Clinical trial NCT00940602
Conditions: Myelodysplastic Syndromes
Keywords: TELESTO MDS Study Myelodysplastic Syndromes Myelodysplastic Syndromes (low-int-1 risk)
Sponsor: Novartis Pharmaceuticals
Start date: 2010-03-22; Completion date: 2018-02-27
Enrollment: 225 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This was a randomized, double-blind trial to evaluate deferasirox vs placebo in patients with myelodysplastic syndromes (low/int-1 risk) and transfusional iron overload .The trial was conducted in 17 countries, started in 2010 and ended in 2018.

Detailed description:
This randomized, double blind trial to evaluate deferasirox vs placebo in patients with myelodysplastic syndromes (low/int-1 risk) and transfusional iron overload consisted of four periods, a screening period, a treatment period, a post treatment follow-up period and a survival period. The trial recruitment period lasted until December 2014 and the trial continued for three years from the date the last patient enrolled until February 2018 (last patient last visit date).

Screening period:

The screening period lasting up to 35 days with two screening visits, at least 14 days apart, used to assess patient eligibility. Eligible patients with low or int-1 risk myelodysplastic syndromes (MDS) with transfusional iron overload were randomized in a 2:1 ratio to deferasirox or placebo respectively. Randomization was also stratified using the International prognostic scoring system of low or int-1 MDS and by geographical region (Asian vs non-Asian countries) since the Asian population has been reported to have a longer survival.

The following concomitant medications could be permitted for use while the patient was on study, and information outlining start date(s) and end date(s) of each medication taken were to be recorded on the appropriate eCRF: Erythropoietin (growth factor), G-CSF (growth factor), GM-CSF growth factor), Azacitidine, Thalidomide, Arsenic trioxide, Lenalidomide, Decitabine, Cyclosporine A, Vitamin C supplements (≤ 200 mg/day)

Treatment period:

The dosing schedule was 10 mg/kg/day (once daily) for the first 2 weeks, followed by 20 mg/kg/day (once daily). After 3 months of treatment at the dose of 20mg/kg/day, the dose could be adjusted by 5 or 10 mg/kg/day up to 40 mg/kg/day based on the serum ferritin response. Placebo matching to each strength of the active deferasirox was utilized to maintain the double-blind trial design.

During the treatment period patients returned to the investigational site every four weeks for routine procedures and to monitor safety, efficacy and compliance to treatment.

An external Data Monitoring Committee (DMC) monitored patient safety and trial conduct and received a blinded summary of serious adverse events.

All suspected endpoint events were reviewed and adjudicated by the Endpoint Adjudication Committee (EAC) to ensure that all events that were reported were judged uniformly using the same criteria. The first confirmed suspected endpoint event for a patient was counted for the trial's composite primary endpoint, "event free survival". The composite primary endpoint, "event free survival," was defined for a patient as the date randomized to trial treatment to the date of the first documented non-fatal event, related to cardiac and liver function, transformation to AML, or death due to any cause.

When a patient had a non-fatal event, related to cardiac and liver function, and transformation to AML, the trial treatment (deferasirox or placebo) was discontinued. After trial treatment was discontinued, a 28 days post treatment safety assessment for AEs and SAEs was completed. Any patient who died during the treatment or 28 day post treatment safety assessment is represented in the all-cause mortality table in the safety section of this result. After trial treatment was discontinued for a patient, their treatment was un-blinded. Subsequent iron chelation treatment was subject to the patient's and investigator's decision. Patients continued to be followed during the post-treatment evaluation or survival follow up period, depending on their choice.

For patients who did not meet a non-fatal event, study treatment was continued as long as the patient and the treating physician felt it was in the best interest for the patient or until the trial terminated/completed. There was no un-blinding of the trial treatment for patients who terminated trial treatment without meeting a non-fatal event. Patients continued to be followed during the post-treatment evaluation or survival follow up period, depending on their choice.

A patient who discontinued study treatment without meeting a non-fatal component of the composite primary endpoint continued to be evaluated every 3 months. Once a patient stopped study evaluations they were followed for at least every 6 months for overall survival and any iron chelation therapies they are receiving up to the end of study.

Post-treatment evaluation period:

For patients who had a non-fatal event: After treatment termination, all patients were followed for safety (28 days) and then evaluated with visits every three months if they agreed to move into the post treatment evaluation phase.

For patients who did not meet a non-fatal event: After termination of study treatment, if a patient and investigator chose the post-treatment evaluation period, the patient was followed for safety and endpoints at visits occurring every three months.

Survival Follow Up period:

Subsequent to the post treatment evaluation period, or at the end of treatment period, if a patient and treating physician decided that the patient would not participate in the post treatment evaluation period, the patient was followed every 6 months for overall survival and iron chelation therapies.

The end of the study was defined as three years from the date the last patient was enrolled (last patient first visit).

The sample size of 210 patients did not provide sufficient power for testing statistical hypotheses. The statistical analysis was revised accordingly to concentrate on evaluating the treatment effect of deferasirox relative to placebo, and the study phase designation was changed from Phase lll to Phase II. Amendment 4 of the study adjusted the sample size, statistical analysis, and duration of the study and added two secondary endpoints: Hematologic improvement (HI) in terms of erythroid response and Frequency and rate of infections requiring intravenous (IV) antimicrobials. Upon approval of the amendment, patients signed a new consent form and continued the appropriate visit schedule.

Arms: arm 1: 10 mg/kg/day (once daily) for the first 2 weeks of treatment, followed by 20 mg/kg/day (once daily) from Week 2 to End of Treatment. After 3 months of treatment at 20 mg/kg/day, the dose was allowed to be adjusted by 5 or 10 mg/kg/day up to 40 mg/kg/day based on serum ferritin responses. When a target serum ferritin level was reached (usually between 500 and 1000 µg/L), the dose could be reduced by 50% to maintain the serum ferritin within the target range. arm 2: 10 mg/kg/day (once daily) for the first 2 weeks of treatment, followed by 20 mg/kg/day (once daily) from Week 2 to End of Treatment. After 3 months of treatment at 20 mg/kg/day, the dose was allowed to be adjusted by 5 or 10 mg/kg/day up to 40 mg/kg/day based on serum ferritin responses. When a target serum ferritin level was reached (usually between 500 and 1000 µg/L), the dose could be reduced by 50% to maintain the serum ferritin within the target range.
Interventions: intervention 1: Deferasirox intervention 2: Placebo
Intervention descriptions: intervention 1: Deferasirox provided as 125 mg, 250 mg, and 500 mg dispersible tablets for oral use intervention 2: Inactive ingredients used as a placebo comparator, provided as 125 mg, 250 mg, and 500 mg dispersible tablets for oral use

Protocol documents:
Prot_001.pdf: 
Clinical Development 
Deferasirox (ICL670, Exjade®) 
Clinical Trial Protocol CICL670A2302 / NCT00940602 
A multi-center, randomized, double-blind, placebo-
controlled clinical trial of deferasirox in patients with 
myelodysplastic syndromes (low/int-1 risk) and 
transfusional iron overload (TELESTO) 
Authors 
 
Document type 
Amended Protocol Version 
EUDRACT number 
2009-012418-38 
Version number 
05 (Clean) 
Development phase 
II 
Document status 
Final 
Release date 
22-Sep-2014
Property of Novartis 
Confidential 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 


Novartis 
Confidential 
Page 2 
Amended Protocol Version 05 (Clean) 
 
Protocol No. CICL670A2302 
 
Table of contents 
Table of contents ............................................................................................................. 2 
List of Post-text supplements .......................................................................................... 5 
List of tables ................................................................................................................... 5 
List of figures .................................................................................................................. 5 
List of abbreviations ........................................................................................................ 6 
Amendment 5.................................................................................................................. 8 
Summary of previous amendments ................................................................................ 12 
Oncology clinical study protocol synopsis ..................................................................... 28 
1 
Background ................................................................................................................... 36 
1.1 
Overview of myelodysplastic syndrome (MDS) ................................................. 36 
1.2 
Overview of deferasirox (ICL670) ..................................................................... 37 
1.3 
Safety profile ..................................................................................................... 38 
2 
Study rationale/purpose ................................................................................................. 38 
3 
Objectives ..................................................................................................................... 39 
3.1 
Primary objective ............................................................................................... 39 
3.1.1 
Endpoints for primary objective ......................................................... 39 
3.2 
Secondary objectives ......................................................................................... 41 
3.2.1 
Endpoints for secondary objectives .................................................... 41 
4 
Study design ................................................................................................................. 42 
5 
Population ..................................................................................................................... 44 
5.1 
Inclusion criteria ................................................................................................ 44 
5.2 
Exclusion criteria ............................................................................................... 44 
6 
Treatment ...................................................................................................................... 46 
6.1 
Investigational and control drugs ....................................................................... 46 
6.1.1 
Study drug ......................................................................................... 46 
6.1.2 
Preparation and storage ...................................................................... 47 
6.2 
Treatment arms .................................................................................................. 52 
6.3 
Patient numbering .............................................................................................. 52 
6.4 
Treatment assignment ........................................................................................ 53 
6.5 
Treatment blinding............................................................................................. 54 
6.6 
Treating the patient ............................................................................................ 54 
6.6.1 
Study drug/study treatment/active control administration ................... 54 
6.7 
Permitted study drug adjustments....................................................................... 55 
6.7.1 
Dosing modifications ......................................................................... 55 
6.7.2 
Follow-up for toxicities ...................................................................... 59 


Novartis 
Confidential 
Page 3 
Amended Protocol Version 05 (Clean) 
 
Protocol No. CICL670A2302 
 
6.7.3 
Rescue medication ............................................................................. 59 
6.7.4 
Other concomitant medications .......................................................... 59 
6.7.5 
Study drug discontinuation................................................................. 61 
6.7.6 
Premature patient withdrawal ............................................................. 62 
6.7.7 
Emergency unblinding of treatment assignment ................................. 63 
7 
Visit schedule and assessments...................................................................................... 64 
7.1 
Information to be collected on screening failures ............................................... 70 
7.2 
Patient demographics/other baseline characteristics ........................................... 70 
7.3 
Treatments ......................................................................................................... 70 
7.4 
Efficacy ............................................................................................................. 71 
7.4.1 
Composite primary endpoint .............................................................. 71 
7.5 
Safety ................................................................................................................ 71 
7.5.1 
Adverse events ................................................................................... 71 
7.5.2 
Physical examination, weight, height ................................................. 72 
7.5.3 
Vital signs .......................................................................................... 73 
7.5.4 
Auditory and ocular examination ....................................................... 73 
7.5.5 
Laboratory evaluations ....................................................................... 73 
7.5.6 
Electrocardiogram (ECG) .................................................................. 76 
7.5.7 
Echocardiogram (ECHO) ................................................................... 76 
7.5.8 
Chest X-ray........................................................................................ 77 
7.5.9 
Bone marrow biopsy or aspirate ......................................................... 77 
7.5.10 
Liver abnormalities ............................................................................ 77 
7.5.11 
Cardiac function ................................................................................ 78 
7.5.12 
Unscheduled safety visits ................................................................... 79 
7.6 
Pharmacokinetics ............................................................................................... 79 
7.7 
Exploratory biomarker studies ........................................................................... 79 
8 
Safety monitoring .......................................................................................................... 79 
8.1 
Serious adverse event reporting.......................................................................... 79 
8.2 
Pregnancies........................................................................................................ 80 
9 
Data review and data management ................................................................................ 80 
9.1 
Site monitoring .................................................................................................. 80 
9.2 
Data collection ................................................................................................... 81 
9.3 
Database management and quality control ......................................................... 81 
9.4 
Data Monitoring Committee .............................................................................. 82 
10 Statistical methods and data analysis ............................................................................. 82 
10.1 
Populations for analysis ..................................................................................... 83 
10.2 
Patient demographics and other baseline characteristics ..................................... 83 


Novartis 
Confidential 
Page 4 
Amended Protocol Version 05 (Clean) 
 
Protocol No. CICL670A2302 
 
10.3 
Treatments (study drug, concomitant therapies, compliance).............................. 83 
10.4 
Primary objective ............................................................................................... 84 
10.4.1 
Variable ............................................................................................. 84 
10.4.2 
Statistical hypothesis, model, and method of analysis ......................... 84 
10.4.3 
Handling of missing values/censoring/discontinuations ...................... 86 
10.4.4 
Supportive and sensitivity analyses .................................................... 88 
10.5 
Secondary objectives ......................................................................................... 89 
10.5.1 
Secondary efficacy objectives ............................................................ 89 
10.5.2 
Secondary safety objectives ............................................................... 93 
10.5.3 
Other safety data ................................................................................ 95 
10.5.4 
Tolerability ........................................................................................ 96 
10.5.5 
Pharmacokinetics ............................................................................... 96 
10.5.6 
Biomarkers ........................................................................................ 96 
10.6 
Interim analysis ................................................................................................. 96 
10.7 
Sample size calculation ...................................................................................... 96 
10.8 
Power for analysis of critical secondary variables .............................................. 96 
11 Administrative procedures............................................................................................. 96 
12 Protocol adherence ........................................................................................................ 99 
13 References (available upon request) ............................................................................ 100 
 


Novartis 
Confidential 
Page 5 
Amended Protocol Version 05 (Clean) 
 
Protocol No. CICL670A2302 
 
List of Post-text supplements 
1. [Post-text supplement 1] - International Prognostic Scoring System 
2. [Post-text supplement 2] - MDS Risks group 
3. [Post-text supplement 3] - ECOG Performance Status 
4. [Post-text supplement 4] - IWS MDS Hematologic Response Criteria 
 
List of tables 
Table 6-1 
Dosing table for 5 mg/kg/d for deferasirox or placebo ........................ 48 
Table 6-2 
Dosing table for 10 mg/kg/d for deferasirox or placebo ...................... 48 
Table 6-3 
Dosing table for 15 mg/kg/d for deferasirox or placebo ...................... 48 
Table 6-4 
Dosing table for 20 mg/kg/d for deferasirox or placebo ...................... 49 
Table 6-5 
Dosing table for 25 mg/kg/d for deferasirox or placebo ...................... 49 
Table 6-6 
Dosing table for 30 mg/kg/d for deferasirox or placebo ...................... 50 
Table 6-7 
Dosing table for 35 mg/kg/d for deferasirox or placebo ...................... 51 
Table 6-8 
Dosing table for 40 mg/kg/d for deferasirox or placebo ...................... 52 
Table 7-1 
Visit evaluation schedule ................................................................... 65 
Table 7-2 
Laboratory evaluations ....................................................................... 75 
 
List of figures 
Figure 4-1 
Study design ...................................................................................... 43 
 


Novartis 
Confidential 
Page 6 
Amended Protocol Version 05 (Clean) 
 
Protocol No. CICL670A2302 
 
List of abbreviations 
AE 
Adverse Event 
ALT/SGPT 
alanine aminotransferase/glutamic pyruvic transaminase/GPT 
AML 
Acute Myeloid Leukemia 
ANCOVA 
Analysis of Covariance 
AST/SGOT 
aspartate aminotransferase/glutamic oxaloacetic transaminase/GOT 
BL 
Baseline Visit 
BNP 
Brain Natriuretic Peptide 
CBC 
Complete Blood Count 
CHF 
Congestive Heart Failure 
CK 
Creatine Kinase 
CoMed 
Concomitant Medication 
CPO 
Country Pharma Organizations 
Cr 
Creatinine 
CRO 
Contract Research Organization 
CTCAE 
Common Terminology Criteria for Adverse Events 
DAR 
Dosage Administration Record 
DFO 
Deferoxamine 
DMC 
Data Monitoring Committee 
DS&E 
Drug Safety and Epidemiology 
DSM 
Drug Supply Management 
EAC 
Endpoint Adjudication Committee 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EPO 
Erythropoietin 
FAS 
Full Analysis Set 
FPFV 
First Patient First Visit 
GCP 
Good Clinical Practice 
GGT 
Gamma-Glutamyl Transpeptidase 
GI 
Gastrointestinal 
HDPE 
High Density Polyethylene 
HI 
Hematologic Improvement 
HR 
Hazard Ratio 
IB 
Investigators’ Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
ICT 
Iron Chelation Therapy 
IN 
Investigator’s Notification 
IO 
Iron Overload 
IPSS 
International Prognostic Scoring System 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
IVRS 
Interactive Voice Response System 


Novartis 
Confidential 
Page 7 
Amended Protocol Version 05 (Clean) 
 
Protocol No. CICL670A2302 
 
IWG 
International Working Group 
IWRS 
Interactive Web Response System 
KM 
Kaplan-Meier 
LDH 
Lactase Dehydrogenase 
LIC 
Liver Iron Concentration 
LVEF 
Left Ventricular Ejection Fraction 
LVIDD 
Left Ventricular Internal end-diastolic dimension 
LVISD 
Left Ventricular Internal end-systolic dimension 
MCV 
Mean Corpuscular Volume 
MDRD 
MoDification of Renal Disease 
MDS 
Myelodysplastic syndromes 
MedDRA 
Medical Dictionary for Regulatory Activities 
OGTT 
Oral Glucose Tolerance Test 
OS 
Overall Survival 
PD 
Pharmacodynamics 
PK 
Pharmacokinetics 
PPS 
Per Protocol Analysis Set 
PRBC 
Packed Red Blood Cells 
PSB 
Program Safety Board 
RAEB 
Refractory Anemia with Excess Blasts 
RAP 
Report and Analysis Plan 
RBC 
Red Blood Count 
REB 
Research Ethics Board 
SAE 
Serious Adverse Event 
SC 
Steering Committee 
SD 
Standard Deviation 
SF 
Serum Ferritin 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
TSH 
Thyroid Stimulating Hormone 
UGT 
Uridine 5'-diphospho-glucuronosyltransferase 
ULN 
Upper Limit of Normal 
UPCR 
Urine Protein: Urine Creatinine Ratio 
WBC 
White Blood Count 
WHO 
World Health Organization 


Novartis 
Confidential 
Page 8 
Amended Protocol Version 05 (Clean) 
 
Protocol No. CICL670A2302 
 
Amendment 5 
Amendment rationale 
At the time of this amendment, 192 patients have been randomized in the study and 175 
patients failed screening. 
The purpose of amendment 5 is to clarify exclusion criteria and provide guidance regarding 
dose modifications, concomitant medications, and contraception as detailed below. 
The exclusion criteria and dose modification guidelines were updated to exclude patients with 
moderate and severe hepatic impairment (Child-Pugh Class B and C). In addition, guidance 
on treating patients who develop moderate hepatic impairment (Child-Pugh Class B) during 
the trial and immediate discontinuation if severe hepatic impairment (Child-Pugh Class C) or 
Stevens-Johnson syndrome occurs is being provided, in alignment with the Exjade prescribing 
information. 
Guidance is included on the use of contraception. Effective contraception is required in 
alignment with the Exjade prescribing information. Highly effective contraception was 
inadvertently added to amendment 4 of this protocol. Embryo-fetal development animal 
studies did not show evidence of teratogenicity and there were no developmental effects noted 
at doses that were not toxic to the maternal animals. Guidance is updated in this amendment 
to correct this administrative error. 
Additional guidance was added regarding treatment discontinuation of patients with creatinine 
clearance < 40 mL/min or serum creatinine > 2 time the age appropriate ULN, and caution in 
patients with creatinine clearance between 40 and less than 60 mL/min, in alignment with the 
Exjade prescribing information. 
Guidance was added regarding the concomitant administration of deferasirox with compounds 
metabolized through CYP3A4, CYP2C8, and CYP1A2; and the concomitant use of UGT 
inducers and bile acid sequestrants in alignment with the Exjade prescribing information. 
Clarification to the visit schedule, adverse events, and collection and reporting bone marrow 
assessments was also added. In addition, modification in hematologic improvement analysis 
was provided for clarification. 
Changes to the protocol amendment 5 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions. 
Changes to Protocol Synopsis 
• Inclusion/exclusion criteria: Child-Pugh Class B and C were added as hepatic diseases 
which would prevent study treatment. 


Novartis 
Confidential 
Page 9 
Amended Protocol Version 05 (Clean) 
 
Protocol No. CICL670A2302 
 
Changes to Section 5.1 Inclusion criteria 
• Contraception requirements were modified to clarify that effective contraception methods 
are required in line with the known safety profile of deferasirox. The Highly effective 
methods were removed as their addition was an administrative error in the previous 
amendment (4). 
Changes to Section 5.2 Exclusion criteria 
• Child-Pugh Class B and C were added to “Systemic diseases which would prevent study 
treatment” as hepatic conditions that would prevent study treatment. 
Changes to Section 6.7.1.3 Elevations in serum creatinine 
• Caution regarding treatment of patients with creatinine clearance between 40 and less than 
60 mL/min, and guidance for discontinuation of study medication in case serum creatinine 
is >2 times the age-appropriate upper limit or if creatinine clearance <40 mL/min, were 
added. 
Changes to Section 6.7.1.6 Skin Rash 
• Guidance was included requiring immediate and permanent discontinuation of study drug 
if Stevens-Johnson Syndrome is suspected. Sections 6.7.1.6.1 and 6.7.1.6.2 were added to 
separate Stevens-Johnson syndrome from other rashes. 
Changes to Section 6.7.1.7 Elevated liver function tests 
• Title of this section was changed from “Elevated liver function tests” to “Liver function 
abnormalities”. 
• Dose modification rules were added related to moderate hepatic impairment (Child-Pugh 
Class B). In the event Child Pugh B criteria are met, study drug dosing will be interrupted. 
If liver disease prognosis improves, study medication can be introduced at 10 mg/kg/day 
or 50% of the previous dose, whichever is less. At the Investigator’s discretion, the dose 
may then be increased by 5 mg/kg/day every 2 weeks to a maximum of 50% of the 
patient’s previous dose. 
• Guidance was included requiring immediate and permanent discontinuation of study drug 
if Child Pugh Class C is suspected. 
Sections 6.7.1.8, 6.7.1.9 and 6.7.1.10 added 
• Guidance was added for dose modifications related to auditory (decreased hearing) and 
ocular (lens opacities) disturbances, hypersensitivity reactions, and cytopenias, to reflect 
the Exjade prescribing information. 
Changes to Section 6.7.4 Other concomitant medications 
• Section 6.7.4.1 “Concomitant therapy requiring caution and/or action” was added. 
• Section 6.7.4.1 “The concomitant administration of deferasirox and vitamin C has not 
been formally studied. Doses of vitamin C up to 200 mg/d have not been associated with 
adverse consequences” was moved from Section 6.7.4 to Section 6.7.4.1. 
• Section 6.7.4.1 “Aluminum containing antacid therapies should be avoided because they 
may bind to deferasirox” was moved from Section 6.7.4 to Section 6.7.4.1. 


Novartis 
Confidential 
Page 10 
Amended Protocol Version 05 (Clean) 
 
Protocol No. CICL670A2302 
 
• Section 6.7.4.1 cautions that taking study drug in combination with medications with 
known ulcerogenic potential may increase the risk of gastrointestinal irritation and 
bleeding. 
• Section 6.7.4.1 cautions that deferasirox may potentially decrease serum levels of 
substances metabolized through CYP3A4 and may increase serum concentrations of 
substances metabolized through CYP2C8. 
• Section 6.7.4.1 cautions that concomitant administration of deferasirox with CYP1A2 
substrates that have a narrow therapeutic index is not recommended. If deferasirox and 
theophylline are used concomitantly, monitoring or theophylline dose reductions should 
be considered. 
• Section 6.7.4.1 cautions that the use of bile acid sequestrants decreases deferasirox 
systemic exposure. 
• Section 6.7.4.1 cautions that the use of potent UGT may result in a decrease in deferasirox 
efficacy. 
Changes to Section 6.7.6.1 End of Treatment 
• Additional reasons for study drug discontinuation were added to align with newly released 
eCRF. 
Changes to Section 6.7.6.2 Study evaluation completion 
• Additional reasons for the end of study evaluation were added to align with newly 
released eCRF. 
Changes to Table 7-1 Visit evaluation schedule 
• A column and footnote were added to the table to show and describe the timing and 
requirements for the 28-day follow up (Visit 501). Footnotes “b” through “d” were 
amended to account for the addition of the visit description. 
• Evaluation period was altered to show that it begins on visit 502. 
• Minor change to footnote #4. “Hematological response” was changed to “hematological 
improvement”. 
• Urine pregnancy test was added for women of child bearing potential at the End of 
Treatment visit (777). 
Changes to Section 7.5.1 Adverse events 
• Clarification was added that MDS is not an adverse event in this study. MDS is a required 
condition for study entry and disease progression (including MDS progression and 
progression to AML) is a secondary efficacy endpoint. 
Changes to Section 7.5.5.5 Pregnancy Test 
• Urine pregnancy testing will be performed locally at the End of Treatment visit and if 
menses are delayed for more than 7 days in a female patient capable of becoming pregnant. 
Changes to Table 7-2 Laboratory evaluations 
• Urine pregnancy testing added to table for the End of Treatment visit (777) for female 
patients capable of becoming pregnant. 


Novartis 
Confidential 
Page 11 
Amended Protocol Version 05 (Clean) 
 
Protocol No. CICL670A2302 
 
Changes to Section 7.5.9 Bone marrow biopsy 
• Title of this section was changed from “Bone marrow biopsy” to “Bone marrow biopsy or 
aspirate” and clarification added regarding bone marrow assessments for Disease 
progression including MDS progression and progression to AML. 
Changes to Section 10.5.1.1 Secondary efficacy variables and related analyses 
• Clarification was added that the last pre-treatment hemoglobin value measured prior to the 
first dose of study medication will be used as the pre-treatment hemoglobin value (If 2 
pre-treatment Hemoglobin values are available and each is at least 7 days after any 
transfusion, an average of the 2 values will be used to determine the pre-treatment 
hemoglobin value). “Only RBC transfusions given for hemoglobin levels of equal to or 
less than 9 g/dL pre-treatment” was changed to “all RBC transfusions regardless of pre-
transfusion hemoglobin level” will count in the RBC transfusion response evaluation”. 
“Only the first episode of HI” was changed to “all episodes of HI” in the patient will be 
considered. 
• Clarification was added for bone marrow collected by biopsy or aspirate. 
IRB/IEC 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. In addition, sites are required to update and submit for approval a revised 
Informed Consent that takes into account the changes described in this amended protocol. 


Novartis 
Confidential 
Page 12 
Amended Protocol Version 05 (Clean) 
 
Protocol No. CICL670A2302 
 
Summary of previous amendments 
Amendment 4 
Amendment rationale 
The purpose of amendment 4 is to adjust the sample size, statistical analysis, and duration of 
the study and to add two secondary endpoints. Editorial and administrative changes are being 
made to ensure consistency and clarity in the protocol as a result of these changes. 
Since the initiation of this study in November 2009 the enrollment projections of 630 patients 
could not be met and as of July 2013 only 124 patients were enrolled. A reduction in the 
sample size to 210, which is based on the enrollment projection until December 2014, will 
support a timely completion of the study. 
The sample size of 210 patients does not provide sufficient power for testing statistical 
hypotheses. The statistical analysis has been revised accordingly to concentrate on evaluating 
the treatment effect of deferasirox relative to placebo, and the study phase designation has 
been changed to Phase II. The end of the study is no longer defined by the number of events 
for the primary endpoint, instead, the study will continue for three years from the date the last 
patient is enrolled. The individual patient treatment duration of at least three years remains 
unchanged. Overall survival has been changed from key secondary to secondary endpoint 
because of the reduction in sample size and statistical power. 
Two secondary endpoints have been added to assess the efficacy of treatment: 
• Hematologic improvement (HI) in terms of erythroid response 
The International Working Group 2006 (IWG 2006) criteria for hematologic 
improvement-erythroid (HI-E) as defined by improvement in hemoglobin levels or 
reduction in transfusion requirement are both particularly relevant in transfusion-
dependent patients with MDS (Cheson 2006). 
• Frequency and rate of infections requiring intravenous (IV) antimicrobials 
Infections are recognized as a cause of morbidity and mortality in MDS patients and the 
reduction of infections which require intravenous antimicrobials is therefore of relevance 
for those patients (Dayyani 2010). Iron availability is known to be essential for 
proliferation of microbes and the development of infections (Schaible 2004). The effect of 
chelation therapy or placebo on the frequency of infections requiring IV antimicrobials 
will be evaluated. 
As of July 2013, 124 patients had been enrolled in the study. Data will be available to support 
the analysis of the additional secondary endpoints for patients enrolled prior to the 
implementation of amendment 4. Upon approval of the amendment, patients will sign a new 
consent form and continue the appropriate visit schedule. 


Novartis 
Confidential 
Page 13 
Amended Protocol Version 05 (Clean) 
 
Protocol No. CICL670A2302 
 
Changes to the protocol amendment 4 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions. 
Changes to Protocol Synopsis 
• Study phase: The study phase was changed from phase III to phase II. 
• Purpose/rationale: The purpose of the study was changed to evaluate clinical benefit 
instead of demonstrating superiority. 
• Objectives: The primary objective was changed from statistical comparison to descriptive 
evaluation of the effect of deferasirox and placebo with regard to event-free survival. 
Overall survival was changed from key secondary to secondary endpoint. Hematological 
function expressed in transfusion requirements was incorporated in the added hematologic 
improvement endpoint based on IWG criteria. MDS progression and progression to AML 
was renamed to disease progression. Frequency of infections requiring IV antimicrobials 
was added. 
• Endpoints (efficacy, safety): Overall survival was changed from key secondary to 
secondary endpoint. Hematological function expressed in frequency/total amount of blood 
transfusions was incorporated in the added endpoint of proportion of patients with 
hematologic improvement. Time to MDS progression and progression to AML was 
renamed to time to disease progression. Frequency and rate of infections requiring IV 
antimicrobials was added. 
• Study design: Interim analyses were removed. The recruitment period was updated from a 
duration of 24 months to completion of recruitment in December 2014. The duration of 
study is no longer events driven. The study will be completed 3 years after the last patient 
is enrolled. 
• Population: The number of patients to be enrolled has been changed to at least 210. 
• Efficacy evaluation(s): Hematologic improvement was added to be evaluated. 
• DMC: Text related to the conduct of the interim analyses has been removed as well as the 
possibility to prematurely stop the study for evidence of a favorable risk/benefit 
relationship of deferasirox compared to placebo. 
• Statistical methods and data analysis: As there will be no key secondary endpoint, the 
analysis done for the per protocol analysis set was removed. The description related to the 
significance level and control of the overall type I error was removed as was any mention 
of the interim analyses. The confirmatory significance test was removed. The difference in 
survival functions will be tested in an exploratory sense only. Two sensitivity analyses 
will no longer be conducted because of the reduced sample size and expected number of 
events (structural-nested failure time model, non-proportional hazards model). 
Assumptions for and calculation of the sample size from the original protocol was 
removed and the new sample size stated. 


Novartis 
Confidential 
Page 14 
Amended Protocol Version 05 (Clean) 
 
Protocol No. CICL670A2302 
 
Changes to Section 3 Objectives 
The purpose of the study was changed to evaluate clinical benefit instead of demonstrating 
superiority. 
Changes to Section 3.2 Secondary objectives 
Changes as addressed above, in the protocol synopsis. 
Changes to Section 3.2.1 Endpoints for secondary objectives 
Changes as addressed above, in the protocol synopsis. 
Changes to Section 4 Study design 
Changes as addressed above, in the protocol synopsis. In addition, the required number of 244 
events has been removed from the explanation of adjudication of events. 
Changes to Section 5 Population 
The number of patients to be enrolled has been changed to at least 210, and Oceania has been 
added to the regions. 
Changes to Section 5.2 Exclusion criteria 
New pregnancy language was included in criterion for patients of child-bearing potential and 
in the definition under the “Women of child-bearing potential” subheading. Both include 
details regarding the use of highly effective methods of contraception. 
Changes to Section 6.5 Treatment blinding 
In the description of accessibility of randomization data prior to unblinding of the final 
database, the two exceptions related to the interim analyses (DMC as well as independent 
statistician and programmer) have been removed. The DMC has also been removed from the 
occasions of unblinding in the last sentence. The DMC may be unblinded on special request 
only. 
Changes to Table 7-1 
Week number of End of Treatment was changed from 260 to 372 to reflect the change in 
study duration specified in newly added footnote ‘a’. Study Evaluation Completion (visit 778) 
column was added to the table. 
Changes to Section 9.4 Data Monitoring Committee 
Text related to the conduct of the interim analyses has been removed as well as the possibility 
to prematurely stop the study for evidence of a favorable risk/benefit relationship of 
deferasirox compared to placebo. 
Changes to Section 10.1 Populations for analysis 
Key secondary endpoint was removed from analyses done for the per protocol analysis set. 
Changes to Section 10.4 Primary objective 
The primary objective was changed from comparison (statistical test) to evaluation 
(description). 


Novartis 
Confidential 
Page 15 
Amended Protocol Version 05 (Clean) 
 
Protocol No. CICL670A2302 
 
Changes to Section 10.4.2 Statistical hypothesis, model, and method of analysis 
A paragraph was added explaining the change in statistical analysis. 
Changes to Section 10.4.2.1 Statistical hypotheses 
The description of the statistical hypotheses was moved after the paragraphs on estimation. 
They were denoted as exploratory. 
Changes to Section 10.4.2.2 Statistical hypothesis test 
The description of the statistical test was moved to the end of Section 10.4.2. The test was 
denoted as exploratory. 
Changes to Section 10.4.2.3 Estimation of survival functions for event-free survival 
Text related to the interim analyses was removed. 
Changes to Section 10.4.2.4 Stratified unadjusted Cox proportional hazards regression 
model 
The last sentence about adjusting the estimates for the group-sequential design has been 
deleted. 
Changes to Section 10.4.3 Handling of missing values/censoring/discontinuations 
Text for the case of censoring at the time of interim analysis has been deleted. 
Changes to Section 10.4.4 Supportive and sensitivity analyses 
The description of the following sensitivity analyses was removed: structural-nested failure 
time model, analysis considering non-proportional hazards, analyses based on the PPS. 
Changes to Section 10.5.1 Secondary efficacy objectives 
Test about overall survival as key secondary endpoint as well as description of the testing 
strategy was removed. Overall survival will only be tested in an exploratory sense. 
Changes to Section 10.5.1.1 Secondary efficacy variables and related analyses 
The analysis of overall survival and further time to event endpoints was changed from testing 
to estimation of hazard ratio. Tests will only be performed in an exploratory sense. 
Hematologic improvement in terms of erythroid response and infections were added as 
secondary endpoints. 
MDS progression or progression to AML was renamed “Disease progression”. 
Changes to Section 10.5.2.2 Secondary safety variables and related analyses 
The analysis of time to study drug discontinuation will concentrate on estimating the hazard 
ratio. The test will be exploratory only. 
Changes to Section 10.6 Interim analysis 
The interim analyses foreseen in the original protocol will not be performed due to the 
reduced sample size. The description was removed from the section and a statement inserted 
that no interim analyses will be done. 


Novartis 
Confidential 
Page 16 
Amended Protocol Version 05 (Clean) 
 
Protocol No. CICL670A2302 
 
Changes to Section 10.7 Sample size calculation 
The sample size calculation from the original protocol was removed and the new sample size 
stated. 
Changes to Section 10.8 Power for analysis of critical secondary variables 
Text related to the power of the key secondary endpoint was removed. 
IRB/IEC 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. In addition, sites are required to update and submit for approval a revised 
Informed Consent that takes into account the changes described in this amended protocol. 
Amendment 3 
Amendment rationale 
The purpose of amendment 3 is to modify some of the inclusion and exclusion criteria, to 
modify the liver function component of the composite endpoint, to incorporate the specific 
wording regarding the sponsor standard Interactive Response Technology (IRT) eligibility 
criteria, and to correct typographical errors and inconsistencies. 
The inclusion/exclusion criteria are being modified to address the most common reasons for 
the 60% screen failure rate observed among patients that are being screened for the study and 
are in alignment with the study steering committee discussions. This would also allow MDS 
patients that are more commonly seen in the real-world setting as described by the 
investigators to be enrolled, hence allowing more patients to participate in the study. The 
upper limit of serum ferritin inclusion criterion is being removed so that patients qualify for 
inclusion if their serum ferritin is >1000 mcg/L. The liver transaminases ALT/AST exclusion 
criterion is being changed from >2.5 x ULN at screening to ALT/AST > 3.5 x ULN at 
screening. The bilirubin exclusion criterion is being changed from total bilirubin > ULN at 
screening to total bilirubin > 1.5 x ULN at screening. The serum creatinine exclusion criterion 
is being changed from serum creatinine > 1.2 x ULN at screening to serum creatinine > 1.5 x 
ULN at screening. 
The change in ALT/AST exclusion criterion is supported by an analysis of pooled data from 
MDS patients enrolled in four studies (Studies A0108 A2204 A2409 US02) that show that 
patients with elevated ALT values up to and including 3.5 X ULN at study entry were not at 
higher risk of notable ALT increase when treated with deferasirox. The shift table below 
shows that only 1 out of 38 (2.6%) treated patients who had baseline ALT >ULN and ≤3.5 × 
ULN worsened to >3.5 x ULN to 5 × ULN at the end of treatment, whereas 15 patients 
(39.5%) remained at >ULN to ≤3.5 x ULN and 22 patients (57.9%) improved to ≤ULN. 
Baseline ALT was >3.5 x ULN - 5 × ULN in one patient and >5 × ULN in another, and both 
patients improved to >ULN - ≤3.5 x ULN at end of treatment. This change in ALT/AST 
exclusion criteria is further supported by previously published data in MDS patients showing 


Novartis 
Confidential 
Page 17 
Amended Protocol Version 05 (Clean) 
 
Protocol No. CICL670A2302 
 
that the decrease in serum ferritin with deferasirox treatment is associated with a decrease in 
ALT indicating a possible association between reduction of iron overload and improvement in 
liver function (Gatterman 2010) 
The serum creatinine exclusion criterion is slightly increased from >1.2 x ULN to > 1.5 ULN 
according to the CTCAE grade 1 which is supported by data from the US03 study. 
Among patients with normal (Grade 0) creatinine at baseline (N = 149), 48 patients (32.2%) 
had shifts to Grade 1 and 4 patients (2.7%) had shifts to Grade 2. A total of 12 patients having 
a Grade 1 serum creatinine at baseline had a Grade 2 value post-baseline; this represented 
54.5% of the 22 patients with a Grade 1 baseline value. Thus, the incidence of treatment 
emergent shifts from baseline in serum creatinine levels was 37.4% (64/171). Shifts of more 
than one grade occurred for just those patients with a normal baseline. 
The component of the composite endpoint defining liver function impairment as reflected by 
ALT or AST changes is being modified in correspondence with the change in ALT/AST 
exclusion criterion from being > 2 x the baseline value and > 3 x ULN to > 2 x the baseline 
value and > 3.5 x ULN. The part of the component related to total bilirubin is left unchanged. 
The component of the secondary efficacy endpoint defining “time to first occurrence of serum 
ferritin” has been modified to correspond with the change in the serum ferritin inclusion 
criterion. 
Shift table of ALT (U/L) from baseline value to end of study value (Pooled MDS 
data (A0108 A2204 A2409 US02) - Per Protocol Set) 
 
End of study 
 
Baseline 
≤ ULN 
> ULN – 
≤ 3.5 × ULN 
> 3.5 × ULN – 
≤ 5 × ULN 
> 5 × ULN 
> 5 × ULN 
and > 2 × BL 
Total 
 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
≤ ULN 
28 (90.3) 
3 (9.7) 
0 (0.0) 
0 (0.0) 
0 (0.0) 
31 (100.0) 
> ULN – 
≤ 3.5 × ULN 
22 (57.9) 
15 (39.5) 
1 (2.6) 
0 (0.0) 
0 (0.0) 
38 (100.0) 
> 3.5 × ULN – 
≤ 5 × ULN 
0 (0.0) 
1 (100.0) 
0 (0.0) 
0 (0.0) 
0 (0.0) 
1 (100.0) 
> 5 × ULN 
0 (0.0) 
1 (100.0) 
0 (0.0) 
0 (0.0) 
0 (0.0) 
1 (100.0) 
Total 
50 (70.4) 
20 (28.2) 
1 (1.4) 
0 (0.0) 
0 (0.0) 
71 (100.0) 
As of this amendment, 42 patients have been enrolled in the study, 81 have failed screening. 
With the implementation of this amendment, more patients are expected to meet the eligibility 
criteria to participate in the study. 
The most frequent reason for screen failure due to laboratory assessment are summarized in 
the table on the next page. 


