Conditions: Non-transfusion Dependent Thalassemia
Keywords: Non-transfusion dependent thalassemia NTDT deferasirox ICL670 LIC Liver Iron Concentration
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 134
Healthy volunteers: no

Brief summary:
Assessed the efficacy of deferasirox in patients with non-transfusion dependent thalassemia based on change in liver iron concentration from baseline after 52 weeks of treatment. Provided further assessment of the long-term efficacy and safety of deferasirox in NTDT patients with iron overload (LIC ≥ 5 mg Fe/g liver dw and SF ≥ 300 ng/mL) for up to 260 weeks.

Detailed description:

Arms:
arm 1: All patients were treated with 10mg/kg/day deferasirox with dose adjustments after 4 weeks of treatment according to baseline Liver Iron Concentration (LIC).

Interventions: intervention 1: deferasirox
Intervention descriptions: intervention 1: Deferasirox dispersible tablets at strengths of 125 mg, 250 mg, and 500 mg were administered by oral daily dosing.

Protocol document:
Prot_001.pdf: 
Clinical Development 
CICL670, Deferasirox, Exjade® 
Protocol CICL670E2419 / NCT01709838
An open label, multi-center, efficacy and safety study of 
deferasirox in iron overloaded patients with non- 
transfusion dependent thalassemia (THETIS) 
Authors 
 
Document type 
Amended Protocol Version 
EUDRACT number 
2012-000650-64 
Version number 
02 (Clean) 
Development phase 
IV 
Document status 
Final 
Release date 
04-Sep-2014
Property of Novartis 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 


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Protocol Summary 
Study title: 
An open label, multi-center, efficacy and safety study of deferasirox in iron overloaded patients with 
non-transfusion dependent thalassemia 
Study phase: 
Phase IV 
Study objectives: 
Primary objective 
To assess the efficacy of deferasirox in patients with non-transfusion dependent thalassemia based on 
change in liver iron concentration (LIC) from baseline after 52 weeks of treatment. 
Secondary objectives 
• 
Assess response rates in patients with baseline LIC values >15 mg Fe/g dw defined as the 
proportion of patients achieving an LIC<5 mg Fe/g dw and time to achieving LIC <5mg Fe/g 
dw 
• 
Assess long-term efficacy and safety of treatment to target LIC of 3 mg Fe/g dw followed by 
one or more treatment holidays until the LIC is ≥5 mg Fe/g dw 
• 
To evaluate the impact of deferasirox on adult Quality of Life (QoL) using the Medical 
Outcomes Study Short Form–36 (SF-36) (in patients >18 years of age) 
• 
To evaluate the impact of deferasirox on pediatric QoL using the Pediatric Quality of Life 
questionnaire (in patients 13 thru 18 years of age) 
• 
To evaluate the efficacy of deferasirox based on changes in LIC from baseline over time 
(approximately six month intervals) 
• 
To assess the correlation of change in SF and LIC at baseline and end of study (EOS) 
• 
To assess the efficacy of deferasirox based on change in LIC from baseline after 52 weeks of 
treatment by non-transfusion dependent thalassemia (NTDT) syndrome 
• 
To assess the efficacy of deferasirox based on change in SF from baseline over time 
• 
To evaluate the safety of deferasirox doses up to 30 mg/kg/day 
• 
To assess the efficacy of deferasirox on endocrine function based on change from baseline 
over time for total and free testosterone (males), luteinizing hormone (LH) and follicle 
stimulating hormone (FSH) (females), thyroid stimulating hormone (TSH), total and free T4, 
total and free T3, insulin, insulin resistance, fasting plasma glucose (FPG) and cortisol 
• 
To conduct pharmacokinetic (PK) analysis in a subset of patients 
Study population: 
Patients with non-transfusion-dependent congenital or chronic anemias inclusive of beta-thalassemia 
intermedia, HbE beta-thalassemia or alpha-thalassemia intermedia (HbH disease). Patients must be ≥ 
10 years of age with a LIC ≥ 5 mg Fe/g dw and a serum ferritin ≥ 300 ng/mL. 
Number of patients: 
117 
Overview of study design: 
This will be an open label, single arm, multi-center study. A four week screening phase will determine 
patient eligibility. Deferasirox will be initiated at a dose of 10 mg/kg/day for 4 weeks. At week 4, dose 
escalation will then be dependent upon baseline LIC severity. At week 24, and approximately every 6 
months thereafter (for up to five years), further dose adjustments may occur based on Week 24 LIC 
severity. The maximum dose of deferasirox throughout the study will be 30 mg/kg/day. 


