% to detect moderate effect size of 0.50 (with p-value of 
0.05). 
On the basis of previous experience, the low dosage, the early 
intervention and the FCT preparation a 20% drop out rate is expected 
(10 additional patients to be enrolled) 
 
Methods: The power test was performed by G power 3.1 software by 
using the t test Means: Difference between two dependent means 
(matched pairs). 
 
As demonstrated by pour sample size analyses, we have enough power 
to detect an effect size between 0.3 and 0.5 considering a potential error 
of 0.05 which is largely accepted from scientific community. 
 
 
 
 
 
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30
40
50
60
70
80
90
100
0
0.2
0.4
0.6
0.8
1
Power (1-β err prob)
 = 0.3
 = 0.5
Effect size dz
t tests -  Means: Dif erence between two dependent means (matched pairs)
Tail(s) =  Two. α err prob =  0.05
Total sample size

 
FISM_ IRON-MDS, version n.2.1, date 22.04.2020. 
 
13 
5. LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS 
 
ABBREVIATION 
TERM 
AE 
Adverse Event 
ALT (SGPT) 
ALanine Transaminase (Serum Glutamic Pyruvic Transaminase) 
AP 
AST (SGOT) 
Activity population 
ASpartate Transaminase (Serum Glutamic Oxaloacetic Transaminase) 
β-HCG 
beta-Human Chorionic Gonadotropin 
BSA 
Body Surface Area 
CBC 
Complete Blood Cell 
CNS 
Central Nervous System 
CR 
Complete Response 
CRF 
Case Report Form 
CTCAE 
Common Terminology Criteria for Adverse Events 
DNA 
Deoxyribonucleic acid 
DSMC 
Data Safety Monitoring Committee 
EASL 
ECG 
European Association for Study of the Liver 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EOR 
End of treatment Response 
EP 
ERC 
Efficacy population 
Ethics Review Committee 
FCBP 
Female of Child Bearing Potential 
FISiM-ETS 
Fondazione Italiana Sindromi Mielodisplastiche-ETS 
FPFV 
First Patient First Visit  
GCP 
Good Clinical Practice 
GDF15 
HBV 
Growth Differentiation Factor15 
Hepatitis B Virus 
HCV 
Hepatitis C Virus 
HIV 
Human Immunodeficiency Virus 
ICH 
International Conference on Harmonization 
IMP 
Investigational Medicine Product 
IP 
Investigational Product 
ITT 
Intention To Treat  
IV 
Intra Venous 
LCI 
LDH 
Labile Cellular Iron 
Lactic DeHydrogenase 
LIC 
LPFV 
Liver iron concentration 
Last patient Fist Visit 
LPI 
LVEF 
Labile Plasma Iron 
Left Ventricular Ejection Fraction 
MDA 
MRI 
Malonildialdehyde  
Magnetic Resonance Imaging 
NGS 
NTBI 
ORR 
New Gereration Sequencing 
Non Transferrin Bound Iron 
Overall Response Rate 
OS 
Overall Survival 
PCR 
Polymerase Chain Reaction 
PD 
Progressive Disease 
PFS 
Progression Free Survival 
PK 
PharmacoKinetics 
PR 
Partial Response 
PS 
Performance Status 
SAE 
Serious Adverse Event 

 
FISM_ IRON-MDS, version n.2.1, date 22.04.2020. 
 
14 
SD 
Stable Disease 
SP 
SUSAR 
Safety population 
Suspected Unexpected Serious Adverse Reaction 
Tsat 
ULN 
Transferrin Saturation 
Upper Limit of Normal 
WHO 
World Health Organization 
 
 
 
 
 
 
 
 
 
 

 
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15 
6. STUDY FLOW CHART 
 
 
 

 
 
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7. INTRODUCTION. AIM OF THE STUDY 
 
Iron chelation therapy in MDS patients receiving transfusion therapy has been developed on the 
basis of the large experience in transfusion dependent Thalassemia. However Thalassemia is a 
different clinical scenario compared to MDS for several different reasons. This study protocol has 
been developed to focus the specific setting of elderly MDS patients, inside the registered 
indications. This protocol has been designed to look whether early intervention with low dose DFX 
improves clinical outcome of patients with MDS. 
 
 
 
 
8.  BACKGROUND 
 
8.1. Disease background 
Myelodysplastic syndromes (MDS) are a wide range of syndromes involving the hemopoietic stem 
cells and clinically expressing with peripheral cytopenias in different forms. Cytopenias mainly 
involve the erythropoietic line and has the clinical picture of anaemia. The clinical course of untreated 
MDS is characterized by worsening of the clinical picture and by a variable risk of developing 
secondary acute leukaemia (range from few months to several years). MDS patients are classified 
following the International Prognostic Scoring System (IPSS)(1) developed in 1997 by Peter 
Greenberg and revised in 2012 (rIPSS)(2) predicting leukaemia free survival and overall survival.  
 
 
MDS and iron overload 
 
Most of the MDS patients require regular packed red blood cells (PRBC) transfusions and finally 
most of them became transfusion dependent. One of the unavoidable consequences of anaemia 
and of transfusion requirement is iron overload which has been proved to be deleterious for different 
categories of patients including MDS patients (3–7).  
Little is known on anaemia contribution to iron overload/toxicity in the specific setting of MDS but a 
worsening impact is likely(8). 
 
Iron overload and iron toxicity in MDS 
 
Iron related tissue and organ damage (and finally mortality) has been, so far, mainly related to what 
has been developed in the field of children, adolescent and young adults with thalassemia major(9). 
Nevertheless some papers(5,10–16) and a meta-analyses(17) have related MDS patients survival 
to serum ferritin level which is a very well known but a-specific marker of iron overload 
 
Tissue and organ damage has been directly and strictly connected to the amount of tissue iron 
deposition (i.e. a “bulky” disease). In other words, tissue/organ damage was directly related and 
dependent to the amount of metal accumulation. All the studies performed in the last years (again 
mainly in transfusion dependent thalassemia) linked survival to markers of iron accumulation 
(indirect markers as serum ferritin and cardiac and liver MRI or direct markers as liver iron 
concentration in biopsy specimens).  
 
New concept of iron toxicity 
 
There are two major limitations to this interpretation: 
 

 
 
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17 
1. The clinical scenario of elderly MDS patients is different from the “pivotal” situation of 
thalassemia major because of age (including tissue reparative mechanisms), comorbidities 
and underlying disease(18,19). 
2. Recent data support the concept that iron disease is not only a “bulky” disease exclusively 
secondary to iron accumulation but rather a toxic disease in which tissue damage is due to 
toxic iron forms (tissue reactive iron i.e. NTBI, LPI etc.) present in plasma since early phase 
of transfusion therapy or even before (20,21).  
 
 
Particularly this second point require detailed explanation:  
Tissue iron toxicity is today expressed by the following formula developed by Thomas Coates 
(22) 
 
 
Fe Toxicity = 
Σtissue reactive iron X genetics X environmental factors X Δ time 
 
Where: 
Σ tissue reactive iron  
= tissue toxicity sums (Σ), ROS generation 
Genetics  
= The marrow pathology, differences in iron transport, antioxidant 
defense mechanisms 
Environmental factors = nutritional status, blood transfusions, drugs that may modulate iron 
toxicity, comorbidities (i.e. viral infections, ecc), Administration of 
chelating agents 
Δ time  
 
 
= time of exposition 
 
 
It is clear from this formula that:  
a) Duration of exposure to tissue reactive iron is the key point to predict the severity of target 
tissues damage  
b) Classic biomarkers of iron overload (serum ferritin, MRI etc.) can be interpreted as 
biomarkers of duration of exposure. 
c) 
Tissue damage starts much sooner than iron accumulation becomes evident, as 
demonstrated by standard parameters like MRI and serum ferritin(21,23,24). 
d) Environmental factors and individual genetics are a substantial difference between 
individuals and diseases (between young patients with hemoglobinopathies and elderly lower 
risk MDS patients). 
 
It has been widely demonstrated that toxic free iron species (NTBI and LPI) appear in the serum 
only once iron binding capacity is saturated in a rate over 60-70%(25–27). Notably these iron 
fractions are chelatable and can be removed from circulation by a chelator (28). 
 
Classical approach to chelation therapy in MDS (29,30) is today overtaken by above reported 
new model. Even the conventional safety issue of minimal serum ferritin level is outdated even in 
the delicate category of children with thalassemia major (31,32). In the phase II KALLISTO trial 
no significant or unexpected Deferasirox side effects were reported in a population of un-
transfused lower risk MDS patients (33). 
 
 
 
8.2. Mechanism of iron accumulation and cellular iron damage 
 

 
 
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Cellular iron influx and accumulation is caused, in a controlled way, by uptake of transferrin-iron by 
transferrin receptors in cells expressing on the membrane transferrin receptors (mainly liver) 
(22,27,34,35). In addition, non-transferrin-bound-iron (NTBI) (36) and Labile Plasma Iron (LPI), a 
directly chelatable form of NTBI, are readily taken up by cells, by an uncontrolled mechanism through 
calcium channels, leading to expansion of the labile cellular iron pool (LIP) (28,37,38). This 
mechanism is the only one in tissue/cells lacking or with minimal transferrin receptor expression 
(heart, pancreas).  
 
The liver is the main site of iron storage and accumulation(27). In transfusion dependent thalassemia 
it has been demonstrated that hepatic iron concentration is proportional to whole body iron stores 
up to a hepatic iron concentration of 25 mg/g dry weight in absence of cirrhosis. The total body iron 
store (mg/kg) can be calculated multiplying hepatic iron concentration (mg/g dry weight) x 10.6 with 
a standard error of ±7.3(39).   
 
In physiologic situation there is a delicate intracellular balance between iron functional and storage 
pool maintaining Labile Iron Pool  levels within a  0.5–1.5 μM physiological range by an  iron-sensing-
transducing machinery that coordinately regulates uptake vs storage so as to support Fe utilization 
and minimize Fe-O-driven oxidations . 
 
Uncontrolled cellular iron uptake leads to increment of cellular labile iron pool.  An excessive rise in 
LPI can promote the generation of reactive Oxygen species (ROS) by reacting with respiratory 
Oxygen intermediates and thereby override the cellular antioxidant defences and chemically damage 
cell components and associated functions (40). This mechanism has as final effect, throughout a 
complex biochemical cascade of cellular damage and apoptosis(41,42). 
 
Prevention of accumulation means therefore regular suppression of reactive oxygen species and 
consequent tissue damage prevention.  
 
Subsequently a rational approach to iron chelation therapy is to use a chelator at the minimum 
efficient dose able to completely and persistently suppress tissue reactive iron species to avoid 
tissue damage and prevent iron accumulation (43).  
 