Novartis 
Confidential 
Page 18 
Amended Protocol Version 05 (Clean) 
 
Protocol No. CICL670A2302 
 
Reason for screen failure due to laboratory assessment 
Reason for Screen failure 
Number of Patients 
ALT or AST >2.5 x ULN 
15 
Total Bilirubin > ULN 
17 
Ferritin > 3500 mcg/L 
5 
Ferritin < 1000 mcg/L 
14 
Serum Creatinine > 1.2 x ULN 
1 
Creatinine Clearance < 40 ml/min 
5 
Significant Proteinuria 
4 
Changes to the protocol amendment 3 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions. 
Changes to List of Abbreviations 
• Abbreviations updated to reflect additions and deletions 
Changes to Protocol Synopsis and Inclusion/Exclusion Criteria (Sections 5.1 & 5.2) 
• The inclusion and exclusion criteria have been modified to remove the upper limit of 
serum ferritin at screening, to increase the ALT or AST exclusion criterion to > 3.5 x ULN 
at screening, to increase the bilirubin exclusion criterion to 1.5xULN at screening, and to 
increase the serum creatinine exclusion criterion to 1.5 x ULN at screening. 
Changes to Section 3.1.1 Endpoints for primary objective 
• ALT or AST > 2 times the baseline value and >3.5 times ULN 
Changes to Section 4 Study design 
• Table 4-1 changed to Figure 4-1 
New study design figure included 
• A screening period lasting up to 35 days with two screening visits (Visit 1 and Visit 2 at 
least 14 days apart) will be used to assess patient eligibility. 
• After 3 months of treatment, at the dose of 20mg/kg/day, dose may be adjusted by 5 to 
10 mg/kg/day up to 40 mg/kg/day based on serum ferritin response. 
Changes to Section 5 Population 
• Male or female patients, > 18 years of age with low/int-1 MDS, as determined by IPSS 
score, who have serum ferritin >1000 mcg/L at screening 
Changes to Section 5.1 Inclusion Criteria 
• Serum ferritin will be measured at Screening Visit 1 and Screening Visit 2 (at least 14 
days apart) and the mean value will be used for eligibility criteria. 
Changes to Section 5.2 Exclusion Criteria 
• Serum creatinine will be measured at Screening Visit 1 and Screening Visit 2 (at least 14 
days apart) and the mean value will be used for eligibility criteria. 


Novartis 
Confidential 
Page 19 
Amended Protocol Version 05 (Clean) 
 
Protocol No. CICL670A2302 
 
Changes to Section 6.1.2.1 Study Drug 
After 3 months of treatment at the dose of 20 mg/kg/day, the dose can be adjusted by 5 or 
10 mg/kg/day up to 40 mg/kg/day based on serum ferritin response. 
Changes to Section title 6.7.1.3 
• Elevations in serum creatinine 
Changes to Section 6.7.6 Premature patient withdrawal 
• If such withdrawal occurs, or if the patient fails to return for visits, the investigator must 
determine the primary reason for a patient’s premature withdrawal from the study and 
record this information on the Study Evaluation Completion (778) eCRF and notify 
IVRS. 
Changes to Section 7 Visit schedule and assessments 
• Following registering in IRT for screening, patient eligibility will be checked once all 
screening procedures are completed. The eligibility check will be embedded in the IRT 
system. Detailed guidelines to be followed can be found in the IRT manual. 
Changes to Table 7-1 Footnote 4 
• Repeat bone marrow aspiration and cytogenetics, iron stains and biopsy recommended at 
the time of major hematological response per IWG criteria. 
Changes to Section 7.5.5 Laboratory Evaluations 
• Safety laboratory parameters monitored at Screening Visit 1 and Weeks 2 – Study 
Evaluation Completion (778) will include… 
Changes to Section 7.5.5.1 Biochemistry 
• Blood samples will be sent to the central laboratory for chemistry analysis at the screening 
Visit 1 and Weeks 2 – End of Treatment (777). 
Change to Section 7.5.5.2 Urinalysis/Proteinuria 
• During Weeks 2-260 and End of Treatment (777), a midstream, non-first voided… 
Changes to Section 7.5.5.3 Transfusion requirements, hematologic counts 
• Complete blood counts will be drawn at screening Visit 1 and Weeks 2-260 and End of 
Treatment (777). 
Changes to Sections 7.5.6 Electrocardiogram and 7.5.7 Echocardiogram 
• Weeks 12, 24, 36, 52, 64, 76, 88, 104, 116, 128, 140, 156, 168, 180, 192, 208, 220, 232, 
244, 260, and End of Treatment Visit (777). 
Changes to Section 13 References (available upon request) 
• Gattermann N. Finelli C, Porta MD, et al (2010). Deferasirox in iron-overloaded patients 
with transfusion-dependent myelodysplastic syndromes: Results from the large 1-year 
EPIC study. Leuk Res 34:1143-1150 


Novartis 
Confidential 
Page 20 
Amended Protocol Version 05 (Clean) 
 
Protocol No. CICL670A2302 
 
IRB/IEC 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. These changes do not affect the global informed consent, If these changes 
affect the country-specific informed consent, sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
amended protocol. 
Amendment 2 
Amendment rationale 
This protocol has been updated to include changes to the inclusion/exclusion criteria, to 
clarify the frequency of assessments listed in Table 7-1 (visit evaluation schedule) and all 
relevant sections, to update the screening visit procedures, to update laboratory evaluation 
parameters and to address several administrative errors. 
The inclusion/exclusion criteria are being changed due a greater than 90% pre-screen failure 
rate in patients being considered for the study, and after discussions with the Study Steering 
Committee members. The notable changes to the inclusion criteria include allowing patients 
into the trial that have been previously iron chelated for no more than six months 
cumulatively (such as daily deferasirox (Exjade) or deferiprone or 5x/week deferoxamine 
from only including those who were chelation naïve. The minimum number of transfused 
units of blood is being changed from 20 units to 15 units and patients entering the study must 
be transfused with at least 8 units of PRBC annually from 8 times annually. The serum 
creatinine entry criteria is being changed from requiring serum creatinine >ULN at screening 
to serum creatinine >1.2x ULN at screening. The exclusion criteria of prior diagnosis of liver 
cirrhosis is being defined as either an established diagnosis or diagnosis by liver biopsy or 
central ultrasound reading. The exclusion criteria pertaining to left ventricular ejection 
fraction <50% by echocardiography must be confirmed by the central reading facility used in 
this trial. Lastly, patients with a history of another malignancy within the past five years, with 
the exception of basal cell skin carcinoma or cervical carcinoma in situ, has been expanded to 
include completely resected colonic polyps carcinoma in situ. 
The visit evaluation schedule is being revised to clarify the procedures required at the week 
260 visit (end of treatment visit) to allow for local laboratories to be used for weekly 
assessments that are required at the initiation of treatment and at the time of dose adjustments, 
as well to as to note that those patients who have a diagnosis of diabetes requiring treatment 
with medication do not require a 2 hour fasting glucose tolerance test to be performed. 
The screening visit period is being revised to allow for a 35 day screening window. This 
amendment also serves to outline the details of the screening visit and further define 
late/missed visits. 
This first center was initiated on 1-December-2009 in Canada. As of 12-November-2010, 15 
subjects have been screened and 5 subjects has been randomized to the trial. 


Novartis 
Confidential 
Page 21 
Amended Protocol Version 05 (Clean) 
 
Protocol No. CICL670A2302 
 
Changes to the protocol Amendment 2 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike-through red font for deletions, red (bold) for insertions. 
Changes to List of Abbreviations 
• Abbreviations updated to reflect additions and deletions 
Changes to Section Protocol Synopsis, Inclusion/Exclusion Criteria 
• Criteria have been amended to allow for ≤6 months of cumulative iron chelation therapy 
(such as daily deferasirox (Exjade) or deferiprone or 5x/week deferoxamine (intermittent 
deferoxamine doses in association with blood transfusions are not exclusionary regardless 
of duration of such treatment), to increase the serum creatinine value, to broaden the 
history of the transfusion range, to clarify transfusion requirements, to specify the central 
reading of echocardiography, to clearly define the liver cirrhosis criteria, and to expand 
the history of malignancies. 
Changes to Section 3.1.1 
• This section is being amended to make it clearer to the reader and to expand the details 
around the screening criteria. 
Changes in Section 4 
• This section is being amended to include further details on the screening procedures. 
Change to Section 5 
• This section is being amended to reflect the revised inclusion/exclusion criteria. 
Changes in Section 5.1 
• Changes as addressed above, in the protocol synopsis. 
Changes in Section 5.2 
• Changes as addressed above, in the protocol synopsis. 
Changes to Tables 6-1- 6-8 
• This section is being amended due to an administrative error. 
Changes to Section 6.4 
• This section is being amended to reflect the updates made in the IVRS process and to 
further define missed/late study visits. 
Changes to Section 6.6.1.1 
• This section is being amended to delete the statement on mixing cups. 
Changes to Section 6.7.5.1 
• This section is being amended to clarify discontinuation of study treatment. 
Changes to Section 6.7.5.2 
• This section is being amended to clarify discontinuation of study treatment. 


Novartis 
Confidential 
Page 22 
Amended Protocol Version 05 (Clean) 
 
Protocol No. CICL670A2302 
 
Changes to Table 7-1 
• Table 7-1 is being amended to correct administrative errors found in the table and 
footnotes section as well as to clarify the use of local laboratories, and to update glucose 
tolerance testing and BNP parameters. 
Changes to Section 7.1 
• This section is being amended to include pre-screening log details and re-screening 
procedures. 
Changes to Section 7.2 
• Changes as addressed above, in the protocol synopsis. 
Changes to Section 7.5.4 
• This section is being amended due to an administrative error. 
Changes to Section 7.5.5 
• This section is being amended to clarify the use of local laboratories. 
Changes to Section 7.5.5.2 
• This section is being amended to clarify serum ferritin testing. 
Changes in Table 7-2 
• This section is being amended to provide details on the oral glucose tolerance testing. 
Changes in Section 7.5.7 
• This section is being amended to clarify the echocardiogram (ECHO) central reading 
process. 
Changes in Section 7.5.9 
• This section is being amended to include the specific bone marrow assessments that are 
required. 
Changes in Section 7.5.10 
• This section is being amended to clarify the liver ultrasound central reading process. 
Changes in Section 8.2 
• This section is being amended to update the pregnancy outcome criteria, since female 
partners of those males participating in the trial are not consented. 
Changes in Section 10.4.3 
• This section is being amended to include “Progression to AML” 
IRB/IEC/REB Approval 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. In addition, if the changes herein affect the Informed Consent, sites are 


Novartis 
Confidential 
Page 23 
Amended Protocol Version 05 (Clean) 
 
Protocol No. CICL670A2302 
 
required to update and submit for approval a revised Informed Consent that takes into account 
the changes described in this amended protocol. 
Amendment 1 
Amendment rationale 
This protocol has been updated to include changes to the inclusion/exclusion criteria, changes 
to Table 7-1 (visit evaluation schedule) and all relevant sections, to update the Study Design 
section and to update the composite primary endpoint, as well as to incorporate changes to the 
statistical analysis agreed upon with the FDA. 
The inclusion/exclusion criteria are being changed due a greater than 90% pre-screen failure 
rate in patients being considered for the study. The notable changes are that the maximum 
serum ferritin level for inclusion is being raised from 2500 to 3500 mcg/L with a concurrent 
increase of the maximum number of transfused units of blood from 50 to 75. Additionally, the 
exclusion criteria of more than 3 years from diagnosis of MDS is being changed to more than 
3 years from the time the patient became transfusion dependent. 
The visit evaluation schedule is being revised to clarify the need for baseline BNP assessment 
and for a baseline chest x-ray, as well as to allow for local laboratories to be used for weekly 
serum creatinine assessments that are required at the initiation of treatment and at the time of 
dose adjustments. 
The composite primary endpoint is being updated to include transformation to AML as one of 
the parameters that composes the primary endpoint. Based upon recent data (Sanz 2008), iron 
overload may play a role in AML transformation in patients with MDS as patients with serum 
ferritin levels of ≥1000 ng/ml had a significantly higher rate of AML transformation than 
patients with serum ferritin levels of < 1000 mg/ml. Given that progression to AML is an 
extremely significant medical event in terms of both morbidity and mortality, it is appropriate 
to include as part of the composite primary endpoint. 
Changes to the protocol Amendment 1 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike-through red font for deletions, red (bold) for insertions. 
Changes to List of Abbreviations 
• Abbreviations updated to reflect additions and deletions 
Changes to Endpoint section 
• The composite primary endpoint has been updated to include transformation to AML as 
one of the parameters that compose the primary endpoint. 
Changes to Secondary Endpoint section 
• This section has been amended to further define the progression of AML. 


Novartis 
Confidential 
Page 24 
Amended Protocol Version 05 (Clean) 
 
Protocol No. CICL670A2302 
 
Changes to Section Protocol Synopsis, Inclusion/Exclusion Criteria 
• Criteria have been amended to allow for an expanded weight range, to increase the upper 
limit of Serum Ferritin and to increase the number of transfusions. The time since 
diagnosis of MDS criteria has been expanded upon and the left ventricular ejection 
fraction value has been decreased. Other exclusion criteria have been clarified. 
Changes to Section Protocol Synopsis, Supply, preparation, and administration 
• This section has been amended to address an administrative error. 
Changes to Protocol Synopsis, Patient Numbering 
• This section has been amended to address an administrative error 
Changes to Protocol Synopsis, Efficacy Assessments 
• This section has been modified to add the bone marrow biopsy performed to confirm the 
diagnosis of the AML transformation. 
Changes to Section Protocol Synopsis, Statistical methods and data analysis, 
• The statistical section has been updated. 
Changes to Special safety assessment(s) Section, Protocol Synopsis 
• This section has been amended to address an administrative error. 
Changes to Section 1.2 
• This section has been amended to address an administrative error. 
Changes to Section 2 
• This section has been amended to address an administrative error. 
Change to Section 3.1 
• Changes as addressed above, in the protocol synopsis. 
Changes to Section 3.2.1 
• Changes as addressed above, in the protocol synopsis. 
Changes to Section 4 
• This section has been amended to make it more clear to the reader. 
Change to Section 5.1 
• Changes as addressed above, in the protocol synopsis. 
Changes to Section 6.3 
• This section has been amended in order to make the IVRS process more defined. 
Changes to Section 6.4 
• This section has been amended in order to make some administrative changes. 
Changes to Section 6.6.1 
• This section was amended to clarify the IVRS procedures. 


Novartis 
Confidential 
Page 25 
Amended Protocol Version 05 (Clean) 
 
Protocol No. CICL670A2302 
 
Changes to Section 6.6.1.1 
• This section was amended to further clarify patient dosing procedures. 
Changes to Section 6.7 
• This section was amended to clarify permitted study dosage changes. 
Changes to Section 6.7.1.2 
• This section was amended to provide guidance surrounding the need to discontinue study 
drug. 
Changes to Section 6.7.1.3 
• This section was amended to clarify the instructions for a specific visit procedure. 
Changes to Section 6.7.1.4 
• See changes to Section 6.7.1.2 
Changes to Section 6.7.1.5 
• See changes to Section 6.7.1.2 
Changes to Section 6.7.1.6 
• See changes to Section 6.7.1.2 
Changes to Section 6.7.1.7 
• See changes to Section 6.7.1.2 
Changes to Section 6.7.4 
• This section was amended due to an administrative error. 
Changes to Section 6.7.5 
• This section was amended to clarify the end of study procedures. 
Changes to Section 6.7.5.2 
• See Section 6.7.5. 
Changes to Section 6.7.6.1 
• See Section 6.7.5. 
Changes to Section 6.7.6.2 
• See Section 6.7.5. 
Changes to Table 7-1 
• Table 7-1 was amended to add procedures as well as to make the visit schedule and all 
procedures more clear. 
Changes to Section 7.1 
• This section was amended to include the word “screening.” 
Changes to Section 7.2 
• This section was amended to include further blood tests. 


Novartis 
Confidential 
Page 26 
Amended Protocol Version 05 (Clean) 
 
Protocol No. CICL670A2302 
 
Changes to Section 7.3 
• This section was amended to include further descriptive information. 
Changes to Section 7.5.2 
• This section was amended due to administrative error. 
Changes to Section 7.5.3 
• This section was amended to include further descriptive information. 
Changes to Section 7.5.4 
• This section was amended to include further descriptive information. 
Changes to Section 7.5.5.2 
• This section was amended to include further descriptive information. 
Changes to Section 7.5.5.3 
• This section was amended to provide guidance surrounding the need to discontinue study 
drug. 
Changes to Section 7.5.5.4 
• This section was amended to include further descriptive information. 
Changes to Table 7-2 
• This section was amended due to administrative error. 
Changes to Section 7.5.6 
• This section was amended to correct the visit numbering. 
Changes to Section 7.5.7 
• This section was amended to correct the visit numbering. 
Changes to Section 7.5.8 
• This section was amended to provide guidance on when chest x-rays need to be performed. 
Changes to Section 7.5.9 
• This section was amended to include language surrounding the addition of the primary 
composite endpoint. 
Changes to Section 7.5.10 
• This section was amended to include further descriptive information. 
Changes to Section 8.1 
• This section was amended to reflect the change from IMS to DS&E. 
Changes to Section 8.2 
• This section was amended for clarification purposes. 
Changes to Section 10 
• This section was amended to further describe the statistical analysis. 


Novartis 
Confidential 
Page 27 
Amended Protocol Version 05 (Clean) 
 
Protocol No. CICL670A2302 
 
Changes to Section 10.4 
• This section was amended for clarification purposes. 
Changes to Section 10.4.3 
• This section was amended to further describe the statistical analysis. 
Changes to Section 10.4.4 
• This section was amended to further describe the statistical analysis. 
Changes to Section 10.5.1.1 
• This section was amended to further describe the statistical analysis. 
Changes to Section 10.5.2.4 
• This section was amended to further describe the statistical analysis. 
Changes to Section 10.7 
• This section was amended to further describe the statistical analysis. 
Changes to Reference Section 13 
• Reference has been added. 
IRB/IEC/REB Approval 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. In addition, if the changes herein affect the Informed Consent, sites are 
required to update and submit for approval a revised Informed Consent that takes into account 
the changes described in this amended protocol. 


Novartis 
Confidential 
Page 28 
Amended Protocol Version 05 (Clean) 
 
Protocol No. CICL670A2302 
 
Oncology clinical study protocol synopsis 
Investigational drug 
Deferasirox (ICL670, Exjade®) 
Protocol no. 
CICL670A2302 
Study phase 
II 
Study title 
A multi-center, randomized, double-blind, placebo-controlled, clinical trial of deferasirox 
in patients with Myelodysplastic Syndromes (Low/Intermediate-1 Risk) and transfusional 
iron overload. 
 
Background 
Myelodysplastic syndromes (MDS) are clonal stem cell disorders characterized by 
ineffective hematopoiesis in one or more cell lineages and has the potential to evolve to 
acute myeloid leukemia (AML). Treatment goals for patients with low/int-1 risk MDS 
primarily involve managing cytopenias. While specific therapies and the use of growth 
factors may alleviate transfusion requirements in some patients, 60-80% of patients do 
not respond and require ongoing platelet and red blood cell (RBC) transfusions due to 
impaired hematopoiesis. In many patients, this leads to chronic RBC transfusion therapy 
and the development of secondary iron overload (IO). Liver dysfunction, cirrhosis and 
endocrinopathies have been described in multi-transfused MDS patients (even with a 
short-term duration of transfusion), where even mild liver function abnormalities have 
been associated with marked hepatic iron overload and portal fibrosis on biopsy (Schafer 
1981, Jaeger 1992). Cardiac complications of iron overload secondary to long-term 
transfusion therapy are well-described in β-thalassemia major, but have not yet been 
well-described for the MDS population. Iron chelation therapy (ICT) has a long history in 
transfusion-dependent patients with hemoglobinopathies, primarily β-thalassemia major, 
with demonstrated improvement in organ dysfunction and survival in patients who are 
compliant with therapy (Olivieri 1997). Use of deferoxamine (DFO) in iron-overloaded 
MDS patients has been reported to improve organ dysfunction (Jensen 2003, Schafer 
1985), and even improve cytopenias (Jensen 1996). With the use of ICT, there have also 
been reports of improvements in glucose metabolism in iron-overloaded thalassemia 
major patients (Farmaki 2006), and reduced insulin requirements in MDS patients 
(Schafer 1985). However, poor patient compliance associated with the necessity of 
repeated subcutaneous infusions, as well as the potential for increased bruising/bleeding 
in patients with thrombocytopenia and/or platelet dysfunction are significant problems 
with DFO, particularly with elderly MDS patients. Therefore, the need exists for an iron 
chelator which could be administered via the more convenient oral route. 
 
Iron overload may impact survival in MDS, which is especially relevant for low-risk 
patients. A recent retrospective analysis of 467 MDS patients demonstrated that cardiac 
failure and liver cirrhosis constituted 51% and 8%, respectively, of the non-leukemic 
causes of death (Malcovati 2005). 
 
Moreover, secondary iron overload, reflected by a serum ferritin level greater than 
1,000 ng/mL, was associated with a poorer overall survival (OS). Recent, uncontrolled 
studies suggest a benefit of ICT upon survival in MDS (Leitch 2007, Rose 2010, Sanz 
2008). Leitch et al. reported results of a retrospective review of 178 MDS patients (60% 
with low/int-1 MDS). 
 
Eighteen patients received ICT for a median of 15 months. In low/int-1 patients, the 
median OS was 40 months for those not receiving ICT compared with a median OS not 
reached at 160 months for patients receiving ICT. Also, 80% of patients receiving ICT 
survived to 4 years from the time of diagnosis compared to 44% without ICT. In a non-
randomized, prospective 2 year follow-up of 165 MDS patients (59% low/int-1 risk) in an 
outpatient setting, Rose reported a median survival from time of diagnosis of 115 months 
in patients receiving ICT compared with 51 months in those who did not receive ICT. 
Sanz reported that the development of iron overload and transfusion dependency were 
strongly associated with AML transformation risk in MDS.These studies included patients 
with a wide range of transfusional iron intake, time since diagnosis of MDS and co-
morbidities. 
 


Novartis 
Confidential 
Page 29 
Amended Protocol Version 05 (Clean) 
 
Protocol No. CICL670A2302 
 
 
Deferasirox (Exjade®) is approved for the treatment of transfusional iron overload in over 
90 countries. Data on 47 MDS patients were included in the registration dossier (Study 
CICL670A0108). Efficacy was demonstrated based on changes in serum ferritin and liver 
iron content. 
 
The relationship between serum ferritin levels and clinical outcome is well described in 
patients with β-thalassemia (Cappellini 2006), but has not been well described in a 
prospective study until now. 
 
Purpose/rationale 
Use of iron chelation therapy has demonstrated benefits in terms of morbidity and 
mortality for chronically-transfused thalassemia patients with iron overload. Recent 
retrospective data (Leitch 2007, Rose 2010, Sanz 2008) suggest that overall survival 
may be improved in adult patients with MDS who receive iron chelation therapy. The 
purpose of this study is to evaluate in low/int-1 risk MDS patients, treated as per 
standard practice, the clinical benefit of deferasirox versus placebo, while rigorously 
monitoring relevant clinical parameters (cardiac and liver function and transformation to 
Acute Leukemia AML) potentially affected by iron overload complications. 
 
Objectives 
The primary objective is to evaluate deferasirox and placebo for event-free survival (a 
composite primary endpoint including death and non-fatal events related to cardiac and 
liver function, and transformation to AML) in low and int-1 risk MDS patients with 
transfusional iron overload. 
The secondary objectives are to evaluate: 
● Hematologic improvement (HI) in terms of erythroid response 
● Overall survival 
● Change in endocrine function (thyroid and glycemic control) 
● Disease progression (which includes MDS progression and progression to AML) 
● Change in serum ferritin level 
● Change in cardiac function 
● Frequency of infections requiring intravenous antimicrobials 
● Safety, in particular to assess the levels of increased risk for pre-specified adverse 
events (renal dysfunction, neutropenia, thrombocytopenia, gastrointestinal bleeding, and 
laboratory abnormalities) that would be clinically unacceptable in the context of the level 
of benefit that is likely to be provided by iron chelation using deferasirox in MDS patients 
with iron overload (see Fleming 2008 for general approach). 
 
Endpoints (efficacy, 
safety) 
Composite primary endpoint (event-free survival): 
Time from date of randomization to date when death or any of the non-fatal events 
defined below has been reached (event-free survival): 
● Death 
● Non-fatal event: 
1. Echocardiographic evidence of worsening cardiac function based on the following 
criteria: 
at least > 15% absolute decrease in left ventricular ejection fraction (LVEF) from 
screening value at two consecutive assessments at least two weeks apart OR LVEF 
below institutional limits of normal and at least > 10% absolute decrease from LVEF 
screening value at two consecutive assessments at least two weeks apart 
2. Hospitalization for congestive heart failure defined as follows: 
Overnight stay (i.e., change in calendar day) due to congestive heart failure confirmed by 
the presence of the following: 
a) 
At least one of the following symptoms: 
● 
Paroxysmal nocturnal dyspnea 
● 
Orthopnea 
● 
Dyspnea on exertion 


Novartis 
Confidential 
Page 30 
Amended Protocol Version 05 (Clean) 
 
Protocol No. CICL670A2302 
 
AND 
b) 
Two or more of the following signs consistent with heart failure: 
● 
Pulmonary edema by radiography 
● 
Rales 
● 
Enlarged heart by radiography 
● 
- Peripheral edema 
● 
- S3 gallop 
● 
- Hepatojugular reflux 
● 
Neck vein distention 
● 
Rapid weight gain 
● 
Elevated brain natriuretic peptide (BNP) 
AND 
c) 
Treatment with either intravenous diuretics, intravenous 
vasodilators, intravenous inotropes, mechanical fluid removal (e.g.,ultrafiltration or 
dialysis), or insertion of an intra-aortic balloon pump for hemodynamic compromise. 
Initiation of oral diuretics or intensification (doubling) of the maintenance diuretic dose 
will also qualify. 
3. Liver function impairment reflected by: 
● 
ALT or AST > 2 times the baseline value and > 3.5 times ULN 
AND 
● 
Total bilirubin > 2 mg/dL at two consecutive visits 
4. Liver cirrhosis confirmed by: 
● 
The presence of at least one of the following symptoms/signs: 
cirrhosis-related ascites, spontaneous bacterial peritonitis, hepatic encephalopathy, 
variceal bleeding due to portal hypertension 
OR 
● 
Abdominal ultrasonography (if clinically indicated) 
OR 
● 
Liver biopsy (if clinically indicated) 
5. Progression to Acute Myeloid Leukemia (confirmed by bone marrow biopsy or 
aspirate) All events which could potentially fulfill the criteria for one of the components of 
the composite primary endpoint, will be reported to the Endpoint Adjudication Committee 
(EAC) for assessment. 
 
Secondary endpoints: 
Efficacy: 
Proportion of patients with hematologic improvement in terms of erythroid response 
Overall survival 
Proportion of patients with hypothyroidism as assessed by annual TSH and free T4 
Proportion of patients with a worsening of glucose metabolism from baseline as 
assessed by annual oral glucose tolerance test (OGTT) 
Time to disease progression, i.e. either MDS progression defined as a transition into a 
higher MDS risk group based on IPSS scoring or progression to AML defined as >20% 
blasts in the bone marrow. 
Time to first occurrence of serum ferritin > 2 times the baseline value at two consecutive 
assessments (at least two weeks apart) 
Time to at least a 10% increase from baseline in left ventricular end-diastolic internal 
dimension (LVIDD) at two consecutive assessments at least two weeks apart 
Time to at least a 10% increase from baseline in left ventricular internal systolic diameter 
(LVISD) at two consecutive assessments at least two weeks apart 
Frequency and rate of infections requiring intravenous antimicrobials 
 


Novartis 
Confidential 
Page 31 
Amended Protocol Version 05 (Clean) 
 
Protocol No. CICL670A2302 
 
Safety: 
Proportion of patients with significant renal dysfunction defined as serum creatinine ≥ 2 
times ULN at two consecutive assessments (at least 7 days apart) 
Proportion of patients with newly occurring severe (CTCAE Grade 4) neutropenia or 
thrombocytopenia 
Proportion of patients with major gastrointestinal bleeding 
Time to study drug discontinuation due to an adverse event or laboratory abnormality 
Incidence of other adverse events and laboratory abnormalities 
 
Study design 
This is a prospective, randomized, double-blind, placebo-controlled, parallel group 
design study. 
 
The recruitment period is planned to last until December 2014. Patients will be assigned 
to either deferasirox or matching placebo (2:1 ratio in favor of deferasirox) by stratified 
randomization using an interactive voice response system (IVRS) and strata defined by 
IPSS (low vs int-1 MDS risk patients) and geographical region (Asian countries versus 
non-Asian countries) since the Asian population have a longer survival. (Matsuda 2005). 
 
The study will continue for 3 years from the date the last patient is enrolled. 
 
The end of study treatment may occur if a patient meets any non-fatal component of the 
composite primary endpoint (confirmed by the EAC). His/her individual randomized study 
treatment will be unblinded and discontinued at that time. The subsequent iron chelation 
treatment is subject to patient’s and the investigator’s decision. Patients will continue to 
be followed every 6 months for iron chelation therapies and overall survival once he/she 
discontinues from the study treatment. 
 
Patients who discontinue study treatment without meeting a non-fatal component of the 
composite primary endpoint will continue to be evaluated every 3 months. Once patients 
stop study evaluations they will be followed for at least every 6 months for overall 
survival and any iron chelation therapies they are receiving up to the end of study. 
 
The EAC is responsible for ensuring whether pre-specified endpoint criteria were met for 
all non-fatal events. The role of the EAC is to ensure that all events that have been 
reported by the sites are judged uniformly using the same criteria. The EAC is blinded to 
study treatment allocation. 
 
Population 
At least 210 adult patients with low or intermediate (int-1) MDS 
(Greenberg 1997) from approximately 126 centers will be enrolled in this protocol. 
Patients receiving locally approved treatment for MDS 
(e.g.,5’-azacitidine, lenalinomide, decitabine, EPO) are allowed to be randomized. 
 
Inclusion/exclusion 
criteria 
Key Inclusion criteria: 
● Male or female patients, ≥18 years of age 
● Patient must weigh between 35-135 kg 
● Patients with low or intermediate (int-1) risk MDS, as determined by IPSS score. This 
must be confirmed by a bone marrow examination within 6 months prior to study entry 
and must be hematologically stable 
● Ferritin > 1000 mcg/L at screening 
● History of transfusion of 15 to 75 PRBC units 
● Anticipated to be transfused with at least 8 units of PRBCs annually during the study 
Key Exclusion criteria: 
● More than 6 months of cumulative iron chelation therapy (such as daily deferasirox 
(Exjade®) or deferiprone or 5x/week deferoxamine) 
● Intermittent deferoxamine doses in association with blood transfusions are not 
exclusionary regardless of duration of such treatment. 


Novartis 
Confidential 
Page 32 
Amended Protocol Version 05 (Clean) 
 
Protocol No. CICL670A2302 
 
● More than 3 years since patient began receiving regular transfusions (2 units per 8 
weeks or 4 units received in a 3 month period) 
● Creatinine clearance <40 mL/min 
● Serum creatinine > 1.5 x ULN at screening 
● Serum creatinine will be measured at Screening Visit 1 and Screening Visit 2 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 at Visit 1 or Visit 2 (or alternatively in two of three 
samples obtained for screening) 
● ECOG performance status > 2 
● Left ventricular ejection fraction < 50% by echocardiography as per the central 
reading assessment 
● A history of hospitalization for congestive heart failure 
● Systemic diseases which would prevent study treatment (e.g. uncontrolled 
hypertension, cardiovascular, renal, hepatic (including Child-Pugh Class B and C), 
metabolic, etc.) 
● Clinical or laboratory evidence of active Hepatitis B or Hepatitis C (HBsAg in the 
absence of HBsAb OR HCV Ab positive with HCV RNA) 
● 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 > 3.5×ULN at screening 
● Total bilirubin > 1.5× ULN at screening 
● Diagnosis of liver cirrhosis (either established diagnosis or diagnosis by liver biopsy 
or central ultrasound reading) 
● 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 cell 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, or breast-feeding patients or patients of child-bearing potential not 
employing an effective method of birth control 
● History of drug or alcohol abuse within the 12 months prior to enrollment. 
 
Patient numbering 
IVRS will be utilized for stratified randomization (see Study Design section). Patient 
identification will incorporate a center number and subject number. 
 
Investigational and 
control drugs 
Investigational drug: ICL670 (deferasirox): 
● Drug formulation: dispersible tablets 
● Strength: - 125 mg, 250 mg, 500 mg 
● Mode of administration: oral use (suspension can be prepared in water, orange or 
apple juice) 
Control drug: placebo matching deferasirox 
 


Novartis 
Confidential 
Page 33 
Amended Protocol Version 05 (Clean) 
 
Protocol No. CICL670A2302 
 
Dose, regimen, 
treatment cycle 
Having completed the screening period, patients enrolled and randomized to deferasirox 
(ICL670, Exjade®) or matching placebo will begin study treatment. The following dosing 
schedule is to be followed: 
● 10 mg/kg/day (once daily) for 2 weeks, followed by 20 mg/kg/day (once daily) 
● After 3 months of treatment at the dose of 20mg/kg/day the dose can be adjusted by 
5 or 10 mg/kg/day up to 40 mg/kg/day based on serum ferritin response 
 
Supply, preparation, 
and administration 
When the patient has signed the informed consent form, the investigator or his/her staff 
will telephone the IVRS and provide the requested identifying information for the patient. 
The IVRS will then assign the medication number. During the scheduled visits, the 
investigator or pharmacist will dispense the appropriate number of drug bottles (125 mg, 
250 mg or 500 mg tablets) to the patient. The number of tablets of each strength, the 
medication numbers, visit number and date of dispensation will be recorded in the drug-
dispensing log. 
 
Visit schedule and 
assessments 
Refer to the attached table. 
Efficacy 
assessment(s) 
An ongoing evaluation of criteria for the composite primary efficacy endpoint must be 
completed for all patients randomized in this trial by the EAC. 
Left heart ventricle function measured by echocardiography at screening and then 
approximately every 3 months. 
Liver function determined by assessment of ALT/AST and total bilirubin at screening, 
and then monthly throughout the study. 
Endocrine function as determined by oral glucose tolerance test, TSH and free T4 
performed at screening and then annually. 
Hematologic improvement in terms of erythroid response (HI-E) based on change in Hgb 
or transfusion requirements pre-treatment and during the study will be evaluated. 
Bone Marrow biopsy or aspiration will be performed to confirm diagnosis of AML 
transformation, if suspected based upon results of peripheral blood analysis. 
Complete blood counts will be drawn at screening, then monthly throughout the study. 
Serum ferritin will be analyzed by a central laboratory, using a validated standard kit 
assay, on samples collected at screening (Visit 1) and prior to commencing study 
treatment (Visit 3), and then monthly during study. 
Infections requiring IV antimicrobials will be identified from the adverse events and the 
concomitant medication page. 
 
Special safety 
assessment(s) 
Clinical symptoms of cardiac dysfunction during the study. 
Hematology, liver enzymes (AST/SGOT and ALT/SGPT) and serum chemistry will be 
determined by a central laboratory at Visit 1 (screening) and then monthly during study. 
Serum creatinine at Visits 1 and 2 (screening) and then monthly during study. 
Proteinuria (urinary protein /creatinine ratio) at Visit 1 (screening) and then monthly 
during study. 
Ocular and auditory examinations will be performed at Visit 1(screening) and then 
annually until Study Evaluation Completion, unless otherwise indicated. 
 
Patient reported 
outcomes 
Not planned 
Pharmacokinetics 
Not planned 
Biomarker 
assessments 
Not planned 


Novartis 
Confidential 
Page 34 
Amended Protocol Version 05 (Clean) 
 
Protocol No. CICL670A2302 
 
Exploratory 
Biomarker 
pharmacodynamic 
studies involving 
tumor samples 
Not planned 
Optional Biomarker 
studies on 
additional or 
remaining samples 
Not planned 
DMC 
An independent Data Monitoring Committee will be established. It will include experts in 
hematology, cardiology, hepatology and biostatistics (the experts will be external to 
Novartis and will not otherwise be involved in this study). The DMC charter will be 
approved prior to enrollment of the first patient. The DMC will monitor patient safety and 
trial conduct, and receive a blinded summary of serious adverse events on a regular 
basis. The composition, frequency of the meetings, and roles will be detailed in the DMC 
charter (in appendix). The DMC may recommend to the Sponsor: 
● To continue the study as planned 
● To continue the study with modifications 
● To prematurely stop the study for unfavorable safety profile of deferasirox compared 
to placebo 
The DMC will give recommendations to the sponsor on any changes in study conduct. 
The DMC will meet prior to First Patient First Visit to finalize the DMC charter describing 
roles and responsibilities. 
 
Statistical methods 
and data analysis 
Analysis sets: 
● The Full Analysis Set (FAS) comprises all patients to whom study treatment has 
been assigned by randomization. According to the intention to treat principle, patients will 
be analyzed according to the treatment and strata they were assigned to during the 
randomization procedure. The FAS will be the primary analysis set for all statistical 
analyses of efficacy. 
● The Per Protocol Analysis Set (PPS) is a subset of the FAS and comprises all 
randomized patients whose first administered study medication was in accordance with 
the randomized assignment, and without protocol deviations regarding inclusion criteria 
with respect to underlying disease (e.g., low or intermediate-1 MDS according to IPSS 
and serum ferritin > 1000 mcg/L at screening). The PPS will be used as the secondary 
analysis set to perform statistical analyses of the primary efficacy endpoint. 
● The Safety Analysis Set includes all randomized patients who received at least one 
dose of study medication. Patients will be analyzed according to the study treatment they 
actually received (defined as the study medication administered first) and according to 
strata information recorded in the (e)CRF. All statistical analyses of safety and tolerability 
will be based on the Safety Analysis Set. 
Significance level: 
No confirmatory hypothesis tests will be performed. Two-sided 95% confidence intervals 
will be provided for estimating treatment effects of deferasirox relative to placebo. For 
some endpoints tests will be performed in an exploratory sense only. 
Statistical analysis methods: 
Patient demographics and baseline characteristics will be summarized by treatment 
group. 
Primary statistical analysis method for the primary endpoint: 
For the primary analysis, the following censoring rule will be applied: 
Patients not known to have experienced any event from the composite primary endpoint 
at the time of a data cut-off will be censored - irrespective of adherence to study 
treatment - at the last date when there has been evidence for being event-free (details in 
the full protocol). 
A point estimate and two-sided confidence interval for an unadjusted hazard ratio will be 
obtained from a Cox proportional hazard regression model stratified for the 


Novartis 
Confidential 
Page 35 
Amended Protocol Version 05 (Clean) 
 
Protocol No. CICL670A2302 
 
randomization factors IPSS and geographical region (Asian countries versus non-Asian 
countries). 
For each treatment group, survival functions for time from randomization to the 
composite primary endpoint (event-free survival) will be estimated and displayed by the 
Kaplan-Meier method. 
Sensitivity/supportive/exploratory analyses for the primary endpoint: 
● Point estimate and two-sided confidence interval for an adjusted hazard ratio from a 
Cox proportional hazard regression model stratified for the randomization factors; 
adjustment for (partly data driven) demographic and/or baseline characteristics of clinical 
interest; 
● Unadjusted hazard ratio estimates for each of the strata defined by the randomization 
factors; 
● Analysis analog to the primary statistical analysis but patients with premature 
discontinuation of randomized study treatment will be censored at the day of last 
administration of randomized study treatment; 
● Summary of the types of events observed; 
● Statistical analyses based on the PPS instead of the FAS. 
Statistical analysis methods for secondary efficacy endpoints: 
Analyses will be described in the full clinical study protocol. 
Statistical analysis methods for safety endpoints: 
Following (Fleming 2008), the goal of this exploratory trial is not to determine whether 
there is significant evidence to rule out the null hypothesis of no increased risk. 
In contrast, the objective here is to exclude levels of increased risk (for pre-specified 
adverse events mentioned in the Endpoints section) that would be clinically 
unacceptable in the context of the level of benefit that is likely to be provided by iron 
chelation using deferasirox in MDS patients with iron overload. Therefore, two-sided 95% 
confidence intervals for risk (or hazard, if applicable) ratios will be calculated. Incidences 
of treatment emergent (serious) adverse events (including combinations of MedDRA 
terms as defined by Standardized MedDRA Queries) will be summarized by treatment 
group. Laboratory data will be summarized using descriptive statistics and shift tables 
(using CTCAE classification where available) by treatment group. 
Sample size: 
The sample size of 210 patients randomized in a ratio of 2:1 in favor of deferasirox is 
based on the enrollment projection. 