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Statistical considerations: 
The sample size was determined on the results observed in the ICL670E2209 trial, assuming a larger 
variance to reflect the broader patients population. 117 patients will have to be enrolled to obtain 90% 
power to detect a LIC absolute change of at least 2 mg Fe at Week 52 from the baseline value with a 
standard deviation of 6 mg Fe using a paired t-test at 5% two-sided significance level. Data from all 
centers participating in this study will be aggregated to have an adequate number of patients for the 
analyses. Standard descriptive analyses will include frequencies and percentages for categorical data, 
n, mean, standard deviation, minimum, median, 25th and 75th percentiles and maximum for continuous 
data. 


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Table of contents 
Protocol Summary ............................................................................................................... 2 
Table of contents ................................................................................................................. 4 
List of figures ...................................................................................................................... 8 
List of tables ........................................................................................................................ 8 
List of abbreviations ............................................................................................................ 9 
Glossary of terms ............................................................................................................... 11 
Amendment 2 .................................................................................................................... 12 
Amendment 1 .................................................................................................................... 16 
1 
Background........................................................................................................................ 20 
1.1 
Overview of disease pathogenesis, epidemiology and current treatments ............ 20 
1.2 
Introduction to investigational treatment(s) and other study treatment(s) ............. 21 
1.2.1 
Overview of deferasirox ........................................................................ 22 
2 
Rationale ............................................................................................................................ 25 
2.1 
Study rationale and purpose ................................................................................... 25 
2.2 
Rationale for the study design ............................................................................... 26 
2.3 
Rationale for dose and regimen selection .............................................................. 26 
2.4 
Rationale for choice of combination drugs............................................................ 26 
2.5 
Rationale for choice of comparators drugs ............................................................ 27 
 
 27 
3 
Objectives and endpoints ................................................................................................... 27 
4 
Study design ...................................................................................................................... 30 
4.1 
Description of study design ................................................................................... 30 
4.2 
Timing of interim analyses and design adaptations ............................................... 31 
4.3 
Definition of end of the study ................................................................................ 31 
4.4 
Early study termination .......................................................................................... 31 
5 
Population .......................................................................................................................... 32 
5.1 
Patient population .................................................................................................. 32 
5.2 
Inclusion criteria .................................................................................................... 32 
5.3 
Exclusion criteria ................................................................................................... 32 
5.4 
Exclusion criteria for pediatric patients ................................................................. 34 
6 
Treatment ........................................................................................................................... 34 
6.1 
Investigational treatment, other study treatment, supportive treatment ................. 34 
6.1.1 
Dosing regimen ..................................................................................... 34 
6.2 
Ancillary treatments ............................................................................................... 39 
6.3 
Concomitant medications ...................................................................................... 39 


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6.4 
Guidelines for continuation of treatment ............................................................... 40 
6.4.1 
Change in patient weight ....................................................................... 40 
6.4.2 
Change in serum ferritin ........................................................................ 40 
6.4.3 
Change in liver iron content (LIC) as determined by liver MRI ........... 40 
6.4.4 
Serum creatinine and Creatinine clearance ........................................... 40 
6.4.5 
Increased urinary proteinuria/creatinine ratio ....................................... 41 
6.4.6 
Stevens-Johnson syndrome ................................................................... 41 
6.4.7 
Skin rash (other than SJS) ..................................................................... 41 
6.4.8 
Gastrointestinal disturbances ................................................................. 42 
6.4.9 
Hepatic impairment ............................................................................... 42 
6.4.10 
Elevated liver function tests .................................................................. 42 
6.4.11 
Auditory (decreased hearing) and ocular (lens opacities) 
disturbances ........................................................................................... 43 
6.4.12 
Hypersensitivity reactions ..................................................................... 43 
6.4.13 
Cytopenias ............................................................................................. 43 
6.4.14 
Follow-up for study drug modifications ................................................ 43 
6.5 
Treatment duration................................................................................................. 43 
6.5.1 
Study drug discontinuation.................................................................... 43 
6.5.2 
Premature patient withdrawal / End of treatment .................................. 44 
6.6 
Dose escalation guidelines (Phase 1 studies only) ................................................. 44 
6.6.1 
Study drug compliance and accountability ........................................... 44 
6.6.2 
Disposal and destruction ....................................................................... 45 
7 
Visit schedule and assessments ......................................................................................... 45 
7.1 
Study flow and visit schedule ................................................................................ 45 
7.1.1 
Pre-screening assessments .................................................................... 53 
7.1.2 
Screening ............................................................................................... 53 
7.1.3 
Run-in period ........................................................................................ 54 
7.1.4 
Treatment period ................................................................................... 54 
7.1.5 
End of treatment visit, including premature withdrawal and study 
discontinuation visit ................................................................................. 54 
7.1.6 
Follow up period ................................................................................... 55 
7.2 
Assessment types ................................................................................................... 55 
7.2.1 
Efficacy assessments ............................................................................. 55 
7.2.2 
Safety and tolerability assessments ....................................................... 56 
7.2.3 
Pharmacokinetics .................................................................................. 59 
 