This approach is theoretically very important in MDS patients because of the major sensitivity of 
several tissues (including vascular) due to aging, comorbidities and absence or deficiency of tissue 
reparative mechanism (44,45). A study on the specific pathogenic role of LPI in MDS is ongoing (20). 
 
In the setting of hemopoietic stem cells, experimental data demonstrates a detrimental effect of  
reactive oxygen species on hemopoietic stem cell maturation and self-renewal capability (46–49). 
Clinical data are in accordance with these experimental data (50–54). Moreover a debate is on-going 
on the possible role of iron related reactive oxygen species in accelerating (favoring) MDS 
progression to acute leukemia (55). 
 
Consistent reports of improvement of hemopoieisis in transfusion dependent MDS patients receiving 
iron chelation (51,55–57) are in accordance with removal by chelation of toxic factors compromising 
hemopoieisis, more that the disease itself.  
 
Laboratory definition of tissue reactive iron has been a challenge for several years (36) and is today 
possible with a standardization on-going (25); however it has been clearly demonstrated that toxic 
free iron form emerge in plasma only once serum transferrin is saturated over 60-70% (22,25). 
 

 
 
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8.3. Current therapies for iron overload in lower risk MDS  
Iron chelation therapy by deferasirox has been approved for low and intermediate-1 IPSS patients 
worldwide and its clinical benefit has been uniformly proved by several retrospective studies, 
prospective case control, registry and prospective (58) not randomized clinical studies. A recent 
meta-analysis confirmed the clinical value of iron chelation for lower risk MDS patients(59). A large, 
confirmatory Canadian prospective registry study (60) has been published after the meta-analysis 
publication    The prospective, randomized placebo control study is expected to provide definite 
information by the end of 2018  (ClinicalTrials.gov Identifier: NCT00940602). 
 
Almost all the scientific societies published guidelines and regulatory agencies have indicated 
/approved chelation therapy in MDS after that a condition of chronic post transfusional iron overload 
has been achieved. Treatment is therefore determined by iron accumulation that is considered a 
mandatory prerequisite for iron toxicity (and not by iron toxicity per se). With minor variations, 
threshold for starting iron chelation has been identified adopting that in place for transfusion 
dependent thalassemia even though levels of accumulation historically associated with organ 
damage (based on data generated in the Thalassemias) are infrequent in MDS: 20 units of packed 
red blood cells and/or in a serum ferritin level of 1000 ng/ml (29,30) even if in real world clinical 
practice a higher threshold is common. 
 
On the same basis indication to lower risk IPSS categories has been established on the idea that 
higher risk MDS patients live not enough to let dangerous iron accumulation (61). 
 
Deferasirox has been proved to suppress toxic – redox active iron species even if the minimum 
necessary dose has not been explored (56,62,63). 
 
Another iron chelator is actually approved worldwide for iron chelation in MDS: Deferoxamine, 
Desferal®. Deferoxamine modality of administration and half-life are not appropriate to patients with 
MDS. Another thalassemia licensed oral iron chelator  (Deferiprone, Ferriprox®) is not approved in 
EU and US for MDS patients and limited MDS-literature is available (64). 
8.4. Study drug (Mechanism of Action, Absorption, Distribution, Metabolism and 
Excretion) 
 
Deferasirox (ICL670, Exjade®) is an N-substituted bis-hydroxyphenyl-triazole, a representative of a 
new class of tridentate iron chelators (65) that has been developed by Novartis for treating 
transfusional iron overload. Two molecules of Deferasirox form a complete complex with Fe3+. The 
high potency of deferasirox in mobilizing tissue iron and promoting iron excretion was demonstrated 
both in vitro and in vivo model systems (65). Deferasirox is eliminated from the body by hepatic 
glucuronidation and biliary excretion.  
Preclinical studies also revealed that deferasirox did not affect fertility and it is neither teratogen nor 
carcinogenic. 
To date, deferasirox has been approved in more than 100 countries, including the European Union, 
the USA, Switzerland, and Japan for the treatment of chronic iron overload due to blood transfusions 
in adult and pediatric patients. Within this indication, deferasirox is approved for use in transfusion-
dependent MDS patients, based on data demonstrating efficacy in reducing hepatic iron 
concentration and serum ferritin. 
Detailed information on preclinical and clinical evaluation of deferasirox is provided in the SmPC. 
Deferasirox was first released as a dispersible tablet (DT) for oral suspension which facilitates 
administration of the appropriate quantity of drug substance to pediatric and adult patients. 
Bioavailability studies with deferasirox dispersible tablets indicated that absorption is increased 
with food, and this is dependent on the fat content and the timing of food intake. Deferasirox 
dispersible tablet was taken on an empty stomach at least 30 minutes prior to food in clinical 
studies; this is also the recommendation in the label. 

 
 
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Deferasirox has demonstrated acceptable safety and tolerability in adult and pediatric patients with 
transfusional iron overload (51,66,67). The most frequent reactions reported during the first year of 
treatment with deferasirox in adult and pediatric patients included gastrointestinal (GI) disturbances 
in about 26% of patients (mainly nausea, vomiting, diarrhea, or abdominal pain), and skin rash in 
about 7% of patients. These reactions were dose-dependent, mostly mild to moderate, generally 
transient and mostly resolved even if treatment was continued. In addition, there have been rare 
reports of upper GI hemorrhage and/or ulceration in patients receiving deferasirox.  
There have been very occasional post-marketing reports of erythema multiforme, leukocytoclastic 
vasculitis and hypersensitivity reactions (including anaphylaxis and angioedema). Alopecia, usually 
comprising thinning of the hair, has been occasionally reported in patients receiving deferasirox. 
Mild, non-progressive increases in serum creatinine, mostly within the normal range, occurred in 
about 36% of patients during the first year of treatment. These were dose-dependent, often resolved 
spontaneously and were sometimes alleviated by reducing the dose. Rare cases of acute renal 
failure, defined as a serum creatinine increases ≥ 2 ULN, and usually reversible after treatment 
interruption (and rarely a brief course of hemodialysis), have been reported following the prescription 
use of deferasirox. 
Elevations of liver transaminases were reported as an adverse reaction in about 2% of patients. 
These were not dose-dependent and most of these patients had elevated levels prior to receiving 
deferasirox. Elevations of transaminases >10 ULN were uncommon (0.3%). There have been post-
marketing reports of hepatic failure, mostly in patients with severe baseline liver disease. 
There have been reports of cytopenias, mostly in patients with pre-existing blood disorders which 
are frequently associated with failure of the bone marrow to produce sufficient amounts of blood 
cells. 
High frequency hearing loss and lenticular opacities (early cataracts) have been uncommonly 
observed in patients treated with deferasirox. As with other iron chelator treatment, the risk of toxicity 
of deferasirox may be increased when inappropriately very high doses are given in patients with a 
low iron burden or with serum ferritin levels that are only slightly elevated. Recent data do not confirm 
these ocular and hearing toxicity in adults (68). 
 
In summary, deferasirox is a once-daily oral iron chelator that has been developed for treating 
transfusional iron overload, with demonstrated efficacy in the reduction or maintenance of body iron 
stores, and an acceptable safety profile. 
 
Recently Deferasirox film coated tables (DFX FCT) has been released (69) and is progressively 
substituting the water dispersible tables. 
Deferasirox FCT can be taken in a single step: swallowed whole with water or other beverages, 
either on an empty stomach or with a light meal (<7% fat and ~250 calories) (69). Deferasirox DT, 
in contrast, requires administration on an empty stomach at least 30 minutes prior to a meal (69).  
When taken with a low-fat meal, there is a modest effect on the bioavailability and maximum plasma 
concentration of deferasirox FCT (reductions of 11% and 16%, respectively) (69).   
Unlike deferasirox DT, deferasirox FCT does not contain lactose or sodium lauryl sulfate; this aspect 
may result in fewer GI side effects with deferasirox FCT compared with deferasirox DT (70). Like 
deferasirox DT, it is preferable to administer deferasirox FCT at the same time each day. 
It is important to note that the dose for deferasirox FCT is approximately 30% lower, rounded to the 
nearest whole tablet, because the bioavailability of deferasirox FCT is higher than that of deferasirox 
DT. Deferasirox FCT is available in 90, 180, and 360 mg tablets. Deferasirox FCT may be crushed 
and mixed with soft foods, such as yogurt or apple sauce (69).   
A recently published Phase II study (71) compared deferasirox DT with deferasirox FCT in patients 
with TDT or MDS (very low, low, or intermediate risk) who had iron overload and required deferasirox 

 
 
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21 
DT (≥30 mg/kg/day for those with TDT or ≥20 mg/kg/day for those with MDS). Safety, GI side effects, 
palatability, satisfaction, and compliance were also assessed. The results of this study showed that 
the FCT formulation of deferasirox was well tolerated. In patients with prior deferasirox DT exposure, 
fewer GI AEs were seen with deferasirox FCT than with deferasirox DT. Compliance of patients 
receiving deferasirox FCT was enhanced, and these patients continued on treatment for longer 
times. More patients were satisfied with the new deferasirox FCT formulation than with the 
deferasirox DT formulation at all visits. Patient-reported outcomes were also improved with 
deferasirox FCT compared with deferasirox DT (71).   
Deferasirox film coated tables (DFX-FCT) is the study drug of this study. 
8.5. Complete and on-going clinical experiences with study drug 
Deferasirox is registered for the treatment of adult and pediatric patients with chronic transfusional 
iron overload. 
 
Thousands of pediatric and adult patients aged 2 to 80 years were enrolled in randomized controlled 
trials evaluating the safety and efficacy of deferasirox in the treatment of transfusional iron overload. 
Thousands of patients have received deferasirox in prospective studies and on clinical indication 
since its release. More than 1500 MDS patients have been included in clinical studies, which 
included iron chelation with DFX.   The studies showed deferasirox to effectively chelate iron in 
patients with transfusional iron overload as demonstrated by decreases of hepatic iron concentration 
and serum ferritin (51,66,67,72,73). 
 
The efficiency of deferasirox DT in chelating iron appears to be constant at all doses ranging from 5 
to 40 mg/kg/day (3.5 to 28 mg/kg/day for the FCT formulation) and is not affected by age, gender, 
baseline LIC or underlying anemia (69). 
 
Deferasirox film coated table (DFX-FCT) has been recently registered for showing an improved  
safety profile particularly regarding gastro-intestinal side effect (71). 
 