Novartis 
Confidential 
Page 36 
Amended Protocol Version 05 (Clean) 
 
Protocol No. CICL670A2302 
 
1 
Background 
1.1 
Overview of myelodysplastic syndrome (MDS) 
Myelodysplastic syndromes (MDS) are clonal stem cell disorders characterized by ineffective 
hematopoiesis in one or more cell lineages and by potential for evolution to acute myeloid 
leukemia (AML). Treatment goals for patients with lower risk MDS primarily involve 
managing cytopenias. While specific therapies and the use of growth factors may alleviate 
transfusion requirements in some patients, 60-80% of patients do not respond and require 
ongoing platelet and red blood cell (RBC) transfusions due to impaired hematopoiesis. 
In many patients, this leads to chronic RBC transfusion therapy, and the development of 
secondary iron overload (IO). Liver dysfunction, cirrhosis and endocrinopathies have been 
described in multi-transfused MDS patients (even with a short-term duration of transfusion), 
where even mild liver function abnormalities have been associated with marked hepatic iron 
overload and portal fibrosis on biopsy (Schafer 1981, Jaeger 1992). Cardiac complications of 
iron overload secondary to long-term transfusion therapy are well-described in β-thalassemia 
major, but have not yet been well-described for the MDS population. 
Iron chelation therapy (ICT) has a long history in transfusion-dependent patients with 
hemoglobinopathies, primarily β-thalassemia major, with demonstrated improvement in organ 
dysfunction and survival in patients who are compliant with therapy (Olivieri 1997). Use of 
deferoxamine (DFO) in iron-overloaded MDS patients has been reported to improve organ 
dysfunction (Jensen 2003, Schafer 1985), and even improve cytopenias (Jensen 1996). 
With the use of ICT, there have also been reports of improvements in glucose metabolism in 
iron-overloaded thalassemia major patients (Farmaki 2006), and reduced insulin requirements 
in MDS patients (Schafer 1985). However, poor patient compliance associated with the 
necessity of repeated subcutaneous infusions, as well as the potential for increased 
bruising/bleeding in patients with thrombocytopenia and/or platelet dysfunction are 
significant problems with DFO, particularly with elderly MDS patients. Therefore, the need 
exists for an iron chelator which could be administered via the more convenient oral route. 
Iron overload may impact survival in MDS, which is especially relevant for low-risk patients. 
A recent retrospective analysis of 467 MDS patients demonstrated that cardiac failure and 
liver cirrhosis constituted 51% and 8%, respectively, of the non-leukemic causes of death 
(Malcovati 2005). Moreover, secondary iron overload, reflected by a serum ferritin level 
greater than 1,000 ng/mL, was associated with a poorer overall survival (OS). 
Recent, uncontrolled studies suggest a benefit of ICT upon survival in MDS (Leitch 2007, 
Rose 2010, Sanz 2008). Leitch et al. reported results of a retrospective review of 178 MDS 
patients (60% with low/int-1 MDS). Eighteen patients received ICT for a median of 15 
months. In low/int-1 patients, the median OS was 40 months for those not receiving ICT 
compared with a median OS not reached at 160 months for patients receiving ICT. Also, 80% 
of patients receiving ICT survived to 4 years from the time of diagnosis compared to 44% 
without ICT. In a nonrandomized, prospective 2 year follow-up of 165 MDS patients (59% 
low/int-1 risk) in an outpatient setting, Rose reported a median survival from time of 
diagnosis of 115 months in patients receiving ICT compared with 51 months in those who did 


Novartis 
Confidential 
Page 37 
Amended Protocol Version 05 (Clean) 
 
Protocol No. CICL670A2302 
 
not receive ICT. Both studies included patients with a wide range of transfusional iron intake, 
time since diagnosis of MDS and co-morbidities. Sanz reported that the development of iron 
overload and transfusion dependency were strongly associated with AML transformation risk 
in MDS 
A recent review of safety data in 584 MDS patients pooled from Novartis-sponsored clinical 
trials confirms the current safety profile of deferasirox in the approved label regarding the 
most frequent adverse events associated with deferasirox such as gastrointestinal disorders 
(abdominal pain, diarrhea, nausea, vomiting) and renal disorders (increased blood creatinine). 
The overall profile of adverse events in the reviewed population was consistent with the 
clinical features of MDS such as age-related co-morbidities, MDS-related clinical symptoms 
and laboratory abnormalities. 
1.2 
Overview of deferasirox (ICL670) 
Deferasirox (ICL670, Exjade®) 
is an N-substituted bis-hydroxyphenyl-triazole, a 
representative of a new class of tridentate iron chelators (Nick 2003) 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 (Nick 
2003). 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 teratogenic nor carcinogenic. 
To date, deferasirox has been approved in more than 90 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 liver iron concentration (LIC) and serum ferritin. 
Detailed information on preclinical and clinical evaluation of deferasirox is provided in the 
current [Investigators’ Brochure]. 
Deferasirox is formulated as a dispersible tablet for oral suspension which facilitates 
administration of the appropriate quantity of drug substance to both pediatric and adult 
patients. Deferasirox is supplied as 125 mg, 250 mg and 500 mg tablets which can be 
dispersed in water, orange juice or apple juice. Bioavailability studies indicate that absorption 
is highly variable when deferasirox is taken together with food. Therefore, it is recommended 
that deferasirox is taken in the morning on an empty stomach, at least 30 minutes prior to food. 
More than 800 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. At least 500 patients received deferasirox. The studies showed 
deferasirox to effectively chelate iron in patients with transfusional iron overload as 
demonstrated by decreases in liver iron concentration (LIC) and serum ferritin (Porter 2008), 
(Cappellini 2006), (Vichinsky 2007). 
The efficiency of deferasirox in chelating iron appears to be constant at all doses ranging from 
5 to 40 mg/kg/day and is not affected by age, gender, baseline LIC or underlying anemia 
(Porter 2005). 


Novartis 
Confidential 
Page 38 
Amended Protocol Version 05 (Clean) 
 
Protocol No. CICL670A2302 
 
1.3 
Safety profile 
Deferasirox has demonstrated acceptable safety and tolerability in adult and pediatric patients 
with transfusional iron overload (Cappellini 2006), (Vichinsky 2007). 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 
postmarketing 
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 sometimes 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 postmarketing 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 high doses are given in patients with a low iron burden or with serum 
ferritin levels that are only slightly elevated. 
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. 
2 
Study rationale/purpose 
The primary purpose of this study is to prospectively assess the efficacy and safety of iron 
chelation therapy with deferasirox compared to placebo in patients with myelodysplastic 
syndromes (low/int-1 risk) and transfusional iron overload. 


Novartis 
Confidential 
Page 39 
Amended Protocol Version 05 (Clean) 
 
Protocol No. CICL670A2302 
 
It is well understood how excess iron damages organs and tissues, and deferasirox has been 
clearly demonstrated to reduce iron burden, as measured by LIC and serum ferritin. Data on 
the correlation between serum ferritin and morbidity and mortality come mainly from the 
thalassemia population, so the relevance of serum ferritin as a surrogate for clinical benefit 
has not been definitively proven in the MDS setting. Recent retrospective data (Leitch 2007), 
(Rose 2010) suggest that overall survival may be improved in adult patients with MDS who 
receive iron chelation therapy. 
3 
Objectives 
The purpose of this study is to evaluate in low/int-1 risk MDS patients, treated as per standard 
practice, the clinical benefit of deferasirox versus placebo, while rigorously monitoring 
relevant clinical parameters (cardiac and liver function) potentially affected by iron overload 
complications. 
3.1 
Primary objective 
The primary objective is to evaluate deferasirox and placebo with regard to event-free 
survival (a composite primary endpoint including death and non-fatal events related to cardiac 
and liver function and transformation to AML) in low and int-1 risk MDS patients with 
transfusional iron overload. 
3.1.1 
Endpoints for primary objective 
The primary endpoint is a composite primary endpoint (event-free survival) defined as time 
from date of randomization to date of death or any of the non-fatal events defined below has 
been reached: 
• Death 
• Non-fatal event (fulfilling the following criteria): 
1. Echocardiographic evidence of worsening cardiac function based on the following criteria: 
at least > 15% absolute decrease in left ventricular ejection fraction (LVEF) from 
screening value at two consecutive assessments at least two weeks apart 
OR 
LVEF below institutional limits of normal and at least > 10% absolute decrease from 
LVEF screening value at two consecutive assessments at least two weeks apart 
2. Hospitalization for congestive heart failure defined as follows: 
Overnight stay (i.e., change in calendar day) due to congestive heart failure confirmed by 
the presence of the following: 
a. At least one of the following symptoms: 
• Paroxysmal nocturnal dyspnea 
• Orthopnea 
• Dyspnea on exertion 
AND 


Novartis 
Confidential 
Page 40 
Amended Protocol Version 05 (Clean) 
 
Protocol No. CICL670A2302 
 
b. Two or more of the following signs consistent with heart failure: 
• Pulmonary edema by radiography 
• Rales 
• Enlarged heart by radiography 
• Peripheral edema 
• S3 gallop 
• Hepatojugular reflux 
• Neck vein distention 
• Rapid weight gain 
• Elevated brain natriuretic peptide (BNP) 
AND 
c. Treatment with either intravenous diuretics, intravenous vasodilators, intravenous 
inotropes, mechanical fluid removal (e.g., ultrafiltration or dialysis), or insertion of an 
intra-aortic balloon pump for hemodynamic compromise. Initiation of oral diuretics or 
intensification (doubling) of the maintenance diuretic dose will also qualify. 
3. Liver function impairment reflected by: 
• ALT or AST > 2 times the baseline value and > 3.5 times ULN 
AND 
• Total bilirubin > 2 mg/dL at two consecutive visits 
4. Liver cirrhosis confirmed by 
• The presence of at least one of the following symptoms/signs: 
cirrhosis-related ascites, spontaneous bacterial peritonitis, hepatic encephalopathy, 
variceal bleeding due to portal hypertension 
OR 
• Abdominal ultrasonography (if clinically indicated) 
OR 
• Liver biopsy (if clinically indicated) 
5. Progression to Acute Myeloid Leukemia (AML) confirmed by bone marrow biopsy or 
aspirate. 
All events which could potentially fulfill the criteria for one of the components of the 
composite primary endpoint, will be reported to the Endpoint Adjudication Committee (EAC) 
for assessment. Details for reporting events to the EAC will be outlined in both the 
investigative site manual and EAC manual. A summary describing the role of the EAC is 
located in Section 11 of this protocol. 


Novartis 
Confidential 
Page 41 
Amended Protocol Version 05 (Clean) 
 
Protocol No. CICL670A2302 
 
3.2 
Secondary objectives 
The secondary objectives are to evaluate: 
• Hematologic improvement (HI) in terms of erythroid response 
• Overall survival 
• Change in endocrine function (thyroid and glycemic control) 
• Disease progression (which includes MDS progression and progression to AML) 
• Change in serum ferritin level 
• Change in cardiac function 
• Frequency of infections requiring intravenous antimicrobials 
• Safety, in particular to assess the levels of increased risk for pre-specified adverse events 
(renal dysfunction, neutropenia, thrombocytopenia, gastrointestinal bleeding, and 
laboratory abnormalities) that would be clinically unacceptable in the context of the level 
of benefit that is likely to be provided by iron chelation using deferasirox in MDS patients 
with iron overload (see Fleming 2008 for general approach). 
3.2.1 
Endpoints for secondary objectives 
Endpoints for the secondary efficacy objectives are as follows (detailed definitions are given 
in Section 10.5.1.1): 
• Proportion of patients with hematologic improvement in terms of erythroid response 
• Overall survival 
• Proportion of patients with hypothyroidism as assessed by annual TSH and free T4 
• Proportion of patients with a worsening of glucose metabolism from baseline as assessed 
by annual oral glucose tolerance test (OGTT) 
• Time to disease progression, i.e. either MDS progression defined as a transition into a 
higher MDS risk group based on IPSS scoring or to progression to AML as defined in 
Section 7.5.9. 
• Time to first occurrence of serum ferritin > 2 times the baseline value at two consecutive 
assessments (at least two weeks apart) 
• Time to at least a 10% increase from baseline in left ventricular end-diastolic internal 
dimension (LVIDD) at two consecutive assessments at least two weeks apart 
• Time to at least a 10% increase from baseline in left ventricular internal systolic diameter 
(LVISD) at two consecutive assessments at least two weeks apart 
• Frequency and rate of infections requiring intravenous antimicrobials (Fenaux 2009) 
Endpoints for the other secondary safety objectives are as follows (detailed definitions are 
given in Section 10.5.2.2): 
• Proportion of patients with significant renal dysfunction defined as serum creatinine ≥ 2 
times ULN at two consecutive assessments (at least 7 days apart) 
• Proportion of patients with newly occurring moderate (CTCAE Grade 3) or severe 
(CTCAE Grade 4) neutropenia or thrombocytopenia 


Novartis 
Confidential 
Page 42 
Amended Protocol Version 05 (Clean) 
 
Protocol No. CICL670A2302 
 
• Proportion of patients with major gastrointestinal bleeding 
• Time to study drug discontinuation due to an adverse event or laboratory abnormality 
• Incidence of other adverse events and laboratory abnormalities 
4 
Study design 
This is a prospective, randomized, double-blind, placebo-controlled, parallel group design 
study. 
A screening period lasting up to 35 days with two screening visits (Visit 1 and Visit 2 - at 
least 14 days apart.) will be used to assess patient eligibility. Should the 35 day screening 
period be exceeded due to delays in scheduling exams as outlined in the protocol (such as 
ocular exams, audiometry testing, ECHO, etc.) this delay will not be considered a protocol 
deviation and all laboratory assessments outlined in Visit 1 must be repeated. In the event that 
it is more convenient for the site, confirmatory laboratory assessments may be collected by a 
local laboratory. Prior to a patient being randomized in the study (Visit 3), both the inclusion 
and exclusion criteria must be evaluated and documented in the source documents as being 
met and the results of all screening assessments must be available and reviewed by the 
investigator. At the randomization visit (Visit 3), patients will be randomized to 10 mg/kg/day 
of either deferasirox or matching placebo in a 2:1 manner in favor of deferasirox. As a control 
medication, placebo matching to each of the strength of the active compound will be utilized. 
Randomization will be stratified using an interactive voice/web response system 
(IVRS/IWRS). The stratification will be defined by IPSS (low or int-1) as well as by 
geographical region (Asian versus non-Asian countries) since the Asian population have a 
longer survival (Matsuda 2005). Details on stratification will be outlined in the study manual 
provided by the IVRS vendor. Starting from Day 1, patients will receive either deferasirox 10 
mg/kg/day or matching placebo for 2 weeks. At Week 2, the dose will be increased to 20 
mg/kg/day deferasirox or matching placebo in all patients. This dose should be maintained 
through Week 14 unless there is a safety related issue (see Section 6.1.2.1). After 3 months of 
treatment, at the dose of 20mg/kg/day, dose may be adjusted by 5 to 10 mg/kg/day up to 40 
mg/kg/day based on serum ferritin response. 
Study treatment should be administered by the patient once per day. During the treatment 
period, patients will return every 4 weeks to the site for routine procedures and for follow-up 
to monitor safety, efficacy and compliance with therapy. Should a patient require dose 
adjustments at any point during the trial, the patient may be asked to return more frequently to 
monitor safety and efficacy. 
The recruitment period is planned to last until December 2014. The study will continue for 3 
years from the date the last patient is enrolled. 
Patients meeting a non-fatal component of the composite primary endpoint 
The end of study treatment will occur if a patient meets any non-fatal component of the 
composite primary endpoint (Section 3.1.1) confirmed by the Endpoint Adjudication 
Committee (EAC). His/her individual randomized study treatment will be unblinded and 
discontinued at that time. The subsequent iron chelation treatment is subject to the patient’s 


Novartis 
Confidential 
Page 43 
Amended Protocol Version 05 (Clean) 
 
Protocol No. CICL670A2302 
 
and the investigator’s decision. After termination of study treatment, all patients will continue 
to be followed for safety and non-fatal components of the primary endpoint during the 
evaluation period at visits occurring every three months. Subsequent to the evaluation period, 
or at the end of treatment if a patient and treating physician decide that a patient will not 
participate in the evaluation period, patients will be followed every 6 months for iron 
chelation therapies and overall survival (“Survival Follow-up”). 
All suspected endpoint events will be reviewed and adjudicated by the EAC; however, only 
the first confirmed endpoint for a patient will be counted for the composite primary endpoint. 
The role of the EAC is to ensure that all events that have been reported are judged uniformly 
using the same criteria. The EAC is blinded to study treatment. 
Patients not meeting a non-fatal component of the composite primary endpoint 
For patients who do not meet a non-fatal component of the composite primary endpoint, study 
treatment will continue as long as the patient and treating physician feel it is in the best 
interest of the patient, or until the study terminates. There is no planned unblinding for 
patients who terminate study treatment without meeting a non-fatal component of the 
composite primary endpoint. After termination of study treatment, all patients will continue to 
be followed for safety and endpoints during the evaluation period at visits occurring every 
three months. Subsequent to the evaluation period, or at the end of treatment if a patient and 
treating physician decide that a patient will not participate in the evaluation period, patients 
will be followed every 6 months for iron chelation therapies and overall survival (“Survival 
Follow-up”). 
An external Data Monitoring Committee (DMC) will monitor patient safety and trial conduct 
and will receive a blinded summary of serious adverse events as detailed in the DMC Charter. 
The DMC may issue the following recommendations to the sponsor: 
• To continue the study as planned 
• To continue the study with modifications 
• To prematurely stop the study for unfavorable safety profile of deferasirox compared to 
placebo. 
Figure 4-1 
Study design 
 


Novartis 
Confidential 
Page 44 
Amended Protocol Version 05 (Clean) 
 
Protocol No. CICL670A2302 
 
5 
Population 
Male or female patients, ≥ 18 years of age with low/int-1 MDS, as determined by IPSS score, 
who have serum ferritin >1000 mcg/L at screening. 
At least 210 patients will be enrolled from North America, Latin America, Europe, Oceania 
and Asia. Patients who drop out from the study will not be replaced with additional patients. 
Patients must have eligibility evaluation performed prior to Visit 3 (randomization). Principal 
investigator must ensure that each patient signed an Informed Consent Form prior to any 
study 
related 
procedures 
and 
all 
inclusion/exclusion 
criteria 
are 
met 
prior 
randomization/enrollment of each patient into the study. The eligibility check will be done 
automatically via IVRS. Details on the patient eligibility review process can be found in the 
IVRS/IWRS site manual. In addition, the patient must be thoroughly informed about all 
aspects of the study, including the study visit schedule and required evaluations, and all 
regulatory requirements for informed consent. Written informed consent must be obtained 
from all patients prior to enrollment. The following criteria apply to all patients enrolled in the 
study unless otherwise specified: 
Inclusion/exclusion criteria 
5.1 
Inclusion criteria 
• Male or female patients, ≥ 18 years of age 
• Patient must weigh between 35–135 kg 
• Patients with low or intermediate (int-1) risk MDS, as determined by IPSS score. This 
must be confirmed by a bone marrow examination within 6 months prior to study entry 
and must be hematologically stable 
• Ferritin > 1000 mcg/L at screening 
• Serum ferritin will be measured at Screening Visit 1 and Screening Visit 2 (at least 14 
days apart) and the mean value will be used for eligibility criteria. 
• History of transfusion of 15 to 75 PRBC units 
• Anticipated to be transfused with at least 8 units of PRBCs annually during the study 
• Women of child-bearing potential using effective methods of contraception during dosing 
of study treatment (see ‘Women of Child-bearing Potential’ section below for details of 
acceptable contraceptive methods). 
5.2 
Exclusion criteria 
• More than 6 months of cumulative iron chelation therapy (such as daily deferasirox 
(Exjade®) or deferiprone or 5×/week deferoxamine) 
• Intermittent deferoxamine doses in association with blood transfusions are not 
exclusionary regardless of duration of such treatment 
• More than 3 years since patient began receiving regular transfusions (2 units per 8 weeks 
or 4 units received in a 3 month period) 
• Creatinine Clearance <40 ml/min 


Novartis 
Confidential 
Page 45 
Amended Protocol Version 05 (Clean) 
 
Protocol No. CICL670A2302 
 
• Serum creatinine > 1.5 × ULN at screening 
• Serum creatinine will be measured at Screening Visit 1 and Screening Visit 2 (at least 
14 days apart) 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 at Visit 1 or Visit 2 (or alternatively in two of three samples 
obtained for screening) 
• ECOG performance status > 2 
• Left ventricular ejection fraction < 50% by echocardiography as per the central reading 
assessment 
• A history of hospitalization for congestive heart failure 
• Systemic diseases which would prevent study treatment (e.g. uncontrolled hypertension, 
cardiovascular, renal, hepatic (including Child-Pugh Class B and C), metabolic, etc.) 
• Clinical or laboratory evidence of active Hepatitis B or Hepatitis C (HBsAg in the absence 
of HBsAb OR HCV Ab positive with HCV RNA positive) 
• 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 > 3.5 × ULN at screening 
• Total bilirubin > 1.5 × ULN at screening 
• Diagnosis of liver cirrhosis (either established diagnosis or diagnosis by liver biopsy or 
central ultrasound reading) 
• 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, or breast-feeding patients, or patients of child-bearing potential not employing 
an effective method of birth control (see Women of child-bearing potential, below, for 
further details regarding effective methods of birth control). 
• History of drug or alcohol abuse within the 12 months prior to enrollment 


Novartis 
Confidential 
Page 46 
Amended Protocol Version 05 (Clean) 
 
Protocol No. CICL670A2302 
 
Women of child-bearing potential 
Women of child-bearing potential, defined as all women physiologically capable of becoming 
pregnant, must use effective contraception during the study. 
Effective contraception methods include: 
• Total abstinence (when this is in line with the preferred and usual lifestyle of the subject. 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) 
and withdrawal are not acceptable methods of contraception. 
• Female sterilization (have had surgical bilateral oophorectomy (with or without 
hysterectomy) or tubal ligation at least six weeks before taking study treatment. In case of 
oophorectomy alone, only when the reproductive status of the woman has been confirmed 
by follow up hormone level assessment. 
• Male partner sterilization (at least 6 m prior to screening). For female subjects on the 
study, the vasectomized male partner should be the sole partner for that subject. 
• Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault 
caps) with spermicidal foam/gel/film/cream/vaginal suppository. 
• Placement of an intrauterine device (IUD) or intrauterine system (IUS). 
The use of hormonal contraceptives (oral or injected) is prohibited in this study due to a 
decrease in efficacy when used in combination with deferasirox. 
Women are considered post-menopausal and not of child bearing potential if they have had 12 
months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age 
appropriate, history of vasomotor symptoms).  
Patients who are found to be ineligible after screening procedures will have this documented 
on the screening log (see Section 6.3 and Section 7.1). These patients will not need to 
complete the end of study assessments. 
6 
Treatment 
6.1 
Investigational and control drugs 
The investigational study drug used in the course of this trial is deferasirox (ICL670, Exjade®) 
provided as 125 mg, 250 mg, and 500 mg dispersible tablets for oral use. As a control 
medication, placebo matching to each of the strength of active compound will be utilized. 
6.1.1 
Study drug 
Deferasirox (ICL670, Exjade®) and matching placebo will be provided as 125 mg, 250 mg, 
and 500 mg dispersible tablets packaged in bulk high density polyethylene (HDPE) bottles 
with induction seals and child resistant closures. Study medications will be blinded, i.e. 
placebo will be formulated and packaged to be indistinguishable from the 125 mg, 250 mg, 
and 500 mg tablets of deferasirox. 


Novartis 
Confidential 
Page 47 
Amended Protocol Version 05 (Clean) 
 
Protocol No. CICL670A2302 
 
Bottles of 35 tablets of each strength of deferasirox or corresponding placebo will be prepared, 
labeled and supplied by Novartis Drug Supply Management (DSM) to the local Country 
Pharma Organizations (CPOs) for further distribution to the study centers. 
Each study site will be supplied by Novartis with study drug in identically-appearing 
packaging. One component of the packaging has a 2-part label. Each part of this label 
contains a medication number corresponding to one of the treatment groups. Investigator staff 
will identify the study drug package to dispense to the patient by contacting the IVRS/IWRS 
and obtaining the medication number(s). Immediately before dispensing the package to the 
patient, investigator staff will detach the outer part of the label from the packaging and affix it 
to the source document (Drug Label Form) containing the patient’s unique patient number. 
Medication labels will comply with the legal requirements of the countries where the study is 
implemented and be printed in the local language. They will supply no information about the 
patient. Only the subject identifier will be entered on the medication label by the investigator 
or pharmacist before the corresponding medication is handed out to the patient. The storage 
conditions and the expiration date for study drug will be described on the medication label. 
6.1.2 
Preparation and storage 
6.1.2.1 
Study drug 
Study medication (deferasirox or placebo) must be taken once daily on an empty stomach at 
least 30 minutes before food consistently at the same time every day. 
The tablets are dispersed by stirring in a glass of water, orange or apple juice (100 ml to 200 
ml) until a fine suspension is obtained. Patients should be instructed to rinse any remaining 
residue from the glass with a small amount of water, orange or apple juice and drink this as 
well. 
Having completed the screening period, patients enrolled and randomized to deferasirox 
(ICL670, Exjade®) or matching placebo will begin study treatment. The following dosing 
schedule is to be followed: 
• 10 mg/kg/day (once daily) for 2 weeks, followed by 20 mg/kg/day (once daily) ( Week 2-
End of treatment) 
• After 3 months of treatment at the dose of 20mg/kg/day the dose can be adjusted by 5 or 
10 mg/kg/day up to 40 mg/kg/day based on serum ferritin response (see Section 6.7.1.2). 
The dose of 10 mg/kg/day given for the first 2 weeks of treatment has been implemented in 
order to reduce the risk of such adverse reactions as diarrhea, nausea, vomiting, and 
abdominal pain. 
Patients will be instructed to take the assigned amount of drug and will be obliged to return all 
unused study medication at their next visit. Study medication returned by the patient will be 
counted and unused tablets will be recorded by the investigator/pharmacist involved in the 
study. 
Drug accountability will be noted by the field monitor during site visits and at the completion 
of the trial. 


Novartis 
Confidential 
Page 48 
Amended Protocol Version 05 (Clean) 
 
Protocol No. CICL670A2302 
 
Table 6-1 
Dosing table for 5 mg/kg/d for deferasirox or placebo 
Pt Weight in Kg 
Closest Dose 
125 mg 
250 mg 
500 mg 
35-37 
125 
1 
 
 
38-62 
250 
 
1 
 
63-87 
375 
3 
 
 
88-112 
500 
 
 
1 
113-132 
625 
1 
 
1 
> 132 
625 
1 
 
1 
Table 6-2 
Dosing table for 10 mg/kg/d for deferasirox or placebo 
Pt Weight in Kg 
Closest Dose 
125 mg 
250 mg 
500 mg 
35-43 
375 
3 
 
 
44-56 
500 
 
 
1 
57-68 
625 
1 
 
1 
69-81 
750 
 
1 
1 
82-93 
875 
3 
 
1 
94-106 
1000 
 
 
2 
107-118 
1125 
1 
 
2 
119-131 
1250 
 
1 
2 
132 
1375 
3 
 
2 
> 132 
1375 
3 
 
2 
Table 6-3 
Dosing table for 15 mg/kg/d for deferasirox or placebo 
Pt Weight in Kg 
Closest Dose 
125 mg 
250 mg 
500 mg 
35-37 
500 
 
 
1 
38-45 
625 
1 
 
1 
46-54 
750 
 
1 
1 
55-62 
875 
3 
 
1 
63-70 
1000 
 
 
2 
71-79 
1125 
1 
 
2 
80-87 
1250 
 
1 
2 
88-95 
1375 
3 
 
2 
96-104 
1500 
 
 
3 
105-112 
1625 
1 
 
3 
113-120 
1750 
 
1 
3 
121-129 
1875 
3 
 
3 
130-132 
2000 
 
 
4 
>132 
2000 
 
 
4 


Novartis 
Confidential 
Page 49 
Amended Protocol Version 05 (Clean) 
 
Protocol No. CICL670A2302 
 
Table 6-4 
Dosing table for 20 mg/kg/d for deferasirox or placebo 
Pt Weight in Kg 
Closest Dose 
125 mg 
250 mg 
500 mg 
35-40 
750 
 
1 
1 
41-46 
875 
3 
 
1 
47-53 
1000 
 
 
2 
54-59 
1125 
1 
 
2 
60-65 
1250 
 
1 
2 
66-71 
1375 
3 
 
2 
72-78 
1500 
 
 
3 
79-84 
1625 
1 
 
3 
85-90 
1750 
 
1 
3 
91-96 
1875 
3 
 
3 
97-103 
2000 
 
 
4 
104-109 
2125 
1 
 
4 
110-115 
2250 
 
1 
4 
116-121 
2375 
3 
 
4 
122-128 
2500 
 
 
5 
129-132 
2625 
1 
 
5 
> 132 
2625 
1 
 
5 
Table 6-5 
Dosing table for 25 mg/kg/d for deferasirox or placebo 
Pt Weight in Kg 
Closest Dose 
125 mg 
250 mg 
500 mg 
35-37 
875 
3 
 
1 
38-42 
1000 
 
 
2 
43-47 
1125 
1 
 
2 
48-52 
1250 
 
1 
2 
53-57 
1375 
3 
 
2 
58-62 
1500 
 
 
3 
63-67 
1625 
1 
 
3 
68-72 
1750 
 
1 
3 
73-77 
1875 
3 
 
3 
78-82 
2000 
 
 
4 
83-87 
2125 
1 
 
4 
88-92 
2250 
 
1 
4 
93-97 
2375 
3 
 
4 
98-102 
2500 
 
 
5 
103-107 
2625 
1 
 
5 
108-112 
2750 
 
1 
5 
113-117 
2875 
3 
 
5 
118-122 
3000 
 
 
6 
123-127 
3125 
1 
 
6 
128-132 
3250 
 
1 
6 
> 132 
3375 
3 
 
6 


Novartis 
Confidential 
Page 50 
Amended Protocol Version 05 (Clean) 
 
Protocol No. CICL670A2302 
 
Table 6-6 
Dosing table for 30 mg/kg/d for deferasirox or placebo 
Pt Weight in Kg 
Closest Dose 
125 mg 
250 mg 
500 mg 
35 
1000 
 
 
2 
36-39 
1125 
1 
 
2 
40-43 
1250 
 
1 
2 
44-47 
1375 
3 
 
2 
48-52 
1500 
 
 
3 
53-56 
1625 
1 
 
3 
57-60 
1750 
 
1 
3 
61-64 
1875 
3 
 
3 
65-68 
2000 
 
 
4 
69-72 
2125 
1 
 
4 
73-77 
2250 
 
1 
4 
78-81 
2375 
3 
 
4 
82-85 
2500 
 
 
5 
86-89 
2625 
1 
 
5 
90-93 
2750 
 
1 
5 
94-97 
2875 
3 
 
5 
98-102 
3000 
 
 
6 
103-106 
3125 
1 
 
6 
107-110 
3250 
 
1 
6 
111-114 
3375 
3 
 
6 
115-118 
3500 
 
 
7 
119-122 
3625 
1 
 
7 
123-127 
3750 
 
1 
7 
128-131 
3875 
3 
 
7 
132 
4000 
 
 
8 
> 132 
4000 
 
 
8 


Novartis 
Confidential 
Page 51 
Amended Protocol Version 05 (Clean) 
 
Protocol No. CICL670A2302 
 
Table 6-7 
Dosing table for 35 mg/kg/d for deferasirox or placebo 
Pt Weight in Kg 
Closest Dose 
125 mg 
250 mg 
500 mg 
35-37 
1250 
 
1 
2 
38-41 
1375 
3 
 
2 
42-44 
1500 
 
 
3 
45-48 
1625 
1 
 
3 
49-51 
1750 
 
1 
3 
52-54 
1875 
3 
 
3 
55-59 
2000 
 
 
4 
60-62 
2125 
1 
 
4 
63-66 
2250 
 
1 
4 
67-69 
2375 
3 
 
4 
70-73 
2500 
 
 
5 
74-76 
2625 
1 
 
5 
77-80 
2750 
 
1 
5 
81-84 
2875 
3 
 
5 
85-88 
3000 
 
 
6 
89-91 
3125 
1 
 
6 
92-94 
3250 
 
1 
6 
95-98 
3375 
3 
 
6 
99-101 
3500 
 
 
7 
102-105 
3625 
1 
 
7 
106-108 
3750 
 
1 
7 
109-112 
3875 
3 
 
7 
113-116 
4000 
 
 
8 
117-119 
4125 
1 
 
8 
120-123 
4250 
 
1 
8 
124-126 
4375 
3 
 
8 
127-130 
4500 
 
 
9 
131-132 
4625 
1 
 
9 
> 132 
4625 
1 
 
9 


Novartis 
Confidential 
Page 52 
Amended Protocol Version 05 (Clean) 
 
Protocol No. CICL670A2302 
 
Table 6-8 
Dosing table for 40 mg/kg/d for deferasirox or placebo 
Pt Weight in Kg 
Closest Dose 
125 mg 
250 mg 
500 mg 
35 
1375 
3 
 
2 
36-39 
1500 
 
 
3 
40-42 
1625 
1 
 
3 
43-45 
1750 
 
1 
3 
46-48 
1875 
3 
 
3 
49-51 
2000 
 
 
4 
52-54 
2125 
1 
 
4 
55-57 
2250 
 
1 
4 
58-60 
2375 
3 
 
4 
61-64 
2500 
 
 
5 
65-67 
2625 
1 
 
5 
68-70 
2750 
 
1 
5 
71-73 
2875 
3 
 
5 
74-76 
3000 
 
 
6 
77-79 
3125 
1 
 
6 
80-82 
3250 
 
1 
6 
83-85 
3375 
3 
 
6 
86-89 
3500 
 
 
7 
90-92 
3625 
1 
 
7 
93-95 
3750 
 
1 
7 
96-98 
3875 
3 
 
7 
99-101 
4000 
 
 
8 
102-104 
4125 
1 
 
8 
105-107 
4250 
 
1 
8 
108-110 
4375 
3 
 
8 
111-114 
4500 
 
 
9 
115-117 
4625 
1 
 
9 
118-120 
4750 
 
1 
9 
121-123 
4875 
3 
 
9 
124-126 
5000 
 
 
10 
127-129 
5125 
1 
 
10 
130-132 
5250 
 
1 
10 
> 132 
5375 
3 
 
10 
6.2 
Treatment arms 
Patients will be assigned to one of the two arms in a ratio of 2:1, deferasirox or matching 
placebo. 
6.3 
Patient numbering 
Each patient in the study is uniquely identified by a 9 digit patient number which is a 
combination of his/her 4-digit center number and 5-digit subject number. The center number 
is assigned by Novartis to the investigative site. Upon signing the informed consent form, the 
patient is assigned a patient number by the investigator. At each site, the first patient is 
assigned patient number 00001, and subsequent patients are assigned consecutive numbers 


Novartis 
Confidential 
Page 53 
Amended Protocol Version 05 (Clean) 
 
Protocol No. CICL670A2302 
 
(e.g., the second patient is assigned patient number 00002, the third patient is assigned patient 
number 00003). The investigator or his/her staff will contact the IVRS/IWRS and provide the 
requested identifying information for the patient to register them into the IVRS. The assigned 
patient number will be entered into the “Subject ID” field on the EDC data entry screen. 
Should a patient screen fail, the patient number must be recorded as a screen failure in the 
IVRS/IWRS within 2 days of failing entry criteria. In addition, the Screening Log and 
Demography eCRFs should be completed for these patients. Any serious adverse events 
which occurred during screening and prior to randomization should be reported. Patient 
numbers will never be re-issued. A patient may be re-screened at the discretion of the 
investigator and assigned a new patient number. 
6.4 
Treatment assignment 
At baseline (Day 1, Visit 3), all eligible patients will be randomized via IVRS/IWRS to one of 
the treatment arms. The investigator or his/her delegate will call or log onto the IVRS/IWRS 
that will assign a randomization number to the patient once a series of eligibility questions are 
confirmed by the investigator or his/her delegate. The randomization number will be used to 
link the patient to a treatment arm and will specify a unique medication number(s) for the first 
package(s) of study drug to dispense to the patient. The randomization number will not be 
communicated to the caller. 
Randomization will be performed using the following procedure to insure that treatment 
assignment is unbiased and concealed from patients and investigator staff. A patient 
randomization list will be produced by the IVRS provider using a validated system that 
automates the random assignment of patient numbers to randomization numbers. The patient 
randomization list will be reviewed and approved by a member of the Biostatistics Quality 
Assurance Group. 
The randomization numbers are linked to the different treatment groups, which in turn are 
linked to medication numbers. A separate medication randomization list will be produced by 
or under the responsibility of Novartis DSM using a validated system that automates the 
random assignment of medication numbers to medication packs containing each of the study 
drugs. 
In the event that a patient is late for a regular scheduled visit, the visit week that should be 
followed and assessments that need to be recorded on the eCRF may vary. As a rule to follow, 
the time interval between the current scheduled “late visit” and the next scheduled visit should 
be divided in half. Should patients present themselves less than mid-way between visits (<15 
days), the assessments that should be taken are those for the earlier visit. Should patients 
present themselves ≥15 days after the scheduled visit, then the previous visit should be 
skipped and the next scheduled visit should be performed. In any event, future scheduled 
study visits must be scheduled based on the date of randomization (baseline visit) not based 
on the date of the previous visit. 