 60 
7.2.5 
Other assessments ................................................................................. 61 


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8 
Safety monitoring and reporting ........................................................................................ 62 
8.1 
Adverse events ....................................................................................................... 62 
8.1.1 
Definitions and reporting ...................................................................... 62 
8.1.2 
Laboratory test abnormalities ................................................................ 63 
8.1.3 
Adverse events of special interest ......................................................... 64 
8.2 
Serious adverse events ........................................................................................... 64 
8.2.1 
Definitions ............................................................................................. 64 
8.2.2 
Reporting ............................................................................................... 64 
8.3 
Emergency unblinding of treatment assignment ................................................... 65 
8.4 
Pregnancies ............................................................................................................ 65 
8.5 
Warnings and precautions...................................................................................... 65 
8.6 
Data Monitoring Committee .................................................................................. 65 
8.7 
Steering Committee ............................................................................................... 65 
9 
Data collection and management ...................................................................................... 66 
9.1 
Data confidentiality ............................................................................................... 66 
9.2 
Site monitoring ...................................................................................................... 66 
9.3 
Data collection ....................................................................................................... 67 
9.4 
Database management and quality control ............................................................ 67 
10 Statistical methods and data analysis ................................................................................ 68 
10.1 
Analysis sets .......................................................................................................... 68 
10.1.1 
Full Analysis Set ................................................................................... 68 
10.1.2 
Safety Set ............................................................................................... 68 
10.1.3 
Pharmacokinetic analysis set ................................................................ 68 
10.2 
Patient demographics/other baseline characteristics ............................................. 68 
10.3 
Treatments (study treatment, concomitant therapies, compliance) ....................... 69 
10.4 
Primary objective ................................................................................................... 69 
10.4.1 
Variable ................................................................................................. 69 
10.4.2 
Statistical hypothesis, model, and method of analysis .......................... 69 
10.4.3 
Handling of missing values/censoring/discontinuations ....................... 69 
10.4.4 
Supportive analyses ............................................................................... 69 
10.4.5 
One-year and Final analysis .................................................................. 70 
10.5 
Secondary objectives ............................................................................................. 71 
10.5.1 
Response analysis in patients with baseline LIC greater than 15 mg 
Fe/g dw .................................................................................................. 71 
10.5.2 
Long-term efficacy of treatment to target LIC of 3 mg Fe/g dw 
followed by one or more treatment holidays until the LIC is greater 
or equal 5 mg Fe/g dw ........................................................................... 71 


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10.5.3 
Absolute change in LIC measured by MRI from baseline over time ... 71 
10.5.4 
Absolute change in LIC measured by MRI from baseline by NTDT 
syndrome ............................................................................................... 72 
10.5.5 
Absolute change in serum ferritin from baseline over time .................. 72 
10.5.6 
Correlation between serum ferritin and LIC at baseline and EOS ........ 72 
10.5.7 
Medical Outcomes Study Short Form-36 (SF-36) ................................ 73 
10.5.8 
Pediatric Quality of Life Questionnaire ................................................ 73 
10.5.9 
Endocrine function ................................................................................ 73 
10.5.10 
Safety objectives ................................................................................... 73 
10.5.11 
Pharmacokinetics .................................................................................. 75 
 
 75 
10.5.13 
Resource utilization ............................................................................... 75 
10.5.14 
Patient-reported outcomes ..................................................................... 75 
 
 75 
 
 75 
10.7 
Interim analysis ...................................................................................................... 76 
10.8 
Sample size calculation .......................................................................................... 76 
10.9 
Power for analysis of key secondary variables ...................................................... 77 
11 Ethical considerations and administrative procedures ....................................................... 77 
11.1 
Regulatory and ethical compliance ........................................................................ 77 
11.2 
Responsibilities of the investigator and IRB/IEC/REB ......................................... 77 
11.3 
Informed consent procedures ................................................................................. 77 
11.4 
Discontinuation of the study .................................................................................. 78 
11.5 
Publication of study protocol and results ............................................................... 78 
11.6 
Study documentation, record keeping and retention of documents ....................... 79 
11.7 
Confidentiality of study documents and patient records ....................................... 79 
11.8 
Audits and inspections ........................................................................................... 80 
11.9 
Financial disclosures .............................................................................................. 80 
12 Protocol adherence ............................................................................................................ 80 
12.1 
Amendments to the protocol .................................................................................. 80 
13 References (available upon request) .................................................................................. 81 