 
9. STUDY RATIONALE 
 
The scientific rationale for this study is the evolving understanding that iron-induced tissue damage 
is not only a process of progressive bulking of organs through high-volumes iron deposition, but also 
a reactive iron species related “toxic” damage. 
Iron mediated damage can occur prior reaching high iron storage thresholds derived from 
thalassemia major setting, free toxic iron species being already present when transferrin saturation 
>60-70% (25); therefore a timely early adoption of iron chelation may be of benefit before overt iron 
overload is seen. 
 
Our hypothesis is that early and low dose DFX-FCT is better tolerated and is able to prevent iron 
accumulation and consequently tissue iron related damage, by consistently suppressing iron 
reactive oxygen species (NTBI and LPI). 
 
If this hypothesis is confirmed this approach could contribute to an improvement of clinical practice 
of patients managements. Additionally this approach might also be a contribute in preventing future 
iron overloaded related complication, in this already frail and co-treated patient population. 
 
 
 

 
 
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10. STUDY OBJECTIVES 
10.1. 
Primary objective 
Balance iron burden in one-year treatment in early phase of transfusion requirement by low dose 
(3.5 mg/kg) DFX-FCT (prevention of iron overload) as demonstrated by MRI (R2) documented 
hepatic iron concentration. 
10.2. 
Secondary objectives  
• 
Descriptive –observational objective: Definition of iron overload (including serological markers 
and MRI definition of iron loading in different tissues: liver, pancreas), tissue reactive iron 
species and oxidative stress in MDS at beginning of transfusional history (descriptive, 
observational). 
• 
On year evolution of iron overload serologic markers  
• 
Presence and quantitative evolution of toxic serum iron forms (iron tissue reactive species) 
under low dose DFX therapy.  
• 
Verify if regular suppression of the “free iron forms” prevent accumulation of tissue iron.  
• 
Evaluate the overall safety of deferasirox FCT formulation in patients with lower risk MDS at 
the beginning of their transfusional history  
• 
Leukemic transformation (progression to leukemia or higher rIPSS scores) 
• 
Hemopoietic response 
• 
Costs analysis 
10.3. 
Exploratory  
 
Study of biological cellular damage by iron toxicity before and during treatment     
 
11. STUDY DESIGN 
11.1. 
Overview of study design 
This is an open label, single arm, phase II, study. 
The study includes a screening period (in which patients eligibility will be assessed) followed by a 1-
year treatment period during which monthly visits will take place to evaluate safety and efficacy 
parameters (total 16 visits + 1 screening visit). 
Study treatment with low dose (3.5 mg/kg/day) DFX-FCT will be given to all enrolled patients at the 
beginning of their transfusional history 
 
Dose activity will be monitored by regular NTBI /LPI suppression and by prevention of iron 
accumulation as demonstrated by hepatic iron concentration, comparing baseline versus end of 
study iron concentration. It has been clearly demonstrated that liver iron concentration is proportional 
to total body iron stores ( LIC x 10.6 = total body iron store in mg/kg)(39)  
 
A standard pre-transfusional Hemoglobin level will be indicated (Hb threshold for transfusion Hb 9 
g/dl or 10 g/dl for patients with cardiac disease) to be maintained during the study year. Pre 
transfusional hemoglobin level and transfusions date and frequencies will be recorded. A 
transfusional ratio will be determined: number of units received in a predetermined period/ mean pre-
transfusional Hb level 
 
 

 
 
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11.2. 
Number of patients 
A total of 60 patients will be enrolled in the study:  50 +10 for a planned 20% drop out rate (drop our 
rate estimated on others DFX DT – MDS prospective studies).   
11.3. 
Duration of the study 
Patients will be recruited over 12 months and followed for 1 year treatment phase.  
The anticipated study dates (start / end) are:  
 
− 
Total accrual period (months/years):12 months 
− 
The duration of the treatment period is 12 months 
− 
End of the study: last patient last visit. 
− 
The Final Study Report will be provided after the end of the Study. 
 
12. STUDY POPULATION 
12.1. 
Inclusion criteria 
• 
Diagnosis: adult Myelodysplastic Syndrome (=> 18 years). 
• 
Revised IPSS: very low. low – intermediate. 
• 
Having received 5-20 packed red blood cell units 
• 
Serum ferritin >300 ng/ml 
• 
Transferrin saturation >60%  
• 
Chelation naïve 
• 
Ability to provide informed consent. 
12.2. 
Exclusion criteria  
• 
Patients aged <18 years old 
• 
Higher risk MDS (Intermediate 2, high) 
• 
Cumulative transfusional history of > 20 packed red cell units 
• 
To be definitely  classified as transfusion depended following published criteria (74) ( having 
received 2 packed red cell units /months for three consecutive months) 
• 
Creatinine Clearance (CrCL):  <60 ml/min. Patients with CrCl of 40-60ml/min will be included 
only individually if no other renal risk factors are present.  
• 
Serum creatinine >2 x ULN at screening.  
• 
Serum creatinine will be measured at screening (repeatable)  
• 
Significant proteinuria as indicated by a urinary protein/creatinine ratio > 0.5 mg/mg in a non-
first void urine sample at screening (repeatable). 

 
 
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• 
ECOG performance status >2. 
• 
Left ventricular ejection fraction < 50% by echocardiography  
• 
A history of hospitalization for congestive heart failure.  
• 
Systemic diseases which would prevent study treatment (e.g. uncontrolled hypertension, 
cardiovascular, renal, hepatic, metabolic, etc.) 
• 
Clinical or laboratory evidence of active Hepatitis B or Hepatitis C (see EASL criteria).   
• 
History of HIV positive test result (ELISA or Western blot).  
• 
Treatment with systemic investigational drug within 4 weeks or topical investigational drug 
within 7 days of study start. 
• 
ANC < 500/ microL  
• 
Platelets transfusion dependency  
• 
ALT or AST >3 x ULN at screening. 
• 
Total bilirubin >1.5x ULN at screening (patients with Gilbert syndrome are allowed to enter 
the study). 
• 
Diagnosis of liver cirrhosis child score C.  
• 
Patients participating in another clinical trial other than an observational registry study.  
• 
Patients with a history of another malignancy within the past five years, with the exception of 
basal skin carcinoma or cervical carcinoma in situ or completely resected colonic polyps 
carcinoma in situ.  
• 
History of non-compliance to medical regimens, or patients who are considered potentially 
unreliable and/or not cooperative. 
• 
Presence of a surgical or medical condition which might significantly alter the absorption, 
distribution, metabolism or excretion of study drug.  
• 
Pregnant, intending-to-become pregnant, or breast-feeding patients. 
• 
Women of potential maternity age who do not agree to practice effective contraceptive 
methods for the entire study duration.  
• 
History of drug or alcohol abuse within the 12 months prior to enrollment. 
• 
Hypersensitivity to the active substance or to any of the excipients. 
• 
Inability to provide a valid informed consent. 
 
13. PATIENTS ENROLLMENT 
13.1. 
Informed consent 
The Investigator(s) must obtain informed consent of a patient or his/her designee prior to any study 
related procedures as per Good Clinical Practices (GCP). Documentation that informed consent 
occurred prior to the patient’s entry into the study and of the informed consent process should be 
recorded in the patient’s source documents. Subjects will be informed that their participation is 
voluntary and that they may withdraw consent to participate at any time. They will be informed that 
choosing not to participate will not affect the care the subject will receive for the treatment of his/her 
disease. Subjects will be told that alternative treatments are available if they refuse to take part and 
that such refusal will not prejudice future treatment. The subject or legally acceptable representative 
will be given sufficient time to read the informed consent form and the opportunity to ask questions. 
After this explanation and before the entry to the study, consent should be appropriately recorded 
by means of either the subject's or his/her legally acceptable representative's dated signature. After 
having obtained the consent, a copy of the informed consent form must be given to the subject.  
If the subject or legally acceptable representative is unable to read or write, an impartial witness 
should be present for the entire informed consent process (which includes reading and explaining 
all written information) and personally date and sign the informed consent form after the oral consent 
of the subject or legally acceptable representative is obtained. 
The original consent form signed and dated by the patient and by the person consenting the patient 
prior to the patient’s entry into the study must be maintained in the Investigator’s study folder and a 

 
 
FISM_ IRON-MDS, version n.2.1 , date 04.03.2020. 
25 
copy given to the patient. In addition, if a protocol is amended and it impacts on the content of the 
informed consent, the informed consent must be revised. Patients participating in the study when 
the amended protocol is implemented must be re-consented with the revised version of the informed 
consent. The revised consent form signed and dated by the patient and by the person consenting 
the patient must be maintained in the Investigator’s study folder and a copy given to the patient. 
13.2. 
Patient registration and data collection 
Following confirmation of eligibility and written informed consent, patients should be registered online 
in the dedicated section of CRF website. 
Each patient will be assigned a sequential patient number by the investigator. Once assigned to 
a patient, a patient number will not be reused. Subject identification numbers of patients who 
did not meet the eligibility criteria or did not start treatment will not be replaced.  
For a given patient, patient number will not be changed throughout the entire study  
 
 
14. TREATMENT 
14.1. 
Drug 1: Deferasirox FCT 
The investigational study drug used in this trial is deferasirox as film coated tablets for oral use (DFX-
FCT) 
14.1.1. Supplier(s)  
Not applicable. The study drug will be prescribed to patients as part of routine clinical 
practice within its approved indication. 
14.1.2. Preparation and administration 
Self-administration following Physician prescription. 
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. The dose 
should be immediately and completely consumed, and not stored for future use. 
 
Patient will be prescribed with an appropriate number of DFX FCT from a choice of 90 mg, 
180 mg, and 360 mg strengths, based on the patient’s weight calculated overall daily dose. 
 
14.1.3. Receipt of study drug  
NA 
14.1.4. Storage and handling 
NA 
14.1.5. Unused study drug supplies 
Patients will be instructed to take the assigned amount of drug and asked to report the exact 
drug dose assumed and any deviation.  
 
14.2. 
Treatment schedule and design 
14.2.1. Single arm (DFX-FCT 3.5 mg/kg/day) 
Having completed the screening period, patients will be assigned to a fixed dose of 3.5 
mg/kg/day of DFX FCT. 