Novartis 
Confidential 
Page 54 
Amended Protocol Version 05 (Clean) 
 
Protocol No. CICL670A2302 
 
6.5 
Treatment blinding 
Patients, investigator staff, persons performing the assessments, and data analysts will remain 
blind to the identity of the study treatment from the time of randomization until database lock, 
using the following methods: 
1. Randomization data are kept strictly confidential until the time of final database 
unblinding, and will not be accessible by anyone else involved in the study with the 
following exceptions: 
• Independent Data Monitoring Committee (DMC) on special request only. 
• Independent statistician and programmer reporting to the DMC, 
• Investigator and patient once a patient meets a non-fatal event which is confirmed by 
the Endpoint Adjudication Committee (EAC). 
2. The identity of the study treatments will be concealed by the use of study drugs that are all 
identical in packaging, labeling, schedule of administration, appearance, and odor. 
Unblinding will only occur in the case of patient emergencies (on a per-patient basis), for 
regulatory reporting, and at the conclusion of the study. 
6.6 
Treating the patient 
6.6.1 
Study drug/study treatment/active control administration 
The patient will be instructed how to prepare his/her daily dose from the three tablet strengths 
of ICL670 or placebo available (125 mg, 250 mg, 500 mg). The dose will be assigned based 
on the patient’s weight (detailed in Table 6-1 through Table 6-8). During the scheduled visits 
the investigator staff will identify the study drug package(s) to dispense to the patient by 
contacting the IVRS/IWRS and obtaining the medication number(s). The investigator will 
distribute the appropriate number of study drug bottles containing tablets of 125 mg, 250 mg 
and/or 500 mg to the patient, including spare medication. 
Each time study medication is dispensed to the patient and/or the legal guardian the 
investigator will provide detailed instructions on how to prepare and administer the study drug 
properly according to Table 6-1 through Table 6-8. 
6.6.1.1 
Study drug administration 
The study medication packaging has a 2-part label. A unique medication number is printed on 
each part of this label which corresponds to one of the treatment arms. Investigator staff will 
identify the study drug package(s) to dispense to the patient by contacting the IVRS/IWRS 
and obtaining the medication number(s). Immediately before dispensing the package to the 
patient, investigator staff will detach the outer part of the label from the packaging and affix it 
to the source document (Drug Label Form) for that patient’s unique patient number. All drug 
kits assigned by the IVRS will be recorded in the IVRS. 
ICL670 and matching placebo should be taken daily at least 30 minutes before food, if 
possible consistently at the same time every morning. The tablets may be dropped into bottled 
water, tap water, apple juice or orange juice and gently stirred for 1 to 3 minutes until 
completely dispersed. Tablets should not be dispersed in carbonated liquids. For daily doses 


Novartis 
Confidential 
Page 55 
Amended Protocol Version 05 (Clean) 
 
Protocol No. CICL670A2302 
 
less than 1 g, the tablets should be dispersed in at least 100 ml (3.5 ounces), and for daily 
doses from 1 g to 3 g, the tablets should be dispersed in at least 200 ml (7 ounces). Following 
full disintegration of the tablets, the liquid should be consumed promptly. Any residue in the 
glass and/or on the stirrer should be dispersed in additional liquid and swallowed. 
6.6.1.2 
Study combination administration 
There is no combination therapy in this protocol. 
6.6.1.3 
Placebo administration 
Placebo will be administered in the same fashion as deferasirox. 
6.6.1.4 
Ancillary treatments 
Any additional therapy aimed to treat iron overload during this trial (e.g. therapy with 
hydroxyurea, butyrate) is not allowed. Except for the study medication, no other iron 
chelation therapy will be administered while patients are receiving study treatment in this trial. 
6.7 
Permitted study drug adjustments 
For patients who are unable to tolerate the protocol-specified dosing schedule, dose 
adjustments are permitted in order to keep the patient on study drug. For example, if the 
patient is unable to tolerate the 10 mg/kg/day dose, the investigator may decrease the dose to 
5 mg/kg/day. These changes must be recorded on the Dosage Administration Record (DAR) 
eCRF and IVRS/IWRS. For safety concerns, the investigator may titrate study drug dose at 
any time during the trial. 
As outlined below, study drug dose adjustments or interruptions will be implemented for 
specific changes in patient weight, serum ferritin, serum creatinine, ALT/AST and skin rash. 
In such cases, the change must always be recorded on the DAR eCRF. 
The majority of dose adjustments are covered in the Section 6.7.1 below. For cases where an 
exceptional dose adjustment (i.e., an adjustment not covered in the following sections) is 
considered necessary, the investigator will send a written request to Novartis. The request 
must justify the dose change and provide all the supportive clinical and laboratory information 
for complete evaluation by Novartis. Any exceptional dose adjustment for deferasirox needs 
to be authorized by Novartis. A written reply will be sent back to the investigator by Novartis 
within 5 working days. 
6.7.1 
Dosing modifications 
6.7.1.1 
Change in patient’s weight 
The dose of study drug will only be recalculated using Dosing Table 6-1 through Table 6-8 
during the study if the change (increase or decrease) in body weight exceeds 10% of the 
weight compared to the randomization visit. 


Novartis 
Confidential 
Page 56 
Amended Protocol Version 05 (Clean) 
 
Protocol No. CICL670A2302 
 
6.7.1.2 
Change in serum ferritin (SF) 
Serum ferritin should be monitored monthly, and the dose adjusted every 3 months according 
to serum ferritin trends. Dose adjustments should be made in steps of 5 or 10 mg/kg/day to 
achieve the desired rate of reduction or maintenance of iron burden. As patients reach a target 
serum ferritin level (usually between 500 and 1000 mcg/L) the dose can be reduced by 50% to 
maintain the serum ferritin within the target range. For most patients, maintenance dose will 
be between 10-20 mg/kg/day. 
If serum ferritin falls to ≤500 mcg/L, the investigator should consider an interruption of study 
medication until serum ferritin rises above 500 mcg/L according to the transfusion 
requirement. 
Dose may be increased by 5 or 10 mg/kg/day (to a maximum of 40 mg/kg/day) for patients 
with: 
1. Ferritin > 500 mcg/L who have an increasing trend of ferritin after a minimum of 3 
months of treatment. 
2. Ferritin > 1000 mcg/L who fail to have a decrease in ferritin after a minimum of 3 months 
of treatment. 
Dose must not be increased higher than 40 mg/kg/day. 
If after dose reduction, a progressive increase in serum ferritin is observed, study drug may be 
discontinued if the investigator believes it is in the best interest of the patient. Novartis may 
be contacted by the investigator to discuss dosing options that fall within the protocol 
guidelines if the investigator so desires. 
6.7.1.3 
Elevations in serum creatinine 
For patients who develop an increase in serum creatinine ≥33% above their baseline value 
(the mean value established at screening Visits 1 and 2) resulting in a serum creatinine above 
the ULN, on two consecutive occasions, a minimum of 7 days apart, the daily dose will be 
reduced by 10 mg/kg (or 5 mg/kg in patients receiving 10 mg/kg). 
If, after a dose reduction, serum creatinine remains above the ULN, a second dose reduction 
or treatment interruption is recommended. After an interruption, if serum creatinine falls 
below the age appropriate ULN on two consecutive visits, the investigator may resume 
therapy at 50% of the last dose and escalate cautiously. 
Serum creatinine should be monitored weekly, preferably by local labs, for the first month 
after study drug initiation or dose modification. Results of these labs need to be entered into 
the CRF only if they are significantly abnormal, defined as at least a 33% increase over the 
baseline value. 
If after dose reduction, a progressive increase in serum creatinine is observed, study drug may 
be discontinued if the investigator believes it is in the best interest of the patient. Novartis 
may be contacted by the investigator to discuss dosing options if the investigator so desires. 
Caution should especially be used in patients with creatinine clearance between 40 and less 
than 60 mL/min, particularly in cases where there are additional risk factors that may impair 
renal function such as concomitant medications, dehydration, or severe infections. 


Novartis 
Confidential 
Page 57 
Amended Protocol Version 05 (Clean) 
 
Protocol No. CICL670A2302 
 
Study medication should be discontinued in case serum creatinine increases >2 times the age-
appropriate upper limit or if creatinine clearance <40 mL/min. 
6.7.1.4 
Gastrointestinal disturbances 
Patients with gastrointestinal symptoms (including abdominal pain, nausea, vomiting, 
diarrhea) and/or patients who are unable to tolerate once a day study drug dosing, the 
following can be tried, in the order specified below: 
• Change the timing of study drug administration from morning to evening and in addition, 
try using an anti-diarrheal agent for 2 days in case of diarrhea. 
• If the symptoms still continue, try administering the daily dose as a split dose b.i.d.(twice 
daily). Once symptoms resolve, b.i.d. should be switched back to once daily. 
Should the gastrointestinal issues persist, study drug may be discontinued if the investigator 
believes it is in the best interest of the patient. Novartis may be contacted by the investigator 
to discuss dosing options if the investigator so desires. 
6.7.1.5 
Increased proteinuria 
For patients who develop proteinuria or a worsening of pre-existing proteinuria (assessed by a 
dipstick) at any visit, urine samples should be collected and assessed by the central laboratory. 
If any other causes of proteinuria have been excluded, the dose should be reduced by 50%. 
Should the proteinuria persist, study drug may be discontinued if the investigator believes it is 
in the best interest of the patient. Novartis may be contacted by the investigator to discuss 
dosing options if the investigator so desires. 
6.7.1.6 
Skin rash 
6.7.1.6.1 Stevens-Johnson syndrome 
Severe skin reactions, including Stevens-Johnson syndrome (SJS), have been reported during 
Exjade therapy. 
If SJS is suspected, study treatment must be immediately discontinued and not be 
reintroduced. 
6.7.1.6.2  Skin Rash (other than SJS) 
For skin rash of mild/moderate severity (defined as those causing minimal symptoms which 
require no or minimal supportive treatment), study drug should be continued without dose 
adjustment. The skin rash may resolve spontaneously without further intervention. 
If the rash persists for >1 week or becomes more severe, hold study drug. After the rash 
resolves, resume study drug at 50% of the patient’s dose level before the skin rash. If the rash 
does not recur after 2 weeks, increase the dose back to 100%. 
For a severe rash (distressing symptoms requiring discontinuation and/or systemic steroids), 
discontinue treatment until resolution of rash. Once the rash has resolved, resume at 50% of 
patient’s dose. If necessary, a brief course of oral steroids may be given concurrently with 


Novartis 
Confidential 
Page 58 
Amended Protocol Version 05 (Clean) 
 
Protocol No. CICL670A2302 
 
resumption of study drug. If the rash does not recur, increase by 5mg/kg/day increments every 
2 weeks until 100% of patient’s dose is achieved. 
If the rash recurs, study drug may be discontinued if the investigator believes that it is in the 
best interest of the patient. Novartis may be contacted by the investigator to discuss dosing 
options if the investigator so desires. 
6.7.1.7 
Liver function abnormalities 
Recommended dose modifications for changes in ALT or AST will be based on the patient’s 
baseline ALT/AST . The baseline ALT/AST value is defined as the mean of the Visit 1 and 
Visit 2 values. 
For patients with a baseline ALT/AST > ULN, study drug will be interrupted if the ALT/AST 
increases to > 5 × baseline ALT/AST or > 10 x ULN. 
For patients with a normal baseline ALT/AST, study drug will be interrupted if the ALT/AST 
increases to > 5 × ULN. 
After drug interruption, the investigator should recheck ALT/AST bi-weekly until ALT/AST 
return to the values prior to the elevation. The study drug may then be restarted at 50% of the 
dose used before the ALT/AST elevation. 
ALT/AST should be monitored bi-weekly for the first month after restarting the drug. Dose 
escalation to the original dose may be instituted after 1 month of treatment with 50% of the 
dose if the re-challenge is not associated with ALT/AST elevations. 
Study drug will be interrupted if elevation of serum total bilirubin to > 2.0 mg/dL. 
Should a subsequent progressive rise in ALT/AST to greater than 5 × baseline occur, study 
drug may be discontinued if the investigator believes that it is in the best interest of the patient. 
Novartis may be contacted by the investigator to discuss dosing options if the investigator so 
desires. 
In patients who develop moderate hepatic impairment (Child-Pugh Class B) during the study, 
the study medication will be interrupted and patient monitored. If liver disease prognosis 
improves, study medication can be reintroduced at 10 mg/kg/day or 50% of previous dose, 
whichever is less. While monitoring continues, dose may be increased by 5 mg/kg/day every 2 
weeks to a maximum of 50% of patient’s previous dose if the investigator determines that 
dose increase is in the best interest of the patient. Study medication must be used with 
caution in such patients. In patients who develop severe hepatic impairment (Child-Pugh 
Class C) during the study, study medication must be discontinued. 
6.7.1.8 
Dose modification criteria for auditory (decreased hearing) and ocular 
(lens opacities) disturbances 
Auditory (decreased hearing) and ocular (lens opacities) disturbances have been reported with 
deferasirox treatment. Auditory and ophthalmic testing (see Section 7.5.4) is recommended 
before the start of deferasirox treatment and at regular intervals thereafter (every 12 months). 
If disturbances are noted, dose reduction or interruption may be considered and a repeated 
testing performed as per investigator’s judgment. 


Novartis 
Confidential 
Page 59 
Amended Protocol Version 05 (Clean) 
 
Protocol No. CICL670A2302 
 
6.7.1.9 
Dose modification criteria for hypersensitivity reactions 
Cases of serious hypersensitivity reactions (such as anaphylaxis and angioedema) have been 
reported in patients receiving deferasirox, with the onset of the reaction occurring in the 
majority of cases within the first month of treatment. If reactions are severe, deferasirox 
should be discontinued and appropriate medical intervention instituted. 
6.7.1.10 Dose modification criteria for cytopenias 
There have been post-marketing reports (both spontaneous and from clinical trials) of 
cytopenias in patients treated with deferasirox. Most of these patients had pre-existing 
hematological disorders that are frequently associated with bone marrow failure. The 
relationship of these episodes to treatment with deferasirox is uncertain. In line with the 
standard clinical management of such hematological disorders, blood counts should be 
monitored regularly. Interruption of treatment with deferasirox should be considered in 
patients who develop unexplained cytopenia. Reintroduction of therapy with deferasirox may 
be considered (as per investigator decision), once the cause of the cytopenia has been 
identified. 
6.7.2 
Follow-up for toxicities 
Patients whose treatment is interrupted or permanently discontinued due to an AE or 
abnormal laboratory value must be followed at least once a week for 4 weeks, and 
subsequently at 4-week intervals, until resolution or stabilization of the event, whichever 
comes first. If treatment is permanently discontinued, all patients will continue to be followed 
for safety and endpoints during the evaluation period at visits occurring every three months. 
Subsequent to the evaluation period, or at the end of treatment if a patient and treating 
physician decide that a patient will not participate in the evaluation period, patients will be 
followed every 6 months for iron chelation therapies and overall survival (“Survival Follow-
up”). 
6.7.3 
Rescue medication 
The use of rescue medication is not permitted during this study. 
6.7.4 
Other concomitant medications 
The investigator should instruct the patient to notify the study site about any new medications 
he/she takes after the start of the study drug. All medications (other than study drug) and 
significant non-drug therapies (including physical therapy and blood transfusions) 
administered after the patient starts treatment with study drug must be listed on the 
appropriate eCRF page. 
The treatment of concomitant medical conditions with non-investigational medications during 
the study may be continued with the exception of other chelating agents. 
The following concomitant medications may be permitted for use while patient is on study 
and information outlining start date(s) and end date(s) of each medication taken must be 
recorded on the appropriate eCRF: 


Novartis 
Confidential 
Page 60 
Amended Protocol Version 05 (Clean) 
 
Protocol No. CICL670A2302 
 
• Erythropoietin (growth factor) 
• G-CSF (growth factor) 
• GM-CSF (growth factor) 
• Azacitidine 
• Thalidomide 
• Arsenic trioxide 
• Lenalidomide 
• Decitabine 
• Cyclosporine A 
• Vitamin C supplements (≤ 200 mg/day) 
Any investigational drug other than study medication is NOT allowed during the study. After 
permanent discontinuation of the randomized study medication, the use of commercially 
available iron chelation therapies is allowed. 
6.7.4.1 
Concomitant therapy requiring caution and/or action 
Caution must be exercised in patients who are taking study drug in combination with the 
following drugs: 
• The concomitant administration of deferasirox and vitamin C has not been formally 
studied. Doses of vitamin C up to 200 mg/d have not been associated with adverse 
consequences. 
• Aluminum containing antacid therapies should be avoided because they may bind to 
deferasirox 
• Concomitant administration of deferasirox with drugs that have known ulcerogenic 
potential, such as NSAIDs, corticosteroids, or oral bisphosphonates, and use of deferasirox 
in patients receiving anticoagulants may increase the risk of gastrointestinal irritation and 
bleeding 
• Deferasirox, as a weak CYP3A4 inducer, may potentially decrease serum levels of 
substances metabolized through CYP3A4 (e.g. cyclosporin, simvastatin, hormonal 
contraceptive agents) 
• Deferasirox is a moderate inhibitor of CYP2C8 and therefore it may increase serum 
concentrations of substances metabolised through CYP2C8 (e.g repaglinide, paclitaxel) 
• Concomitant administration of deferasirox with CYP1A2 substrates that have a narrow 
therapeutic index (e.g. theophylline, clozapine, tizanidine), is not recommended. When 
deferasirox and theophylline are used concomitantly, monitoring of theophylline 
concentration and theophylline dose reduction should be considered. 
• The concomitant use of deferasirox with potent UGT (Uridine 5'-diphospho-
glucuronosyltransferase) inducers (e.g. rifampicin, phenytoin, phenobarbital, ritonavir) 
may result in a decrease in deferasirox efficacy. 
• Concomitant use of bile acid sequestrants (e.g., cholestyramine, colesevelan, colestipol) 
that decrease deferasirox systemic exposure should be avoided. 


Novartis 
Confidential 
Page 61 
Amended Protocol Version 05 (Clean) 
 
Protocol No. CICL670A2302 
 
6.7.5 
Study drug discontinuation 
Patients who discontinue study drug entirely before completing the study should be scheduled 
for the End of Treatment visit as soon as possible, at which time all of the assessments listed 
for Study End of Treatment visit will be performed. This will document the date and reason 
for stopping randomized study treatment. It must be completed for all patients. Any safety 
finding that leads to discontinuation of study drug should be captured on the AE eCRF. 
All patients who discontinue study drug, including those who refuse to return for a final visit, 
will be contacted by the investigational site for safety evaluations during the 28 days 
following the last dose of study drug. All patients must have the 28 Day Follow-Up completed 
after they discontinue from the study drug. 
All iron chelation therapies given to a patient after the last dose of study treatment must be 
recorded in the ‘Chelation therapies given since discontinuation of study drug’ eCRF during 
the 28 day follow up, Evaluation and Survival phases of the study. Patients who discontinue 
study drug and do not wish to be followed for post-treatment evaluations and survival should 
be considered withdrawn from the study after the final visit assessments are performed or 
when it is clear that the patient will not return for these assessments. The End of Treatment 
eCRF should be completed and the Study Evaluation Completion visit should be performed at 
this time. 
All patients must be followed for AEs and SAEs for 28 days after the last dose of study 
treatment. Patients lost to follow up should be recorded as such on the Study Evaluation 
Completion eCRF. If the patient is at the end of treatment, the End of Treatment eCRF must 
also be completed. For patients who are lost to follow-up, the investigator should show "due 
diligence" by documenting in the source documents steps taken to contact the patient, e.g., 
dates of telephone calls, registered letters, etc. 
The investigator must contact IVRS/IWRS to register discontinued patients. 
6.7.5.1 
Discontinuation of study treatment after an event contributing to the 
primary endpoint 
The end of study treatment visit may occur if a patient meets any non-fatal component of the 
composite primary endpoint (confirmed by the EAC). His/her individual randomized study 
treatment will be unblinded and discontinued at that time via IVRS/IWRS. The unblinded 
information will only be shared with the investigator and patient. The subsequent iron 
chelation treatment is subject to the patient’s and the investigator’s decision. After termination 
of study treatment, all patients will continue to be followed for safety and non-fatal 
components of the primary endpoint during the evaluation period at visits occurring every 
three months. Subsequent to the evaluation period, or at the end of treatment if a patient and 
treating physician decide that a patient will not participate in the evaluation period, patients 
will be followed every 6 months for iron chelation therapies and overall survival (“Survival 
Follow-up”). 


Novartis 
Confidential 
Page 62 
Amended Protocol Version 05 (Clean) 
 
Protocol No. CICL670A2302 
 
6.7.5.2 
Discontinuation of study treatment without an event contributing to 
the primary endpoint 
For patients who do not meet a non-fatal component of the composite primary endpoint, study 
treatment will continue as long as the patient and treating physician feel it is in the best 
interest of the patient, or until the study terminates. There is no planned unblinding for 
patients who terminate study treatment without meeting a non-fatal component of the 
composite primary endpoint. After termination of study treatment, all patients will continue to 
be followed for safety and endpoints during the evaluation period at visits occurring every 
three months. Subsequent to the evaluation period, or at the end of treatment if a patient and 
treating physician decide that a patient will not participate in the evaluation period, patients 
will be followed every 6 months for iron chelation therapies and overall survival (“Survival 
Follow-up”). 
6.7.6 
Premature patient withdrawal 
Patients may voluntarily withdraw from the study for any reason at any time. Patients may be 
dropped from the study at the discretion of the investigator at any time. They may be 
considered withdrawn if they fail to return for visits, or become lost to follow up for any other 
reason. Patients must be withdrawn from the study if any of the following occur: discovery of 
not having been randomized, unwillingness to comply with procedures as outlined in the 
study protocol, female patient pregnancy, or withdrawal of informed consent. 
If such withdrawal occurs, or if the patient fails to return for visits, the investigator must 
determine the primary reason for a patient’s premature withdrawal from the study and record 
this information on the Study Evaluation Completion eCRF and notify IVRS. 
6.7.6.1 
End of Treatment 
If study drug is discontinued, IVRS is to be notified and the End of Treatment Page is to be 
completed with the ‘last known date the patient took study drug’ and one of the following 
reasons: 
• Adverse Event 
• Abnormal laboratory value(s) 
• Abnormal test procedure result(s) 
• Protocol deviation 
• Subject withdrew consent 
• Lost to follow-up 
• Administrative problems 
• Death 
• Disease progression 
• Pregnancy 
• Physician’s decision 
• Treatment duration completed as per protocol 
• Subject / Guardian Decision 


Novartis 
Confidential 
Page 63 
Amended Protocol Version 05 (Clean) 
 
Protocol No. CICL670A2302 
 
• Study terminated by sponsor 
6.7.6.2 
Study evaluation completion 
At the end of the study evaluation period, the Study Evaluation Completion Page is filled out 
for all patients with the following options: 
• Adverse event(s) 
• Disease progression 
• Pregnancy 
• Protocol deviation 
• Study terminated by sponsor 
• Physician’s decision 
• Patient withdrew consent 
• Lost to follow-up 
• Administrative problems 
• Death 
• Subject / Guardian Decision 
For patients who are lost to follow-up, the investigator should show "due diligence" by 
documenting in the source documents steps taken to contact the patient, e.g., dates of 
telephone calls, registered letters, etc. 
6.7.7 
Emergency unblinding of treatment assignment 
Emergency unblinding should only be undertaken when it is essential for effective treatment 
of the patient. Most often, study drug discontinuation and knowledge of the possible treatment 
assignments are sufficient to treat a study patient who presents with an emergency condition. 
Emergency code breaks are performed using the IVRS. When the investigator contacts the 
IVRS/IWRS to unblind a patient, he/she must provide the requested patient identifying 
information and confirm the necessity to unblind the patient. The investigator will then 
receive details of the drug treatment for the specified patient and a fax confirming this 
information. The system will automatically inform the Novartis monitor for the site and the 
Clinical Trial Head that the code has been broken. 
It is the investigator’s responsibility to ensure that there is a procedure in place to allow access 
to the IVRS in case of emergency. The investigator will inform the patient how to contact 
his/her backup in cases of emergency when he/she is unavailable. The protocol number, study 
drug name if available, patient number and instructions for contacting the local Novartis CPO 
(or any entity to which it has delegated responsibility for emergency code breaks) will be 
provided to the patient in case emergency unblinding is required at a time when the 
investigator and backup are unavailable. 


Novartis 
Confidential 
Page 64 
Amended Protocol Version 05 (Clean) 
 
Protocol No. CICL670A2302 
 
7 
Visit schedule and assessments 
Following registering in IVRS/IWRS for screening, patient eligibility will be checked once all 
screening procedures are completed. The eligibility check will be embedded in the 
IVRS/IWRS system. Detailed guidelines to be followed can be found in the IRT manual. 
Table 7-1 lists all of the assessments and indicates with an “X” the visits when they are 
performed. All data obtained from these assessments must be supported in the patient’s source 
documentation. Assessments such as laboratory data, ECG, ECHO and assessments by the 
EAC will be transferred to the database electronically. 


Novartis 
Confidential 
Page 65 
Amended Protocol Version 05 (Clean) 
 
Protocol No. CICL670A2302 
 
Table 7-1 
Visit evaluation schedule 
 
Screening 
Randomization 
Treatment Period 
Week 372a End of 
Treatment
28-day Follow Upb 
Evaluationc Period 
Study Evaluation 
Completion 
Survivald 
Follow-Up 
Visit 
1 
2 
3e 
4f
5
6
7 
8 
9 
10
11
12
13
14 
15 
16
17
18-96 
777
501
502, 
503, 
etc. 
778 
701, 702, 
etc. 
Week18 
-5 to -
1 
Day 
1 
2
4
8
12
16
20
24
28
32
36
40 
44 
48
52
56--
368 
372
 
 
 
 
Informed consent g 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examinatione 
X 
 
X 
X
X
X
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
Vital signs 
X 
X 
X 
X
X
X
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
Weight 
X 
 
X 
 
X
X
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hemoglobin/Transfusion/RBC 
History1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bone Marrow2,3,4 
X 
 
X 
 
ECG5 
X 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
X 
X 
 
X 
X 
 
ECHO5 
X 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
X 
X 
 
X 
X 
 
Chest X-ray6 
 
 
X 
X 
 
Abdominal Ultrasound/liver 
biopsy7 
X 
 
X 
 
Ocular Exam8 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
 
X 
X 
 


Novartis 
Confidential 
Page 66 
Amended Protocol Version 05 (Clean) 
 
Protocol No. CICL670A2302 
 
 
Screening 
Randomization 
Treatment Period 
Week 372a End of 
Treatment
28-day Follow Upb 
Evaluationc Period 
Study Evaluation 
Completion 
Survivald 
Follow-Up 
Visit 
1 
2 
3e 
4f
5
6
7 
8 
9 
10
11
12
13
14 
15 
16
17
18-96 
777
501
502, 
503, 
etc. 
778 
701, 702, 
etc. 
Week18 
-5 to -
1 
Day 
1 
2
4
8
12
16
20
24
28
32
36
40 
44 
48
52
56--
368 
372
 
 
 
 
Audiometry8 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
 
X 
X 
 
Hematology 
X 
 
 
X
X
X
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
BNP9 
 
 
X 
X9 
 
Reticulocyte Count 
X 
 
 
X
X
X
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
Biochemistry 
X 
 
 
X
X
X
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
Hepatitis Viral Serology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Ferritin10 
X 
X 
 
X
X
X
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
Serum Creatinine11 
X 
X 
X 
X
X
X
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
Creatinine Clearance 12 
X 
X 
X 
X
X
X
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
ALT/AST 
X 
X 
 
X
X
X
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
Direct/Indirect/Total Bilirubin 
X 
X 
 
X
X
X
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
TSH/Free T4 13 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
X 
X 
 
OGTT17 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
X 
X 
 
Serum pregnancy test16 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine dipstick14 
X 
 
 
X
X
X
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
Microscopic urine14 
 
 
 
 
X14 
 
Urine creatinine/ Protein total 
urine/ urinary protein ratio14 
X 
X 
 
X
X
X
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
Urine Pregnancy16 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 


Novartis 
Confidential 
Page 67 
Amended Protocol Version 05 (Clean) 
 
Protocol No. CICL670A2302 
 
 
Screening 
Randomization 
Treatment Period 
Week 372a End of 
Treatment
28-day Follow Upb 
Evaluationc Period 
Study Evaluation 
Completion 
Survivald 
Follow-Up 
Visit 
1 
2 
3e 
4f
5
6
7 
8 
9 
10
11
12
13
14 
15 
16
17
18-96 
777
501
502, 
503, 
etc. 
778 
701, 702, 
etc. 
Week18 
-5 to -
1 
Day 
1 
2
4
8
12
16
20
24
28
32
36
40 
44 
48
52
56--
368 
372
 
 
 
 
Transfusions15 
 
 
X 
X
X
X
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
Concomitant medication 
X 
 
Continuous
 
 
Drug Dispensing 
 
 
X 
X
X
X
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Overall Survival 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Xd 
Iron Chelation Therapy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
Adverse events 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
a. Week 372 End of Treatment: The recruitment period is planned to last until December 2014. The study duration will be up to 3 years after the last patient is enrolled. 
b. Follow up must occur 28 days after the last dose of study treatment for adverse event reporting/follow up and chelation therapy reporting 
c. Evaluation Period: Patient evaluation required every 3 months after study treatment discontinuation. 
d. Survival Follow Up: Patient follow up required every 6 months after study discontinuation. 
e. Visit 3.01: At Week 1, Serum Creatinine is drawn and Creatinine Clearance is calculated 
f. Visit 4.01: At Week 3, Serum Creatinine is drawn and Creatinine Clearance is calculated 
g. Captured in Source Documentation only 
1. 
Hemoglobin/Transfusion History: collect retrospective data for the 6 months prior to study entry 
2. 
Bone marrow for cytogenetics and morphology is not required if the exam has been completed within 6 months of the screening date and the patient has been 
hematologically stable. Patients with a major hematological response per IWG criteria (Post Text Supplement 4) may undergo an additional bone marrow biopsy or 
aspiration plus bone marrow examination at the time of response if in the opinion of the investigator the information may be helpful in the management of the patient. 
Bone marrow examination should also be performed if the patient is suspected to have had an AML progression. 
3. 
Bone marrow aspirate should include cytogenetics and morphology 
4. 
Repeat bone marrow aspiration and cytogenetics, iron stains and biopsy recommended at the time of hematological improvement per IWG criteria (Post Text 


Novartis 
Confidential 
Page 68 
Amended Protocol Version 05 (Clean) 
 
Protocol No. CICL670A2302 
 
 
Screening 
Randomization 
Treatment Period 
Week 372a End of 
Treatment
28-day Follow Upb 
Evaluationc Period 
Study Evaluation 
Completion 
Survivald 
Follow-Up 
Visit 
1 
2 
3e 
4f
5
6
7 
8 
9 
10
11
12
13
14 
15 
16
17
18-96 
777
501
502, 
503, 
etc. 
778 
701, 702, 
etc. 
Week18 
-5 to -
1 
Day 
1 
2
4
8
12
16
20
24
28
32
36
40 
44 
48
52
56--
368 
372
 
 
 
 
Supplement 4). Bone marrow examination should also be performed if the patient is suspected to have experienced disease progression. 
5. 
ECG and ECHO will be performed at screening and approximately every 3 months (Weeks 12, 24, 36, 52, 64, 76, 88, 104, 116, 128, 140, 156, 168,180,192,208 
220, 232, 244, 260, 272, 284, 296, 312, 324, 336, 348, 364, 372). Patients in the Evaluation Period will have ECGs, ECHOs performed approximately every 3 
months 
6. 
Chest x-ray to be performed at baseline and for any hospitalization related to CHF (pulmonary edema) 
7. 
Liver Ultrasound will be performed at Screening Visit 1 and anytime during the trial if liver function impairment or liver cirrhosis is suspected. Liver biopsy will be 
performed if abdominal ultrasound results indicated liver damage/failure and there are no contraindications, then liver biopsy is recommended 
8. 
Ocular and Audiometry examinations must be performed at screening, should a patient have evidence at the screening visit that the examination(s) were performed 
6 months prior to screening then the examination(s) do not need to be repeated. The examination(s) can be performed at any time at the investigators discretion if 
symptomatically/clinically indicated, otherwise ocular and audiometry exams should be performed annually. The ocular and audiometry exams should be performed 
annually during the Evaluation Period. 
9. 
Brain natriuretic peptide (BNP) blood sample should be obtained at baseline and at any time during the study when there is evidence of CHF 
10. Serum ferritin: Two samples at screening done at least 14 days apart. If a transfusion is scheduled, draw serum ferritin PRIOR to transfusion or two weeks post-
transfusion. The serum ferritin samples should be obtained in the absence of known infection. 
11. Serum creatinine will be measured at Screening Visit 1 and Screening Visit 2 and the mean value will be used for eligibility criteria. Serum creatinine will also be 
measured weekly between the randomization visit and Week 4 visit. For the first month after initiation or modification of dose, labs may be obtained locally until the 
subject’s next scheduled visit. Local labs need only be included on the eCRF in the case of a result that is a 33% increase greater than baseline result. 
12. Creatinine clearance will be calculated by the central laboratory at every visit. 
13. TSH and Free T4 will be measured at screening, annually and at study treatment discontinuation. TSH and Free T4 should be performed annually during the 
Evaluation Period. 
14. At screening Visit 1 and 2 a urine sample (at least 15 ml) will be collected and sent to the central laboratory for urinary protein and urinary creatinine to assess the 
eligibility of the patient. Microscopic analysis will be performed only in case of positive dipstick. Dipsticks will be supplied by the central lab. Proteinuria (urinary 
protein /creatinine ratio) at Visit 1 and Visit 2 (screening) and then monthly during study. 


Novartis 
Confidential 
Page 69 
Amended Protocol Version 05 (Clean) 
 
Protocol No. CICL670A2302 
 
 
Screening 
Randomization 
Treatment Period 
Week 372a End of 
Treatment
28-day Follow Upb 
Evaluationc Period 
Study Evaluation 
Completion 
Survivald 
Follow-Up 
Visit 
1 
2 
3e 
4f
5
6
7 
8 
9 
10
11
12
13
14 
15 
16
17
18-96 
777
501
502, 
503, 
etc. 
778 
701, 702, 
etc. 
Week18 
-5 to -
1 
Day 
1 
2
4
8
12
16
20
24
28
32
36
40 
44 
48
52
56--
368 
372
 
 
 
 
15. Transfusions may be administered as necessary throughout the study and number and volume (ml) of PRBC and platelets administered are to be recorded in eCRF.
16. Required for Females of child bearing potential only. 
17. A 2 hour fasting Glucose Tolerance test will be done at screening and annually (Weeks 52, 104, 156, 208, 260, 312, 364) and at study treatment discontinuation. 
Patients should fast for at least 5 hours prior to the test being drawn. Should a patient have a documented diagnosis of diabetes requiring treatment with medication, 
the Glucose Tolerance Test is not mandatory and is up to the Investigator’s discretion. The Glucose Tolerance Test should be performed annually during the 
Evaluation Period. 
18. Visit Windows: The following visit windows are permitted: ±3 days Weeks 2 & 4; ±7 days for every monthly visit (Weeks 8, 12, 16, 20 through EOT); ±2 weeks for 
Evaluation and Survival Follow-Up visits 


Novartis 
Confidential 
Page 70 
Amended Protocol Version 05 (Clean) 
 
Protocol No. CICL670A2302 
 
7.1 
Information to be collected on screening failures 
A screening log of all patients screened for this study, at each study center, will be kept. This 
log will include patient number, demographic details, and reason why the patient was a screen 
failure. Sites should also maintain pre-screening logs capturing all of the reasons why a 
patient was not eligible for screening. The following information of patients who are screened 
but fail to be randomized will be collected in the eCRF: demographics, screening log and 
serious adverse events. 
Should a patient screen fail but subsequently become eligible by newly meeting entry criteria 
resulting from a change in their parameters or due to a protocol amendment, patients may be 
re-screened. All screening labs outlined in Screening Visit 1 and Screening Visit 2 must be 
repeated. All other procedures (ECHO, abdominal ultrasound, bone marrow biopsy or 
aspiration, ocular and audiometery examinations, etc.) do not need to be repeated if they have 
been performed within 6 months of the original screening visit date. 
7.2 
Patient demographics/other baseline characteristics 
At Visits 1 and/or 2, data will be collected on patient characteristics including demographic 
information (age, sex, ethnicity, etc.), other background or relevant medical history/current 
medical condition (6 months) prior to study entry: hemoglobin and transfusion history, 
disease history, vital signs, previous iron chelation therapies). 
Other assessments done for the purpose of determining eligibility for the study include IPSS, 
history of HIV positive test result (ELISA or Western Blot), active hepatitis B and/or C, 
urinalysis, ALT/AST, serum creatinine, serum ferritin, serum pregnancy test, other 
biochemistry studies, echocardiography, bone marrow history/examination. 
7.3 
Treatments 
Information on study drug will be collected on the Dose Administration Record (DAR) eCRF 
and will include the planned dose (mg/kg/day), actual total daily dose (mg) taken, reason for 
the dose, start date and end date. 
Compliance will be assessed by the investigator and/or study personnel at each visit using 
tablets/vial counts and information provided by the patient or the caregiver. This information 
should be captured in the source document at each visit, and also entered on the appropriate 
eCRF. Concomitant medications/significant non-drug therapies both prior to start of study 
drug and after start of study drug will be assessed and thus have to be recorded in the eCRF. 
Information collected on the Concomitant Medications/Significant Non-drug Therapies eCRF 
will include concomitant medications/significant non-drug therapy, reason for the 
medication/therapy, start date, and end date. 
The number of tablets of study medication of each strength (125 mg, 250 mg, 500 mg) 
dispensed will be recorded during the study in the source documents using a drug dispensing 
log (see [Post-text supplement 2]) and Drug Compliance eCRF. Empty bottles and unused 
medication will be returned by the patient to the study site. Unused study medication tablets 
will be counted and recorded by the investigator/pharmacist/study staff involved in the study, 
according to local legal requirements. 


Novartis 
Confidential 
Page 71 
Amended Protocol Version 05 (Clean) 
 
Protocol No. CICL670A2302 
 
7.4 
Efficacy 
7.4.1 
Composite primary endpoint 
The primary objective is to evaluate deferasirox and placebo with regard to event-free 
survival (including death and non-fatal events related to cardiac and liver function and 
transformation to AML). The EAC will evaluate the criteria for the composite primary 
efficacy endpoint on an ongoing basis. 
The composite primary endpoint (event-free survival) consists of both death and non-fatal 
events. Non-fatal events include worsening cardiac function based on echocardiographic 
evidence, hospitalization for congestive heart failure, liver function impairment reflected by 
elevated ALT or AST and bilirubin values, confirmed liver cirrhosis, and transformation to 
AML. Details regarding the components of the composite endpoint are described in 
Section 7.5.7, Section 7.5.10 and Section 7.5.11. 
7.5 
Safety 
Safety assessments will consist of monitoring and recording all AEs and SAEs, laboratory 
safety assessments (hematology, blood chemistry and urinalysis) and clinical evaluations 
(physical examinations, vitals signs, body weight, auditory and ocular tests, ECG) as outlined 
in Table 7-1. 
7.5.1 
Adverse events 
An adverse event for the purposes of this protocol is the appearance of (or worsening of any 
pre-existing) undesirable sign(s), symptom(s), or medical condition(s) occurring after signing 
the informed consent even if the event is not considered to be related to the study drug(s). 
However, it must be noted that MDS is not considered an adverse event. MDS is a required 
condition for study entry and is expected to be reported as Medical History for all patients. 
Time to disease progression is a secondary efficacy endpoint. Please refer to Section 6.1 for 
the protocol-specific definitions of study drug and study treatment. 
Adverse events (but not serious adverse events) occurring before starting study treatment but 
after signing the informed consent form are recorded on the Medical History/Current Medical 
Conditions eCRF. Abnormal laboratory values or test results that induce clinical signs or 
symptoms, are considered clinically significant, require therapy (e.g., any hematological 
abnormality that requires transfusion or cytokine treatment), or interruption of study 
medication should be recorded on the Adverse Events eCRF under the signs, symptoms or 
diagnosis associated with them. Abnormal Laboratory values that do not meet this criteria are 
not reported as Adverse Events. SAEs occurring after signing the Informed Consent are 
recorded on the Adverse Event eCRF. 
The occurrence of adverse events should be sought by non-directive questioning of the patient 
at each visit during the study. Adverse events also may be detected when they are volunteered 
by the patient during or between visits or through physical examination, laboratory test, or 
other assessments. As far as possible, each adverse event should be evaluated to determine: 
1. The severity grade (mild, moderate, severe) 
2. Its relationship to deferasirox (suspected/not suspected) 


Novartis 
Confidential 
Page 72 
Amended Protocol Version 05 (Clean) 
 
Protocol No. CICL670A2302 
 
3. Its duration (start and end dates or if continuing at final examination) 
4. Action taken (no action taken; study drug dosage adjusted/temporarily interrupted; study 
drug permanently discontinued due to this adverse event; concomitant medication taken; 
non-drug therapy given; hospitalization/prolonged hospitalization) 
5. Whether it is serious, where a serious adverse event (SAE) is defined as one which: 
• Is fatal or life-threatening 
• Results in persistent or significant disability/incapacity 
• Constitutes a congenital anomaly/birth defect 
• Requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 
• Routine treatment or monitoring of the studied indication, not associated with 
any deterioration in condition 
• Elective or pre-planned treatment for a pre-existing condition that is unrelated to 
the indication under study and has not worsened since signing the informed 
consent 
• Treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of an SAE given above and not resulting in hospital admission 
• Social reasons and respite care in the absence of any deterioration in the patient’s 
general condition 
• 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 
Unlike routine safety assessments, SAEs are monitored continuously and have special 
reporting requirements; see Section 8.1. 
All adverse events should be treated appropriately. Such treatment may include changes in 
study drug treatment including possible interruption or discontinuation, starting or stopping 
concomitant treatments, changes in the frequency or nature of assessments, hospitalization, or 
any other medically required intervention. Once an adverse event is detected, it should be 
followed until its resolution, an assessment should be made at each visit (or more frequently, 
if necessary) of any changes in its severity, its suspected relationship to the study drug(s), any 
of the interventions required to treat it, and its outcome. 
Information about common side effects already known about the investigational drug can be 
found in the [Investigators’ Brochure] or will be communicated between IB updates in the 
form of Investigator Notifications. This information will be included in the patient informed 
consent and should be discussed with the patient during the study as needed. 
7.5.2 
Physical examination, weight, height 
A physical examination will be performed as outlined in Table 7-1. The physical examination 
at the randomization visit will serve as the baseline physical examination for the entire study. 
The exam will entail an examination of general appearance, skin, neck (including thyroid), 
eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, extremities and nervous 
system. 