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List of figures 
Figure 4-1 
Study Design ......................................................................................... 31 
 
 
List of tables 
Table 3-1 
Objectives and related endpoints .......................................................... 29 
Table 6-1 
Deferasirox dosing table for 5 mg/kg/day ............................................. 36 
Table 6-2 
Deferasirox dosing table for 10 mg/kg/day ........................................... 37 
Table 6-3 
Deferasirox dosing table for 15 mg/kg/day ........................................... 37 
Table 6-4 
Deferasirox dosing table for 20 mg/kg/day ........................................... 37 
Table 6-5 
Deferasirox dosing table for 25 mg/kg/day ........................................... 38 
Table 6-6 
Deferasirox dosing table for 30 mg/kg/day ........................................... 38 
Table 7-1 
Visit evaluation schedule....................................................................... 46 
Table 7-2 
Laboratory assessment schedule ........................................................... 50 
Table 7-3 
Pharmacokinetic Log ............................................................................ 60 
Table 10-1 
One-year analysis and Final analysis .................................................... 70 
Table 10-2 
Definition of notable/extended ranges for laboratory tests ................... 74 
Table 10-3 
Absolute change in LIC (mg Fe/ g dw), Full Analysis Set ................... 76 


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List of abbreviations 
 
AE 
Adverse event 
 
 
ALT/SGPT 
Alanine aminotransferase/serum glutamic pyruvic transaminase 
AST/SGOT 
Aspartate aminotransferase/serum glutamic oxaloacetic transaminase 
AUC 
Area under the curve 
 
 
BUN 
Blood Urea Nitrogen 
Cmax 
Maximum (peak) observed plasma concentration after single dose administration 
CRO 
Contract Research Organization 
CS&E 
Clinical Safety and Epidemiology 
CSR 
Clinical study report 
CTGF 
Urinary connective tissue growth factor 
DMC 
Data Monitoring Committee 
dw 
Dry weight 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report/Record Form 
EOS 
End of study 
FAS 
Full analysis set 
FE 
Iron 
FPFV 
First patient first visit 
FPG 
Fasting plasma glucose 
FSH 
Follicle stimulating hormone 
GGT 
Gamma glutamyl transferase 
GSTA 
Glutathione transferase alpha 
HbE 
Hemoglobin E 
HbH 
Hemoglobin H 
HBsAb 
Hepatitis B surface antibody 
HBsAg 
Hepatitis B surface antigen 
HCV 
Hepatitis C virus 
HDPE 
High density polyethylene 
HRQOL 
Health-related quality of life 
i.v. 
Intravenous(ly) 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
 
 
LDH 
Lactate dehydrogenase 
LH 
Luteinizing hormone 
LIC 
Liver iron content 
LOCF 
Last observation carried forward 
LPI 
Labile plasma iron 
LPLV 
Last patient last visit 
MRI 
Magnetic resonance imaging 
 
 
NTBI 
Non-transferrin-bound iron 


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NTDT 
Non-transfusion dependent thalassemia 
o.d. 
Omnia die/once a day 
p.o. 
Per os/by mouth/orally 
PK 
Pharmacokinetic 
PROs 
Patient reported outcomes 
QoL 
Quality of Life 
REB 
Research Ethics Board 
SAE 
Serious adverse event 
SD 
Standard deviation 
SF 
Serum ferritin 
SF-36 
Medical Outcomes study short form-36 
SJS 
Stevens-Johnson syndrome 
SOP 
Standard Operating Procedure 
SSC 
Study steering committee 
T 1/2 
The elimination half-life associated with the terminal slope of a semi logarithmic 
concentration-time curve 
THALASSA 
Novartis Study CICL670E2209 
 
 
Tmax 
Time to reach maximum (peak) plasma concentration after single dose administration 
TSH 
Thyroid stimulating hormone 
VEGF B 
Vascular endothelial growth factor B 