 
 
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26 
14.3. 
Premedication 
           No need of premedication  
14.4. 
Prophylactic measures 
14.4.1. Prevention of infections 
As per clinical practice at investigator discretion. List of drug interaction is provided in the 
Summary of Product CharacteristicS (SmPC) 
 
14.4.2. Patients HBV positive 
Patients with HBV positive can enter the study only after adequate treatment on hepatologist 
or infection disease specialists. Therapy as per standard care (Indication to HBV therapy as 
per by EASL criteria 2017) (appendix F) 
14.4.3. Patients HCV positive 
Anti HCV positive, HCV RNA negative patients can be enrolled without any active measure 
14.4.4. Patients HIV positive 
Not admitted 
14.4.5. Contraception 
Non-sterilized female patients of reproductive age group and male patients should use 
effective methods of contraception through defined periods during and after study treatment 
as specified below. 
Female patients must meet 1 of the following: 
− 
Postmenopausal for at least 1 year before the screening visit, or surgically sterile, or 
− 
If they are of childbearing potential, agree to practice 2 effective methods of 
contraception from the time of signing of the informed consent form through 6 
months after the last dose of study drug (since Deferasirox can reduce the 
effectiveness of hormonal contraceptives, it is recommended that women of 
childbearing age use additional or alternative non-hormonal contraceptice methods), 
or 
− 
Agree to practice true 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.) 
 
14.5. 
Excluded/admitted concomitant medication. 
Admitted concomitant medication: as per clinical practice. Concomitant rHuEpo is admitted and 
registered (patients who receive rHuEpo during the year study will not be evaluated for erythroid 
response). No additional experimental therapy is admitted. 
A standard pre-transfusion Hemoglobin level will be indicated (Hb threshold for transfusion Hb 9 g/dl 
or 10 g/dl for patients with cardiac disease) to be maintained during the study year. Pre transfusion 
hemoglobin level and transfusions date and frequencies will be recorded.  
A transfusional ratio will be determined: number of units received in a predetermined period/ mean 
pre-transfusion Hb level. 
 

 
 
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27 
14.6. 
Toxicity  
14.6.1. Hematological and non hematological toxicity 
A summary of the safety profile of DFX-FCT is available in the approved SmPC (section 4.8 
approved label) 
 
14.7. 
 (Drug) dose modification  
A summary of the information and specials warnings and precautions for use as per clinical practice 
is available the approved SmPC section 4.4 approved label) 
 
Table 1. (Drug) dose modification  
NCI CTCAE Toxicity Grade 
ACTION REQUIRED 
Grade III-IV 
Drug deferral by PI judgment 
Serum ferritin < 300 ng/ml  
DFX deferral  
 
Table 2: Dose modification steps for patients who need DFX dose modifications 
during the study   
 
Planned dose 
Modified dose 
DFX FCT 3.5 mg/kg/day 
No dose modification allowed. 
 
14.8. 
Toxicities management  
As per approved label (Summary of Product Characteristic (SmPC)  
 
14.9. 
Rescue Medication 
This study propones low doses of well-known drug. Recent studies clearly demonstrated safety of 
Deferasirox even in patients with low ferritin level receiving standard Deferasirox doses. Criteria for 
premature protocol termination for toxicity of lack of efficacy has been above specify. No specific 
rescue medication is applicable. 
 
14.10. 
Benefit/Risk assessment 
Because of the low doses, the ability to directly measure toxic iron species and the potential to 
remove them from circulation, the protocol tries to define the minimum effective dose of iron chelating 
therapy. Therefore, the risk/benefit ratio appears clearly in favor of benefit (iron toxicity and iron 
overload prevention, drug toxicity prevention). 
 
 
 

 
 
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28 
15. REMOVAL OF SUBJECTS FROM TREATMENT AND/OR STUDY 
 
15.1. 
Discontinuation from study treatment 
 
Patients may voluntarily discontinue from the study treatment for any reason at any time. 
If a patient decides to discontinue from the study treatment, the investigator should make a 
reasonable effort (e.g. telephone, e-mail, letter) to understand the reason for this decision and record 
this information in the patient’s chart and on the appropriate CRF pages.  
Patients may be considered withdrawn if they state an intention to withdraw, fail to return for visits / 
lost to follow-up for any other reason. 
The investigator should discontinue study treatment for a given patient if, he/she believes that 
continuation would be detrimental to the patient’s well-being. 
 
Study treatment must be discontinued under the following circumstances: 
 
• 
Death 
• 
Adverse Events 
• 
Abnormal laboratory value 
• 
Pregnancy 
• 
Unsatisfactory therapeutic effect 
o patients with evident inadequate chelation (Transfusion burden > 4 units/month over 
a three consecutive months period and > 1 PRBC unit/week and a total number of 
PRBC received >20) the protocol will be discontinued and the patient will be treated 
as clinically (by label) indicated 
• 
Unwillingness to comply with study procedures/treatment as per protocol 
• 
Discovery of patient ineligibility 
• 
Intake of prohibited medications 
• 
Protocol violation 
• 
Consent withdrawal 
• 
Lost to follow-up 
• 
Administrative problems 
• 
Premature termination of the study 
• 
In patients with serum ferritin <300 ng/ml therapy will be suspended and the patient will 
remains in study, with the same transfusion ( minimal Hb level 9 g/dl) and study criteria. 
Patients will restart treatment as soon as serum ferritin arise >300 ng/ml. 
 
15.2. 
Withdrawal of Consent 
Patients are free to withdraw from the study at any time without prejudice to their treatment. When a 
patient decides to withdraw from the study, she/he should always be contacted in order to obtain 
information about the reason for withdrawal and to record any adverse events. When possible, the 
patient should return for a study visit at the time of, or soon after withdrawal, and the relevant 
assessments should be performed.  
If the patient explicitly states his/her wish not to contribute with further data to the study, the assigned 
FISiM-ETS Study Coordinator should be informed and the withdrawal of consent should be 
documented by the investigator in the patient’s case report form. Information from subsequent 
ambulatory visits, laboratory or instrumental assessments and any other information on the patient 
status after consent withdrawal won’t be collected in the data base or used for analysis. However, 
both clinical data collected until patient’s withdrawal as well as the data coming from the central 
review will still be considered as available for the study analysis. 

 
 
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29 
15.3. 
Patients Lost to Follow up 
Every effort will be made to contact patients who fail to return for scheduled visits. A patient is 
considered lost to follow-up if no information has been obtained when the last patient has completed 
the clinical phase of the study. During this time site investigator must document attempts to contact 
the patient either by phone or by letter. 
15.4. 
Premature termination of the study 
The sponsor reserves the right to stop the trial at any time. The investigators will be informed of this 
decision in writing. 
The same applies to any investigator willing to discontinue his/her participation to the trial. The 
investigator must immediately inform the sponsor in writing of this decision. 
 
 
 
16. STUDY PROCEDURES TIMEPOINTS 
16.1. 
Screening period (within 3 weeks prior to Study Cycle 1 Day 1) 
All subjects will be screened for study eligibility including: 
• 
Medical History; 
• 
Physical Examination; 
• 
ECOG; 
• 
Vital Signs; 
• 
See schedule of assessments 
 
A physical examination will be performed at screening and subsequent study visit. Information about 
the physical examination must be present in the source documentation at the study site. Significant 
findings that are present prior to the start of the study drug must be included in the Medical History. 
Significant findings made after the study drug which meet the definition of an AE must be recorded 
as Adverse event. All patient will have standing height measured at the screening visit. Body weight 
and ECOG sate will be recorded at screening and then at every clinic visit  
 
Vital signs determinations are of sitting blood pressure, heart rate, respiratory rate and body 
temperature and are taken at every visit. All vital sign measurement should be recorded every visit. 
 
• 
Clinical Laboratory Evaluations; 
• 
12 lead Electrocardiograms;  
• 
Echocardiogram 
• 
Pregnancy test (if applicable); 
• 
Ophthalmologic examination and audiometry 
 
Patients will undergo auditory and ocular examinations at screening and at end of treatment or at 
unscheduled visit if needed. 
If a patient had an auditory or ophthalmologic exam 6 months prior to the screening and the test 
results are available, then these tests will not need to be done at screening. 
The auditory examination as per clinical practice.  
The ophthalmologic examination as per clinical practice 
Information about the audiometry and the ocular examinations must be present at the source 
documentation at the study site. Significant findings made after the study drug which meet the 
definition of an AE must be recorded as Adverse event.  
 
• 
A bone marrow aspirate for diagnosis purpose (optional bone marrow biopsy with immune-
histochemical and fibrosis evaluation);  

 
 
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30 
• 
A Marrow aspiration obtained in the six months preceding trial enrollment is considered 
adequate. 
• 
Peripheral blood samples biological tests; 
• 
NGS (molecular tumor analysis) 
 
16.2. 
Treatment 
According to the label during the first month of treatment renal function ( serum creatinine  and 
creatinine clearance) will be checked weekly, liver function (ASL, ALT and serum bilirubin) will be 
checked every other week). 
 
At any month step and at any transfusional event: 
• 
Physical Examination; 
• 
ECOG; 
• 
Vital Signs; 
• 
Clinical Laboratory Evaluations (see scheduled laboratory examination); 
• 
In addition, at any transfusional event: CBC, Renal function (creatinine and blood urea) and 
liver function (bilirubin, AST, ALT) 
• 
Peripheral blood immunophenotyping in case of suspicious leukemic dissemination; 
 
16.3. 
EOT phase  
• Physical Examination; 
• ECOG; 
• Vital Signs; 
• Clinical Laboratory Evaluations (see schedule of assessments); 
• 12 lead electrocardiograms;  
• Echocardiogram 
• bone marrow aspirate (if clinically indicated) 
• Peripheral blood immunophenotyping in case of suspicious leukemic dissemination; 
 
16.4. 
Early withdrawn (discontinuation from study treatment)  
• Physical Examination; 
• ECOG; 
• Vital Signs; 
• Clinical Laboratory Evaluations; 
• Electrocardiograms;  
• Peripheral blood / bone marrow immunophenotyping in case of suspicious leukemic 
dissemination; 
• Any test needed if withdrawal is for toxic reason. 
 
16.5. 
Investigations tests  
See schedule of assessments for experimental studies. 
 
Note that sample shipment will be a pre-requisite for study inclusion at some specific time points.  