Novartis 
Confidential 
Page 73 
Amended Protocol Version 05 (Clean) 
 
Protocol No. CICL670A2302 
 
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 
(randomization visit) must be included in the Relevant Medical History/Current Medical 
Conditions eCRF page. Significant findings made after the start of study drug which meet the 
definition of an AE must be recorded in the Adverse Event eCRF summary page. 
All subjects will have standing height measured at the screening visit(s). This height 
measurement must be captured in the eCRF. Body weight will be recorded in all patients at 
screening, then at every clinic visit and captured on the eCRF. Weight should be measured 
while the patient is wearing ordinary clothing without shoes. 
7.5.3 
Vital signs 
Vital sign determinations are of sitting blood pressure, heart rate, respiratory rate, and body 
temperature and are taken as outlined in Table 7-1. Systolic and diastolic blood pressure and 
pulse rate is to be measured after the patient has rested in the sitting position for at least 3 
minutes. Blood pressure should be assessed using the same arm at each visit. All 
measurements will be recorded in metric units when applicable. All vital sign measurements 
should be recorded on the appropriate eCRF for every visit. 
7.5.4 
Auditory and ocular examination 
Patients will undergo auditory and ocular examinations as outlined in Table 7-1. 
If a patient had an auditory or ophthalmologic exam 6 months prior to the screening Visit 1 
and the test results are available, then these tests will not need to be re-done at screening. 
The auditory examination include the following assessments: 
• Comprehensive audiometry threshold examination 
• Speech recognition 
The ophthalmologic examination include the following assessments: 
• Visual acuity test (refraction) 
• Tonometry 
• Slit lamp exam of anterior segment 
• Slit lamp exam of the lens 
• A fundoscopic and retinal examination 
Information about the audiometry and ocular examinations must be present in the source 
documentation at study site and will be captured on the eCRF. Significant findings of the 
audiometry and ocular examinations that meet the definition of an AE must be recorded in the 
AE summary page of the eCRF. Significant findings at the Screening visit will be reported as 
Medical History. 
7.5.5 
Laboratory evaluations 
A certified central laboratory will be utilized to process and provide results for the clinical 
laboratory tests summarized in Table 7-2. The central laboratory chosen for this study will 
provide instructions regarding the collection, processing and shipment of appropriate samples. 


Novartis 
Confidential 
Page 74 
Amended Protocol Version 05 (Clean) 
 
Protocol No. CICL670A2302 
 
For first month after study drug initiation or dose modification, labs may be obtained locally 
until the subject’s next scheduled visit. Local lab results only need to be entered on the eCRF 
in the event that the result demonstrates a significant change from baseline. A significant 
change in serum creatinine is defined as an increase of 33% greater than the baseline result. A 
significant change for ALT/AST/Total Bilirubin is defined as an increase of 2× the baseline 
value. For any other laboratory assessment, it is up to the Investigator’s opinion if a laboratory 
result represents a significant abnormality. In the event that a local laboratory is used for 
assessing patient samples for trial purposes, the site/CRA must complete and submit the 
Novartis Local Laboratory Normal Ranges (LNR) form to the Data Manager. 
7.5.5.1 
Hematology 
Safety laboratory parameters will be monitored as outlined in Table 7-1. 
7.5.5.2 
Biochemistry 
Blood samples will be sent to the central laboratory as outlined in Table 7-1. 
During the first month of treatment, serum creatinine will be measured weekly and preferably 
via local laboratory assessment. From Week 4 through-End of treatment, serum creatinine 
levels will be checked at every routine clinic visit. The central laboratory will calculate the 
creatinine clearance at every visit. 
Serum ferritin test will also be performed at screening (Visit 1 and Visit 2) to assess the 
eligibility of the patient and should be drawn at least 14 days apart. The baseline serum 
ferritin value is defined as the average of the two measurements obtained during the screening 
period. Serum ferritin testing will also be performed at every visit starting at week 2 (Visit 4) . 
Samples should be obtained in the absence of known inflammation or infection. If transfusion 
is scheduled, blood should be drawn for serum ferritin collection prior to transfusion or two 
weeks post-transfusion. Results will be provided to the sites within 24 hours after the central 
laboratory receives the sample. 
7.5.5.3 
Urinalysis/proteinuria 
At screening (Visit 1 and 2) a urine sample (at least 15 ml) will be collected and sent to the 
central laboratory for urinary protein and urinary creatinine to assess the eligibility of the 
patient. First morning void samples should not be used for this analysis. Significant 
proteinuria is indicated by a urinary protein/creatinine ratio > 0.5 mg/mg. 
For patients who develop proteinuria or a worsening of pre-existing proteinuria (assessed by a 
dipstick) at any visit, urine samples should be collected and urine protein assessed by the 
central laboratory. If any other causes of proteinuria have been excluded, the dose should be 
reduced by 50%. Should the proteinuria persist, study drug may be discontinued if the 
investigator believes it is in the best interest of the patient. Novartis may be contacted by the 
investigator to discuss dosing options if the investigator so desires. 
At a frequency outlined in Table 7-1, a midstream, non-first voided urine sample will be 
obtained. Specific gravity, pH, blood, glucose, protein, bilirubin, ketones, and leukocyte 
esterase should be assessed. Microscopic analysis will be performed only in case of positive 
dipstick. Dipsticks will be supplied by the central lab. 


Novartis 
Confidential 
Page 75 
Amended Protocol Version 05 (Clean) 
 
Protocol No. CICL670A2302 
 
7.5.5.4 
Transfusion requirements, hematologic counts 
Transfusions (i.e. number and volume (ml) of PRBC and platelets administered during the 
course of the study) will be recorded in the appropriate transfusion eCRF. 
For a 6 month period prior to randomization, detailed platelet and PRBC transfusionrecords, 
and hemoglobin levels associated with these transfusions will be collected. During this time 
period, complete blood counts (CBCs) must be available. These data will be used to establish 
baseline transfusion frequency and hematologic counts. 
At each visit during the trial beginning at week 2, the number of units of PRBCs administered 
since the prior study visit will be recorded. 
Complete blood counts will be drawn as outlined in Table 7-1. 
7.5.5.5 
Pregnancy test 
All female patients capable of becoming pregnant will have a pregnancy test (serum β-HCG) 
at screening visit 1. When performed at screening, the results of the test must be available 
prior to initiating treatment with any study medication. Positive pregnancy tests will exclude a 
patient from participating in this trial. 
Urine pregnancy testing will be performed locally at the End of Treatment visit and if menses 
are delayed for more than 7 days in a female patient capable of becoming pregnant. See 
Section 8.2 for procedures to report pregnancy. 
Table 7-2 
Laboratory evaluations 
Evaluation 
Sample 
collection 
Analysis 
Collection 
Time-point 
Hematology (CBC) 
4 mL blood 
Hemoglobin, RBC, MCV, hematocrit, WBC 
count with differential, and platelet count 
Screening Visit 1, 
Weeks 2-Visit 778 
Biochemistry 
8.5 mL blood
Sodium, potassium, chloride, BUN/Urea, 
*Creatinine, glucose, calcium, phosphorous, 
total protein, albumin, total bilirubin, AST, ALT, 
GGT, Alkaline phosphatase, LDH, CK,CRP, 
Uric acid, (total bilirubin > 1.5 times ULN will 
be reported as direct and indirect bilirubin), 
Screening Visit 1, 
Weeks 2-Visit 778,
*creatinine will be 
measured once 
weekly for 3 weeks 
following 
randomization 
Iron metabolism 
8.5 mL blood
Serum ferritin 
Screening V1, V2, 
Weeks 2-Visit 778 
Viral Serology 
Same sample 
as for 
chemistry 
Hepatitis B: HBsAg and anti-HBs 
Hepatitis C: Anti-HCV, HCV RNA 
quantification 
Screening Visit 1 
Serum Pregnancy Test 
Same sample 
as for 
chemistry 
Serum β-HCG for women of child-bearing 
potential 
Screening Visit 1 
Urine Pregnancy Test 
> 1 mL urine 
in clean 
container 
Urine HCG for women of child-bearing 
potential 
Visit 777 
Urinalysis 
30 mL 
(midstream 
urine sample)
Specific gravity, pH, semi-quantitative 
“dipstick” evaluation of glucose, protein, 
bilirubin, ketones, leukocytes, blood. 
Screening Visit 1 
and Weeks 2-Visit 
778 


Novartis 
Confidential 
Page 76 
Amended Protocol Version 05 (Clean) 
 
Protocol No. CICL670A2302 
 
Evaluation 
Sample 
collection 
Analysis 
Collection 
Time-point 
Urinary protein / 
creatinine ratio 
10 mL urine 
(non-first void 
morning 
specimen) 
Total protein and creatinine 
Screening Visits 1 
and 2, Weeks 2-
Visit 778. 
Oral Glucose Tolerance 
Testing * 
2 mL blood, 
two times 
Blood glucose test 
Screening Visit 1, 
then every year 
Brain Natriuretic Peptide 
(BNP) 
2 mL blood 
BNP 
Randomization, 
then unscheduled 
visits if CHF is 
suspected 
* Patients should fast for at least 5 hours prior to the test being drawn. Should a patient have a documented 
diagnosis of diabetes requiring treatment with medication, the glucose tolerance test is not mandatory and is up to 
the Investigator’s discretion. 
7.5.6 
Electrocardiogram (ECG) 
A 12-lead ECG will be performed as outlined in Table 7-1. All ECGs will be read centrally. 
Details will be outlined in the site manual provided by the central laboratory, and the exam 
must be performed by the methods described in the manual. 
7.5.7 
Echocardiogram (ECHO) 
Complete two dimensional echocardiograms with two dimensional imaging, color flow, 
pulsed-wave and continuous Doppler recordings will be performed at screening Visit 1 and 
approximately every 12 weeks as outlined in Table 7-1. 
Congestive heart failure is a clinical syndrome caused by cardiac dysfunction. Left ventricular 
dysfunction can be asymptomatic or symptomatic and is evaluated by measuring LVEF. All 
adverse events related to congestive heart failure should be recorded in the appropriate 
Adverse Event eCRF. 
Patients whose left ventricular ejection fraction is < 50% confirmed by the ECHO obtained at 
Screening, will not be eligible for randomization. 
Patients with echographic evidence of worsening cardiac function based on the following 
criteria will have met a non-fatal component of the primary endpoint event-free survival. 
• At least > 15% absolute decrease in left ventricular ejection fraction (LVEF) from 
screening value at two consecutive assessments at least two weeks apart 
OR 
• LVEF below institutional limits of normal and at least > 10% absolute decrease from 
LVEF screening value at two consecutive assessments at least two weeks apart 
All events which could potentially fulfill the criteria for one of the components of the 
composite primary endpoint, will be reported to the Endpoint Adjudication Committee (EAC) 
for assessment. 
For standardization purposes, all echocardiograms must be sent to the central imaging 
laboratory and will be interpreted by a central reader. Analysis from a central reader will only 
include endpoints specified in the protocol. Investigators may have images read locally for 
complete analysis and full report of all other parameters. A detailed manual will be provided 


Novartis 
Confidential 
Page 77 
Amended Protocol Version 05 (Clean) 
 
Protocol No. CICL670A2302 
 
to the sites by the central imaging laboratory and the exam must be performed by the methods 
described in the manual. The echocardiography reports must be filed with the patient’s record 
and source documentation. 
7.5.8 
Chest X-ray 
A chest x-ray will be performed during the randomization visit (Visit 3) and for any 
hospitalization related to congestive heart failure. The chest x-ray will be performed and read 
locally at the study site. The chest x-ray taken at Visit 3 will be used as a baseline reading for 
any x-rays obtained during the study when an endpoint of congestive heart failure is suspected. 
If a patient has been randomized without a chest x-ray, then a chest x-ray should be done at 
the next scheduled visit. 
If a patient had a chest x-ray 6 months prior to the randomization visit and the test results are 
available, then a chest x-ray will not need to be done at Visit 3. 
7.5.9 
Bone marrow biopsy or aspirate 
If a patient develops laboratory abnormalities suggestive of Disease progression (MDS 
progression or AML transformation) in the opinion of the investigator, a bone marrow biopsy 
or aspiration should be conducted in order to confirm the diagnosis. Based upon the most 
current classification guidelines (Vardiman 2009), AML transformation should be suspected 
if 20% or more blasts are present in the peripheral blood. A bone marrow biopsy or aspirate 
with 20% or more blasts seen in the bone marrow would confirm the diagnosis of AML. An 
unconfirmed diagnosis of AML will not be considered as a “progression to AML” and 
subsequently will not be considered as an event for the composite primary endpoint. It may, 
however, meet the criteria for the disease progression (MDS progression) secondary efficacy 
endpoint (See Section 3.2.1). All bone marrow results must be recorded in the eCRF for 
utilization in IPSS scoring and subsequent analyses. 
Bone marrow biopsy or aspiration and examination must include the following assessments: 
• Cellularity 
• % Blasts 
• Iron Stains (>15% ringed siderblasts, Dysplasia, Myeloid: Erythroid ratio) 
• Cytogenetics (isolated 5q deletions, 20q deletions, chromosome 7 abnormalities, absent Y 
chromosome (males), complex abnormalities (>3 abnormalities)). 
7.5.10 
Liver abnormalities 
Non- fatal events related to liver function are classified by either liver function impairment or 
liver cirrhosis and should be recorded on the appropriate AE eCRF. 
Liver function impairment is reflected by: 
• ALT or AST > 2 times the baseline value and > 3.5 times ULN 
AND 
• Total bilirubin > 2 mg/dL at two consecutive visits 
Liver cirrhosis confirmed by the presence of at least one of the following symptoms/signs: 


Novartis 
Confidential 
Page 78 
Amended Protocol Version 05 (Clean) 
 
Protocol No. CICL670A2302 
 
• Cirrhosis-related ascites, 
• Spontaneous bacterial peritonitis, 
• Hepatic encephalopathy 
• Variceal bleeding due to portal hypertension 
OR 
• Abdominal ultrasonography (if clinically indicated) 
OR 
• Liver biopsy (if clinically indicated) 
All events which could potentially fulfill the criteria for one of the components of the 
composite primary endpoint will be reported to the Endpoint Adjudication Committee (EAC) 
for assessment. 
For standardization purposes, all liver ultrasounds must be sent to the central imaging 
laboratory and will be interpreted by a central reader. Analysis from a central reader will only 
include endpoints specified in the protocol. Investigators may have images read locally for 
complete analysis and full report of all other parameters. A detailed manual will be provided 
to the sites by the central imaging laboratory and the exam must be performed by the methods 
described in the manual. The reports must be filed with the patient’s record and source 
documentation. 
7.5.11 
Cardiac function 
Non- fatal events related to congestive heart failure (CHF) requiring hospitalization are 
defined as meeting the following criteria: 
Overnight stay (i.e., change in calendar day) due to congestive heart failure confirmed by the 
presence of the following: 
a. At least one of the following symptoms: 
• Paroxysmal nocturnal dyspnea 
• Orthopnea 
• Dyspnea on exertion 
AND 
b. Two or more of the following signs consistent with heart failure: 
• Pulmonary edema by radiography 
• Rales 
• Enlarged heart by radiography 
• Peripheral edema 
• S3 gallop 
• Hepatojugular reflux 
• Neck vein distention 
• Rapid weight gain 


Novartis 
Confidential 
Page 79 
Amended Protocol Version 05 (Clean) 
 
Protocol No. CICL670A2302 
 
• Elevated brain natriuretic peptide (BNP) or pro-BNP 
AND 
c. Treatment with either intravenous diuretics, intravenous vasodilators, intravenous 
inotropes, mechanical fluid removal (e.g., ultrafiltration or dialysis), or insertion of an 
intra-aortic balloon pump for hemodynamic compromise. Initiation of oral diuretics or 
intensification (doubling) of the maintenance diuretic dose will also qualify. 
All events which could potentially fulfill the criteria for one of the components of the 
composite primary endpoint will be reported to the Endpoint Adjudication Committee (EAC) 
for assessment. 
7.5.12 
Unscheduled safety visits 
Unscheduled safety visits will be permitted at any time during the study if deemed clinically 
necessary by the investigator. Should the patient require an unscheduled safety visit, the study 
staff will measure vital signs, record AEs, concomitant medications if applicable, and perform 
those evaluations deemed clinically necessary for the visit. 
7.6 
Pharmacokinetics 
There will be no pharmacokinetics studies completed during this study. 
7.7 
Exploratory biomarker studies 
There will be no exploratory biomarker studies completed during this study. 
8 
Safety monitoring 
8.1 
Serious adverse event reporting 
To ensure patient safety, every SAE, regardless of suspected causality, occurring after 
protocol-specified procedures begin and until 4 weeks after the patient has stopped study 
treatment must be reported to Novartis within 24 hours of learning of its occurrence. Any 
SAEs experienced after this 4 week period should only be reported to Novartis if the 
investigator suspects a causal relationship to the study drug. Recurrent episodes, 
complications, or progression of the initial SAE must be reported as follow-up to the original 
episode within 24 hours of the investigator receiving the follow-up information. An SAE 
occurring at a different time interval or otherwise considered completely unrelated to a 
previously reported one should be reported separately as a new event. 
Information about all SAEs is collected and recorded on the SAE Report Form. The 
investigator must assess and record the relationship of each SAE to the study drug, complete 
the SAE Report Form in English, and send the completed, signed form by fax within 24 hours 
to the local Novartis Drug Safety and Epidemiology (DS&E). 
The telephone and fax number of the contact persons in the local department of DS&E, 
specific to the site, are listed in the investigator folder provided to each site. The original copy 
of the SAE Report Form and the fax confirmation sheet must be kept with the case report 
form documentation at the study site. 


Novartis 
Confidential 
Page 80 
Amended Protocol Version 05 (Clean) 
 
Protocol No. CICL670A2302 
 
Follow-up information is sent to the same person to whom the original SAE Report Form was 
sent, using a new SAE Report Form stating that this is a follow-up to the previously reported 
SAE and giving the date of the original report. Each re-occurrence, complication, or 
progression of the original event should be reported as a follow-up to that event regardless of 
when it occurs. The follow-up information should describe whether the event has resolved or 
continues, if and how it was treated, whether the blind was broken or not, and whether the 
patient continued or withdrew from study participation. 
If the SAE is not previously documented in the IB or Package Insert (new occurrence) and is 
thought to be related to the Novartis study drug, an DS&E associate may urgently require 
further information from the investigator for Health Authority reporting. Novartis may need to 
issue an IN, to inform all investigators involved in any study with the same drug that this SAE 
has been reported. Suspected Unexpected Serious Adverse Reactions (SUSARs) will be 
collected and reported to the competent authorities and relevant ethics committees in 
accordance with Directive 2001/20/EC or as per national regulatory requirements in 
participating countries. 
8.2 
Pregnancies 
To ensure patient safety, each pregnancy in a patient on study drug must be reported to 
Novartis within 24 hours of learning of its occurrence. The pregnancy should be followed up 
for 3 months after the termination of the pregnancy to determine outcome, including 
spontaneous or voluntary termination, details of the birth, and the presence or absence of any 
birth defects, congenital abnormalities, or maternal and/or newborn complications. 
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the oncology local Novartis Drug Safety and Epidemiology (DS&E) 
department. Pregnancy follow-up should be recorded on the same form and should include an 
assessment of the possible relationship to the Novartis study treatment of any pregnancy 
outcome. Any SAE experienced during pregnancy must be reported on the SAE Report Form. 
Deferasirox is a category B drug. There has not been any evidence of teratogenic effects in 
animal studies. At the Screening Visit a serum pregnancy test will be performed. Positive 
results will deem a patient not eligible for participation in the trial. 
A urine pregnancy test must be performed locally at the End of Treatment visit and if menses 
are delayed for more than 7 days in a female patient capable of becoming pregnant. 
Each pregnancy must be reported to Novartis as soon as the site becomes aware of it. All 
pregnancies occurring from the start of study medication administration on Day 1 through 
End of Treatment for all patients will be reported and followed. 
9 
Data review and data management 
9.1 
Site monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and eCRFs with the investigators and their staff. 
During the study, the field monitor will visit the site regularly to check the completeness of 
patient records, the accuracy of entries on the eCRFs, the adherence to the protocol and to 


Novartis 
Confidential 
Page 81 
Amended Protocol Version 05 (Clean) 
 
Protocol No. CICL670A2302 
 
Good Clinical Practice (GCP), the progress of enrollment, and to ensure that study drug is 
being stored, dispensed, and accounted for according to specifications. Key study personnel 
must be available to assist the field monitor during these visits. 
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, ECGs, and the results of any other tests or assessments. All 
information on eCRFs 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 eCRF entries. Novartis 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 eCRFs are 
performed according to the study-specific monitoring plan. No information in source 
documents about the identity of the patients will be disclosed. 
9.2 
Data collection 
Novartis will supply the investigator site with an Electronic Data Capture (EDC) system that 
has been fully validated and conforms to 21 CFR Part 11 requirements. Novartis personnel (or 
designated CRO) will train designated investigator site staff on the EDC system. Investigator 
site staff will not be given access to the EDC system until they have been trained. Designated 
investigator staff will enter the data required by the protocol into the Novartis eCRFs using 
the Novartis-supplied system. Automatic validation programs check for data discrepancies in 
the eCRFs and, by generating appropriate error messages, allow modification or verification 
of the entered data by the investigator staff before transfer to Novartis via a secure network. If 
applicable, the investigator must certify that the data are complete and accurate by signing a 
memo that will be sent to him by Novartis personnel after the last transfer of the data prior to 
analysis. After database lock, the investigator will receive a CD-ROM or paper copies of the 
patient data for archiving at the investigational site. 
9.3 
Database management and quality control 
The designated Contract Research Organization (CRO) Data Management group will review 
the eCRFs entered by investigational staff for completeness and accuracy and instruct the site 
personnel to make any required corrections or additions. Obvious errors are corrected by the 
CRO personnel. Queries are sent to the investigational site using an electronic data query. 
Designated investigator site staff are required to respond to the query and make any necessary 
changes to the data. 
Concomitant medications entered into the database will be coded using the World Health 
Organization (WHO) Drug Reference List, which employs the Anatomical Therapeutic 
Chemical classification system. Medical history/current medical conditions and AEs will be 
coded using the Medical dictionary for regulatory activities (MedDRA) terminology. 


Novartis 
Confidential 
Page 82 
Amended Protocol Version 05 (Clean) 
 
Protocol No. CICL670A2302 
 
Third-party vendor data (IVRS, central laboratory, ECG, ECHO, liver biopsy) will be 
processed centrally and the results will be sent electronically to Novartis (or a designated 
CRO). 
Randomization codes and data about all study drug dispensed to the patient and all dosage 
changes will be tracked using an IVRS. The system will be supplied by a vendor(s), who will 
also manage the database. The database will be sent electronically to Novartis (or a designated 
CRO). 
At the conclusion of the study, the occurrence of any emergency code breaks will be 
determined after return of all code break reports and unused drug supplies to Novartis. The 
occurrence of any protocol deviations will be determined. After these actions have been 
completed and the database has been declared to be complete and accurate, it will be locked. 
Any changes to the database after that time can only be made by joint written agreement 
between the Global Head of Biometrics and Data Management and the Global Head of 
Clinical Development. 
9.4 
Data Monitoring Committee 
An external DMC will meet prior to First Patient First Visit to finalize the DMC charter. 
The composition, frequency of the meetings, and roles will be detailed in the DMC charter. 
The DMC charter will be approved prior to randomization of the first patient. In brief, the 
DMC will be composed of 5 members including experts in hematology, cardiology, 
hepatology and biostatistics. All DMC members will be non-Novartis employees and not 
participating otherwise in the study (detailed description of potential conflicts of interests will 
be part of the DMC charter). 
The independent DMC will monitor patient safety and trial conduct and will receive a blinded 
summary of serious adverse events on a regular basis (see DMC charter). 
The DMC may recommend to the Sponsor: 
• To continue the study as planned 
• To continue the study with modifications 
• To prematurely stop the study for unfavorable safety profile of deferasirox compared to 
placebo 
10 
Statistical methods and data analysis 
The data will be analyzed by Novartis and/or a designated CRO. 
Data will be summarized with respect to demographic and baseline characteristics, efficacy 
observations and measurements, safety observations and measurements, and other 
assessments. Continuous variables will be summarized by number of patients, mean, standard 
deviation, minimum, 25th-quantile, median, 75th-quantile and maximum. Categorical variables 
will be summarized by absolute and relative frequencies. Discrete (count) variables will be 
summarized by appropriate descriptive statistics depending on the number of observed levels. 


Novartis 
Confidential 
Page 83 
Amended Protocol Version 05 (Clean) 
 
Protocol No. CICL670A2302 
 
Unless otherwise stated the “baseline value” is defined as the last available measurement prior 
to randomization. Whenever an event is required to have a confirmation at a later assessment, 
time to event will be calculated from randomization to the initial instance. 
Analyses by stratum (i.e., 4 combinations of MDS risk group and region) will be considered 
as a subgroup analysis. For analyses of parameters describing hematological function 
subgroups are defined by patients who did/did not receive growth factors or treatment for 
MDS (see Section 10.5.1.1). 
In addition to the statistical methods outlined below, further details and additional, 
exploratory analyses might be performed and determined in the study’s report and analysis 
plan (RAP). 
10.1 
Populations for analysis 
Full Analysis Set (FAS): the FAS comprises all patients to whom study treatment has been 
assigned by randomization. According to the intention to treat principle, patients will be 
analyzed according to the study treatment and strata they were assigned to during the 
randomization procedure. 
Per Protocol Analysis Set (PPS): the PPS is a subset of the FAS and comprises all randomized 
patients: 
• Whose first administered study medication was in accordance with the randomized 
assignment, and 
• Without protocol deviations regarding inclusion criteria with respect to underlying disease 
(e.g., low or intermediate-1 MDS according to IPSS and serum ferritin > 1000 mcg/L at 
Screening). 
Safety analysis set: the safety set includes all randomized patients who received at least one 
dose of study medication. Patients will be analyzed according to the study treatment they 
actually received (defined as the study medication administered first) and according to strata 
information recorded in the eCRF. 
The FAS will be the primary analysis set for all statistical analyses of efficacy. The PPS will 
be used as the secondary analysis set to perform statistical analyses of the primary efficacy 
endpoint. All analyses of safety will be based on the safety analysis set. 
10.2 
Patient demographics and other baseline characteristics 
Demographic and other BL data (including disease characteristics) will be summarized 
descriptively for all patients for the FAS. 
10.3 
Treatments (study drug, concomitant therapies, compliance) 
The descriptive analysis listed below will be reported for the safety set. Duration of study 
drug exposure as well as average and cumulative planned (mg/kg/day) and prescribed doses 
(mg/day) will be summarized. Frequency tables for dose adjustments and related reason will 
be provided as well as number and duration of dose interruptions. Any dose adjustments and 
reasons will be listed. 


Novartis 
Confidential 
Page 84 
Amended Protocol Version 05 (Clean) 
 
Protocol No. CICL670A2302 
 
The prescribed amount of study medication (deferasirox/placebo) versus the amount of 
medication taken based on dispensed and returned amount of study medication will be 
described. 
Prior and concomitant medications and significant non-drug therapies will be coded according 
to the WHO Drug Reference List (which employs the Anatomical Therapeutic Chemical 
classification system). Frequencies will be provided by treatment group. 
10.4 
Primary objective 
The primary efficacy objective is to evaluate event-free survival in low and int-1 risk MDS 
patients with transfusional iron overload treated with either deferasirox or placebo. 
10.4.1 
Variable 
The composite primary endpoint (event-free survival, a composite including death and non-
fatal events related to cardiac, liver and hematological function, see Section 3.1.1) is defined 
as time from date of randomization to date when death (irrespective of cause) or any of the 
non-fatal events has been reached (whatever occurred first). Time is measured in days and is 
defined as date of event minus date of randomization plus 1. 
Censoring for patients without information on date of event at the time of a data cut-off (for 
interim or final analysis) is described in Section 10.4.3. 
10.4.2 
Statistical hypothesis, model, and method of analysis 
The sample size of 210 patients does not provide sufficient power for testing confirmatory 
statistical hypotheses. The analysis will therefore concentrate on estimating the treatment 
effect of deferasirox relative to placebo to evaluate potential event-free survival benefit and 
other descriptions of the survival functions. 
Statistical tests will be performed in an exploratory sense only. There will be no procedures to 
control multiple/family-wise type-I-error probabilities regarding the different endpoints. 
10.4.2.1 Estimation of survival functions for event-free survival 
A graphical estimate of the survival function separately for each treatment group will be 
obtained by the Kaplan-Meier (KM) product-limit method as implemented in SAS PROC 
LIFETEST. 
If available, median survival for each treatment group will be obtained by SAS PROC 
LIFETEST along with 95% confidence intervals calculated using the method of (Brookmeyer 
and Crowley 1982). Additional percentiles might be specified in the RAP. 
KM estimates with 95% confidence intervals at days 365, 730, 1095 and 1460 will be 
provided. The confidence intervals will be constructed using Greenwood’s formula (Collett 
1994) for the standard error of the Kaplan-Meier estimate. 


Novartis 
Confidential 
Page 85 
Amended Protocol Version 05 (Clean) 
 
Protocol No. CICL670A2302 
 
10.4.2.2 Stratified unadjusted Cox proportional hazards regression model 
The stratified unadjusted Cox model and its assumptions are described by 
 
with 
h (.) hazard function as a function of time (relative to date of randomization), the randomized 
study treatment of patient j in stratum k and the unknown regression parameter 
h0k(t) unspecified baseline hazard function for stratum k at time t 
xjk1 
randomized study treatment for patient j in stratum k coded as 0 (placebo) or 1 
(deferasirox) 
β1 
unknown regression parameter for the treatment effect on the log-scale (the log hazard 
ratio), to be estimated. 
The hazard ratio (HR) is a multiplicative constant, exp(β1), comparing the hazard function in 
the deferasirox group relative to the hazard function in the placebo group. The latter is called 
the baseline hazard function which is allowed to vary across strata. However, the HR 
comparing study treatments is assumed to be common across strata. A HR < 1 would indicate 
a decreased hazard for deferasirox as compared to placebo. 
The Cox proportional hazards model will be evaluated by using SAS PROC PHREG with the 
TIES = EXACT option in the MODEL statement. The HR point estimate will be based on the 
partial maximum likelihood function, and a 95% Wald-test-based two-sided confidence 
interval will be requested by the RISKLIMITS option. 
10.4.2.3 Statistical hypotheses (exploratory) 
Suppose that SD(t) and SP(t) denote the survival functions regarding event-free survival for 
deferasirox and placebo, respectively. The null hypothesis 
H0: 
SD(t) = SP(t) for all t ≥ 0 (identical survival functions for both groups) 
will be tested against the one-sided alternative hypothesis 
HA1: SD(t) ≥ SP(t) for all t ≥ 0 and SD(t) > SP(t) for at least some t > 0 (event-free survival 
benefit in the deferasirox group over the placebo group). 
10.4.2.4 Statistical hypothesis test (exploratory) 
An exploratory stratified log-rank test with stratification variables used in the randomization, 
i.e. IPSS (low or int-1) and geographical region (Asian versus non-Asian countries), will be 
implemented as follows: In each of the K strata separately (by using a BY statement), the SAS 
LIFETEST procedure with a STRATA statement including only the treatment group variable 
will be used to obtain the rank statistic Sk and variance var(Sk) where k = 1, 2, …, K. 
The final test statistic will then be constructed as: 
Z = [S1 +…+ SK]/√[var(S1) +…+ var(Sk)]. 


Novartis 
Confidential 
Page 86 
Amended Protocol Version 05 (Clean) 
 
Protocol No. CICL670A2302 
 
Under the null hypothesis, the test statistic Z is approximately normally distributed (Z2 is 
approximately chi-square distributed with one degree of freedom). A one-sided (exploratory) 
p-value will be obtained using the Z statistic. 
10.4.3 
Handling of missing values/censoring/discontinuations 
Event-free survival 
For the primary analysis of event-free survival, 
• Patients who have not experienced any of the non-fatal events from the composite primary 
endpoint and have not stopped study participation at the time of data cut-off (end of study) 
will be censored - irrespective of adherence to study treatment - considering the following 
dates for the components and taking the earliest (minimum) of these as the censoring date: 
• Worsening of cardiac function: the last date when echocardiography results were 
available, 
• Hospitalization for congestive heart failure: the data cut-off date, 
• Liver function impairment: the last date when laboratory values for ALT, AST and 
bilirubin were available, 
• Liver cirrhosis: the data cut-off date, 
• Progression to AML: the data cut-off date; 
• Patients who have not experienced any of the non-fatal events from the composite primary 
endpoint but have stopped study participation before the time of data cut-off will be 
censored - irrespective of adherence to study treatment - considering the following dates 
for the components and taking the earliest (minimum) of these as the censoring date: 
• Worsening of cardiac function: the last date when echocardiography results were 
available, 
• Hospitalization for congestive heart failure: the last date when the patient had some 
documented personal contact (visit or phone call) with the investigator, 
• Liver function impairment: the last date when laboratory values for ALT, AST and 
bilirubin were available, 
• Liver cirrhosis: the last date when the patient had some documented personal contact 
(visit or phone call) with the investigator, 
Progression to AML: the last date when the patient had some documented personal contact 
(visit or phone call) with the investigator. Suspected progression to AML without 
confirmation by bone marrow biopsy or aspiration does not constitute an event and censoring 
will be applied as described. 
For the first main sensitivity analysis described in Section 10.4.4, patients with premature 
discontinuation of randomized study treatment and subsequent treatment with marketed iron 
chelation therapy (including Exjade®) will be censored at the date of first administration of the 
subsequent iron chelation therapy. 
For the second main sensitivity analysis described in Section 10.4.4, patients with premature 
discontinuation of randomized study treatment (regardless of whether they were subsequently 


Novartis 
Confidential 
Page 87 
Amended Protocol Version 05 (Clean) 
 
Protocol No. CICL670A2302 
 
treated with marketed iron chelation therapy) will be censored at the date of last 
administration of randomized study treatment. 
The third sensitivity analysis described in Section 10.4.4 will employ the following censoring 
rules. 
• If an event is documented after three or more consecutive missing biochemistry laboratory 
assessments (regarding results for ALT, AST, and total bilirubin), the event-free survival 
time of these patients will be censored at the date of the last assessment with complete 
information for ALT, AST, and total bilirubin. 
• If an event is documented after two or more consecutive missing echocardiogram (ECHO) 
assessments (for left ventricular ejection fraction), the event-free survival time of these 
patients will be censored at the date of the last ECHO assessment. 
• If an event is documented after at least three consecutive missing biochemistry laboratory 
assessments (ALT, AST, and total bilirubin) and at least two consecutive missing ECHO 
assessments simultaneously, the event-free survival time will be censored at the date of 
the last assessment with both biochemistry laboratory and ECHO assessments completed. 
• As the three other components, ‘hospitalization for congestive heart failure’, ‘liver 
cirrhosis’, and ‘Progression to AML’ are symptom-based, i.e., assessed in unscheduled 
examinations, missing assessments for them cannot be determined. 
Overall survival 
For the analysis of overall survival (see Section 10.5.1.1), patients will be censored at the last 
date when the patient had some documented personal contact (visit or phone call) with the 
investigator. 
Worsening of cardiac function 
For the analysis of worsening of cardiac function (as defined in Section 3.1.1), patients who 
have not experienced a worsening of cardiac function will be censored at the last date when 
echocardiography results were available. 
Hospitalization for congestive heart failure 
For the analysis of hospitalization for congestive heart failure (as defined in Section 3.1.1), 
patients who have not experienced any hospitalization for congestive heart failure will be 
censored at the last date when the patient had some documented personal contact (visit or 
phone call) with the investigator. 
Liver function impairment 
For the analysis of liver function impairment (as defined in Section 3.1.1), patients who have 
not experienced any liver function impairment will be censored at the last date when 
laboratory values for ALT, AST and bilirubin were available. 


Novartis 
Confidential 
Page 88 
Amended Protocol Version 05 (Clean) 
 
Protocol No. CICL670A2302 
 
Liver cirrhosis 
For the analysis of liver cirrhosis, patients who have not experienced liver cirrhosis will be 
censored at the last date when the patient had some documented personal contact (visit or 
phone call) with the investigator. 
Progression to AML 
For the analysis of progression to AML, patients who have not experienced progression to 
AML will be censored at the last date when the patient had some documented personal 
contact (visit or phone call) with the investigator. 
Disease progression 
For the analysis of time to disease progression (see Section 10.5.1.1), patients who did not 
experience an MDS progression or progression to AML will be censored at the last date when 
the patient had some documented personal contact (visit or phone call) with the investigator. 
Increase in serum ferritin 
For the analysis of time from randomization to the first occurrence of serum ferritin > 2 times 
the baseline value at two consecutive assessments (see Section 10.5.1.1), patients who did not 
experience such an increase in serum ferritin will be censored at the last date when serum 
ferritin was available. 
Increase in LVIDD or LVISD 
For the two analyses of time from randomization to the first occurrence of an increase of at 
least 10% from the baseline value of LVIDD and time from randomization to the first 
occurrence of an increase of at least 10% from the baseline value of LVISD (see Section 
10.5.1.1), respectively, patients who did not experience such an increase will be censored at 
the last date when LVIDD (or LVISD, respectively) was available. 
Study drug discontinuation due to an AE or laboratory abnormality 
For the analysis of time from randomization to study drug discontinuation due to an AE or 
laboratory abnormality (see Section 10.5.2.2), patients who did not discontinue study 
medication due to an AE or laboratory abnormality will be censored at the date of study drug 
discontinuation. 
10.4.4 
Supportive and sensitivity analyses 
The two main sensitivity analyses for the primary efficacy analysis (event-free survival) will 
be based on the two alternative censoring rules described in Section 10.4.3. Otherwise, the 
same statistical methods will be used as for the primary analysis of event-free survival. A 
third sensitivity analysis using the same methodology will address the issue of partial data for 
the composite endpoint (i.e. a patient has missing data on some but not all of the components). 
The censoring rules for this analysis are also described in Section 10.4.3. 