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Glossary of terms 
Assessment 
A procedure used to generate data required by the study 
Control drug 
A study treatment used as a comparator to reduce assessment bias, preserve 
blinding of investigational drug, assess internal study validity, and/or evaluate 
comparative effects of the investigational drug 
Enrollment 
Point/time of patient entry into the study; the point at which informed consent 
must be obtained (i.e. prior to starting any of the procedures described in the 
protocol) 
Investigational drug 
The study treatment whose properties are being tested in the study; this 
definition is consistent with US CFR 21 Section 312.3 and is synonymous with 
“investigational new drug.” 
Investigational treatment 
Drug whose properties are being testing in the study as well as their associated 
placebo and active treatment controls (when applicable). This also includes 
approved drugs used outside of their indication/approved dosage, or that are 
tested in a fixed combination. Investigational treatment generally does not 
include other study treatments administered as concomitant background 
therapy required or allowed by the protocol when used in within approved 
indication/dosage 
Medication number 
A unique identifier on the label of each study treatment package which is linked 
to one of the treatment groups of a study 
Other study treatment 
Any drug administered to the patient as part of the required study procedures 
that was not included in the investigational treatment 
Subject Number (Subject No.) 
A unique identifying number assigned to each patient/healthy volunteer who 
enrolls in the study 
Period 
A subdivision of the study timeline; divides stages into smaller functional 
segments such as screening, baseline, titration, washout, etc. 
Premature patient withdrawal 
Point/time when the patient exits from the study prior to the planned completion 
of all study treatment administration and/or assessments; at this time all study 
treatment administration is discontinued and no further assessments are 
planned, unless the patient will be followed for progression and/or survival 
Randomization number 
A unique treatment identification code assigned to each randomized patient, 
corresponding to a specific treatment arm assignment 
Stage related to study timeline 
A major subdivision of the study timeline; begins and ends with major study 
milestones such as enrollment, randomization, completion of treatment, etc. 
Stage in cancer 
The extent of a cancer in the body. Staging is usually based on the size of the 
tumor, whether lymph nodes contain cancer, and whether the cancer has 
spread from the original site to other parts of the body 
Stop study participation 
Point/time at which the patient came in for a final evaluation visit or when study 
treatment was discontinued whichever is later 
Study treatment 
Includes any drug or combination of drugs in any study arm administered to the 
patient (subject) as part of the required study procedures, including placebo and 
active drug run-ins. 
In specific examples, it is important to judge investigational treatment 
component relationship relative to a study treatment combination; study 
treatment in this case refers to the investigational and non-investigational 
treatments in combination. 
Study treatment 
discontinuation 
Point/time when patient permanently stops taking study treatment for any 
reason; may or may not also be the point/time of premature patient withdrawal 
Variable 
Identifier used in the data analysis; derived directly or indirectly from data 
collected using specified assessments at specified time points 


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Amendment 2 
Amendment rationale 
At the time of this amendment, the study is closed for recruitment. One hundred thirty four 
(134) patients were enrolled in the study and 19 patients were discontinued. 
The main purpose of this amendment is to provide guidance regarding dose modifications, 
concomitant medications, and contraception as detailed below. This amendment also clarifies 
the timing of the 2 analyses of this study: a one-year analysis and a final analysis. 
The dose modification guidelines were updated to provide guidance on treating patients with 
moderate hepatic impairment (Child-Pugh Class B) and immediate discontinuation if Stevens- 
Johnson syndrome or severe hepatic impairment (Child-Pugh Class C) occurs, in alignment 
with the approved Exjade prescribing information. 
Guidance on the use of contraception: “highly effective” (inadvertently introduced in 
Amendment 1) was changed to “effective” methods of contraception, in alignment with the 
approved Exjade prescribing information. 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. 
Additional guidance was added regarding treatment discontinuation of patients with creatinine 
clearance < 40 mL/min or serum creatinine > 2 times the age appropriate ULN and caution 
should 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 in alignment with the 
approved Exjade prescribing information. 
Guidance was added regarding the concomitant administration of deferasirox with CYP1A2 
substrates that have a narrow therapeutic index and the concomitant use of bile acid 
sequestrants in alignment with the approved Exjade prescribing information. Vitamin C was 
moved from the prohibited concomitant medication category to drugs that should be 
administered with caution in combination with deferasirox. 
Criteria on when patients must be withdrawn from the study were clarified. 
Clarification was added for visit schedules, liver function tests (serum transaminases, bilirubin, 
and alkaline phosphatase) and pregnancy testing. 
In Amendment 1, the duration of the study was extended from one year to up to five years in 
order to evaluate long-term efficacy and safety of deferasirox in patients with NTDT and iron 
overload. The one-year analysis and the one-year clinical study report will be generated in 
alignment with the study’s primary objective to assess the efficacy of deferasirox in patients 
with NTDT based on an absolute change in LIC from baseline after 52 weeks of treatment and 
will include all assessments and events within treatment Year 1. The one-year study report 
will be issued at the end of the one-year treatment period. The final analysis and the final 
clinical study report will be prepared at the end of the study. 
This amendment also clarifies the definition of the end of study. The maximum recommended 
restart dose is clarified when there is a change of serum ferritin. 