 
 
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31 
16.6. 
Schedule of assessments 
  
Site 
Screening 
Baseline 
Month 1 
M 2 
M 3 
M 4 M 5 M 6 M 7 M 8 
M 9 
M 10 M 11 
EOS 
Informed consent 
Local 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
Inclusion /exclusion criteria 
Local 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
Medical history 
Local 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
Physical examination (including height, weight 
and BSA)* 
Local 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy test  
Local 
if indicated 
  
  
  
if 
indicated 
  
  
  
  
  
if 
indicated 
  
  
  
ECOG* 
Local 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
CBC (including reticulocytes) 
Local 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Creatinine clearance 
Local 
X 
X 
 X 
X  
X  
X  
X 
X  
X  
X  
X  
X  
X  
X 
Serum Creatinine 
Local 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood Urea 
Local 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine proteins  (measured in non first void sample urine) 
Local 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ASL 
Local 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ALT 
Local 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 Bilirubin  
Local 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum Ferritin 
Local 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Transferrin saturation 
Local 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum Erythropoietin 
Local 
X 
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
Ophthalmology examination** 
Local 
X 
  
  
  
  
  
  
  
  
  
  
  
X 
Audiometry** 
Local 
X 
  
  
  
  
  
  
  
  
  
  
  
X 
12 Lead ECG 
Local 
X 
  
  
  
  
  
  
  
  
  
  
  
  
X 
Echocardiography 
Local 
X 
  
  
  
  
  
  
  
  
  
  
  
  
X 
Marrow aspiration (WHO 2016 criteria) or biopsy Local 
If clinical 
indicated  
  
  
  
  
  
  
  
  
  
  
  
  
X 
Qol Questionnaire 
Local 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
§During the first month of treatment additional laboratory checks must be performed: serum creatinine and calculated creatinine clearance every week, transaminases and serum 
bilirubin every two weeks  (according to SmPC – RCP) 

 
 
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32 
 
Concomitant Medications 
Recorded from the screening through 30 days after the last dose of treatment 
PRBC transfusions 
A standard pre-transfusional Hemoglobin level will be indicated (Hb threshold for transfusion Hb 9 g/dl or 10 g/dl for patients with 
cardiac disease) to be maintained during the study year. Pre transfusional hemoglobin level and transfusions date and frequencies 
will be recorded. A transfusional ratio will be determined: number of units received in a predetermined period/ Mean pre-
transfusional Hb level 
Adverse events 
Recorded from the first dose of study drug through last patient last visit 
Serious Adverse Events 
Recorded from signing of the informed consent form through last patient last visit 
 
* A physical examination will be performed at screening and subsequent study visit. Information about the physical examination must be present 
in the source documentation at the study site. Significant findings that are present prior to the start of the study drug must be included in the 
Medical History. Significant findings made after the study drug which meet the definition of an AE must be recorded as Adverse event. All patient 
will have standing height measured at the screening visit. Body weight and ECOG sate will be recorded at screening and then at every clinic visit  
 
Vital signs determinations are of sitting blood pressure, heart rate, respiratory rate and body temperature and are taken at every visit. All vital sign 
measurement should be recorded for every visit. 
 
** Patients will undergo auditory and ocular examinations at screening and at end of treatment or at unscheduled visit if needed. 
If a patient had an auditory or ophthalmologic exam 6 months prior to the screening and the test results are available, then these tests will not 
need to be done at screening 
The auditory examination includes the following assessments: comprehensive audiometry threshold examination, speech recognition 
The ophthalmologic examination includes the following assessments: vital acuity test (refraction), tonometry, slit lamp exam of anterior segment, 
slit lamp exam of the lens, a funduscopic and retinal examination  
Information about the audiometry and the ocular examinations must be present at the source documentation at the study site. Significant findings 
made after the study drug which meet the definition of an AE must be recorded as Adverse event  
 
 
 

 
 
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33 
16.7. 
Schedule of blood samples assessments for experimental biological study 
 
  
Baseline 
Month 1 
M 2 
M 3 
M 4 
M 5 
M 6 
M 7 
M 8 
M 9 
M 10 
M 11 
EOS 
Liver and pancreas MRI (MRI done 
locally and sent for hepatic and 
pancreatic iron determination). See 
Appendix I 
 
Centralized 
X 
  
  
  
  
  
  
  
  
  
  
  
X 
NTBI 
Centralized 
X 
X 
X 
X 
X 
X 
X 
LPI 
Centralized 
X 
X 
X 
X 
X 
X 
X 
Epcidine; sTR  
Centralized 
X 
X 
  
  
X 
  
  
X 
  
  
X 
Erythroferrone, GDF15, GDF11 
Centralized 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
MDA Membrane lipid peroxidation  Centralized 
X 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
NGS study 
Centralized 
X 
  
  
  
  
  
  
  
  
  
  
  
X 
NGS study (molecular tumor analysis) to be performed in case of disease progression 

 
FISM_ IRON-MDS, version n.2.1, date 03.03.2020. 
 
34 
17. EFFICACY MEASUREMENTS AND PARAMETERS 
17.1. 
Efficacy measurement 
Patients receiving at least 1 dose of DFX-DT will be considered as Efficacy Population (EP). 
17.2. 
Efficacy parameters  
17.2.1. Primary endpoints 
 
 
Objective 
Endpoint 
Primary 
Objective 
and endpoints 
Balance iron burden in one-year 
treatment in early phase of 
transfusion requirement by low 
dose 
(3.5 
mg/kg) 
DFX-FCT 
(prevention of iron overload) as 
demonstrated by hepatic iron 
concentration. 
 
 
 
 
Change of hepatic iron from the 
baseline according to baseline 
hepatic iron level: 
For patients with baseline  LIC ≤5 
mg/g dry weight (dw) ± 1.5 mg/g 
dw. 
For patients with baseline LIC >5 
mg/g dw ±20% 
 
The as demonstrated by R2- MRI 
(test performed in a 1.5 tesla MRI 
machine and analyzed following 
R2 method (75)- Baseline versus 
EOS.  
 
The 
corresponding 
secondary 
efficacy variable will be the 
absolute change in hepatic iron 
concentration 
EOS 
versus 
baseline. 
 
 
 
17.2.2. Secondary objective and endpoints 
 
 
Secondary Objectives 
Secondary Endpoints 
Descriptive-
observational objective  
 
Definition 
of 
iron 
overload 
(including serological markers 
and MRI definition of iron loading 
in 
different 
tissues: 
liver, 
pancreas), tissue reactive iron 
species and oxidative stress in 
MDS 
at 
beginning 
of 
transfusional history.  
Absolute values of serum ferritin, 
transferrin saturation, NTBI, LPI, 
liver and pancreas MRI and 
oxidative stress at baseline.  
 
Efficacy 
Absolute change in hepatic iron 
concentration 
EOS 
versus 
baseline. 
 
 
On 
year 
evolution 
of 
iron 
overload serologic markers  
Absolute and relative changes in 
serum ferritin and transferrin 

 
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35 
 
saturation from baseline to every 
visit during the whole treatment 
period. 
 
Presence 
and 
quantitative 
evolution of toxic serum iron 
forms 
(iron 
tissue 
reactive 
species) under low dose DFX 
therapy.  
 
Proportion of patients with NTBI 
> normal values and/or LPI > 
normal values at end of study vs 
baseline. 
Changes in NTBI and LPI from 
baseline to every visit during the 
whole treatment period. 
 
Verify if regular suppression of 
the “free iron forms” prevent 
accumulation of tissue iron.  
Relationship between NTBI and 
LPI with serum ferritin and liver 
and 
pancreas 
iron 
overload 
(MRI) at end of study versus 
baseline  
 
Evaluate the overall safety of 
deferasirox FCT formulation in 
patients with lower risk MDS at 
the 
beginning 
of 
their 
transfusional history  
 
Overall safety, as measured by 
frequency 
and 
severity 
of 
reported AEs and SAEs and 
changes in laboratory values 
from baseline: serum creatinine, 
creatinine clearance ALT, AST, 
complete blood count (platelets, 
RBC and WBC) and total direct 
and indirect bilirubin).  
 
Leukemic 
transformation 
(progression 
to 
leukemia 
or 
higher rIPSS scores) 
 
Proportion of patients with a 
disease 
progression 
(progression 
defined 
as 
a 
transition into a higher MDS risk 
group based on revised IPSS 
scoring or progression to AML) 
Time to progression (defined as 
above) 
or 
to 
leukemia 
transformation. 
 
Hemopoietic response 
Percentage 
of 
patients 
with 
hematologic improvements in 
term 
of 
erythroid 
response 
following IWG 2006 criteria.  
Time 
to 
reach 
transfusion 
dependence defined as > 2 
PRBC units/months for 3 months 
for patients with pre-transfusional 
Hb < 9.0 g/dl (or <10 g/dl for 
patients with cardiac disease) or 
a total number of PRBC units 
received = 20 from baseline. 
Absolute reticulocytes count from 
baseline to every visit during the 
whole treatment period. 
 
Absolute values and evolution of 
serum 
transferrin 
receptor, 
GDF11, 
GDF 
15 
and 
erythroferrone 
from baseline to every visit during 
the whole treatment period. 
 
Evaluation of transfusional ratio: 
number of units received in a 

 
FISM_ IRON-MDS, version n.2.1, date 03.03.2020. 
 
36 
predetermined period/ Mean pre-
transfusional 
Hb 
level. 
Compared with other studies on 
general population (study and 
FISiM-ETS registry). 
Patients 
receiving 
concurrent 
rHuEpo will not be considered for 
erythroid response 
 
Costs analysis 
Cost and outcome with low dose 
in early chelation vs. chelation 
treatment in MDS patients with 
transfusional iron overload in 
accordance with either local or 
international guidelines 
 
Exploratory 
objective and 
endpoint 
Study 
of 
biological 
cellular 
damage by iron toxicity before 
and during treatment     
 
MDA values during the study and 
relationship to NTBI and LPI 
values 
 
 
18. SAFETY MONITORING AND REPORTING 
 
Safety monitoring will be based on the i) evaluation of changes from baseline throughout the whole study 
in physical examination, heart rate/rhythm, blood pressure, renal function, liver function and laboratory 
findings, ii) a global assessment of organ function; and iii) the observation and report of any adverse 
event (AE). 
18.1. 
Adverse Events 
 
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. 
Once the study ICF is signed, all AEs will be captured in the Adverse Event CRF. 
The severity of an AE will be assessed on the basis of the NCI CTCAE version 4.03 (please    see 
forreference:https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_ 
8.5x11.pdf.). 
 
All non-Serious Adverse Events, all reports of drug exposure during pregnancy, all reports of misuse and 
abuse of the drug, all reports describing the occurrence of other “special scenarios” (including reports of 
drug-drug/drug-food interaction, drug use during lactation or breast-feeding, lack of effectiveness, 
overdose, drug maladministration or accidental exposure, dispensing   errors/medication   errors, 
withdrawal   or   rebound   symptoms, irrespective of whether a clinical event has occurred) and all SAEs 
will be collected into the patients case report form. The same will be done for any other information that 
may suggest a change in the benefit-risk profile for the drug. 
Conditions that were already present at the time of informed consent should be recorded in the Medical 
History page of the patient’s CRF. Adverse event monitoring should be continued for at least 30 days  
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. AEs will not be collected beyond 30 days after the last dose of study 
treatment.   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 evaluated to determine: 
 

 
FISM_ IRON-MDS, version n.2.1, date 03.03.2020. 
 