Novartis 
Confidential 
Page 89 
Amended Protocol Version 05 (Clean) 
 
Protocol No. CICL670A2302 
 
Supportive analyses include: 
• KM curves by treatment and unadjusted HR (point estimate and two-sided 95% 
confidence interval) for each of the strata defined by the randomization factors; 
• KM curves by treatment and unadjusted HR (point estimate and two-sided 95% 
confidence interval) for each component of event-free survival (overall survival is also a 
secondary efficacy endpoint, see Section 10.5.1.1); 
Sensitivity analyses include: 
• Point estimate and two-sided 95% confidence interval for the adjusted HR from a Cox 
proportional hazard regression model stratified for the randomization factors with 
adjustment for (partly data-driven) demographic or baseline characteristics of clinical 
interest; 
• Statistical analyses based on the PPS instead of the FAS. 
10.5 
Secondary objectives 
10.5.1 
Secondary efficacy objectives 
All analyses of secondary efficacy endpoints will be based on the FAS. 
If applicable, nominal significance levels will be set to comparison-wise one-sided 
alpha = 0.025; all confidence intervals will be two-sided using a ordinary confidence level of 
95%. 
10.5.1.1 Secondary efficacy variables and related analyses 
Hematologic improvement 
Hematologic improvement in terms of erythroid responses during treatment will be assessed 
based on IWG criteria (Cheson 2006). 
The variable used in the analysis of HI will be the proportion of patients who satisfy the 
erythroid response criteria, namely 
• Hemoglobin increase of ≥ 1.5 g/dL 
OR 
• Reduction of ≥ 4 RBC transfusions/8 weeks 
in comparison to pre-treatment values and lasting at least 8 weeks. According to IWG criteria, 
HI is measured in patients with pre-treatment hemoglobin levels of less than 11 g/dL or RBC 
transfusion dependence. Pre-treatment hemoglobin levels must not be influenced by 
transfusions (no transfusion received for at least one week preceding the hemoglobin 
measurement). The last hemoglobin value measured prior to randomization will be used as the 
pre-treatment value. (If 2 pre-treatment Hemoglobin values are available and each is at least 7 
days after any transfusion, an average of the 2 values will be used to determine the pre-
treatment hemoglobin value). Similarly, measurements after randomization influenced by 
preceding transfusions within one week will not contribute to the response criteria. All RBC 


Novartis 
Confidential 
Page 90 
Amended Protocol Version 05 (Clean) 
 
Protocol No. CICL670A2302 
 
transfusions regardless of pre-transfusion hemoglobin level will count in the RBC transfusion 
response evaluation. 
All episodes of HI in the patient will be considered. 
The percentage of responders will be reported for the two treatment groups. The equality of 
proportions in the two groups will be analyzed by an exploratory test. Further details will be 
described in the RAP. 
Overall survival 
Overall survival (OS) will be evaluated in patients treated with either deferasirox or placebo. 
The variable used in the analysis of overall survival is time to death measured in days. It is 
defined as date of death (irrespective of cause) minus date of randomization plus 1. 
Censoring is described in Section 10.4.3. The estimation of survival functions and the Cox 
model to estimate the HR are defined in analogy to Section 10.4.2.1 and Section 10.4.2.2. An 
exploratory statistical test will be performed analog to the description in Section 10.4.2.3 and 
Section 10.4.2.4. In this analysis SD(t) and SP(t) denote the survival functions regarding 
overall survival for deferasirox and placebo, respectively. 
Proportion of patients with hypothyroidism 
Hypothyroidism will be evaluated by the annual measurement of TSH and free T4. The 
proportion of patients with normal thyroid function, primary hypothyroidism, secondary 
hypothyroidism or subclinical hypothyroidism will be determined at each time point (i.e. 1, 2, 
years after randomization). 
Definitions: 
• 
normal thyroid function: serum TSH and free T4 within normal limits; 
• 
primary hypothyroidism: serum TSH >ULN and free T4 <LLN; 
• 
secondary hypothyroidism: serum TSH <ULN and free T4 <LLN; 
• 
subclinical hypothyroidism: TSH >ULN and a free T4 within normal limits. 
TPO antibodies will be measured in patients with elevated TSH levels to determine the status 
of thyroid autoimmunity. 
Frequency of newly occurring hypothyroidism and shift tables will be provided for each 
treatment group. Results will also be shown separately for each year since randomization. 
Proportion of patients with worsening of glucose metabolism 
An annual oral glucose tolerance test will be carried out to evaluate changes of glucose 
metabolism compared to the baseline status. The proportion of patients with an increase in 
glucose metabolism category (normal, impaired glucose metabolism, diabetes mellitus) based 
on the American Diabetes Association criteria (American Diabetes Association 2009) 
compared to their baseline result will be determined at each timepoint, i.e. 1, 2, years after 
randomization. For this classification, fasting and 2-hour post-prandial plasma glucose levels 
will be measured. 


Novartis 
Confidential 
Page 91 
Amended Protocol Version 05 (Clean) 
 
Protocol No. CICL670A2302 
 
Criteria for impaired glucose metabolism: 
• fasting plasma glucose (FPG) levels ≥ 100 mg/dl (5.6 mmol/L) but <126 mg/dl 
(7.0 mmol/L) 
OR 
• 2-h values in the oral glucose tolerance test (OGTT) of ≥ 140 mg/dl (7.8 mmol/L) but 
<200 mg/dl (11.1 mmol/L). 
Criteria for diabetes mellitus: 
• symptoms of diabetes plus casual plasma glucose concentration ≥ 200 mg/dl 
(11.1 mmol/L) Casual is defined as any time of day without regard to time since last meal. 
The classic symptoms of diabetes include polyuria, polydipsia, and unexplained weight 
loss. 
OR 
• FPG ≥ 126 mg/dl (7.0 mmol/L). Fasting is defined as no caloric intake for at least 8 hours. 
OR 
• 2 hour postload glucose ≥ 200 mg/dl (11.1 mmol/L) during an OGTT. The test should be 
performed as described by WHO, using a glucose load containing the equivalent of 75 g 
anhydrous glucose dissolved in water. 
Frequency and shift tables will be provided for each treatment group. Results will also be 
shown separately for each year since randomization. 
Disease progression 
An evaluation of the time from randomization to either MDS progression or progression to 
AML in the treatment groups will be done based on date of diagnosis of MDS progression or 
date of first diagnosis of AML minus date of randomization plus 1. 
MDS progression will be defined as a transition into a higher MDS risk group based on IPSS 
scoring. Progression to AML will be defined based upon the most current classification 
guidelines (Vardiman 2009), as 20% or more blasts seen in the bone marrow collected by 
biopsy or aspirate. 
The time-to-event analysis follows the description given in Section 10.4.2.1 to Section 
10.4.2.4. Censoring for patients with neither MDS progression nor progression to AML at the 
time of a data cut-off is described in Section 10.4.3. Further details will be described in the 
RAP. 
Time to first occurrence of serum ferritin > 2 times the baseline value 
An evaluation of the time from randomization to the first occurrence of serum ferritin > 2 
times the baseline value at two consecutive assessments (at least two weeks apart) will be 
performed per treatment group based on the following variable: 
• date of the first of the two consecutive laboratory assessment fulfilling the criterion of SF 
> 2 × baseline value minus date of randomization plus 1. 


Novartis 
Confidential 
Page 92 
Amended Protocol Version 05 (Clean) 
 
Protocol No. CICL670A2302 
 
The time-to-event analysis follows the description given in Section 10.4.2.1 to Section 
10.4.2.4. Censoring for patients without such a serum ferritin increase at the time of a data 
cut-off is described in Section 10.4.3. 
Time to at least a 10% increase from baseline in LVIDD 
An evaluation of the time from randomization to the first occurrence of an increase of at least 
10% from the baseline value of LVIDD will be performed based on the following variable: 
• date of echocardiography assessment where a minimum of 10% increase first occurred 
minus date of randomization plus 1. 
The time-to-event analysis follows the description given in Section 10.4.2.1 to Section 
10.4.2.4. Censoring for patients without such an increase in LVIDD at the time of a data cut-
off is described in Section 10.4.3. If necessary, further details will be described in the RAP. 
Time to at least a 10% increase from baseline in LVISD 
An evaluation of the time from randomization to the first occurrence of an increase of at least 
10% from the baseline value of LVISD will be performed based on the following variable: 
• date of echocardiography assessment where a minimum of 10% increase first occurred 
minus date of randomization plus 1. 
The time-to-event analysis follows the description given in Section 10.4.2.1 to Section 
10.4.2.4. Censoring for patients without such an increase in LVISD at the time of a data cut-
off is described in Section 10.4.3. If necessary, further details will be described in the RAP. 
Infections 
Infections requiring intravenous antimicrobials during the treatment period (until the 28 day 
follow-up visit) will be evaluated separately for each treatment group. 
Definitions: 
• Infections will be determined from the reported adverse events with system organ class 
"Infections and infestations" and action taken “Concomitant medication taken”. 
• Antimicrobial therapy will be determined from the reported concomitant medications for 
patients who had an infection AE. The selection of medications will be based on a pre-
specified list of WHO low level ATC codes. The route of administration needs to be 
specified as “intravenous (i.v.)”. 
• Contemplable events will be combined with medications (of the same patient) based on 
the following criterion: start date of medication ≥ start date of AE and start date of 
medication ≤ minimum (start date of AE + 1, end date of AE). 
The total number of infections will be counted and summarized per treatment group. For this 
number one patient can contribute more than one infection event. To account for different 
lengths of observation time in the two groups, the rate of infections will be calculated with the 
number of recorded infections treated with intravenous antimicrobials divided by the total 
number of patient-years of follow-up. The relative risk of infection will be calculated as the 
rate of infection in the treatment group compared with the rate in the placebo group. 


Novartis 
Confidential 
Page 93 
Amended Protocol Version 05 (Clean) 
 
Protocol No. CICL670A2302 
 
10.5.2 
Secondary safety objectives 
10.5.2.1 Observation periods for safety 
The overall observation period will be divided into three mutually exclusive segments: 
1. Pre-treatment period: from day of patient’s informed consent to the day before first dose 
of study medication. 
2. On-treatment period: from day of first dose of study medication to 28 days after last dose 
of study medication. 
3. Post-treatment period: starting at day 29 after last dose of study medication. 
Safety summaries (tables and figures) have to include only data from the pre-treatment period 
(to display “baseline status”) and the on-treatment period, i.e. no data from the post-treatment 
period are to be included. In particular, summary tables for adverse events (AEs) will include 
only AEs that occurred or worsened during the on-treatment period, the so-called treatment-
emergent AEs. 
However, all safety data (including those from the post-treatment period) will be listed and 
those collected during the pre-treatment and post-treatment periods will be flagged. 
10.5.2.2 Secondary safety variables and related analyses 
Analyses of safety endpoints related to secondary objectives of the trial will be analyzed for 
the safety analysis set. Descriptive statistics and two-sided 95% confidence intervals (without 
adjustment for multiplicity) for evaluation of deferasirox in contrast to placebo will be used as 
appropriate. 
Proportion of patients with significant renal dysfunction 
Treatment groups will be evaluated regarding the proportion of patients experiencing a 
significant renal dysfunction. This is defined as a serum creatinine value ≥ 2 times ULN at 
two consecutive assessments. The two assessments need to be at least 7 days a part. 
Frequency tables by treatment group will be prepared. Results will also be provided for 
annual time intervals. 
Proportion of patients with severe neutropenia or thrombocytopenia 
Proportion of patients with newly occurring CTCAE grade 4 neutropenia or 
thrombocytopenia will be displayed by treatment group. Results will also be provided for 
annual time intervals. 
Proportion of patients with major gastrointestinal bleeding 
An evaluation of the proportion of patients with major gastrointestinal bleeding will be 
performed. Major gastrointestinal bleeding is defined as an AE that may include one of the 
following MedDRA preferred terms: 


Novartis 
Confidential 
Page 94 
Amended Protocol Version 05 (Clean) 
 
Protocol No. CICL670A2302 
 
 
Gastric haemorrhage 
Gastrointestinal haemorrhage 
Small intestinal haemorrhage 
Oesophageal haemorrhage 
Large intestinal haemorrhage 
Rectal haemorrhage 
Melaena 
Duodenal ulcer haemorrhage 
Gastric ulcer haemorrhage 
Peptic ulcer haemorrhage 
Large intestinal ulcer haemorrhage 
Oesophageal ulcer haemorrhage 
Haematochezia 
Frequency tables will be prepared by treatment group. Results will also be provided for 
annual time intervals. 
In addition, a statistical analysis of the multivariate (recurrent) major gastrointestinal bleeding 
data will be performed. 
Time to study drug discontinuation due to an AE or laboratory abnormality 
An evaluation of the time from randomization to study drug discontinuation due to an AE or 
laboratory abnormality will be performed. The variable will be based on the date and reason 
given on the Study Treatment Completion eCRF page. Only patients for whom the reason for 
stopping study medication was entered as AE or laboratory abnormality will be considered. 
The definition of the variable is: 
• date of study drug discontinuation due to an AE or laboratory abnormality minus date of 
randomization plus 1. 
The time-to-event analysis follows the description given in Section 10.4.2.1 to Section 
10.4.2.4. The statistical test will be exploratory. Censoring is described in Section 10.4.3. 
10.5.2.3 Adverse events (AE) 
Frequency tables for treatment-emergent AEs (see Section 10.5.2.1) will present, for each 
treatment group, the number of patients and the percentage of patients experiencing the AE. 
Multiple occurrences of the same event in the same patient will be counted only once in the 
frequency tables. However, all adverse events will be included in the AE listings. 
Frequency tables will display at least the MedDRA system organ class and preferred term, AE 
severity (mild, moderate, severe), and relationship to study drug. 
Deaths reportable as SAEs and non-fatal serious adverse events will be listed by patient and 
tabulated by MedDRA preferred term and treatment group. 


Novartis 
Confidential 
Page 95 
Amended Protocol Version 05 (Clean) 
 
Protocol No. CICL670A2302 
 
10.5.2.4 Analysis of laboratory data 
For analyzing laboratory data, data from all sources (central and local laboratories) will be 
combined. Other than for weekly serum creatinine monitoring visits, central laboratory results 
are the only laboratory results that will be captured in the database. 
Grading of laboratory data 
For laboratory tests covered by the Common Terminology Criteria for Adverse Events 
(CTCAE) version 3.0 NCI 2006, the study’s biometrics team will grade laboratory data 
accordingly with the exception of grade 5 (death). For laboratory tests covered by CTCAE, a 
grade 0 will be assigned for all non-missing values not graded as 1 or higher. For laboratory 
tests where grades are not defined by CTCAE, results will be graded by the low/normal/high 
classification based on laboratory normal ranges. 
Reporting of laboratory data 
The following by-treatment summaries will be generated separately for hematology, 
biochemistry and urinary laboratory tests: 
• Frequency table for newly occurring on-treatment grades 3 or 4. 
• Shift tables using CTCAE grades to compare baseline to the worst on-treatment value. 
• For laboratory tests where CTCAE grades are not defined, shift tables using the 
low/normal/high/(low and high) classification to compare baseline to the worst on-
treatment value. 
For a specific laboratory test, patients with newly occurring on-treatment grade 3 or 4 are 
defined as: 
• Patients with baseline grade missing, 0, 1 or 2 and worst on-treatment grade 3 or 4 
(percentage to be based on all patients with baseline grade missing, 0, 1 or 2). 
• Patients with baseline grade missing, 0, 1, 2 or 3 and worst on-treatment grade 4 
(percentage to be based on all patients with baseline grade missing, 0, 1, 2 or 3). 
The following listings will be generated: 
• Listing of laboratory data for patients with newly occurring grade 3 or 4 laboratory 
toxicities. 
• Listing of laboratory data for patients with values outside the laboratory normal ranges 
with values flagged to show the corresponding CTCAE grades and the classifications 
relative to the laboratory normal ranges. 
• Listing of all laboratory data with values flagged to show the corresponding CTCAE 
grades and the classifications relative to the laboratory normal ranges. 
10.5.3 
Other safety data 
Data from other safety tests or assessments will be summarized descriptively and listed, with 
notable values flagged. 


Novartis 
Confidential 
Page 96 
Amended Protocol Version 05 (Clean) 
 
Protocol No. CICL670A2302 
 
10.5.4 
Tolerability 
Not applicable. 
10.5.5 
Pharmacokinetics 
Not applicable. 
10.5.6 
Biomarkers 
Not applicable. 
10.6 
Interim analysis 
No interim analysis will be performed. 
10.7 
Sample size calculation 
The foreseen sample size of 210 patients randomized in a ratio of 2:1 in favor of deferasirox is 
based on the feasibility of enrolling the patients and consultations with the Health Authorities. 
10.8 
Power for analysis of critical secondary variables 
Power calculations for secondary variables were not done for the determination of sample size. 
11 
Administrative procedures 
Regulatory and ethical compliance 
This clinical study was designed and shall be implemented and reported in accordance with 
the protocol, the International Conference on Harmonization (ICH) Harmonized Tripartite 
Guidelines for GCP, with applicable local regulations (including European Directive 
2001/20/EC and US Code of Federal Regulations Title 21), and with the ethical principles laid 
down in the Declaration of Helsinki. 
Responsibilities of the investigator and IRB/IEC/REB 
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly constituted Institutional Review Board/Independent Ethics Committee/Research 
Ethics Board (IRB/IEC/REB) before study start. A signed and dated statement that the 
protocol and informed consent have been approved by the IRB/IEC/REB must be given to 
Novartis before study initiation. Prior to study start, the investigator is required to sign a 
protocol signature page confirming his/her agreement to conduct the study in accordance with 
these documents and all of the instructions and procedures found in this protocol and to give 
access to all relevant data and records to Novartis monitors, auditors, Novartis Clinical 
Quality Assurance representatives, designated agents of Novartis, IRBs/IECs/REBs and 
regulatory authorities as required. 


Novartis 
Confidential 
Page 97 
Amended Protocol Version 05 (Clean) 
 
Protocol No. CICL670A2302 
 
Informed consent 
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC/REB-approved informed consent, or, if incapable of 
doing so, after such consent has been provided by a legally acceptable representative of the 
patient. In cases where the patient’s representative gives consent, the patient should be 
informed about the study to the extent possible given his/her understanding. If the patient is 
capable of doing so, he/she should indicate assent by personally signing and dating the written 
informed consent document or a separate assent form. Informed consent must be obtained 
before conducting any study-specific procedures (i.e. all of the procedures described in the 
protocol). The process of obtaining informed consent should be documented in the patient 
source documents. 
Novartis will provide to investigators in a separate document a proposed informed consent 
form that complies with the ICH/GCP guideline and regulatory requirements and is 
considered appropriate for this study. Any changes to the proposed consent form suggested by 
the investigator must be agreed to by Novartis before submission to the IRB/IEC/REB, and a 
copy of the approved version must be provided to the Novartis after IRB/IEC/REB approval. 
Women of child bearing potential should be informed that taking the study medication may 
involve unknown risks to the fetus if pregnancy were to occur during the study and agree that 
in order to participate in the study they must adhere to the contraception requirement for the 
duration of the study. If there is any question that the patient will not reliably comply, they 
should not be entered in the study. 
Amendments to the protocol 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, Health Authorities where required, and the IRB/IEC/REB. 
Only amendments that are required for patient safety may be implemented prior to 
IRB/IEC/REB approval. Notwithstanding the need for approval of formal protocol 
amendments, the investigator is expected to take any immediate action required for the safety 
of any patient included in this study, even if this action represents a deviation from the 
protocol. In such cases, Novartis should be notified of this action and the IRB/IEC/REB at the 
study site should be informed within 10 working days. 
Discontinuation of the study 
Novartis reserves the right to discontinue this study under the conditions specified in the 
clinical trial agreement. 
Study drug supply and resupply, storage, and tracking/drug accountability 
Study drugs must be received by a designated person at the study site, handled and stored 
safely and properly, and kept in a secured location to which only the investigator and 
designated assistants have access. Upon receipt, the study medication (deferasirox or placebo) 
should be stored according to the instructions specified on the drug labels. Clinical supplies 
are to be dispensed only in accordance with the protocol. 


Novartis 
Confidential 
Page 98 
Amended Protocol Version 05 (Clean) 
 
Protocol No. CICL670A2302 
 
Medication labels will be in the local language and comply with the legal requirements of 
each country. They will include storage conditions for the drug and the medication number 
but no information about the patient. 
The investigator must maintain an accurate record of the shipment and dispensing of study 
drug in a drug accountability ledger. Drug accountability will be noted by the field monitor 
during site visits and at the completion of the trial. Patients will be asked to return all unused 
study drug and packaging at the end of the study or at the time of study drug discontinuation. 
At the conclusion of the study, and, as appropriate during the course of the study, the 
investigator will return all used and unused study drug, packaging, drug labels, and a copy of 
the completed drug accountability ledger to the Novartis monitor or to the Novartis address 
provided in the investigator folder at each site. 
Steering Committee 
A Steering Committee (SC) will be constituted prior to the randomization of the first patient. 
The composition of the SC will be described in a charter. It will include approximately 4 
study investigators and the Novartis Clinical Trial Head, statistician and clinical research 
physician/clinical program leader. 
The responsibilities of the SC will include on-going reviews of trial progress, scientific input 
into protocol revisions, review of safety reports, advising on dosing modifications, interaction 
with the DMC, and the writing of all scientific publications. The details will be provided in 
the SC charter. 
Endpoint Adjudication Committee 
A Endpoint Adjudication Committee (EAC) will be constituted prior to the randomization of 
the first patient. The composition of the EAC will be described in the EAC charter. The EAC 
is responsible for ensuring whether pre-specified endpoint criteria were met for all non-fatal 
events. The role of the EAC is to ensure that all events that have been reported by the sites are 
judged uniformly using the same criteria. The EAC is blinded to study treatment allocation. 
In the event that a patient experiences a suspected non-fatal event, the appropriate Site 
Reported Endpoint eCRF must be completed. The investigative sites will be responsible for 
reporting all suspected non-fatal event cases in the eCRF for EAC review. Further details are 
available in the EAC site guide. The EAC will determine in a blinded fashion if the event 
submitted satisfied the pre-specified endpoint criteria and rule if the case is an endpoint. This 
information will be communicated to the investigative site by the Sponsor. Refer to protocol 
Section 6.7.5 for study drug discontinuation details. 


Novartis 
Confidential 
Page 99 
Amended Protocol Version 05 (Clean) 
 
Protocol No. CICL670A2302 
 
12 
Protocol adherence 
Investigators ascertain they will apply due diligence to avoid protocol deviations. Under no 
circumstances should the investigator contact Novartis or its agents, if any, monitoring the 
trial to request approval of a protocol deviation, as no authorized deviations are permitted. If 
the investigator feels a protocol deviation would improve the conduct of the study this must 
be considered a protocol amendment, and unless such an amendment is agreed upon by 
Novartis and approved by the IRB/IEC/REB it cannot be implemented. All significant 
protocol deviations will be recorded and reported in the Clinical Study Report. 


Novartis 
Confidential 
Page 100 
Amended Protocol Version 05 (Clean) 
 
Protocol No. CICL670A2302 
 
13 
References (available upon request) 
Brookmeyer R, Crowley J (1982). A Confidence Interval for the Median Survival Time. 
Biometrics 38: 29 - 41. 
Cappellini MD, Cohen A, Piga A, et al (2006). A Phase III study of deferasirox (ICL670), a 
once-daily oral iron chelator, in patients with β-thalassemia. Blood; 107:3455-62. 
Cheson BD, Greenberg PL, Bennett JM, et al (2006). Clinical application and proposal for 
modification of the International Working Group (IWG) response criteria in myelodysplasia. 
Blood; 108:419–25. 
Collett D (1994). Modelling Survival Data in Medical Research. London, Chapman & Hall. 
Dayyani F, Conley AP, Strom SS, et al (2010). Cause of death in patients with lower-risk 
myelodysplastic syndrome. Cancer; 116(9):2174-9. 
Diabetes Care January 2009 vol. 32 no. Supplement 1 S13-S61. 
Farmaki K, Angelopoulos N, Anagnostopoulos G, et al (2006). Effect of enhanced iron 
chelation therapy on glucose metabolism in patients with beta-thalassaemia major. Br J 
Haematol; 134:438-44. 
Fenaux P, Mufti GJ, Hellstrom-Lindberg E, et al (2009). Efficacy of azacitidine compared 
with that of conventional care regimens in the treatment of higher-risk myelodysplastic 
syndromes: a randomised, open-label, phase III study. Lancet Oncol; 10(3):223-32. 
Fleming TR (2008). Identifying and addressing safety signals in clinical trials. N Engl J Med; 
359(13):1400-2. 
Gattermann N, Finelli C, Porta MD, et al (2010). Deferasirox in iron-overloaded patients with 
transfusion-dependent myelodysplastic syndromes : Results from the large 1-year EPIC study. 
Leuk Res 34:1143–1150Greenberg P, Cox C, Le Beau MM, et al (1997). International scoring 
system for evaluating prognosis in myelodysplastic syndromes. Blood; 89: 2079-2088. 
Greenland S, Lanes S, Jara M (2008). Estimating effects from randomized trials with 
discontinuations: the need for intent-to-treat design and G-estimation. Clinical Trials; 5: 5-13. 
Jaeger M, Aul C, Sohngen D, et al (1992). Iron overload in polytransfused patients with 
MDS: the use of L1 for oral iron chelation. Drugs of Today; 28(Suppl A): 143-47. 
Jensen PD, Heickendorff L, Pedersen B, et al (1996). The effect of iron chelation on 
haemopoiesis in MDS patients with transfusional iron overload. Br J Haematol; 94:288-299. 
Jensen PD, Jensen FT, Christensen T, et al (2003). Relationship between hepatocellular injury 
and transfusional iron overload prior to and during iron chelation with desferrioxamine: a 
study in adult patients with acquired anemias. Blood;101:91-96. 
Lan KKG, DeMets DL (1983). Discrete sequential boundaries for clinical trials. Biometrika 
70: 649-53. 
Leitch HA (2007). Improving clinical outcome in patients with myelodysplastic syndrome 
using iron chelation therapy. Leuk Res; 31S3: S7-S9. 


Novartis 
Confidential 
Page 101 
Amended Protocol Version 05 (Clean) 
 
Protocol No. CICL670A2302 
 
Lin J, Knight EL, Hogan ML, et al (2003). A Comparison of Prediction Equations for 
Estimating Glomerular Filtration Rate in Adults without Kidney Disease. J Am Soc Nephrol; 
14: 2573-2580. 
Malcovati L, Della Porta MG, Pascutto C, et al (2005). Prognostic factors and life expectancy 
in myelodysplastic syndromes classified according to WHO criteria: a basis for clinical 
decision making. J Clin Oncol 23:7594-7603. 
Matsuda A, Germing, U, Jinnai I, et al (2005). Difference in clinical features between 
Japanese and German patients with refractory anemia in myelodysplastic syndromes. Blood; 
(106) 8: 2633-2640. 
NCI (2006). Common Terminology Criteria for Adverse Events v3.0 (CTCAE). 
Nick H, Acklin P, Lattmann R, et al (2003). Development of tridentate iron chelators: from 
desferrithiocin to ICL670. Curr Medicinal Chemistry; 10(12):1065-76. 
Oken MM, Creech RH, Tormey DC, et al (1982). Toxicity And Response Criteria Of The 
Eastern Cooperative Oncology Group. Am J Clin Oncol;5:649-655. 
Olivieri NF, Brittenham GM (1997). Iron-chelating therapy and the treatment of thalassemia. 
Blood; 89:739-761. 
Porter J, Galanello R, Saglio G, et al (2007). Relative response of patients with 
myelodysplastic syndromes and other transfusion-dependent anaemias to deferasirox 
(ICL670): a 1-yr prospective study. Eur J Haematol; 2008 ;80:168-76. 
Porter JB, Borgna-Pignatti C, Baccarani M, et al (2005). Iron Chelation Efficiency of 
Deferasirox (Exjade®, ICL670) in Patients with Transfusional Hemosiderosis. Blood; 106: 
2690. 
Robins JM (1998). Structural Nested Failure Time Models. Encyclopedia of Biostatistics. 
Rose C, Brechignac S, Vassilier D, et al (2010). Does iron chelation therapy improve survival 
in regularly transfused lower risk MDS patients? A multicenter study by the GFM. Leuk Res. 
2010 Feb 1. [Epub ahead of print]. 
Sanz G, Nomdedeu B, Such E, et al (2008). Independent Impact of Iron Overload and 
Transfusion Dependency on Survival and Leukemic Evolution in Patients with 
Myelodysplastic Syndrome. Presented at 50th Annual Meeting of ASH, Dec 8, 2008, Abstract 
640. 
Schafer AI, Cheron RG, Dluhy R, et al (1981). Clinical consequences of acquired 
transfusional iron overload in adults. NEJM;304: 319-324. 
Schafer AI, Rabinowe S, Le Boff MS, et al (1985). Long-term efficacy of deferoxamine iron 
chelation therapy in adults with acquired transfusional iron overload. Arch Intern Med; 145: 
1217-1221. 
Schaible UE, Kaufmann SH (2004). Iron and microbial infection. Nat Rev Microbiol; 
2(12):946-53. 


Novartis 
Confidential 
Page 102 
Amended Protocol Version 05 (Clean) 
 
Protocol No. CICL670A2302 
 
Therneau TM, Grambsch PM (2000). Modeling Survival Data: Extending the Cox Model. 
New York, Springer. 
Vardiman JW, Thiele J, Arber DA, et al (2009). The 2008 revision of the World Health 
Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and 
important changes. Blood; 115:5:937-951. 
Vinchinsky E, Onyekwere O, Porter J, et al (2007). A randomized comparison of deferasirox 
verus deferoxamine for the treatment of transfusional iron overload in sickle cell disease; 
British Journal of Haematology: (136), 501-508. 

SAP_000.pdf: 
Clinical Development
ICL670/Deferasirox/Exjade®
Study Number: CICL670A2302 / NCT00940602 
A multi-center, randomized, double-blind, placebo-controlled clinical trial 
of deferasirox in patients with myelodysplastic syndromes (low/int-1 risk) 
and transfusional iron overload (TELESTO)
RAP Module 3- Detailed Statistical Methodology
Author:
Trial Statistician
Document type:
RAP Documentation
Document status:
Amendment 4
Release date:
19-Apr-2018
Number of pages:
46
Property of Novartis
For business use only
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


Novartis
For business use only
Page 2
RAP M3 Amendment 4
ICL670A2302
Document History – Changes compared to previous final version of RAP M3
Date
Version
Outcome/changes 
11Mar2015
04Apr2017
Final
Amend
ment 1

RAP M3

The previous final RAP was lean and did not include 
standard sections. Examples include, study design, 
definitions of baseline, etc. The amendment is an 
adaptation of the new SAP template. Section numbers 
listed in the current RAP amendment follow the current 
M3 template. 

Per new template, added study design (Section 1.1)

Tabulated study objectives and endpoints (Section 1.2)

Added a few definitions including last contact date 
(Section 2.1.2.4)

Clarified baseline definition (Section 2.1.2.8)

Added two observational periods: study evaluation
period and survival follow-up period (Section 2.1.2.9)

Elaborated and added the criteria for Per Protocol Set 
(PPS) associated with severity code 1 (Section 2.2.2)

Deleted randomized population set (Section 2.2.3)

Modified the language for disposition table (Section 2.3)

Added analysis language for relevant medical history 
and current medical condition  and also for hemoglobin 
history (Section 2.3) 

Included time-intervals for duration of exposure 
categories (Section 2.4)

Clarified primary endpoint definition (Section 2.5.1)

Clarified that statistical significance level is indeed 
2.5% in a one sided test (Section 2.5.2.1)

Clarified HI (Hematologic Improvement) definition 
(Section 2.7.1.1) 

Elaborated time-to event analysis in terms of what will
be displayed (Section 2.7.1.1) 

Added the definition of treatment emergent AEs and 
also list of AE tables (Section 2.8.1)

Included two AE tables for the requirement of 
ClinicalTrials.gov and EudraCT: Non-serious adverse 


Novartis
For business use only
Page 3
RAP M3 Amendment 4
ICL670A2302
Date
Version
Outcome/changes 
events and deaths due to SAEs suspected to be study 
drug related (Section 2.8.1)

Explained AESI mapping from the AESI search table 
with the notable adverse event groupings (Section 
2.8.1.1)

Added notable criteria for total bilirubin (Section 2.8.3)

Elaborated the ECG notable values (Section 2.8.6) 

Added criteria for notable vital signs (Section 2.8.6.1)

Added auditory and ophthalmic data listings (Section 
2.8.6.2)

Explained 
imputation 
rules 
for 
study 
drug 
administration date (Section 5.1.1); AE date (Section 
5.1.2); Concomitant medication start date (Section 
5.1.3); prior and post-therapy start and end date (Section 
5.1.3.1 and 5.1.3.2), and other dates, such as death date 
(Section 5.1.3.3)

Elaborated STRATA options in Cox’s proportional 
hazard model (Section 2.5.2.3 and 5.5.1.1)
March5, 
2018
Amend
ment 2

Revised per protocol set by updating prohibited 
concomitant medication (Section 2.2.2)

Deleted age specific subgroup analysis (Section 2.2.4) 
per DMC comment. Note that age specific subgroup 
analyses are not required by the protocol.