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Typographic errors were corrected, including the planned study visits every 4-weeks period 
between the visits described in the protocol and the deferasirox dosing table. Deferasirox 
background and reference sections were updated to include the recently approved indication  
in NTDT patients and the most recent available clinical information. 
 
Changes to the protocol 
Changes to Section “List of abbreviations” 
• “LPI”: A typographic error in the definition of “LPI” abbreviation was corrected. 
Change to Section 1 Background: Updated with the latest approved indication in NTDT 
patients and the most recent available clinical information. 
Changes to Section 4 Study design: 
• Section 4.3 Definition of end of the study: was updated to specify the time-point of final 
analysis 
Changes to Section 5 Population: 
• Section 5.3 Exclusion criteria: “Highly effective” birth control methods changed to 
“effective” 
• Subheading ‘Women of child-bearing potential’: Definition of child bearing potential was 
updated and pregnancy prevention guidance was modified to describe “effective” methods 
of contraception 
Changes to Section 6 Treatment: 
• Table 6-1 Deferasirox dosing table for 5 mg/kg/day: Corrected a typographic error in the 
weight range requiring a dose of 375mg (the correct range is 62.6 - 87.5 kg). 
• Table 6-6 Deferasirox dosing table for 30 mg/kg/day: Corrected a typographic error in the 
number of 500mg tablets required to achieve recommended dose (1250mg) when a 
patient’s weight is between 39.7 - 43.8kg. 
• Section 6.3 Concomitant medications: Guidance was added regarding the concomitant 
administration of deferasirox with CYP1A2 substrates that have a narrow therapeutic 
index (to be administered with caution) and with bile acid sequestrants (prohibited). 
• Section 6.4.2 Change in serum ferritin: the maximum dose at which study treatment 
should be restarted was clarified 
• Section 6.4.4 Serum creatinine and Creatinine clearance: Caution added for creatinine 
clearance between 40 and less than 60 mL/min, especially in patients with additional risk 
factors. Added dose adjustment guidance regarding treatment discontinuation in case 
creatinine > 2xULN and/or creatinine clearance < 40 mL/min 
• Section 6.4.6 Stevens-Johnson syndrome (SJS): New section added for patients with SJS 
• Section 6.4.7 Skin rash (other than SJS): Dose adjustment guidance updated 
• Section 6.4.9 Hepatic impairment: New section added, providing guidance to treatment 
dose modifications for patients with moderate or severe hepatic impairment (Child-Pugh 
class B or C). 
• Section 6.5.2 Premature patient withdrawal / End of treatment: Criteria on when patients 
must be withdrawn from the study were clarified. 


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Changes to Section 7 Visit schedule and assessments: 
• Table 7-1 Visit evaluation schedule: screening evaluations which could be performed at 
visit 1 or visit 2 were clarified to reflect the screening assessments planned in the protocol. 
• Table 7-1 Visit evaluation schedule and Table 7-2 Laboratory assessment schedule: 
Corrected to include the visits W108-124 and W160-176 missing from these tables but 
planned and described in the protocol as part of the 4-weeks between visits schedule 
during the 5 years study duration. 
• Table 7-2 Laboratory assessment schedule: in the “Category” column: The category was 
updated from “S” (Source document) to “D” (database) for the evaluation “Serum/Urine 
Pregnancy test” as this assessment is recorded in the database and not only in source 
document as indicated in the protocol. 
• Table 7-2 Laboratory assessment schedule: Liver function tests (serum transaminases, 
bilirubin, and alkaline phosphatase) are part of the monthly biochemistry panel; additional 
LFTs are required only at visits 5, 9, 17, 27, 36, 46, 55, 65, 74, 84, and 93 (2 weeks after 
dose initiation and after each dose escalation); all other visits overlapping with 
biochemistry tests were deleted in the LFT row, to avoid duplication. 
• Table 7-2 Laboratory assessment schedule was amended to separate serum pregnancy 
from urinary pregnancy testing and to indicate that serum testing is required shortly before 
treatment initiation and urinary testing at the End of Treatment visit. A corresponding 
footnote was added in the table legend. 
• Section 7.2.2.3 Height and weight: clarified that weight assessment can be done at 
screening either at visit 1 or at visit 2. 
• Section 7.2.2.5.2 Clinical chemistry: clarified that estimated Creatinine clearance is 
obtained monthly and at EoT (Serum creatinine is obtained more often, per Table 7-2) 
• Section 7.2.2.5.4 Pregnancy and assessment of fertility: Clarified that urinary pregnancy 
testing is required during the study in case of delayed menses and at the end of treatment 
visit. Added instruction to discontinue study in case of pregnancy. Deleted text on 
reporting and recording pregnancy events during the study, to avoid redundancy with 
Section 8.4 (already referenced). 
Change to Section 9 Data collection and management 
• Section 9.4 Database management and quality control was updated to include information 
concerning the final data lock. 
Change to Section 10 Statistical methods and data analysis 
• Analyses to be performed at one-year and at end of study (final analysis) were defined. 
• Section 10.4.5 One-year and final analysis were added to define both analyses. 
• Section 10.5.1 Response analysis in patients with baseline LIC greater than 15 mg Fe/g 
dw: a formatting error was corrected in the 97% quantile of the standard normal 
distribution described in the Agresti and Coull 1998 formula. 
Change to Section 11.5 Publication of study protocol and results 
• Information on two study reports to reflect the one-year analysis and the final study 
reports was added. 