37 
− 
The severity grade (CTCAE Grade 1-5) 
− 
Its duration (Start and end dates) 
− 
Its relationship to the study treatment (Reasonable possibility that AE is related: No, Yes) 
− 
Action taken with respect to study treatment (none, dose adjusted, temporarily interrupted,  
permanently discontinued, unknown, not applicable). 
− 
Whether medication or therapy was given (no concomitant medication/non-drug therapy, 
concomitant medication/non-drug therapy) 
− 
Whether it is serious, where a serious adverse event (SAE) is defined as in Section 18.2 
and which seriousness criteria have been met. 
− 
Outcome  (not  recovered/not  resolved,  recovered/resolved,  recovering/resolving, 
recovered/resolved with sequalae, fatal, unknown) 
 
If the event worsens the event should be reported a second time in the CRF noting the start date when 
the event worsens in toxicity. For grade 3 and 4 adverse events only, if improvement to a lower grade is 
determined a new entry for this event should be reported in the CRF noting the start date when the event 
improved from having been Grade 3 or Grade 4. 
 
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. 
 
18.2. 
Serious Adverse Events 
18.2.1 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 study indication 
− 
Progression/relapse of underlying disease (including fatal outcomes) 
− 
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. 
− 
 
18.2.2 Reporting 
For patients who sign the Screening ICF, SAE collection will start upon signing the Screening ICF. SAEs 
will only be reported if the event is suspected to be causally related to a study procedure as assessed by 
the investigator (e.g. an invasive procedure such as biopsy). SAEs will be followed until resolution or until 
clinically relevant improvement or stabilization. If the Study ICF is not signed (screen failure), SAE 
collection ends 30 days after the last study related procedure. 

 
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38 
 
For patients who sign the Study ICF, SAE collection starts at time of Study informed consent whether the 
patient is a screen failure or not. 
 
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the patient has 
provided Study informed consent and until at least 30 days after the patient has stopped study treatment 
must be reported to Safety Responsible within 24 hours of learning of its occurrence. Any additional 
information for the SAE including complications, progression of the initial SAE, and recurrent episodes 
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. 
 
Any  SAEs  experienced  after  the  30  day  safety  evaluation  follow-up  should  only  be reported to 
Safety Responsible if the investigator suspects a causal relationship to the study treatment. 
 
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 submit the 
completed form within 24 hours to the Safety Responsible of the study.   Detailed instructions regarding 
the SAE submission process and requirements for signatures are to be found in the investigator folder 
provided to each site. 
 
Follow-up information is submitted in the same way as the original SAE 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 patient continued or withdrew from study participation. 
 
If  the  SAE  is  not  previously  documented  and  is  thought  to  be  related  to  the  study treatment, the 
Safety Responsible of the study and the Novartis safety desk  may urgently require further information 
from the investigator for Health Authority reporting. 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. 
 
 
All Collected SAEs in patients exposed to the Novartis drug and SUSARs should be transferred to Novartis 
safety desk within 15 calendar days of awareness. 
 
 
The FISiM-ETS Pharmacovigilance will provide Novartis with a copy of the development safety 
update report (DSUR) at the time of submission to the Regulatory Authority and Ethics Committees.   
 
CONTACT DETAILS FOR PHARMACOVIGILANCE 
 
          Daniela Gioia  
 
         : +39 0131.033156  
Fax: +39 0131 263455  
         e-mail:drugvigilance@filinf.it 
 
 
 
19. PREGNANCIES 
 

 
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39 
To ensure patient safety, each pregnancy occurring while the patient is on study treatment must be 
reported to the Safety Responsible of the study within 24 hours of learning of its occurrence. Occurrence 
of Pregnancy should be monitored for 90 days after stopping treatment (i.e. End of treatment or Cross-
Over End of treatment whichever comes last). 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. The 
follow- up to three months after delivery is mandatory for all reported pregnancy cases and in cases of 
live birth, the follow-up on any development issues or abnormality that would not be seen at birth. 
 
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the investigator to 
the Safety Responsible of the study within 24 hours from its learning. 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. 
 
Pregnancy outcomes must be collected for the female partners of any males who took study  treatment.  
Consent  to  report  information  regarding  these  pregnancy  outcomes should be obtained from the 
mother. 
 
Pregnancy and its follow-up should be also reported to Novartis safety desk within 15 calendar days of 
awareness. 
e-mail:drugvigilance@filinf.it 
Fax number: +39 0131 263455 
 
 
20.  STATISTICAL CONSIDERATIONS 
20.1. 
Study design 
One year low dose (3,5 mg/kg/day DFX-FCT) in patients at the beginning of their transfusion history. 
Dose activity will be monitored by regular NTBI /LPI suppression and by prevention of iron accumulation 
(hepatic iron concentration and other tissue and serologic parameters) comparing baseline versus end 
of study iron concentration. 
 
A standard pre-transfusional hemoglobin level will be indicated (Hb threshold for transfusion Hb 9 g/dl or 
10 g/dl for patients with cardiac disease) to be maintained during the study year. Pre transfusional 
hemoglobin level and transfusions date and frequencies will be recorded. A transfusional ratio will be 
determined: number of units received in a predetermined period/ mean pre-transfusional Hb level. 
 
Open label, single arm, fixed dose phase II study. 
 
20.2. 
Sample size calculation  
Including 50 subjects in the study, we can reach almost 60% power to detect small effect size 0.30 (with 
p value of 0.05) whereas, we have almost 100% to detect moderate effect size of 0.50 (with p-value of 
0.05). On the basis of previous experience, the low dosage, the early intervention and the FCT 
preparation a 20% drop out rate is expected (10 additional patients to be enrolled)  
 
 
 
 
 
 
 
 
 
 
 

 
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40 
Methods:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The power test was performed by G power 3.1 software by using the t test Means: Difference between 
two dependent means (matched pairs). 
 
As demonstrated by pour sample size analyses, we have enough power to detect an effect size between 
0.3 and 0.5 considering a potential error of 0.05, which is largely accepted from scientific community. 
 
The effect size is calculated on a common scale by G-power program which allows to compare the 
effectiveness of different variables on the same outcome. In other words, quantifies the magnitude of 
the difference of a variable between two population groups. 
 
 
To interpret the resulting number, most scientists use this general guide developed by Cohen: 
• 
< 0.1 = trivial effect 
• 
0.1 - 0.3 = small effect 
• 
0.3 - 0.5 = moderate effect 
• 
> 0.5 = large difference effect 
 
 
20.3. 
Statistical method and data analyses. 
 
Analysis population: the planned enrolment target is 50 patients (+ 20% drop out rate) for a total number 
of 60 patients. 
 
Data from all centers participating in this study will be pooled for analyses. 
Standard descriptive analyses will include: 
•           Frequencies and percentages for categorical data; 
•           n, mean, standard deviation, minimum, median, 25th and 75th percentiles and maximum for 
continuous data. 
  
Whenever possible, the analysis will be performed by visit.  
  
Analysis sets  
 
Full Analysis Set (FAS): All enrolled patients. 
 
10
20
30
40
50
60
70
80
90
100
0
0.2
0.4
0.6
0.8
1
Power (1-β err prob)
 = 0.3
 = 0.5
Effect size dz
t tests -  Means: Dif erence between two dependent means (matched pairs)
Tail(s) =  Two. α err prob =  0.05
Total sample size

 
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41 
Safety analysis set (SS): All enrolled patients who will have received at least one dose of study drug 
and have at least one post-baseline safety assessment. Note that an entry on the Adverse Event CRF 
of a statement that a patient had no adverse events constitutes a safety assessment. 
 
Per Protocol analysis set (PP): All enrolled patients who will have received at least one dose of study 
drug without any major protocol violations and complete the treatment study phase or withdraw from 
the study due to unsatisfactory therapeutic effect. 
   
Patient demographics/other baseline characteristics  
Demographic and other baseline data (including disease characteristics and transfusion history, etc) 
will be summarized descriptively for the Safety analysis set by means of the statistics above mentioned. 
Summary tables will be provided about medical history coded by System Organ Class and Preferred 
Term of MedDRA dictionary.  
 
Treatments (study treatment, concomitant therapies,compliance) 
The descriptive analysis listed below will be reported for the safety analysis set. 
 
Study drug  
The duration of study drug exposure, as well as average prescribed doses, will be summarized. Any 
dose adjustments and reasons that led to the adjustments will be listed. The number and duration of 
dose interruptions will also be described.  
 
Compliance 
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 Therapies  
Concomitant medications and significant non-drug therapies prior to and after the start of the study 
treatment will be coded by WHO Drug Reference List dictionary and frequencies will be calculated 
according to drug classes. 
 
 
The primary objective is prevention of iron accumulation measured by (primary variable) Change of 
hepatic iron from baseline according to baseline hepatic iron level: Baseline versus end of study. 
For patients with baseline  LIC ≤5 mg/g dry weight (dw) ± 1.5 mg/g dw. 
For patients with baseline LIC >5 mg/g dw ±20% (by R2- MRI ; test performed in a 1.5 tesla MRI machine 
and analyzed following R2 method (75). 
The corresponding secondary efficacy variable will be the absolute change in hepatic iron concentration 
EOS versus baseline. 
 
Difference between baseline versus EOT will be measured as continuous variables and analyzed with 
parametric or non parametric statistical tests depending by normality of distribution. 
 
Secondary endpoint:  
 
Observational: demographics and other baseline characteristics will be study with descriptive statistics. 
Analysis will be done on FAS and PP. 
 
As the same way secondary endpoints will be evaluated as continuous or nominal variables and analyzed 
accordingly with parametric or non parametric tests. Efficacy parameters analysis will be done on FAS 
and PP. 
 
Final Safety parameters will be measured in full analyses set and in all patients who received at least 
one dose of study drug (safety set).  
 
 
 

 
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42 
21. INDEPENDENT DATA SAFETY MONITORING COMMITTEE (DMSC) 
 
The FISiM-ETS on its own initiative and responsibility set up an independent external DSMC. The DSMC 
consist in experts independent from the sponsor. 
The aim of the DSMC is to assess, at intervals during the course of the trial, the progress of the trial, the 
trial safety data and the trial outcome data with a view to recommending whether the trial should continue, 
be modified or be terminated. 
 
The DSMC will be composed by: 
1. Two independent scientists with expertise in the treatment of iron overload and or MDS 
2. The biostatistician of the study 
3. An independent statistician with expertise in the methodology of clinical trials and data analysis. 
 
Roles of DSMC (suggested, not exclusive): 
1. To review ongoing safety data throughout the study.  
2. To monitor evidence for treatment benefit and thus decide when/whether the main trial question has 
been answered. 
3. To monitor evidence for treatment harm (toxicity). 
4. To decide whether to recommend changes to the protocol.  
5. To decide whether to recommend that the trial continues to recruit participants or whether 
recruitment should be terminated. 
6. To review final analysis of the data. 
7. To discuss final data with PI and the sponsor. 
 