Revised disposition table by deleting analysis of  
“Number (%) for the primary reason of the end of study 
completion except completion per protocol and death” 
(Section 2.3)

Deleted analysis for drug accountability analysis due to 
fact that it is not required by HA (Section 2.4) 

Added descriptive analysis for deaths and non-fatal 
events, adjudicated by the Endpoint Adjudication 
Committee (Section 2.5.4)

Clarification added regarding nominal p-value for 
overall survival analysis by DMC comment (Section 
2.7.1.1)

Clarified what to be included in the safety tables and 
listings and corrected the neutrophils count criteria 
(Section 2.8)


Novartis
For business use only
Page 4
RAP M3 Amendment 4
ICL670A2302
Date
Version
Outcome/changes 
April 9, 
2018
Amend
ment 3

Added time to event analysis for the  first occurrence of 
serum ferritin > 2 times the baseline value (section 
2.5.3.6 and section 2.7.1.7) as this is a secondary 
endpoint

Deleted the reason of not performing the time to event 
analysis for the first occurrence of serum ferritin > 2 
times the baseline value from section 4

Added analysis for moderate or severe anemia (section 
2.8)
April 19, 
2018
Amend
ment 4

Added repeated time-to-event analyses for the primary 
endpoint excluding patients from one site for data 
integrity issue (section 2.5.4)


Novartis
For business use only
Page 5
RAP M3 Amendment 4
ICL670A2302
Table of contents
1
Introduction........................................................................................................................................... 10
1.1
Study design ............................................................................................................................ 10
1.2
Study objectives and endpoints ............................................................................................... 11
2
Statistical methods ................................................................................................................................ 13
2.1
Data analysis general information........................................................................................... 13
2.1.1
General presentation of descriptive summaries.................................................... 13
2.1.2
General definitions ............................................................................................... 14
2.1.2.1
Investigational drug and study treatment...............................................................14
2.1.2.2
Date of first administration of study treatment......................................................14
2.1.2.3
Date of last administration of study treatment.......................................................14
2.1.2.4
Last contact date....................................................................................................14
2.1.2.5
Screening failure....................................................................................................14
2.1.2.6
Study day...............................................................................................................15
2.1.2.7
Month ....................................................................................................................15
2.1.2.8
Baseline .................................................................................................................15
2.1.2.9
On-treatment assessment/event and observation periods ......................................16
2.2
Analysis sets............................................................................................................................ 16
2.2.1
Full Analysis Set................................................................................................... 16
2.2.2
Per Protocol Analysis Set ..................................................................................... 16
2.2.3
Safety Analysis Set............................................................................................... 17
2.2.4
Subgroup of interest.............................................................................................. 17
2.3
Patient disposition, demographics and other baseline characteristics ..................................... 18
2.4
Treatments (study treatment, compliance) .............................................................................. 18
2.4.1
Duration of exposure ............................................................................................ 19
2.4.2
Cumulative dose ................................................................................................... 20
2.4.3
Average planned and actual dose.......................................................................... 20
2.4.4
Percent dose taken ................................................................................................ 20
2.4.5
Concomitant, prior and post therapies.................................................................. 20
2.4.5.1
Prior chelation therapy...........................................................................................21
2.4.5.2
Chelation therapy after discontinuation of study treatment...................................21
2.4.5.3
Blood transfusion...................................................................................................21
2.5
Analysis of the primary objective............................................................................................ 21
2.5.1
Primary endpoint .................................................................................................. 21
2.5.2
Statistical hypothesis, model, and method of analysis.......................................... 22
2.5.2.1
Statistical hypotheses (exploratory).......................................................................22
2.5.2.2
Estimation of survival functions for event-free survival .......................................22
2.5.2.3
Stratified unadjusted Cox proportional hazards regression model ........................22
2.5.2.4
Statistical hypothesis test (exploratory).................................................................23
2.5.3
Handling of missing values/censoring/discontinuations....................................... 23
2.5.3.1
Worsening of cardiac function...............................................................................24
2.5.3.2
Hospitalization for congestive heart failure...........................................................24


Novartis
For business use only
Page 6
RAP M3 Amendment 4
ICL670A2302
2.5.3.3
Liver function impairment.....................................................................................24
2.5.3.4
Liver cirrhosis........................................................................................................24
2.5.3.5
Progression to AML ..............................................................................................24
2.5.3.6
Increase in serum ferritin.......................................................................................24
2.5.4
Sensitivity and supportive analyses...................................................................... 24
2.6
Analysis of the key secondary objective ................................................................................. 26
2.7
Analysis of secondary efficacy objective(s)............................................................................ 26
2.7.1
Secondary efficacy endpoints............................................................................... 26
2.7.1.1
Hematologic improvement ....................................................................................26
2.7.1.2
Proportion of patients with hypothyroidism..........................................................27
2.7.1.3
Proportion of patients with worsening of glucose metabolism..............................27
2.7.1.4
Disease progression...............................................................................................28
2.7.1.5
Time to at least a 10% increase from baseline in LVIDD .....................................28
2.7.1.6
Time to at least a 10% increase from baseline in LVISD......................................29
2.7.1.7
Time to first occurrence of serum ferritin > 2 times the baseline value ................29
2.7.1.8
Infections ...............................................................................................................29
2.7.2
Statistical hypothesis, model, and method of analysis.......................................... 30
2.7.3
Handling of missing values/censoring/discontinuations....................................... 30
2.7.3.1
Overall survival .....................................................................................................30
2.7.3.2
Disease progression to MDS .................................................................................30
2.7.3.3
Increase in LVIDD or LVISD ...............................................................................30
2.8
Safety analyses ........................................................................................................................ 30
2.8.1
Adverse events (AEs)........................................................................................... 31
2.8.1.1
Adverse events of special interest / grouping of AEs............................................32
2.8.2
Deaths................................................................................................................... 33
2.8.3
Laboratory data..................................................................................................... 33
2.8.4
Other safety data................................................................................................... 34
2.8.4.1
ECG and cardiac imaging data ..............................................................................34
2.8.4.2
Vital signs..............................................................................................................35
2.8.4.3
Auditory and ophthalmic findings.........................................................................35
2.9
Pharmacokinetic endpoints...................................................................................................... 35
2.10
Patient-reported outcomes....................................................................................................... 35
2.11
Biomarkers .............................................................................................................................. 35
2.12
Other Exploratory analyses ..................................................................................................... 36
2.13
Interim analysis ....................................................................................................................... 36
3
Sample size calculation......................................................................................................................... 36
4
Change to protocol specified analyses.................................................................................................. 36
5
Appendix............................................................................................................................................... 36
5.1
Imputation rules....................................................................................................................... 36
5.1.1
Study drug ............................................................................................................ 36
5.1.2
AE date imputation............................................................................................... 37
5.1.3
Concomitant medication date imputation............................................................. 38
5.1.3.1
Prior therapies date imputation..............................................................................38
5.1.3.2
Post therapies date imputation...............................................................................39


Novartis
For business use only
Page 7
RAP M3 Amendment 4
ICL670A2302
5.1.3.3
Other imputations ..................................................................................................39
5.2
AEs coding/grading................................................................................................................. 39
5.3
Laboratory parameters derivations.......................................................................................... 40
5.3.1
Creatinine clearance estimation............................................................................ 40
5.3.2
Terminology IPSS score and MDS risk group ..................................................... 41
5.4
Dose interruption and modification......................................................................................... 41
5.5
Statistical models..................................................................................................................... 41
5.5.1
Primary analysis ................................................................................................... 41
5.5.1.1
Stratified unadjusted Cox model ...........................................................................41
5.5.2
Key secondary analysis......................................................................................... 42
5.5.3
Confidence interval for the difference of proportions .......................................... 42
5.5.4
Treatment switching to new chelator(s)................................................................ 42
5.5.5
Time point windows ............................................................................................. 42
6
Reference.............................................................................................................................................. 45


Novartis
For business use only
Page 8
RAP M3 Amendment 4
ICL670A2302
List of abbreviations
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALT
Alanine aminotransferase/serum glutamic pyruvic transaminase/SGPT
AML
Acute Myeloid Leukemia 
AST
Aspartate aminotransferase/serum glutamic oxaloacetic transaminase/SGOT
BMI
Body Mass Index
CI
Confidence Interval
CrCl
Creatinine Clearance
CTC
Common terminology criteria
CTCAE
Common Terminology Criteria for Adverse Events
CRF
Case report/record form
DFX
Deferasirox/ICL670/Exjade®
DFO
Deferoxamine/Desferal®
DMC
Data monitoring committee
EAC
Endpoint Adjudication Committee
eCRF
Electronic case report/record form
FAS
Full Analysis Set
FPG
Fasting plasma glucose
HI
Hematological Improvement
HR
Hazard Ratio
ICL670
Deferasirox/Exjade®
IPSS
International Prognostic Scoring System
IVRS
Interactive Voice Response System
IWRS
Interactive Web Response System
KM
Kaplan-Meier
LIC
Liver iron concentration
LVEDVI
Left ventricular end-diastolic volume index
LVEF
Left Ventricular Ejection Fraction
LVESVI
Left ventricular end-systolic volume index
LVMI
Left ventricular mass index
LVIDD
Left Ventricular Internal diameter end-diastole
LVISD
Left Ventricular Internal diameter end-systole
MDRD
Modification of Diet in Renal Disease
MDS
Myelodysplastic Syndrome
MedDRA
Medical Dictionary for Regulatory Activities
OGTT
Oral Glucose Tolerance Test
PPS
Per Protocol Analysis Set
RAP
Reporting and Analysis Plan
PRBC
Packed Red Blood Cells
RBC
Red Blood Cells
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan


Novartis
For business use only
Page 9
RAP M3 Amendment 4
ICL670A2302
SCr
Serum Creatinine
SD
Standard deviation
SI
System International (or International System)
SSC
Study steering committee
T4
Thyroxine
TSH
Thyroid Stimulated Hormone


Novartis
For business use only
Page 10
RAP M3 Amendment 4
ICL670A2302
1
Introduction
The purpose of this Reporting and Analysis Plan (RAP) is to describe the implementation of 
the statistical analysis specified in the protocol. The final Clinical Study Report (CSR) will be 
written based on this RAP. It is not intended to produce any other report resulting from this 
RAP. The current RAP is written following the finalized protocol version 5, disease area 
standards, and Exjade project-specific standard TFLs.      
1.1
Study design
This is a prospective, randomized, double-blind, placebo-controlled, parallel group design 
study. Two-hundred and ten patients (per protocol amendment 5) are planned to be enrolled in 
this study.  A screening period lasting up to 35 days with two screening visits (Visit 1 and 
Visit 2 - at least 14 days apart.) will be used to assess patient eligibility. Eligible patients will 
be randomized in 2:1 ratio in deferasirox and placebo arms respectively. Randomization will 
be stratified by IPSS (low or int-1), as well as by geographical region (Asian versus non-
Asian countries). All patients who are randomized in this study will start study treatment at 10 
mg/kg/day and may be titrated up to 40 mg/kg/day based on dose modification guidelines (see 
protocol section 6.7.1).  
The primary endpoint is a composite endpoint including death and non-fatal events related to 
cardiac and liver function. Patients who meet a non-fatal events (see protocol Section 3.1.1 for 
the definition of non-fatal events) will be discontinued from the study treatment. After 
treatment termination, all patients will be followed for safety (28 days) and then evaluated 
with visits every three months. Subsequent to the Evaluation period, or at the end of treatment 
if a patient and treating physician decide that a patient will not participate in the evaluation 
period, patients will be followed by phone monitoring every 6 months for their need for iron 
chelation therapies and overall survival (“Survival Follow-up”) until study end.  
Patients not meeting a non-fatal event will continue study treatment as long as the patient and 
the treating physician feel it is in the best interest for the patient. Following discontinuation 
from study treatment, they will be followed for safety (28 days).
They may choose to be 
evaluated with visits every three months, then subsequent to the Evaluation period, or at the 
end of treatment, if a patient and treating physician decide that a patient will not participate in 
the evaluation period, patients will be followed every 6 months by phone for their need for 
iron chelation therapies and overall survival (“Survival Follow-up”).
An external Data Monitoring Committee (DMC) will monitor patient safety and trial conduct 
and will receive a blinded summary of serious adverse events as detailed in the DMC Charter. 
A complete analysis following the specifications in the RAP document will be done 
subsequent to the last visit at least 3 years after the last-patient-first-visit unless all patients 
will have met the endpoint or discontinued the study earlier.
There will be no interim analysis for this study.  


Novartis
For business use only
Page 11
RAP M3 Amendment 4
ICL670A2302
1.2
Study objectives and endpoints
The study objectives and endpoints are described in the following table:  
Table 1-1 Study objectives and endpoints 
Objective
Endpoint
Primary
The primary objective is to 
evaluate deferasirox and 
placebo for event-free 
survival (a composite 
primary endpoint including 
death and non-fatal events 
related to cardiac and liver 
function, and 
transformation to AML) in 
low and int-1 risk MDS 
patients with transfusional 
iron overload. 
Composite primary endpoint (event-free survival) : 
Time from date of randomization to date when death or any of 
the non-fatal events defined below has been reached (event-
free survival): 
● Death 
● Non-fatal event: 
1. Echocardiographic evidence of worsening cardiac function 
based on the following criteria: at least > 15% absolute 
decrease in left ventricular ejection fraction (LVEF) from 
screening value at two consecutive assessments at least two
weeks apart OR LVEF below institutional limits of normal 
and at least > 10% absolute decrease from LVEF screening 
value at two consecutive assessments at least two weeks 
apart.
2. Hospitalization for congestive heart failure defined as 
follows: Overnight stay (i.e., change in calendar day) due to 
congestive heart failure confirmed by the presence of the 
following: 
     a) At least one of the following symptoms: 
● Paroxysmal nocturnal dyspnea 
● Orthopnea 
● Dyspnea on exertion  
    AND 
    b) Two or more of the following signs consistent with heart 
failure: 
● Pulmonary edema by radiography 
● Rales 
● Enlarged heart by radiography 
       - Peripheral edema 
       - S3 gallop 
       - Hepatojugular reflux 
● Neck vein distention 
● Rapid weight gain
● Elevated brain natriuretic peptide (BNP) 
AND 
      c) Treatment with either intravenous diuretics, intravenous 
vasodilators, intravenous inotropes, mechanical fluid removal 
(e.g., ultrafiltration or dialysis), or insertion of an intra-aortic 


Novartis
For business use only
Page 12
RAP M3 Amendment 4
ICL670A2302
balloon pump for hemodynamic compromise. Initiation of 
oral diuretics or intensification (doubling) of the maintenance 
diuretic dose will also qualify. 
3. Liver function impairment reflected by: 
● ALT or AST > 2 times the baseline value and > 3.5 
times ULN 
                AND 
● Total bilirubin > 2 mg/dL at two consecutive visits 
4. Liver cirrhosis confirmed by: 
● The presence of at least one of the following 
symptoms/signs: cirrhosis-related ascites, spontaneous 
bacterial peritonitis, hepatic encephalopathy, variceal 
bleeding due to portal hypertension 
                OR 
● Abdominal ultrasonography (if clinically indicated) 
                OR 
● Liver biopsy (if clinically indicated) 
5. Progression to Acute Myeloid Leukemia (confirmed by 
bone marrow biopsy or aspirate) 
Secondary
Hematologic improvement 
(HI) in terms of erythroid 
response
Proportion of patients with hematologic improvement in 
terms of erythroid response 
Overall survival 
Overall survival 
Change in endocrine 
function (thyroid and 
glycemic control) 

Proportion of patients with hypothyroidism as 
assessed by annual TSH and free T4.

Proportion of patients with a worsening of glucose 
metabolism from baseline as assessed by annual oral 
glucose tolerance test (OGTT) 
Disease progression (which 
includes MDS progression 
and progression to AML) 
Time to disease progression, i.e. either MDS progression 
defined as a transition into a higher MDS risk group based on 
IPSS scoring or progression to AML defined as >20% blasts 
in the bone marrow
Change in serum ferritin 
level
Time to first occurrence of serum ferritin > 2 times the 
baseline value at two consecutive assessments (at least two 
weeks apart) (See Section 4 for details)
Change in cardiac function

Time to at least a 10% increase from baseline in left 
ventricular end-diastolic internal dimension (LVIDD) 
at two consecutive assessments at least two weeks 
apart

Time to at least a 10% increase from baseline in left 
ventricular internal systolic diameter (LVISD) at two 
consecutive assessments at least two weeks apart 


Novartis
For business use only
Page 13
RAP M3 Amendment 4
ICL670A2302
Frequency of infections 
requiring intravenous 
antimicrobials 
Frequency and rate of infections requiring intravenous 
antimicrobials 
Assess the levels of 
increased risk for pre-
specified adverse events 
(renal dysfunction, 
neutropenia, 
thrombocytopenia, 
gastrointestinal bleeding, 
and laboratory 
abnormalities) that would 
be clinically unacceptable 
in the context of the level 
of benefit that is likely to 
be provided by iron 
chelation using deferasirox 
in MDS patients with iron 
overload (see Fleming 
2008 for general approach). 

Proportion 
of 
patients 
with 
significant 
renal 
dysfunction defined as serum creatinine ≥ 2 times 
ULN at two consecutive assessments (at least 7 days 
apart) 

Proportion of patients with newly occurring severe 
(CTCAE Grade 4) neutropenia or thrombocytopenia 

Proportion of patients with major gastrointestinal 
bleeding 

Time to study drug discontinuation due to an adverse 
event or laboratory abnormality 

Incidence of other adverse events and laboratory 
abnormalities 
2
Statistical methods
This section contains information that will be used to draft CSR Section 9.7 on statistical 
analysis.
2.1
Data analysis general information
Data will be analyzed by Novartis according to the data analysis section 10 of the study 
protocol as detailed in this analysis plan. SAS version 9.4 or later (upon availability) will be 
used. As specified in the protocol, a complete analysis following the specification in this RAP 
documentation will be done subsequent to last visit at least three years after last-patient-first-
visit unless all patients will have met an endpoint or discontinued from the study earlier.
2.1.1
General presentation of descriptive summaries
Qualitative data (e.g., gender, race, etc.) will be summarized by frequency count and 
percentages. Percentages will be calculated using the number of patients in the relevant 
population or subgroup as the denominator.
Quantitative data (e.g., age, body weight, etc.) will be summarized by appropriate 
descriptive statistics (e.g., mean, standard deviation, median, minimum, and maximum).


Novartis
For business use only
Page 14
RAP M3 Amendment 4
ICL670A2302
2.1.2
General definitions
2.1.2.1
Investigational drug and study treatment 
Investigational drug, will refer to the deferasirox only; whereas, investigational treatment
will refer to deferasirox or placebo treatment. In this document, the term investigational 
treatment will be referred as study treatment and will be used throughout this document.
2.1.2.2
Date of first administration of study treatment
The date of first administration of study treatment will be derived as the first date when a non-
zero dose of study treatment is administered as per the Dosage Administration eCRF. For the 
sake of simplicity, the date of first administration of study treatment will also be referred to as 
start of study treatment.
2.1.2.3
Date of last administration of study treatment
The date of last administration of study treatment is defined as the last date when a non-zero 
dose of study treatment was administered as per Dose Administration eCRF. 
2.1.2.4
Last contact date
The last contact date will be derived for patients not known to have died at the analysis cut-off
date using the latest complete date among the following:

All assessment dates, such as vital signs, physical, audiometry, ophthalmologic exam
and third-party assessment date, such as central laboratory, ECG, ECHO, ultrasound,
and liver biopsies

Medication dates including study medication, concomitant medications, iron chelation
therapies administered after study treatment discontinuation, and transfusions during 
the study

Adverse events start/end dates

Last contact date collected on the ‘Survival information’ eCRF

Study treatment start/end date

Randomization date
Only dates associated with patient visits (scheduled or unscheduled) or actual examinations of 
the patient will be used in the derivation. Dates associated with a technical operation unrelated 
to patient status, such as the date a blood sample was processed, will not be used. An imputed 
partial date will not be used to derive the last contact date. The assessment dates after the 
cutoff date will not be applied to derive the last contact date. The last contact date will be used 
for censoring of patients in the analysis of overall survival.
2.1.2.5
Screening failure
Screening failures are patients who enrolled and failed screening criteria in a study. These 
patients are never randomized. Patients who are randomized, but never received study
treatment in a randomized study, are not screening failures.


Novartis
For business use only
Page 15
RAP M3 Amendment 4
ICL670A2302
2.1.2.6
Study day
The study day for safety assessments (e.g. adverse event onset, laboratory abnormality 
occurrence, vital sign measurement, dose interruption etc.) will be calculated as the difference 
between the date of the event (onset date of an event, assessment date etc.) and the start of 
study treatment plus 1. The first day of study treatment is therefore study day 1. If an event 
starts after the start date of study treatment, the study day will be calculated as:
Study day=date of event – start date of study treatment+1
If an event date is before the treatment start date, the study day will be calculated using the 
below formula:
Study day= date of event – start date of study treatment
The study day for efficacy assessments will be calculated as:
Study day = The date of the assessment / event - randomization date + 1
In other words, all efficacy, including time-to-event variables (event-free survival, overall 
survival, time to disease progression), will be calculated from the date of randomization.
For any assessment or events, such as baseline disease characteristics or medical history (e.g.,
time since diagnosis of disease) collected prior to randomization date, the study day will be 
negative and will be calculated as:
Study Day = Event date – Randomization date.
The study day will be displayed in the data listings.
2.1.2.7
Month
A month will be calculated as (365.25 / 12) = 30.4375 days. If duration is to be reported in 
months, duration in days will be divided by 30.4375.
2.1.2.8
Baseline
Unless otherwise specified below, for efficacy evaluations, the baseline value is defined as 
the last available measurement before or on the day of randomization (including results from 
unscheduled visits analyzed by the central laboratory). It is assumed that assessments 
scheduled for Visit 3 – the randomization visit – were done prior to randomization in order to 
be interpreted as prior to or on the day of randomization (e.g. physical examination, chest x-
ray). If an assessment is done at both screening visits, Visit 1 and Visit 2, the value of Visit 2 
is considered the baseline value.
Differing definitions for baseline values were specified for the following assessments or 
parameters:

Serum creatinine, creatinine clearance, ALT/AST, serum ferritin, total and direct
bilirubin: the baseline value is defined as the mean of the Visit 1 and Visit 2 values.  If 
additional measurements analyzed by the central laboratory are available from 


Novartis
For business use only
Page 16
RAP M3 Amendment 4
ICL670A2302
unscheduled visits in the screening period, they will be included in the average. Only 
the central lab values between -35 days and day 1 from randomization date will be 
considered to determine baseline.  

Transfusion history: data of platelet and PRBC transfusion records in the 6-month 
period prior to study start (randomization) will be used to establish baseline 
transfusion frequency and hematologic counts.
For safety evaluations (e.g., laboratory and vital signs etc.), the last available assessment 
before or on the date of start of study treatment is taken as the ‘baseline’ assessment. 
If patients have no value as defined above, the baseline result will be missing.
2.1.2.9
On-treatment assessment/event and observation periods
The overall observation period will be divided into three mutually exclusive segments: 
1. pre-treatment period: before the first administration of study treatment
2. on-treatment period: from date of first administration of study treatment to 28 days 
after date of last actual administration of any study treatment (including start and stop 
date)
3. post-treatment period: starts on day 28+1 after last administration of study treatment.
Per study design, there will be two additional observation periods:
4. study evaluation period: starts on day 29 after last administration of study treatment 
until study evaluation completion period (visit frequency every three months)
5. survival follow-up period: starts after study evaluation completion visit until LPFV 
plus three years or death. If a patient declines to participate in the evaluation period, 
the survival follow-up period will start on day 29 after last administration of study 
treatment until LPFV plus three years or death (visit frequency is every 6 months).
2.2
Analysis sets
The following three analysis sets were defined for analyses in the study protocol.
2.2.1
Full Analysis Set 
The Full Analysis Set (FAS) includes all patients to whom study treatment has been assigned 
by randomization. According to the intention to treat principle, patients will be analyzed 
according to the study treatment and strata they were assigned to during the randomization 
procedure (IVRS).
2.2.2
Per Protocol Analysis Set 
The per protocol analysis set (PPS) is a subset of the FAS and comprises all randomized 
patients:

Whose first administered study medication is in accordance with the randomized 
assignment, and 


Novartis
For business use only
Page 17
RAP M3 Amendment 4
ICL670A2302

Without protocol deviations regarding inclusion or exclusion criteria with respect to 
underlying disease, such as:

No low or intermediate-1 MDS according to IPSS score in the eCRF, 

Serum ferritin ≤1000 µg/L at Screening, 

More than 3 years since patient began receiving regular transfusions, 

LVEF < 50%, 

Diagnosis of liver cirrhosis
Also patients with the following protocol deviation will be excluded from the PPS:

No bone marrow biopsy within 6 months of entering study

Stratum assignment differs from MDS risk and / or country reported by 
investigator

Patient randomized but received wrong study drug (first administered study 
medication)

Prohibited concomitant medications: 

Aluminium containing antacid therapies (aluminium hydroxide and magnesium 
hydroxide)

Use of bile sequestrants ( e.g. cholestyramine, colesevelam,  colestipol)

Use of any other chelation therapy (e.g. deferoxamine, deferiprone)

Any investigational drugs other than study medication.

Use of hormonal contraceptive (oral or injected)
Patients will also be excluded from per-protocol set according to VAP M3.  
2.2.3
Safety Analysis Set
The Safety Analysis Set (SAS) includes all randomized patients who received at least one 
dose of study medication. Patients will be analyzed according to the study treatment they 
actually received (defined as the study medication administered first) and according to strata 
information (MDS risk score/IPSS score) recorded in the eCRF.
The FAS is the primary analysis set for the statistical analyses of efficacy. The PPS will be 
used as the secondary analysis set to perform sensitivity analyses of the primary efficacy 
endpoint. All analyses of safety are based on the safety analysis set. 
2.2.4
Subgroup of interest
The following subgroups will be considered for selected figures and tables: 

IPSS low risk and Asian; IPSS low risk and Non-Asian; IPSS Intermediate 1 risk and 
      Asian; IPSS Intermidiate1 and Non-Asian
For efficacy subgroups, stratification factors i.e., IPSS score (low vs Int-1 risk) and 
geographical region (Asian countries vs non-Asian Countries) as in the randomization (IVRS)
will be used. Asian countries are China, Hong Kong, Malaysia, Thailand, and Taiwan.


Novartis
For business use only
Page 18
RAP M3 Amendment 4
ICL670A2302
For safety subgroups, definition of strata is based on IPSS score and geographical region as in 
the eCRF.
2.3
Patient disposition, demographics and other baseline 
characteristics
A breakdown of reasons will be provided for patients excluded during screening.
The number and percentage of patients randomized will be summarized by region, country, 
center and treatment arm.
Patient disposition will be summarized for the treatment period, as well as for evaluation and 
survival follow-up period using the FAS. The disposition table will include:

Number (%) of treated and untreated patients

Number (%) of patients who completed the end of treatment

Number (%) for the primary reason of the end of treatment completion 

Number (%) of patients followed for evaluation period

Number (%) for the reason of evaluation period completion

Number (%) of patients entering the survival follow-up

Number (%) for the primary reason of study evaluation completion

Number (%) of patients alive at last contact
The number and percentage of patients with any protocol deviation will be tabulated by the 
deviation type and treatment arm using FAS.
Demographic data and baseline characteristics will be summarized descriptively based on the 
FAS. Demographic data include age, age group, gender, race, and ethnicity. Age will be 
presented by region (Asian countries vs non-Asian Countries). Age will be calculated based 
on patient’s first screening date. Baseline characteristics are weight group (<35 kg, 35 –
<55 kg, 55 – <75 kg, 75 – < 95 kg, ≥95 kg), and IPSS score (low vs int-1 risk as in 
randomization) and will be summarized categorically by treatment arm and for all patients. 
Height, weight will be summarized continuously using FAS by each treatment arm and for all 
patients.  
Relevant medical histories and current medical condition will be summarized and listed. The 
summaries will be presented by primary system organ class and preferred term. (Medical 
history/current medical conditions are coded using MedDRA) using FAS.
Hemoglobin history will be listed using FAS. The listing will include hemoglobin value, unit, 
sample collection date and study day.
2.4
Treatments (study treatment, compliance)
Duration of study treatment exposure (days), average planned daily dose (mg/kg/day), and
average actual daily dose (mg/kg/day) will be summarized by treatment arm and for all 


Novartis
For business use only
Page 19
RAP M3 Amendment 4
ICL670A2302
patients. Duration of exposure will be categorized into time intervals. The upper limit of each 
time interval is calculated based on  364 days (defined as 52 weeks x 7 days)  +/- 14 days for 
each year (< 379 days; 379- <743 days; 743- <1107 days; 1107- <1471 days, 1471- <1835 
days; >=1835 days). Frequency counts and percentages will be presented for the number of 
patients in each interval. Total patient years will also be reported.
Average (actual) and planned dose (mg/kg/day) will be summarized similarly. 
The frequency in changes of planned dose (reductions and increases), overall and by reason 
for change, will be summarized. Reasons for interruptions (actual dose zero) will also be 
summarized by treatment arm and for all patients.
Listings of all doses of the study treatment along with dose change and dose interruption
reasons will be produced.
The percentage of total dose taken will be used as an assessment of a patient’s compliance and 
calculated as the amount of medication (deferasirox/placebo) taken versus the planned amount 
of study medication. Percentage of total dose taken will be summarized by treatment arm and 
for all patients.
The Safety Analysis Set will be used for all summaries and listings of study treatment.
2.4.1
Duration of exposure
The following algorithm will be used to calculate the duration of study treatment exposure for
patients who took at least one dose of any study treatment (DFX or placebo):
Duration of exposure (days) = [(date of last administration of study treatment) – (date of first
                                                   administration of study treatment) + 1]
The date of last administration of study treatment (treatment component) is taken from the 
DAR eCRF. The calculation of ‘duration of exposure ‘does not consider the potential lagging 
effect’ from the last dose.
Duration includes the periods of temporary interruption of the study treatment for any reason. 
‘Date of first administration of study treatment ‘and ‘date of last administration of study 
treatment’ are defined in Section 2.1.2.2 and Section 2.1.2.3 respectively.
Exposure duration excluding interruption will also be calculated using the following 
algorithms:
Duration of exposure excluding interruption = duration of exposure (days) – number of days 
drug being interrupted (0 dose)


Novartis
For business use only
Page 20
RAP M3 Amendment 4
ICL670A2302
2.4.2
Cumulative dose
Cumulative dose (mg/kg) is defined as sum over daily doses of all days between first and last 
dose. For patients who did not take any drug, the cumulative dose is by definition equal to 
zero. In this study, dose is weight adjusted.
The planned cumulative dose for a study treatment component refers to the total planned 
dose as per the protocol up to the last date of investigational drug administration. The actual
cumulative dose refers to the total actual dose administered, over the duration for which the 
subject is on the study treatment as documented in the Dose Administration eCRF.
2.4.3
     Average planned and actual dose
Average planned and actual dose are defined by the following algorithm:
Average planned dose (mg/kg/day) = [Cumulative planned dose during the time of 
exposure]/Duration of exposure (days)
Average actual dose (mg/kg/day) = [Cumulative actual dose during the time of 
exposure]/Duration of exposure (days) 
2.4.4
Percent dose taken
Percent dose taken = 100 times ratio of average (actual) dose and average planned dose                               
2.4.5
Concomitant, prior and post therapies
Concomitant therapy is defined as all interventions (therapeutic treatments and procedures)
besides the study treatment that were administered to a subject preceding or coinciding with 
the study assessment period.
Concomitant medications entered into the database will be coded using the World Health 
Organization (WHO) Drug Reference List to allow for categorization by preferred term. In 
addition to categorizing medication data by preferred term, drugs are classified according to 
their ATC classification in order to present and compare how they are being utilized.
Concomitant medications and significant non-drug therapies taken concurrently with the study 
drug(s) will be listed and summarized categorically by Anatomical Therapeutic Chemical
(ATC) class and preferred term for each treatment arm. These summaries will include 
medications starting on or after the start of study treatment or medications starting prior to the 
start of study treatment and continuing after the start of study treatment.
Any prior concomitant medications or significant non-drug therapies starting and ending prior 
to the start of study treatment will be listed separately.
Patients discontinue from study drug may receive post-treatment chelation therapy. Statistical 
analysis for post-treatment chelation therapy will be outlined in Section 2.4.5.2. 


Novartis
For business use only
Page 21
RAP M3 Amendment 4
ICL670A2302
2.4.5.1
Prior chelation therapy 
History of iron chelation therapy and blood transfusions will be collected retrospectively six 
months prior to study entry.
Duration of iron chelation prior to study entry will be categorized into time intervals (< 1, 1-
<3, 3-<6 months of cumulative therapy). Frequency counts and percentages will be presented 
for the number of patients in each interval. The number of patients who received different 
prior iron chelators will also be summarized by treatment and for all patients.
Prior chelation therapy will be listed using FAS.
2.4.5.2
Chelation therapy after discontinuation of study treatment
The number of patients chelated since discontinuation of study drug will be summarized and 
categorized as reported within 28 days since discontinuation or later. In the summary table,
deferoxamine mesilate will be displayed as “deferoxamine”.
Chelation therapy after discontinuation of study treatment will be listed using the FAS.
2.4.5.3
Blood transfusion
The number of blood transfusions during the study will be summarized by type of transfusion,
e.g., packed red blood cells (PRBC), platelets, or whole blood. Statistics on average 
hematocrit per patient, total number of units transfused during the study, and total number of 
transfusion received six months prior to study start will also be provided using the FAS. To 
calculate the total volume, only PRBC and whole blood will be taken into account. 450 mL of 
whole blood is assumed to correspond to 185 mL of PRBC and will be considered as one unit. 
Data on blood transfusions will be presented in a listing using FAS. 
2.5
Analysis of the primary objective
2.5.1
Primary endpoint
Event-free survival is the composite primary endpoint which is defined by the time from the 
date of randomization to the date of the first documented non-fatal event or death due to any 
cause. Non-fatal events comprise:

Echocardiographic evidence of worsening cardiac function

Hospitalization for congestive heart failure (CHF)

Liver function impairment

Liver cirrhosis

Progression to Acute Myeloid Leukemia (AML) confirmed by bone marrow biopsy
Criteria for these events are detailed in Section 3.1.1 of the study protocol. All events which 
could potentially fulfill the criteria for one of the components of the endpoint (except death) 


Novartis
For business use only
Page 22
RAP M3 Amendment 4
ICL670A2302
will be reported to the Endpoint Adjudication Committee (EAC) for blinded assessment. 
Evaluation by the EAC is decisive for the analysis, i.e. the analysis only takes those events 
into account that are confirmed by the EAC.
2.5.2
Statistical hypothesis, model, and method of analysis
The sample size of 210 patients does not provide sufficient power for testing confirmatory 
statistical hypotheses. The analysis will therefore concentrate on estimating the treatment 
effect of deferasirox relative to placebo to evaluate potential event-free survival benefit and 
other descriptions of the survival functions.
Statistical tests will be performed in an exploratory sense only. There will be no procedures to 
control multiple/family-wise type-I-error probabilities regarding the different endpoints.
2.5.2.1
Statistical hypotheses (exploratory)
Suppose that SD(t) and SP(t) denote the event-free survival function for deferasirox and 
placebo, respectively. The null hypothesis:
H0:
SD(t) = SP(t) for all t ≥0 (identical survival functions for both groups)
will be tested against the one-sided alternative hypothesis:
HA:
SD(t) > SP(t) for all t ≥0 and SD(t) > SP(t) for at least some t > 0 (event-free 
survival benefit in the deferasirox group over the placebo group).
The significance level will be 2.5%, and it will be a one-sided test.
2.5.2.2
Estimation of survival functions for event-free survival
A graphical estimate of the survival function for each treatment group will be obtained 
separately by the Kaplan-Meier (KM) product-limit method as implemented in SAS PROC 
LIFETEST.
If available, median survival for each treatment group will be obtained by SAS PROC 
LIFETEST along with 2-sided 95% confidence intervals calculated using the method of 
(Brookmeyer and Crowley 1982). 
KM estimates with 2-sided 95% confidence intervals at days 364, 728, 1092 and 1456 will be 
provided. The confidence intervals will be constructed using Greenwood’s formula (Collett 
1994) for the standard error of the Kaplan-Meier estimate.
2.5.2.3
Stratified unadjusted Cox proportional hazards regression model
For the primary analysis, an unadjusted Cox model will be used. Hazard ratio as a treatment 
effect measure for time to event endpoints will be derived from the Cox proportional hazards 
model using SAS procedure PHREG (with TIES=EXACT option in the MODEL statement as 
explained in Section 5.5.1.1). STRATA options will be used to account for variations in 
baseline hazards across strata. 


Novartis
For business use only
Page 23
RAP M3 Amendment 4
ICL670A2302
2.5.2.4
Statistical hypothesis test (exploratory)
A stratified log-rank test with stratification variables used in the randomization, i.e. IPSS (low 
or int-1) and geographical region (Asian versus non-Asian countries), will be implemented as 
follows: For each of the K strata, a BY statement will be used with the  SAS LIFETEST 
procedure, while a STRATA statement including a variable for identifying the treatment 
group will be used to obtain the rank statistic Sk and variance var(Sk) where k = 1, 2, …, K.
The final test statistic will then be constructed as:
Z = [S1 +…+ SK]/[var(S1) +…+ var(Sk)].
Under the null hypothesis, the test statistic Z is approximately normally distributed (Z2 is 
approximately chi-square distributed with one degree of freedom). A one-sided (exploratory)
p-value will be obtained using the Z statistic:
p = P(Z>z) = 1-Probnorm(z) 
where z is the observed value of Z and Probnorm denotes the inverse of the normal 
cumulative distribution function.
2.5.3
Handling of missing values/censoring/discontinuations
Event-free survival
For the primary analysis of event-free survival, the following censoring rules will be applied:

Patients who have not experienced any of the non-fatal events from the composite primary 
endpoint and have not stopped study participation at the time of data cut-off (end of study) 
will be censored - irrespective of adherence to study treatment - considering the following 
dates for the components and taking the earliest (minimum) of these as the censoring date:

Worsening of cardiac function: the last date when echocardiography results will be
available

Hospitalization for congestive heart failure: the data cut-off date

Liver function impairment: the last date when laboratory values for ALT, AST and 
bilirubin will be available

Liver cirrhosis: the data cut-off date

Progression to AML: the data cut-off date

Patients who have not experienced any of the non-fatal events from the composite primary 
endpoint, but have stopped study participation before the time of data cut-off, will be 
censored - irrespective of adherence to study treatment - considering the following dates 
for the components and taking the earliest (minimum) of these as the censoring date:

Worsening of cardiac function: the last date when echocardiography results will be
available

Hospitalization for congestive heart failure: the last date when the patient will 
have some documented personal contact (visit or phone call) with the investigator

Liver function impairment: the last date when laboratory values for ALT, AST and 
bilirubin will be available


Novartis
For business use only
Page 24
RAP M3 Amendment 4
ICL670A2302

Liver cirrhosis: the last date when the patient had documented personal contact 
(visit or phone call) with the Investigator regarding imaging, laboratory data, or 
biopsy results regarding cirrhosis

Progression to AML: the last date when the patient will have some documented 
personal contact (visit or phone call) with the Investigator. Suspected progression 
to AML without confirmation by bone marrow biopsy or aspiration does not 
constitute an event and censoring will be applied at last contact.
2.5.3.1
Worsening of cardiac function
For the analysis of worsening of cardiac function, patients who have not experienced a 
worsening of cardiac function will be censored at the last date when echocardiography results 
are available.
2.5.3.2
Hospitalization for congestive heart failure
For the analysis of hospitalization for congestive heart failure, patients who have not 
experienced any hospitalization for congestive heart failure will be censored at the last contact 
date. 
2.5.3.3
Liver function impairment
For the analysis of liver function impairment, patients who have not experienced any liver 
function impairment will be censored at the last date when laboratory values for ALT, AST 
and bilirubin are available.
2.5.3.4
Liver cirrhosis 
For the analysis of liver cirrhosis, patients who have not experienced liver cirrhosis will be 
censored at the last contact date. 
2.5.3.5
Progression to AML
AML progression will be determined by the bone marrow aspirate. In case of AML suspicion, 
bone marrow aspirate will be performed to confirm AML at any time until study evaluation 
completion. Thus, for the analysis of progression to AML, patients who have not experienced 
progression to AML will be censored at the last contact date.  
2.5.3.6
Increase in serum ferritin
For the analysis of time from randomization to the first occurrence of serum ferritin > 2 times the 
baseline value at two consecutive assessments (at least two weeks apart), patients who did not 
experience such an increase in serum ferritin will be censored at the last date when serum ferritin 
was available or at the date of randomization if no post baseline serum ferritin is available.
2.5.4
Sensitivity and supportive analyses
The two main sensitivity analyses for the primary efficacy analysis (event-free survival) will 
be based on the two alternative censoring rules. Otherwise, the same statistical methods will 
be used for the primary analysis of event-free survival. A third sensitivity analysis using the 


Novartis
For business use only
Page 25
RAP M3 Amendment 4
ICL670A2302
same methodology will address the issue of partial data for the composite endpoint (i.e., a 
patient with some missing data but not all of the components of composite endpoints). 
For the first main sensitivity analysis patients with premature discontinuation of randomized 
study treatment and subsequent treatment with marketed iron chelation therapy (including 
Exjade®) will be censored at the date of first administration of the subsequent iron chelation 
therapy.
For the second main sensitivity analysis patients with premature discontinuation of 
randomized study treatment (regardless of whether they were subsequently treated with 
marketed iron chelation therapy) will be censored at the date of last administration of 
randomized study treatment.
The third sensitivity analysis will employ the following censoring rules:

If an event is documented after three or more consecutive missing biochemistry 
laboratory assessments (regarding results for ALT, AST, and total bilirubin), the 
event-free survival time of these patients will be censored at the date of the last 
assessment with complete information for ALT, AST, and total bilirubin. 

If an event is documented after two or more consecutive missing echocardiogram 
(ECHO) assessments (for left ventricular ejection fraction), the event-free survival 
time of these patients will be censored at the date of the last ECHO assessment.

If an event is documented after at least three consecutive missing biochemistry 
laboratory assessments (ALT, AST, and total bilirubin) and at least two 
consecutive missing ECHO assessments simultaneously, the event-free survival 
will be censored at the date of the last assessment with both biochemistry 
laboratory and ECHO assessments completed.

As the three other components, ‘hospitalization for congestive heart failure’, ‘liver 
cirrhosis’ and ‘Progression to AML’, i.e. assessed in unscheduled examinations, 
missing assessments for them cannot be determined.
Sensitivity analyses include:

Point estimate and two-sided 95% confidence interval for the adjusted HR from a Cox 
proportional hazard regression model stratified for the randomization factors with 
adjustment for demographic or baseline characteristics of clinical interest. The 
adjustment will be made for age (≥65 vs < 65), Asian vs non-Asian, MDS risk group
(low vs intermediate).  

Statistical analyses based on the PPS instead of the FAS.
Supportive analyses include:

KM curves by treatment and unadjusted HR (point estimate and two-sided 95% 
confidence interval) for each of the strata defined by the randomization factors.

KM curves by treatment and unadjusted HR (point estimate and two-sided 95% 
confidence interval) for each component of event-free survival (overall survival is also 
a secondary efficacy endpoint, see Section 2.7.1.1).

Number of deaths and non-fatal events adjudicated by the endpoint adjudication 
committee


Novartis
For business use only
Page 26
RAP M3 Amendment 4
ICL670A2302

Primary endpoint analyses will be repeated for the FAS excluding patients from one 
site due to data integrity issue. The time to event analyses will be performed and will
include:

Stratified log-rank test and Cox-regression model for event-free survival

Overall summary of event free survival
These patients will be excluded from per-protocol set for the sensitivity analyses.
2.6
Analysis of the key secondary objective
There is no key secondary objective for this study.
2.7
Analysis of secondary efficacy objective(s)
2.7.1
Secondary efficacy endpoints
All analyses of secondary efficacy endpoints will be based on the FAS. 
If applicable, nominal significance levels will be set to one-sided alpha = 0.025; all confidence 
intervals will be two-sided using an ordinary confidence level of 95%.
2.7.1.1
Hematologic improvement 
Hematologic improvement (HI) in terms of erythroid response during treatment will be 
assessed based on International Working Group (IWG) criteria (Cheson 2006).
The variable used in the analysis of HI will be the proportion of patients who satisfy the
erythroid response criteria; namely,

Hemoglobin increased  ≥ 1.5 g/dL 
      OR

Reduction of ≥ 4 units of RBC transfusions over 8 weeks, in comparison to 8 weeks’ pre-
treatment values, and lasting at least 8 weeks. 
For purposes of calculating the reduction in transfusions component of this endpoint, a 
transfusion unit is defined as 185 mL of PRBC (Cohen Glimm Porter 2008). According to 
IWG criteria, HI is measured in patients with pre-treatment hemoglobin levels of less than 11 
g/dL or RBC transfusion dependence. The definition of transfusion dependency is based on
IWG criteria (Cheson 2006). All patients included in this study are transfusion dependent. In 
order to measure hemoglobin increase, the last hemoglobin value measured prior to 
randomization will be used as the pretreated value. If 2 pre-treated (prior randomization) 
hemoglobin values are available and each is at least 7 days after any transfusion, an average of 
the 2 values will be used to determine the pre-treatment hemoglobin level. All RBC 
transfusions regardless of pre-transfusion hemoglobin level, will count in the RBC transfusion 
response criteria. If any pre-treatment hemoglobin value or transfusion history over 8-week
period cannot be determined, they will not be a part of risk set and will not be included in the 
percentage calculation.
All episodes of HI in the patient will be considered.