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Change to References: Updated to reflect the references introduced to the background section. 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through font for deletions and underlined font for insertions. 
 
IRB/IEC/HA 
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. 
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 
protocol amendment. 


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Summary of previous amendment(s) 
 
Amendment 1 
Amendment rationale 
The purpose of this amendment is to modify the duration of the study and to generate long- 
term efficacy and safety data of deferasirox in patients with NTDT and iron overload. The 
pivotal trial in NTDT (THALASSA) consisted of a one year core and a one year extension 
with a total study duration of only two years. To generate longer term data beyond two years, 
amendment 1 will extend the study duration to up to five years follow-up. 
Secondary objectives have been added to assess the efficacy of treatment in patients with very 
high LIC (>15 mg Fe/g dw) at baseline and those who need re-treatment after having reached 
the target LIC < 3 mg Fe/g dw during the study. The THALASSA study duration did not 
allow for the subgroup of patients with LIC 15 mg Fe/g dw to reach the therapeutic target LIC 
and for the subgroup of patients who reach the LIC <3mg Fe/g dw to re-accumulate enough 
iron overload that would necessitate re-treatment with deferasirox. Analyses of the secondary 
objectives have been modified to add these endpoints and reflect the change in study duration 
to include up to five year follow-up. 
The interruption of treatment based on serum ferritin value <300 ng/mL was changed based 
on safety data from the THALASSA study and in accordance with the label recommendation 
of deferasirox treatment interruption in patients with NTDT and iron overload. 
Dose adjustments based on LIC have been modified for clarification and extended duration of 
study. 
The schedule of assessments has added the analysis of serum transaminases, bilirubin, and 
alkaline phosphatase at two weeks following the initiation of study drug, as per recommended 
safety monitoring. The schedule of assessments has also been modified to extend the visits to 
five years. 
Clarifications regarding sample handling, ocular and auditory examination details, and new 
pregnancy language are also included in this amendment. 
At the time of this amendment, 35 patients have started treatment in Thailand, Italy, Turkey, 
and Lebanon. Eight sites in five countries are actively screening patients. All 117 patients are 
expected to be enrolled by December 2013. Upon approval of amendment, patients who have 
already been enrolled in the study will sign a new consent form for the extended study 
duration and continue the appropriate visit schedule. 


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Changes to the protocol 
Changes to Protocol Summary: 
• Added two secondary objectives and changed wording to account for extended study 
duration. Replaced “genotype” with NTDT syndrome 
• Overview of study design: Changed to account for extended study duration 
Change to Section 2.1 Study rationale and purpose: 
• Added “long-term” 
• Replaced “escalations” with “adjustments” 
Change to Section 2.2 Rationale for the study design: 
• Replaced “52 week” with “five year” 
• Added text with reason for extension of study duration 
Change to Section 2.3 Rationale for dose regimen selection: Replaced “week 24” with 
“adjustments” and changed wording to account for extended study duration 
 
 
Changes to Section 3 Objectives and endpoints: 
• Added two secondary objectives and changed wording to account for extended study 
duration. 
• Replaced “genotype” with “NTDT syndrome” 
Changes to Table 3-1 Objectives and related endpoints: Added two secondary objectives with 
corresponding endpoints and changed wording for endpoints related to Quality of Life 
 
 
Changes to Section 4.1 Description of study design: 
• Dose adjustment guidance was clarified and language reflects change in study duration. 
• Added guidance on study drug interruption and change to visit frequency. 
Change to Figure 4-1 Study design: Replaced figure to reflect dose adjustment clarification. 
Changes to Section 5.3 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 Treatment: 
• Section was updated to include extended study duration and clarification of dose 
adjustments. 
• Added assessments of serum transaminases, bilirubin, and alkaline phosphatase 2 weeks 
after the initiation of treatment. 
Change to Figure 6-1: Removed as it is a duplicate of Figure 4-1. 