Planned meetings: 
1. A minimum of two call conferences that include preparation, working time during the meeting, and 
writing reports. 
 
22. GOOD CLINICAL PRACTICE, QUALITY CONTROL AND QUALITY ASSURANCE 
22.1. 
Monitoring, Audits and Inspections  
During the study the monitoring will be prevalently made by e-mail and telephone. The field monitor will 
visit the site, when needed, mainly in presence of data incongruity, to check the completeness of patient 
records, the accuracy of entries on the CRFs, the adherence to the protocol and to Good Clinical Practice 
and the progress of enrolment. 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 
on CRFs must be traceable to these source documents in the patient's file. The investigator must also 
keep the original informed consent form signed by the patient (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. FISiM-ETS Safety Monitoring standards require full verification for the 
presence of informed consent, adherence to the inclusion/exclusion criteria, documentation of SAEs, and 
the recording of data that will be used for all primary and safety variables. Additional checks of the 
consistency of the source data with the CRFs are performed according to the study-specific monitoring 
plan. No information in source documents about the identity of the patients will be disclosed. 
22.2. 
Investigator(s) responsibilities 
Investigator responsibilities are set out in the ICH guideline for Good Clinical Practice. The investigator 
must give the monitor access to relevant records to confirm the above.   
The Investigator(s) is responsible for keeping a record of all patients who sign an Informed Consent Form 
and are screened for entry into the study. For those patients who fail screening the reason(s) for exclusion 
must be recorded in the patient’s source documents. 
No procedure/assessment/measurement/test other than those outlined here, or in the schedule of study 
assessments, is to be performed without the prior written approval of Principal Investigator, or unless 
deemed by the investigator(s) as necessary for the patient’s medical care. Investigator(s) and/or 

 
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43 
authorized designee(s) must enter study data onto electronic CRFs supplied by FISiM-ETS. The data on 
the CRF will be recorded in an anonymous manner to protect the patient’s identity by using a unique 
identifier that will prevent personal identifiable information. 
The Investigator(s), or a designated member of the Investigators’ staff, must be available at some time 
during monitoring visits to review data and resolve any queries and to allow direct access to the patient’s 
records (e.g., medical records, office charts, hospital charts, and study related charts) for source data 
verification. The CRFs must be completed as soon as possible after the patient’s visit, but no later than 
prior to each monitoring visit and be made available to the FISiM-ETS representative(s) so that the 
accuracy and completeness may be checked. 
 
 
23. ETHICAL AND REGULATORY STANDARDS 
23.1. 
Institutional Review Board/Independent Ethics Committee Review Approval
 
 
This study will be conducted according to the Declaration of Helsinki Ethical Principles for Medical 
Research Involving Human Patients (see: https://www.wma.net/policies-post/wma-declaration-of-
helsinki-ethical-principles-for-medical-research-involving-human-subjects/ for more information). The 
review of this protocol by the IRB/IEC and the performance of all aspects of the study, including the 
methods used for obtaining informed consent, must also be in accordance with principles enunciated in 
the declaration, as well as ICH Guidelines, Title 21 of the Code of Federal Regulations (CFR), Part 50 
Protection of Human Patients and Part 56 Institutional Review Boards. Before implementing this study, 
the protocol, the proposed informed consent form and other information to patients, must be reviewed by 
a properly constituted IRB/IEC. A signed and dated statement that the protocol and informed consent 
have been approved by the IRB/IEC must be given to FISiM-ETS before the study initiation. The names 
and occupations of the chairman and the members of the IRB/IEC must be supplied to FISiM-ETS. 
The FISiM-ETS as sponsor of the study, together with site Investigator(s), will be responsible for 
preparing documents, where ever applicable, for submission to the relevant IRB/IEC and obtaining 
written approval for this study. The approval will be obtained prior to the initiation of the study. 
A copy of the IRB/IEC approval for the protocol and the Informed Consent is to be provided to FISiM and 
site Investigator(s). The approval for both the protocol and informed consent must specify the date of 
approval, protocol number and version, or amendment number. 
The Investigator(s) is responsible for notifying the FISiM Safety Monitoring Office and the IRB/IEC of any 
serious deviations from the protocol, or anything else that may involve added risk to patients. 
Any advertisements used to recruit patients for the study must be reviewed and approved by FISiM and 
the IRB/IEC prior to use. 
Before the start of the study, the FISiM-ETS will provide the IRB/IEC with current and complete copies 
of the following documents: 
1. 
final protocol and, if applicable, amendments 
2. 
informed consent form (and any other written materials to be provided to the subjects) 
3. 
Currently approved SmPC 
4. 
information on compensation for study-related injuries  
5. 
investigator’s curriculum vitae or equivalent information (unless not required, as documented 
by IRB/IEC) 
6. 
any other documents that the IRB/IEC requests to fulfill its obligation. 
 
During the study the FISiM-ETS according with site investigators will send the following documents to 
the IRB/IEC for their review and approval, where appropriate: 
1. 
protocol amendments 
2. 
revision(s) to informed consent form and any other written materials to be provided to subjects 
3. 
revisions to compensation for study-related injuries or payment to subjects for participation in 
the study, if applicable 
4. 
currently approved SmPC summaries of the status of the study (at least annually or at intervals 
stipulated in guidelines of the IRB/IEC) 
5. 
reports of adverse events that are serious, unexpected and associated with the investigational 
drug 
6. 
new information that may affect adversely the safety of the subjects or the conduct of the study 

 
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44 
7. 
deviations from or changes to the protocol to eliminate immediate hazards to the subjects 
8. 
report of deaths of subjects under the investigator's care 
9. 
notification if a new investigator is responsible for the study at the site 
10. any other requirements of the IRB/IEC      
23.2. 
Protocol Amendments Approval 
Any amendment to this protocol that seems appropriate, as the study progresses will be submitted to the 
IRB/IEC for written approval before the implementation of the amended version. The written signed 
approval from the IRB/IEC should refer specifically to the investigator(s) and to the protocol number and 
title and mention any amendment numbers that are applicable. Amendments that are administrative in 
nature do not require IRB/IEC approval but will be submitted to the IRB/IEC for information purposes. 
 
24. ADMINISTRATIVE PROCEDURES 
24.1. 
Curriculum vitae 
An updated copy of the curriculum vitae of each investigator and sub-investigator will be provided to the 
FISiM-ETS Start Up prior to the beginning of the study. 
24.2. 
Confidentiality agreement 
All goods, materials, information (oral or written) and unpublished documentation provided to the 
investigators (or any company acting on their behalf), inclusive of this study, the patient case report forms 
are the exclusive property of FISiM-ETS. 
They may not be given or disclosed by the investigator or by any person within his authority either in part 
or in totality to any unauthorized person without the prior written formal consent of FISiM-ETS. 
It is specified that the submission of this study and other necessary documentation to the Ethics Review 
Committee or a like body is expressly permitted, the Ethics Committee members having the same 
obligation of confidentiality. 
The investigator shall consider as confidential and shall take all necessary measures to ensure that there 
is no breach of confidentiality in respect of all information accumulated, acquired or deduced in the course 
of the trial, other than that information to be disclosed by law. 
24.3. 
Record retention in investigating centers. 
The investigator must maintain all study records, patient files and other source data for the maximum 
period of time permitted by the hospital, institution or private practice. 
However national regulations should be taken into account, the longest time having to be considered. 
For trials performed in the European Community, the investigator is required to arrange for the retention 
of the patient identification codes for at least 15 years after the completion or discontinuation of the trial. 
Any center will notify the sponsor before destroying any data or records. 
24.4. 
Ownership of data and use of the study results.  
The sponsor has the ownership of all data and results collected during this study. In consequence the 
sponsor reserves the right to use the data of the present study, either in the form of case report forms (or 
copies of these), or in the form of a report, with or without comments and with or without analysis.  
24.5. 
Authorship 
The first results of the trial will be published after complete data collection and evaluation of the primary 
endpoint. Partial or preliminary results can be published beforehand. Publication is to be initiated by the 
chairmen in charge of the study with approval of coordinators. 
Any publication in the form of a lecture, poster or article must be prospectively approved by the Scientific 
Committee of FISiM-ETS. 
The authors will be proposed (according to the updated FISiM-ETS publication rules) by the chairmen in 
charge of the study, approved by coordinators following recruitment criteria and scientific contribution. 
All study data and publications are the property of the FISiM-ETS. 
 
 

 
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45 
The target publication plan will include: 
 
- 
ASH 2019 abstract: Study presentation and enrolment status  
- 
SIE 2019 encore abstract: Study presentation and enrolment status 
- 
EHA 2020 abstract: baseline study population  
- 
ASH 2020 encore abstract: baseline study population 
- 
ASH 2021 abstract: primary data 
 
24.6. 
Insurance coverage 
The Investigator-sponsor of the Study must ensure that adequate insurance coverage is available to the 
patients, in accordance with the ICH Guidelines of Good Clinical Practice. Such coverage must extend 
to all damages deriving from the study, to the Protocol Study exclusion of those attributable to willful 
misconduct or negligence of the institution or investigator. A copy, or excerpt, or insurer’s certificate, 
attesting the existence and amount of such coverage at least for the duration of the study must be 
supplied as part of the study documentation to the review and approval of the IEC. 
A specific insurance with company [HDI Gerling number 390-01583564-30010) has been concluded for 
patients enrolled in this study. No extra expenses, neither for therapies nor for clinical or laboratory 
procedures can be asked or expected to be paid by SSN or patients. 
 
24.7. 
Protocol amendments procedures 
It is specified that the appendices attached to this study and referred to in the main text of this study, 
form an integral part of the study. 
No changes or amendments to this study may be made by the investigator or by the sponsor after the 
study has been agreed to and signed by both parties unless such change(s) or amendment(s) have been 
fully discussed and agreed upon by the investigator and the FISiM-ETS.  
Any change agreed upon will be recorded in writing, the written amendment will be signed by the 
investigator and by the sponsor and the signed amendment will be appended to this study. 
Approval / advice of amendments by Ethics Review Committee and Competent Authorities are required 
prior to their implementation, unless there are overriding safety reasons. 
If the change or deviation increases risk to the study population, or adversely affects the validity of the 
clinical investigation or the subject's rights, full approval / advice must be obtained prior to 
implementation. For changes that do not involve increased risk or affect the validity of the investigation 
or the subject's rights, approval / advice may be obtained by expedited review, where applicable. 
In some instances, an amendment may require a change to a consent form. The investigator must receive 
approval / advice of the revised consent form prior to implementation of the change. In addition, changes 
to the case report forms, if required, will be incorporated in the amendment. 
 