Novartis
For business use only
Page 27
RAP M3 Amendment 4
ICL670A2302
The percentage of responders will be summarized for the two treatment groups and 100(1-)% 
confidence intervals with  of 0.05 will be provided. The 95% confidence limits for the 
difference of two proportions will be derived by the Wilson score test (see Section 5.5.3).
Overall survival
Overall survival (OS) will be evaluated in patients treated with either deferasirox or placebo. 
The variable used in the analysis of overall survival is time to death measured in days. It is 
defined as date of death (irrespective of cause) minus date of randomization plus 1.
Censoring is described in Section 2.7.3.1. The estimation of survival functions and the Cox 
model to estimate the HR are defined in Section 2.5.2.2 and Section 2.5.2.3. An exploratory 
statistical test will be performed analogously to the description in Section 2.5.2.4.
The Kaplan-Meier curves, medians, and Kaplan-Meier estimates with 95% confidence 
intervals at specific time points will also be displayed by treatment and stratum.
In Kaplan-Meier plots, statistics such as p-value, hazard ratio, etc. will also be displayed. Note 
that only nominal p-values are provided with no statistical interpretation.
Survival information will be listed. The listing will include if patients survived (Yes/No), last 
contact date, study day, date of death if not survived and principal cause of death. 
Unless otherwise specified, all time-to-event analysis will be analyzed in a similar fashion. 
2.7.1.2
Proportion of patients with hypothyroidism
Hypothyroidism will be evaluated by the annual measurement of TSH and free T4. The 
proportion of patients with normal thyroid function, primary hypothyroidism, secondary 
hypothyroidism or subclinical hypothyroidism will be determined at each time point (i.e. 1, 
2, …, years after randomization).
Definitions:

normal thyroid function: serum TSH and free T4 within normal limits;

primary hypothyroidism: serum TSH >ULN and free T4 <LLN;

secondary hypothyroidism: serum TSH <ULN and free T4 <LLN;

subclinical hypothyroidism: TSH >ULN and a free T4 within normal limits.
Frequency of newly occurring hypothyroidism and shift tables will be provided for each 
treatment group. Results will also be shown separately for each year since randomization. A
combined listing for hypothyroidism and glucose metabolism will be provided.
2.7.1.3
Proportion of patients with worsening of glucose metabolism
An annual oral glucose tolerance test will be carried out to evaluate changes of glucose 
metabolism compared to the baseline status. The proportion of patients with an increase in 
glucose metabolism category (normal, impaired glucose metabolism, diabetes mellitus) based 
on the American Diabetes Association criteria (American Diabetes Association 2009) 
compared to their baseline result will be determined at each time point, i.e. 1, 2, …, years 


Novartis
For business use only
Page 28
RAP M3 Amendment 4
ICL670A2302
after randomization. For this classification, fasting and 2-hour post-prandial plasma glucose 
levels will be measured.
Criteria for impaired glucose metabolism:

fasting plasma glucose (FPG) levels ≥100 mg/dL (5.6 mmol/L) but <126 mg/dL
(7.0 mmol/L)
OR

2-h values in the oral glucose tolerance test (OGTT) of ≥140 mg/dL (7.8 mmol/L) but 
<200 mg/dl (11.1 mmol/L)
Criteria for diabetes mellitus:

non-fasting plasma glucose  ≥200 mg/dL (11.1 mmol/L)   
OR

FPG ≥126 mg/dL (7.0 mmol/L). Fasting plasma glucose is defined as no caloric intake for 
at least 8 hours
     OR

2 hour post load glucose ≥200 mg/dL (11.1 mmol/L) during an OGTT. As described by 
WHO, the test use a glucose load containing the equivalent of 75 g anhydrous glucose 
dissolved in water
Frequency and shift tables will be provided for each treatment group. Results will also be 
shown separately for each year since randomization.
2.7.1.4
Disease progression
An evaluation of the time from randomization to either MDS progression or progression to 
AML in the treatment groups will be done based on date of diagnosis of MDS progression or 
date of first diagnosis of AML minus date of randomization plus 1.
MDS progression will be defined as a transition into a higher MDS risk group based on IPSS 
scoring (see Section 5.3.2). Progression to AML will be defined based upon the most current 
classification guidelines (Vardiman 2009), as 20% or more blasts seen in the bone marrow 
collected by biopsy or aspirate.
The time-to-event analysis follows the description given in Section 2.5.2.2. Censoring for 
patients with neither MDS progression nor progression to AML at last contact is described in 
Section 2.7.3.2 and Section 2.5.3.5. 
2.7.1.5
Time to at least a 10% increase from baseline in LVIDD
An evaluation of the time from randomization to the first occurrence of an increase of at least 
10% from the baseline value of LVIDD (Left Ventricular Internal end-diastolic dimension) 
will be performed based on the following variable:

date of echocardiography assessment where a minimum of 10% increase first occurred 
minus date of randomization plus 1.


Novartis
For business use only
Page 29
RAP M3 Amendment 4
ICL670A2302
The time-to-event analysis follows the description given in Section 2.5.2.2. Censoring for 
patients without such an increase in LVIDD will be at the time of last LVIDD assessment 
(Section 2.7.3.3). 
2.7.1.6
Time to at least a 10% increase from baseline in LVISD
An evaluation of the time from randomization to the first occurrence of an increase of at least 
10% from the baseline value of LVISD (Left Ventricular Internal end-systolic dimension) will 
be performed based on the following variable:

date of echocardiography assessment where a minimum of 10% increase first occurred 
minus date of randomization plus 1.
The time-to-event analysis follows the description given in Section 2.5.2.2. Censoring for 
patients without such an increase in LVISD will be at the time of a last LVISD assessment 
(Section 2.7.3.3). 
2.7.1.7
Time to first occurrence of serum ferritin > 2 times the baseline value
An evaluation of the time from randomization to the first occurrence of serum ferritin > 2 times 
the baseline value at two consecutive assessments (at least two weeks apart) will be performed per 
treatment group based on the following variable: 

date of the first of the two consecutive laboratory assessment fulfilling the criterion of SF > 2 
× baseline value minus date of randomization plus 1 
The time-to-event analysis follows the description given in Section 2.5.2.2. Censoring for 
patients without such a serum ferritin increase is described in Section 2.5.3.6.
2.7.1.8
Infections
Infections requiring intravenous antimicrobials during the treatment period (until the 28 day 
follow-up visit) will be evaluated separately for each treatment group.
Definitions:

Infections will be determined from the reported adverse events with system organ class 
"Infections and infestations" and action taken “Concomitant medication taken”.

Antimicrobial therapy will be determined from the reported concomitant medications for 
patients who had an infection AE. The medications will be based on a pre-specified list of 
WHO low level ATC codes. The route of administration needs to be specified as 
“intravenous (i.v.)”.

Identified events will be combined with medications (of the same patient) based on the 
following criterion: start date of medication ≥start date of AE and start date of medication 
≤minimum (start date of AE + 1, end date of AE).
The total number of infections requiring intravenous antimicrobials will be counted and 
summarized per treatment group. For this number, one patient can contribute more than one 
infection event. To account for different lengths of observation time in the two groups, the 
rate of infections will be calculated with the number of recorded infections treated with 
intravenous antimicrobials divided by the total number of patient-years of follow-up. The 
relative risk of infection will be calculated as the rate of infection in the treatment group 
compared with the rate in the placebo group.


Novartis
For business use only
Page 30
RAP M3 Amendment 4
ICL670A2302
2.7.2
Statistical hypothesis, model, and method of analysis
No hypothesis will be tested for secondary endpoints.
2.7.3
Handling of missing values/censoring/discontinuations
2.7.3.1
Overall survival
For the analysis of overall survival (see Section 2.7.1.1), patients will be censored at the last
contact date.
2.7.3.2
Disease progression to MDS
For the analysis of time to disease progression (see Section 2.7.1.4), patients who did not 
experience an MDS progression will be censored at the last contact date.
2.7.3.3
Increase in LVIDD or LVISD
For the two analyses of time from randomization to the first occurrence of an increase of at 
least 10% from the baseline value of LVIDD and time from randomization to the first 
occurrence of an increase of at least 10% from the baseline value of LVISD (see Section 
2.7.1.5 & 2.7.1.6), respectively, patients who did not experience such an increase will be 
censored at the last date when LVIDD (or LVISD, respectively) was available.
2.8
Safety analyses
As stated in the protocol (Section 3.2), one of the secondary objectives was to evaluate safety, 
in particular to assess the levels of increased risk for pre-specified adverse events (renal 
dysfunction, neutropenia, thrombocytopenia, gastrointestinal bleeding, and laboratory 
abnormalities) that would be clinically unacceptable in the context of the level of benefit that 
is likely to be provided by iron chelation using deferasirox in MDS patients with iron 
overload. 
Endpoints for the secondary safety objectives are as follows:
1. Proportion of patients with significant renal dysfunction 
2. Proportion of patients with newly occurring moderate or severe neutropenia or 
thrombocytopenia
3. Proportion of patients with major gastrointestinal bleeding
4. Time to study drug discontinuation due to an adverse event or laboratory abnormality
5. Incidence of other adverse events and laboratory abnormalities
The first four endpoints are defined and evaluated as follows:
Endpoint
Analysis
Proportion of patients with significant renal 
dysfunction defined as serum creatinine ≥ 2 
times ULN at two consecutive assessments 
(at least 7 days apart)
Frequency tables by treatment group will be 
prepared along with a two-sided 95% 
confidence interval for evaluation of DFX in 
contrast to placebo. Results will also be 


Novartis
For business use only
Page 31
RAP M3 Amendment 4
ICL670A2302
Endpoint
Analysis
Proportion of patients with newly occurring 
neutropenia (absolute neutrophils count 
<1.0×109/L) or thrombocytopenia (platelets 
<50×109/L)
provided for annual time intervals. 
Proportion of patients with major 
gastrointestinal bleeding. 
Time to study drug discontinuation due to an 
AE or laboratory abnormality, more 
specifically date of study drug 
discontinuation due to an AE or laboratory 
abnormality minus date of randomization 
plus 1.
The time-to-event analysis follows the 
description given in Section 2.5.2.2 The 
statistical test will be exploratory in nature. 
For the analysis of time from randomization 
to study drug discontinuation due to an AE or 
laboratory abnormality (see Section 2.8.3), 
patients who did not discontinue study 
medication due to an AE or laboratory 
abnormality will be censored at the date of 
study drug discontinuation.
Proportion of patients with moderate or severe anemia will be analyzed  like newly occurring 
neutropenia.
Other analyses and other safety data (ocular and auditory examinations, electrocardiogram, 
and vital signs) will be also considered. 
Safety summary includes baseline and on-treatment period. All safety data (including those from 
the post-treatment period) will be listed and those collected during the pre-treatment and post-
treatment periods will be flagged.
2.8.1
Adverse events (AEs)
All AEs recorded during the study are coded using the latest version of the medical dictionary 
for regulatory activities (MedDRA) and summarized by treatment group and overall. Adverse 
events are not assessed according to the common terminology criteria for AEs (CTCAE);  
instead, AE severity (mild, moderate, severe) is used to report treatment-emergent AEs
starting on or after the date of first study medication (including AEs that start within 28 
days after the discontinuation of the study medication).
Frequency tables for treatment-emergent AEs will be presented, for each treatment group, the 
number of patients, and the percentage of patients experiencing the AE. Multiple occurrences 
of the same event in the same patient will be counted only once in the frequency tables. 
However, all adverse events will be included in the AE listings.
Frequency tables will display at least the MedDRA system organ class and preferred term, AE 
severity (mild, moderate, severe), and relationship to study drug. The following tables will be 
generated:

Adverse events, regardless of study drug relationship 


Novartis
For business use only
Page 32
RAP M3 Amendment 4
ICL670A2302

Serious adverse events, regardless of study drug relationship 

Serious adverse events, suspected to be study drug relationship 

Adverse events leading to study drug discontinuation, regardless of study drug 
relationship 

Adverse events requiring dose adjustment or interruption, regardless of study drug 
relationship 

Adverse events requiring additional therapy, regardless of study drug relationship 

Adverse events, suspected to be study drug related 

Adverse events which are not serious adverse events, regardless of study drug relationship
For the requirements of ClinicalTrials.gov and EudraCT, two required tables on <on-
treatment/treatment emergent> adverse events which are not serious adverse events with an 
incidence greater than 5% and on <on-treatment/treatment emergent> serious adverse events 
and SAE suspected to be related to study treatment will be provided by system organ class 
and preferred term on the safety set population.
If for a same patient, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same SOC and PT:

a single occurrence will be counted if there is ≤ 1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE

more than one occurrence will be counted if there is > 1 day gap between the end date 
of the preceding AE and the start date of the consecutive AE
For occurrence, the presence of at least one SAE/SAE suspected to be related to study 
treatment / non SAE has to be checked in a block e.g., among AE's in a ≤ 1 day gap block, if 
at least one SAE is occurring, then one occurrence is calculated for that SAE.
The number of deaths resulting from SAEs suspected to be related to study treatment will be
tabulated by SOC and PT and a listing will be generated.
2.8.1.1
Adverse events of special interest / grouping of AEs
Specific groupings of adverse events of special interest will be considered and the number of 
patients with at least one event in each grouping will be reported. Such groups consist of 
adverse events for which there is a specific clinical interest in connection with deferasirox 
treatment. Note that certain adverse events may be reported within multiple groupings/AESIs.
AESIs are defined by MedDRA terms. Definition for retrieval (maintenance of terms 
considered AESI) is in a separate document in the Novartis Documentum management system 
at the path “CREDI Projects/I/ICL670A/Integrated Medical Safety”. The MedDRA codes will 
be used to generate the outputs.
The AESI search table will be used to map reported adverse events to the notable adverse
events groupings. The list of adverse events of special interest may be updated during the


Novartis
For business use only
Page 33
RAP M3 Amendment 4
ICL670A2302
course of the trial based on accumulating safety data. Therefore the clinical study report will 
list the AE groupings used and provide a listing of the corresponding AESI search table.
AESI will be summarized regardless of study drug relationship, by grouping, preferred term
and treatment arm.
2.8.2
Deaths
Separate summaries for on-treatment and all deaths (including post-treatment deaths) will be 
produced by treatment arm, system organ class, and preferred term using the Safety set. 
All deaths will be listed for the safety set, and post-treatment deaths will be flagged. A 
separate listing of deaths prior to starting treatment will be provided for all screened subjects.
2.8.3
Laboratory data
All laboratory values are generally converted into SI units and the severity grade calculated 
using notable and extended ranges as available in the deferasirox program standards. All 
values from central laboratory will be used to evaluate the primary and secondary endpoints.
Any tests that are performed at local laboratories will not be used for either secondary or 
primary endpoints evaluation; however, collected local laboratory values will be listed along 
with central laboratory results and also for safety tables, all values for central and local 
laboratory results will be considered.
The frequency of laboratory abnormalities is displayed by parameter and treatment group. 
Laboratory data is summarized by presenting summary statistics of raw values and absolute 
and relative change from baseline. 
Shift tables from baseline to highest (or lowest) post baseline value are provided for 
hematology: hemoglobin, WBC count, absolute neutrophils and platelets, biochemistry: 
alanine aminotransferase (ALT), aspartate aminotransferase (AST), serum creatinine and 
creatinine clearance and urinalysis: urinary total protein/creatinine ratio using normal or 
extended ranges. Standard oncology shift tables for laboratory parameters, based on normal 
ranges, are also provided.
Box plots of absolute value and the absolute change from baseline in absolute neutrophils, 
platelets, ALT, AST, 
serum creatinine, 
creatinine 
clearance 
and urinary 
total 
protein/creatinine ratio by time points are provided. The last available value in a time point 
window is used.


Novartis
For business use only
Page 34
RAP M3 Amendment 4
ICL670A2302
Criteria for clinically notable and extended laboratory ranges
Parameter
Criteria
Absolute neutrophils
<1.5×109/L (extended range <0.5×109/L)
Platelets
<100×109/L (extended range <50×109/L)
ALT/AST
>5×ULN and >2×baseline value (extended range >10×ULN 
and >2×baseline value)
Serum creatinine
>33% increase from baseline and >ULN at two consecutive 
measurements at least 7 days apart
Creatinine clearance
<60 mL/min at two consecutive measurements at least 7 days 
apart (extended range <40 mL/min)
Urinary total protein/creatinine ratio
>1.0 mg/mg at two consecutive measurements at least 7 days 
apart
Total bilirubin
>2.0 mg/dL (>34.2 umol/L)
The number and percentage of patients with laboratory results (from scheduled and 
unscheduled visits) meeting the criteria for notable values (see table above) will be presented. 
2.8.4
Other safety data
2.8.4.1
ECG and cardiac imaging data
2.8.4.1.1 Data handling
In case the study requires ECG replicates at any assessment, the average of the ECG 
parameters at that assessment should be used in the analyses.
2.8.4.1.2 Data analysis
12-lead ECGs with PR, QRS, QT, QTcF, QTcB, and HR intervals will be obtained for each 
subject during the study. ECG data will be read and interpreted centrally.
The number and percentage of subjects with notable ECG values will be presented by 
treatment arm. 

QT,  QTcF and QTcB
o
New value of >450 and ≤480 ms
o
New value of >480 and ≤500 ms
o
New value of >500 ms
o
Increase from baseline of >30 ms to ≤60 ms
o
Increase from baseline of >60 ms

HR
o
Increase from baseline >25% and to a value >100 bpm
o
Decrease from baseline >25% and to a value <50 bpm

PR
o
Increase from baseline >25% and  to a value >200 ms
o
New value of >200 ms


Novartis
For business use only
Page 35
RAP M3 Amendment 4
ICL670A2302

QRS
o
Increase from baseline >25% and  to a value >120 ms 
o
New values of QRS >120 ms 
A listing of all ECG assessments will be produced by treatment arm and notable values will 
be flagged. A separate listing of only the subjects with notable ECG values may also be
produced. In the listing, assessments collected during the post-treatment period will be 
flagged. 
2.8.4.2
Vital signs
Vital sign assessments are performed in order to characterize basic body function. The 
following parameters are collected: height (cm), weight (kg), body temperature (°C), 
respiratory rate (beats per minute), sitting systolic and diastolic blood pressure (mmHg). 
The change from baseline in systolic and diastolic blood pressures, respiratory rate,
temperature and weight will be summarized by scheduled visit with n, mean, SD, median, 
minimum and maximum values.
A listing will be provided for all vital signs and BMI (Body Mass Index). Notable vital signs 
are flagged. The criteria for notable abnormal vital signs are displayed in Table 2-1.
Table 2-1
Definition of notable ranges for blood pressure and weight
Parameter
Criteria for notable ranges
Systolic blood pressure
≥ 180 mmHg / ≤ 90 mmHg with increase / decrease from baseline ≥ 20 mmHg
Diastolic blood pressure
≥ 105 mmHg / ≤ 50 mmHg with increase / decrease from baseline ≥ 15 mmHg
Weight
≥ 10% increase or decrease from baseline weight
2.8.4.3
Auditory and ophthalmic findings
Auditory and ophthalmic overall interpretation data will be summarized using shift tables 
comparing baseline result to most extreme post-baseline value.
Auditory data will be listed using the Safety set. The listing will include when tests are 
performed, overall interpretation, and any clinical significant abnormality findings. 
Ophthalmic data includes visual acuity, slit lamp findings, tonometry, and fundus oculi. 
Results will be listed by test date using Safety Set.
2.9
Pharmacokinetic endpoints
Not applicable.
2.10
Patient-reported outcomes
Not applicable.
2.11
Biomarkers
Not applicable.


Novartis
For business use only
Page 36
RAP M3 Amendment 4
ICL670A2302
2.12
Other Exploratory analyses
No exploratory analyses are planned for this study.
2.13
Interim analysis
No interim analysis will be performed. 
3
Sample size calculation
The sample size of 210 patients randomized in a ratio of 2:1 in favor of deferasirox is based 
on the feasibility of enrolling the patients and consultations with the Health Authorities. As 
noted earlier, this study is not powered for any confirmatory primary or secondary endpoints.
4
Change to protocol specified analyses
The following change was made: 

Newly occurring thrombocytopenia and neutropenia was redefined using the definition of 
the corresponding notable laboratory abnormalities
5
Appendix
5.1
Imputation rules
5.1.1
Study drug
The following rule will be used for the imputation of date of last administration for a given 
study treatment component. 
Case 1: The date of last administration is completely missing, and the EOT visit date is 
complete, then this latter date should be used.  
Case 2: Only Year (yyyy) of the dose end date is available and yyyy < the year of EOT date:  
Impute date= Dec31yyyy
Case 3: Only Year (yyyy) of the dose end date is available and yyyy = the year of EOT date: 
Impute date=EOT date
Case 4: Both Year (yyyy) and Month (mm) are available for the date of last administration, 
and yyyy = the year of EOT date and mm < the month of EOT visit:  
Impute date= last day of the Month (mm).
After imputation, compare the imputed date with the start date of that specific record, if the 
imputed date is < start date of that record
           Impute date= the start date of that record.
Subjects with missing start dates will be considered missing and no imputation will be made.
If the date of first administration is missing, then the date of last administration should not be 
imputed.


Novartis
For business use only
Page 37
RAP M3 Amendment 4
ICL670A2302
5.1.2
AE date imputation
Date imputation is the creation of a new, complete date from a partial one according to an 
agreed and acceptable algorithm. The missing date for AEs will be handled according to STL
(Standard Tables and Listings) standard.
A partial date is simply an incomplete date e.g., ddOCT2001 the days are missing from this 
DDMMMYYYY date.
Partial adverse event start dates, if left partial, will ultimately mean the following
It will not be possible to place the adverse event in time.
Therefore, the treatment/dosage at the time of the event will be unknown. 
Therefore, the event could not be reported/summarized appropriately – if at all.
There will be no attempt to impute the following

Missing AE start dates 

AE start dates missing the year

Partial/missing AE end dates
Table 5-1      AE/treatment date abbreviations
Day
Month
Year
Partial AE start date
<not used>
AEM
AEY
Treatment start date (TRTSTD)
<not used>
TRTM
TRTY
The following matrix Table 5-2 describes the possible combinations and their associated 
imputations. In the light grey boxes the upper text indicates the imputation and the lower
text is the relationship of the AE start date to the treatment start date (TRTSTD).
Table 5-2
AE partial date imputation algorithm
AEM Missing
AEM < TRTM
AEM = TRTM
AEM > TRTM
AEY Missing
NC
Uncertain
(D)
NC
Uncertain
(C)
NC
Uncertain
(C)
NC
Uncertain
(C)
AEY < TRTY
Before TRTSTD
(B)
Before TRTSTD
(C)
Before TRTSTD
(B)
Before TRTSTD
(A)
AEY = TRTY
Uncertain
(E)
Before TRTSTD
(A)
Uncertain
(A)
After TRTSTD
(A)
AEY > TRTY
After TRTSTD
(E)
After TRTSTD
(A)
After TRTSTD
(B)
After TRTSTD
(A)
Table 5-3       AE/treatment date relationship and imputation


Novartis
For business use only
Page 38
RAP M3 Amendment 4
ICL670A2302
Relationship
Before TRTSTD
Indicates AE start date prior to Treatment Start Date 
After TRTSTD
Indicates AE start date after Treatment Start Date
Uncertain
Insufficient to determine the relationship of AE start date to 
Treatment Start Date
Imputation Calculation
NC/Blank 
No convention/imputation
(A)
01MONYYYY
(B)
TRTSTD+1
(C)
15MONYYYY
(D)
01JULYYYY
(E)
01JANYYYY
The following Table 5-4 gives a few examples.
Table 5-4 Example Scenarios
Partial AE start 
date
Treatment start 
date
Relationship
Imputation 
calculation
Imputed date
12mmyyyy
20OCT2001
Uncertain
NC
<blank>
ddmmm2000
20OCT2001
Before
(D)
01JUL2000
ddmmm2002
20OCT2001
After
(E)
01JAN2002
ddmmm2001
20OCT2001
Uncertain
(B)
21OCT2001
ddSEP2001
20OCT2001
Before
(C)
15SEP2001
ddOCT2001
20OCT2001
Uncertain
(B)
21OCT2001
ddNOV2001
20OCT2001
After
(A)
01NOV2001
5.1.3
Concomitant medication date imputation
The imputation of the start date of concomitant medication will follow the same convention as
for the AE date. A partial concomitant medication end date will not be imputed.
5.1.3.1
Prior therapies date imputation
Start date:
The same rule which is applied to the imputation of AE/concomitant medication start date 
will be used with the exception that for scenario (B) will be replaced to be 
‘start date of study drug -1’.
End date:
Imputed date = min (start date of study drug, last day of the month), if day is missing; 
Imputed date = min (start date of study drug, 31DEC), if month and day are missing.
If the end date is not missing and the imputed start date is after the end date, use the end 
date as the imputed start date.


Novartis
For business use only
Page 39
RAP M3 Amendment 4
ICL670A2302
If both the start date and the end date are imputed and if the imputed start date is after the 
imputed end date, use the imputed end date as the imputation for the start date.
5.1.3.2
Post therapies date imputation
Start date
  Imputed date = max (last date of study drug + 1, first day of the month), if day is missing;
  Imputed date = max (last date of study drug + 1, 01JAN), if day and month are missing.
End date: No imputation.
5.1.3.3
Other imputations
Incomplete date for death
All dates must be completed with day, month, and year.
If the day or month is missing, death will be imputed to the maximum of the last contact 
date (excluding the date of death) and the following:

Missing day:                    15th of the month and year of death

Missing day and month:  July 1st of the year of death  
5.2
AEs coding/grading
Major gastrointestinal bleeding
Major gastrointestinal bleeding (See Section 2.8) is defined as an AE that may include one of 
the following MedDRA preferred terms:
Gastric haemorrhage
Gastrointestinal haemorrhage
Small intestinal haemorrhage
Oesophageal haemorrhage
Large intestinal haemorrhage
Rectal haemorrhage
Melaena
Duodenal ulcer haemorrhage
Gastric ulcer haemorrhage
Peptic ulcer haemorrhage
Large intestinal ulcer haemorrhage
Oesophageal ulcer haemorrhage
Haematochezia


Novartis
For business use only
Page 40
RAP M3 Amendment 4
ICL670A2302
Infections requiring intravenous antimicrobials- definition (Section 2.7.1.8)

Infections will be determined from the reported adverse events with system organ 
class "Infections and infestations" and action taken “Concomitant medication taken”.

Antimicrobial therapy will be determined from the reported concomitant medications 
for patients who had an infection AE. 

The selection of medications will be based on the following categories of WHO low 
level ATC codes: D01, D04, J01, J02, J04, J05, P01, and P02. 

The route of administration must be specified as “intravenous (i.v.)”.

Contemplable events will be combined with medications (of the same patient) based 
on the following criteria: start date of medication ≥start date of AE and start date of 
medication ≤minimum (start date of AE + 1, end date of AE).
5.3
Laboratory parameters derivations
Grade categorization of lab values will be assigned programmatically as per NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.03 or later. The calculation of 
laboratory CTC grades will be based on the observed laboratory values only; clinical 
assessments will not be taken into account. 
For laboratory tests where grades are not defined by CTCAE 4.03 or latest version, results 
will be graded by the low/normal/high (or other project-specific ranges, if more suitable) 
based on laboratory normal ranges.                                                                                                                  
A severity grade of 0 will be assigned for all non-missing lab values not graded as 1 or higher. 
Grade 5 is not applicable. For laboratory tests that are graded for both low and high values, 
summaries will be done separately and labelled by direction, e.g., sodium will be summarized 
as hyponatremia and hypernatremia.
5.3.1
Creatinine clearance estimation
An estimated creatinine clearance based on the Schwartz or Cockroft-Gault formula will be
used. The modification of diet in renal disease (MDRD) derivation is provided in derived 
datasets only for possible future requests.
In the formulae below, CrCl denotes creatinine clearance, SCr denotes serum creatinine in 
µmol/L; age in years is calculated from date of birth and date of the relevant blood sample. 
Weight and height are the last available measurements at the time of the relevant blood 
sample.
Cockroft-Gault formula, CrCl (mL/min)=
Male patients: (140-age)×weight/(815×0.001×SCr)
Female patients: (140-age)×weight×0.85/(815×0.001×SCr) 
Abbreviated MDRD formula, CrCl (mL/min/1.73m2)=
186.3×(SCr×0.01131) – 1.154×age– 0.203×E×S where,
E is ethnicity: E=1.212 if patient is black, else E=1 
S is gender: S=0.742 if patient is female, else S=1


Novartis
For business use only
Page 41
RAP M3 Amendment 4
ICL670A2302
5.3.2
Terminology IPSS score and MDS risk group
In the study protocol, both “IPSS score” and “MDS risk group” are used. In the randomization 
(IVRS) system, the baseline IPSS score is collected. However, the eCRF collects “MDS risk 
group” to “indicate patient’s MDS Risk Group by International Prognostic Scoring System“. 
Post-text supplement 1 of the protocol includes the following table:
MDS Risk Group
Total score
Low
0
int-1
0.5 – 1.0
int-2
1.5 – 2.0
High
≥ 2.5
The total score is derived by summing up the score for each prognostic variable (Marrow 
Blasts, Karyotype, and Cytopenia). The score for each prognostic variable is given in table
below:
Score
Prognostic Variable
0 
0.5
1.0
1.5
2.0
Marrow Blasts (%)1
<5
5-10
--
11-20
21-30
Karyotype2
Good
Intermediate
Poor
Cytopenia3
0/1
2/3
1 Patients with 21-30% blasts may be considered as MDS or AML
2 Cytogenetics: Good = Normal, -Y, del(5q), del(20q); Poor = Complex ( ≥ 3 abnormalities) or 
chromosome 7 anomalies; Intermediate = other abnormalities
3 Cytopenias: neutrophil count < 1.8 10E9/L, platelets < 100 10E9/L, hemoglobin < 10 g/dL
5.4
Dose interruption and modification
The following definitions will be used to define dose interruption and dose change:
Term
Details
Interruption
An interruption is a period with a zero actual dose preceded and followed 
by a period with a non-zero actual dose.
Dose change
A planned dose reduction is where a planned dose is lower than the 
previous planned dose; a planned zero dose is included as a dose 
reduction record. A planned dose increase is where a planned dose is 
higher than the previous planned dose. Patients with more than one 
reason for planned dose change are counted once per reason in each 
category (reduction or increase).
5.5
Statistical models
5.5.1
Primary analysis
5.5.1.1
Stratified unadjusted Cox model
The stratified unadjusted Cox model and its assumptions are described by
ℎ, 	
, = ℎ(). exp	
. 


Novartis
For business use only
Page 42
RAP M3 Amendment 4
ICL670A2302
where h (.) is the hazard function as a function of time (relative to date of randomization), the 
randomized study treatment of patient j in stratum k and the unknown regression parameter.
h0k(t) be the unspecified baseline hazard function for stratum k at time t.
xjk1 is the randomized study treatment for patient j in stratum k coded as 0 for placebo and 1 
for deferasirox.
1 is the unknown regression parameter for the treatment effect on the log-scale (the log 
hazard ratio), to be estimated.
The hazard ratio (HR) is a multiplicative constant, exp(1), comparing the hazard function in 
the deferasirox group relative to the hazard function in the placebo group. The latter is called 
the baseline hazard function which is allowed to vary across strata. However, the HR 
comparing study treatments is assumed to be common across strata. A HR <1 would indicate 
a decreased hazard for deferasirox as compared to placebo.
The Cox proportional hazards model will be evaluated by using SAS PROC PHREG with the 
TIES = EXACT option in the MODEL statement. STRATA options will be used to account 
for variations in baseline hazards across strata. The HR point estimate will be based on the 
partial maximum likelihood function, and a two-sided 95% on confidence interval based on 
Wald test will be generated by the RISKLIMITS option. The detailed SAS code will be 
provided in the programming note in RAP M7.
5.5.2
Key secondary analysis
Not applicable 
5.5.3
Confidence interval for the difference of proportions
The 95% confidence limits for the difference of two proportions will be derived as the  
Wilson score confidence limits, i.e. in Proc Freq riskdiff-option: CL=WILSON(CORRECT). 
5.5.4
Treatment switching to new chelator(s)
If there is a high differential in the proportion of patients (more than 10%) of switching to 
new chelation therapy prior to experiencing event-free survival event in the placebo arm 
compared to Deferesirox arm, then a set of additional analyses may be performed: descriptive 
summaries of a selected set of baseline and disease characteristics and a model-based analysis 
such as IPCW or RPSFT to account for potential confounding of new chelation therapy. 
5.5.5
Time point windows
For summaries by time periods (e.g. Year or Quarter), windows are based on scheduled days 
and separating time between visits into halves as in table below. Day of randomization will be 
considered as Day 1:


Novartis
For business use only
Page 43
RAP M3 Amendment 4
ICL670A2302
Visit
Description
First day in 
window
Scheduled 
day in 
window
Last day in 
window
Quarter
Year
Baseline
-35
1
Week 2
2
14
21
1
1
Week 4
22
28
42
1
1
Week 8
43
56
70
1
1
Week 12
71
84
98
1
1
Week 16
99
112
126
2
1
Week 20
127
140
154
2
1
Week 24
155
168
182
2
1
Week 28
183
196
210
3
1
Week 32
211
224
238
3
1
Week 36
239
252
266
3
1
Week 40
267
280
294
4
1
Week 44
295
308
322
4
1
Week 48
323
336
350
4
1
Week 52
351
364
378
4
1
Week 56
379
392
406
1
2
Week 60
407
420
434
1
2
Week 64
435
448
462
1
2
Week 68
463
476
490
2
2
Week 72
491
504
518
2
2
Week 76
519
532
546
2
2
Week 80
547
560
574
3
2
Week 84
575
588
602
3
2
Week 88
603
616
630
3
2
Week 92
631
644
658
4
2
Week 96
659
672
686
4
2
Week 100
687
700
714
4
2
Week 104
715
728
742
4
2
Week 108
743
756
770
1
3
Week 112
771
784
798
1
3
Week 116
799
812
826
1
3
Week 120
827
840
854
2
3
Week 124
855
868
882
2
3
Week 128
883
896
910
2
3
Week 132
911
924
938
3
3
Week 136
939
952
966
3
3
Week 140
967
980
994
3
3
Week 144
995
1008
1022
4
3
Week 148
1023
1036
1050
4
3
Week 152
1051
1064
1078
4
3
Week 156
1079
1092
1106
4
3
Week 160
1107
1120
1134
1
4
Week 164
1135
1148
1162
1
4


Novartis
For business use only
Page 44
RAP M3 Amendment 4
ICL670A2302
Visit
Description
First day in 
window
Scheduled 
day in 
window
Last day in 
window
Quarter
Year
Week 168
1163
1176
1190
1
4
Week 172
1191
1204
1218
2
4
Week 176
1219
1232
1246
2
4
Week 180
1247
1260
1274
2
4
Week 184
1275
1288
1302
3
4
Week 188
1303
1316
1330
3
4
Week 192
1331
1344
1358
3
4
Week 196
1359
1372
1386
4
4
Week 200
1387
1400
1414
4
4
Week 204
1415
1428
1442
4
4
Week 208
1443
1456
1470
4
4
Week 212
1471
1484
1498
1
5
Week 216
1499
1512
1526
1
5
Week 220
1527
1540
1554
1
5
Week 224
1555
1568
1582
2
5
Week 228
1583
1596
1610
2
5
Week 232
1611
1624
1638
2
5
Week 236
1639
1652
1666
3
5
Week 240
1667
1680
1694
3
5
Week 244
1695
1708
1722
3
5
Week 248
1723
1736
1750
4
5
Week 252
1751
1764
1778
4
5
Week 256
1779
1792
1806
4
5
Week 260
1807
1820
1834
4
5
Week 264
1835
1848
1862
1
6
Week 268
1863
1876
1890
1
6
Week 272
1891
1904
1918
1
6
Week 276
1919
1932
1946
2
6
Week 280
1947
1960
1974
2
6
Week 284
1975
1988
2002
2
6
Week 288
2003
2016
2030
3
6
Week 292
2031
2044
2058
3
6
Week 296
2059
2072
2086
3
6
Week 300
2087
2100
2114
4
6
Week 304
2115
2128
2142
4
6
Week 308
2143
2156
2170
4
6
Week 312
2171
2184
2198
4
6
Week 316
2199
2212
2226
1
7
Week 320
2227
2240
2254
1
7
Week 324
2255
2268
2282
1
7
Week 328
2283
2296
2310
2
7
Week 332
2311
2324
2338
2
7
Week 336
2339
2352
2366
2
7


Novartis
For business use only
Page 45
RAP M3 Amendment 4
ICL670A2302
Visit
Description
First day in 
window
Scheduled 
day in 
window
Last day in 
window
Quarter
Year
Week 340
2367
2380
2394
3
7
Week 344
2395
2408
2422
3
7
Week 348
2423
2436
2450
3
7
Week 352
2451
2464
2478
4
7
Week 356
2479
2492
2506
4
7
Week 360
2507
2520
2534
4
7
Week 364
2535
2548
2562
4
7
Week 368
2563
2576
2590
1
8
Week 372
2591
2604
2618
1
8
Week 376
2619
2632
2646
1
8
Week 380
2647
2660
2674
2
8
Week 384
2675
2688
2702
2
8
Week 388
2703
2716
2730
2
8
Week 392
2731
2744
2758
3
8
Week 396
2759
2772
2786
3
8
Week 400
2787
2800
2814
3
8
Week 404
2815
2828
2842
4
8
Week 408
2843
2856
2870
4
8
Week 412
2871
2884
2898
4
8
Week 416
2899
2912
2926
4
8
Week 420
2927
2940
2954
1
9
Week 424
2955
2968
2982
1
9
Week 428
2983
2996
3010
1
9
Week 432
3011
3024
3038
2
9
Week 436
3039
3052
3066
2
9
Week 440
3067
3080
3094
2
9
Week 444
3095
3108
3122
3
9
Week 448
3123
3136
3150
3
9
Week 452
3151
3164
3178
3
9
Week 456
3179
3192
3206
4
9
Week 460
3207
3220
3234
4
9
Week 464
3235
3248
3262
4
9
Week 468
3263
3276
3290
4
9
6
Reference
Brookmeyer R, Crowley J (1982). A Confidence Interval for the Median Survival Time. 
Biometrics 38: 29 - 41.
Cheson BD, Greenberg PL, Bennett JM, et al (2006). Clinical application and proposal for 
modification of the International Working Group (IWG) response criteria in myelodysplasia. 
Blood; 108:419–25.


Novartis
For business use only
Page 46
RAP M3 Amendment 4
ICL670A2302
Cohen AR, Glimm E, Porter JB (2008). Effect of transfusional iron intake on response to 
chelation therapy in β-thalassemia major. Blood 111(2): 583-587.
Collett D (1994). Modelling Survival Data in Medical Research. London, Chapman & Hall.
Fleming TR (2008). Identifying and addressing safety signals in clinical trials. N Engl J Med; 
359(13):1400-2.
Diabetes Care January 2009 vol. 32 no. Supplement 1 S13-S61.
Therneau TM, Grambsch PM (2000). Modeling Survival Data: Extending the Cox Model. 
New York, Springer.
Vardiman JW, Thiele J, Arber DA, et al (2009). The 2008 revision of the World Health 
Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and 
important changes. Blood; 115:5:937-951. 
Robins JM, Tsiatis AA (1991). Correcting for non-compliance in randomized trials using rank
preserving structural failure time models (RPSFTM). Commun. Statist.-Theory Meth., 20(8), 
2609-31.
Robins JM, Finkelstein DM. Correcting for noncompliance and dependent censoring in an
AIDS Clinical Trial with inverse probability of censoring weighted (IPCW) log-rank tests. 
Biometrics. 2000 Sep;56(3):779-88.
Novartis oncology guideline for treatment switching and analysis- final version, Feb 22,2017