25. DATA HANDLING AND RECORD KEEPING 
25.1. 
Data/documents 
The investigator(s) must ensure that the records and documents pertaining to the conduct of the study 
and the distribution of the study drug, that is copies of CRFs and source documents original documents, 
data, and records (e.g., hospital records; clinical and office charts; laboratory notes; memoranda; 
patient’s diaries or evaluation checklists; pharmacy dispensing records; recorded data from automated 
instruments; copies or transcriptions certified after verification as being accurate copies; microfiches; 
photographic negatives, microfilm, or magnetic media; x-rays; patient files) and records kept at the 
pharmacy, at the laboratories, and at medico-technical departments involved in the clinical study are 
complete, accurate, filed and retained. 
25.2. 
Data Management 
Data will be entered into the clinical database as per FISiM-ETS SOPs. These data will be electronically 
verified through use of on-line checks during data entry, and through programmed edit checks specified 
by the clinical team. Discrepancies in the data will be brought to the attention of the clinical team, and 
investigational site personnel, if necessary, in the form of a Data Clarification Form (DCF). Resolutions 

 
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46 
to these issues will be reflected in the database. An audit trail within the system will track all changes 
made to the data. 
25.3. 
Retention of Records 
The investigator(s) must maintain records of all study documents and supporting information relating to 
the conduct of the study. This documentation includes, but is not limited to, protocols, case report forms, 
advertising for patient participation, adverse event reports, patient source data, correspondence with 
health authorities and IRBs/IECs, informed consent forms, investigator(s) curricula vitae, monitor visit 
logs, laboratory reference ranges, laboratory certification or quality control procedures and laboratory 
director curriculum vitae. Patient files and other source data must be kept for the maximum period of time 
permitted by the hospital, institution or private practice specified below. The study monitor must be 
consulted if the investigator(s) wishes to assign the study files to someone else, remove them to another 
location or is unable to retain them for a specified period. The investigator(s) must retain study records 
for the time period according to local laws or requirements, whichever is longer. The monitor will inform 
the investigator(s) of the dates for retention. All study documents should be made available if required 
by relevant health authorities. The investigator(s) records must be retained until at least 2 years after the 
last approval of a marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or at least 2 years have elapsed since the formal discontinuation 
of clinical development of the investigational product. These documents should be retained for a longer 
period if required by other applicable regulatory requirements. 
 
26. PRIVACY OF PERSONAL DATA 
 
The collection and processing of personal data from subjects enrolled in this study will be limited to those 
data that are necessary to investigate the efficacy, safety, quality, and utility of the investigational 
product(s) used in this study. These data must be collected and processed with adequate precautions to 
ensure confidentiality and compliance with applicable data privacy protection laws and regulations. 
The investigator-sponsor ensures that the personal data will be: 
1. 
processed fairly and lawfully 
2. 
collected for specified, explicit, and legitimate purposes and not further processed in a way 
incompatible with these purposes 
3. 
adequate, relevant, and not excessive in relation to said purposes 
4. 
accurate and, where necessary, kept current 
Explicit consent for the processing of personal data will be obtained from the participating subject (or 
his/her legally acceptable representative) before collection of data. Such consent should also address 
the transfer of the data to other entities and to other countries. The subject has the right to request 
through the investigator access to his/her personal data and the right to request rectification of any data 
that are not correct or complete. Reasonable steps should be taken to respond to such a request, taking 
into consideration the nature of the request, the conditions of the study, and the applicable laws and 
regulations. 
Patients will be registered in the study via web site the end of their staging, before beginning the 
treatment. The name of the patient will not be asked for not recorded at the Data Center. A sequential 
identification number will be automatically attributed to each patient registered in the trial. This number 
will identify and must be included on all case report form. 
 
 
 

 
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27. REFERENCES 
 
1.  
Greenberg P, Cox C, LeBeau MM, Fenaux P, Morel P, Sanz G, et al. International scoring 
system for evaluating prognosis in myelodysplastic syndromes. Blood. Am Soc Hematology; 
1997;89(6):2079–88.  
2.  
Greenberg PL, Tuechler H, Schanz J, Sanz G, Garcia-Manero G, Sol?? F, et al. Revised 
international 
prognostic 
scoring 
system for 
myelodysplastic syndromes. 
Blood. 
2012;120(12):2454–65.  
3.  
Cazzola M, Della Porta MG, Malcovati L. Clinical relevance of anemia and transfusion iron 
overload in myelodysplastic syndromes. Hematology Am Soc Hematol Educ Program. 
2008;166–75.  
4.  
Malcovati L. Impact of transfusion dependency and secondary iron overload on the survival 
of patients with myelodysplastic syndromes. Leuk Res [Internet]. Elsevier; 2016 Dec 
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28. APPENDICES 
 
28.1. 
APPENDIX A: ECOG Performance Status 
SOURCE: Oken MM et al, Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. 
Am J Clin Oncol 5:649-655, 1982. 
 
Grade 
ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work  
of a  light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities.  
Up  and about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of 
 waking hours 
 4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed  
or chair 
5 
Dead 
 
 
 
 

 
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28.2. 
APPENDIX B: Common Terminology Criteria for Adverse Events   (CTCAE) 
 
In the present study, adverse events and/or adverse drug reactions will be recorded according to: 
 
Common Terminology Criteria for Adverse Events (CTCA), version 5.0. 
 
At the time this protocol was issued, the full CTC document was available on the NCI web site, at the 
following address: 
 https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_50 
 
 
 
 

 
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28.3. 
APPENDIX C: Questionnaire-QOL  
 
http://qol-e.com/MDS.asp  
 
 
 

 
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28.4. 
APPENDIX D: Questionnaire- CIRS 
Parmelee PA, Thuras PD, Katz IR, Lawton MP. Validation of the Cumulative Illness Rating Scale in a 
geriatric residential population J Am Geriatr Soc. 1995 Feb;43(2):130-7. 
 
 

 
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28.5. 
APPENDIX E: IPSS and Revised IPSS 
IPSS: (https://qxmd.com/calculate/calculator_123/mds-intnl-prognostic-scoring-sys-ipss)  
Revised IPSS: https://www.mds-foundation.org/ipss-r-calculator/ 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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28.6. 
APPENDIX F: EASL criteria for Chronic hepatitis EASL 2017 Clinical Practice  
 
Guidelines on the management of hepatitis B virus infection. European Association for the Study of the 
Liver.  
Electronic address: easloffice@easloffice.eu 
J Hepatol. 2017 Aug;67(2):370-398. doi: 10.1016/j.jhep.2017.03.021. Epub 2017 Apr 18. PMID: 
28427875 
 
 
 

 
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28.7. 
APPENDIX G: Transferrin saturation calculation 
[Serum iron / (serum transferrina x 1.42)] x 100 
 
Serum iron (microgr/dl), Serum transferrin (mg/dl)]  
 
www.emocromatosi.it/test.asp 
 
 

 
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28.8. 
APPENDIX H: Sampling, conservation and shipment modality for centralized 
tests 
 
Sampling for NTBI and LPI and other centralized tests 
 
Baseline tests sampling must be performed before any chelation therapy and as far as possible before 
PRBC transfusion (ideally before transfusion). All test during the year of therapy must be obtained as far 
as possible the daily DFX assumption (before daily DFX assumption) and as far as possible any 
transfusional event (distance from transfusion must be recorded). Distance from DFX assumption and 
transfusional event must be registered. 
 
A certified central laboratory will be utilized to process and provide results for the experimental laboratory 
tests (NTBI/LPI/MDA/ epcidine/ heritroferrone/ GDF11 ,   GDF 15/ sTR ecc).(for evaluation tests list and 
collection time-point see TAB 15.7) 
 
Every laboratory chosen for this study will provide instruction regarding the collection, processing and 
shipment of appropriate simples. 
 
Others samples will be referred to the local lab. (for evaluation tests list and collection time-point see 
TAB 15.6) 
• 
Hematology CBC sample collection 4mL blood 
• 
 Biochemistry sample collection 8,5 mL blood 
• 
 Serum ferritin 8,5 mL blood 
• 
 Urine analysis sample collection 10 mL urine  
 
All samples should be obtained in the absence of known inflammation or infection. If transfusion is 
scheduled, blood should be drawn for serum collection prior to transfusion. No indication regarding 
daily drug administration (other DFX) and samples collections. 
 
Conservation 
 
Every laboratory chosen for this study will provide instruction regarding the collection, processing, 
preservation and shipment of appropriate simples. 
 
Shipment 
 
Every laboratory chosen for this study will provide instruction regarding the collection, processing, 
preservation and shipment of appropriate samples. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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28.9. 
APPENDIX I: Image acquisition guidelines for liver/spleen/pancreas MRI 
 
▪ 
The table below shows preferred parameters. Use parameters as close to these as 
possible. 
▪ 
Once these values have been selected, they must remain consistent throughout 
this examination and study follow-up examinations. 
▪ 
The Same Imaging Protocol Must Be Used at all Visits 
 
 
Scanner Type 
1.5 T (GE, Siemens, Philips) 
Important Reminder: Please save an optimized MRI protocol for the study on the 
scanner and use consistent parameters across all time points. 
Anatomical coverage 
(Required Anatomy) 
Localizer must be used to get liver, spleen and pancreas – this will serve as 
the reference scan. T2*w protocol must be slice matched with this anatomical 
scan. Acquire 3 slices to capture liver, spleen and pancreas. Please make sure 
each organ is captured within at least one slice. 
Sequence details 
Localizer 
T2*w BREATHHOLD 
Contrast Agent 
NO contrast agent shall be administered during/before/after any scan for this MRI 
protocol 
Pulse sequence 
Fast Spin Echo 
Multi-Echo FGRE/FFE with fat suppression 
RF coil 
Phased-Array Torso Coil 
Plane 
Axial 
TR (ms) 
1000 – 4000 
(or optimal) 
200 
(or optimal) 
TE (ms) 
65 
(or optimal) 
Preferred: Multi-Echo FGRE/FFE with fat suppression 
Min TE possible (maximum value can be 1ms) , 8 to 12 
echoes, 2ms increments 
For example: TEs = 1, 3, 5, 7, 9, 11, 13, 15 
Flip angle (degrees) 
Optimal 
20 
Slice thickness (mm) 
15 
15 
Slice gap (mm) 
5 
5 
Matrix 
(Frq x Ph) 
320 x 192 
(or optimal) 
96 X 128 
FOV (cm) 
32 – 44 
(or optimal to include all 
anatomy) 
32-44 
(or optimal to include desired anatomy) 
Fat suppression 
- 
ON 
Receiver bandwidth 
Optimal 
Optimal