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Change to Section 6.3 Concomitant medications: Added hormonal contraceptives to 
treatments NOT allowed 
Change to Section 6.5 Treatment duration: Added five years. 
Changes Section 7 Visit schedule and assessments: 
• Table 7-1 Visit evaluation schedule: Table reflects the increase in number of visits due to 
five year study duration. 
• Replaced “S” with “D” in category column for ocular and audiometry exams. 
• Added assessments of serum transaminases, bilirubin, and alkaline phosphatase 2 weeks 
after the initiation of treatment. 
Changes to Section 7.1.2 Screening: Added pregnancy test assessment and guidance on 
additional laboratory assessments in the event that 4-week screening period is exceeded. 
Changes to Section 7.1.4 Treatment period: Added five year study duration and assessments 
of serum transaminases, bilirubin, and alkaline phosphatase 2 weeks after initiation of 
treatment. 
Change to Section 7.2.1.3 Endocrine function laboratory parameters: Added assessment of 
endocrine function to be every three months following the first year of treatment. 
Changes to Section 7.2.2.3 Height and Weight: Added visit dates 
Added Section 7.2.2.4 Auditory and ocular examination: Added assessments included in 
exams 
Changes to Section 7.2.2.5.2 Clinical chemistry: 
• Added assessments of serum transaminases, bilirubin, and alkaline phosphatase 2 weeks 
after initiation of treatment. 
• Added weekly serum creatinine assessment following dose escalation during study. 
Change to Section 7.2.2.6.1 Electrocardiogram (ECG): Added annual ECG assessment 
Change to Section 7.2.3 Pharmacokinetics: Added pediatric patients will not participate in PK 
subgroup. 
 
Clarification of sample handling and shipment to 
 central lab. 
Change to Section 7.2.5.1 Health-related Quality of Life: Added additional assessments for 
extended study duration. 
Change to Section 10.4 Primary Objective: Replaced “one year” with “52 weeks” 
Change to Section 10.4.4 Supportive analyses: Added descriptive statistics for the proportion 
of patients with LIC decrease by at least 30% from baseline at week 52. 
Change to Section 10.5 Secondary Objectives 
• Added Section 10.5.1 Response analysis in patients with baseline LIC >15 mg Fe/g dw 
• Added Section 10.5.2 Long term efficacy of treatment to target LIC of <3 mg Fe/g dw 
followed by one or more treatment holidays until the LIC is ≥5 mg Fe/g dw 


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Change to Section 10.5.3 Absolute change in LIC measured by MRI from baseline: Added 
analyses of additional measurements for five year study duration 
Change to Section 10.5.4 Absolute change in LIC measured by MRI from baseline by 
underlying disease: 
• Replaced “underlying disease” with NTDT syndrome in header 
• Added analyses of additional measurement for five year study duration 
Change to Section 10.5.5 Absolute change in serum ferritin from baseline: 
• Replaced “52” with “260” 
• Clarified definition of quarter for ferritin analyses 
Change to Section 10.5.6 Correlation between serum ferritin and LIC at baseline and EOS”: 
Added analysis 
Change to Section 10.5.7 Medical Outcomes Study Short Form-36 (SF-36): Added additional 
visits 
Change to Section 10.5.8 Pediatric Quality of Life Questionnaire: Added additional visits 
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. 
 
IRB/IEC/HA 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. In addition, if the changes herein affect the Informed Consent, sites are 
required to update and submit for approval a revised Informed Consent that takes into account 
the changes described in this amended protocol. 


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1 
Background 
1.1 
Overview of disease pathogenesis, epidemiology and current 
treatments 
The thalassemias comprise a heterogeneous group of inherited disorders in which normal 
hemoglobin production is partly or completely suppressed due to the defective synthesis of 
one or more of the components of the globin chains. Depending upon the genes involved, the 
defect is classified as α-thalassemia or β-thalassemia. β-thalassemia and α-thalassemia are the 
most common types of thalassemia (Thalassaemia International Federation 2008). β- 
thalassemia is prevalent in Mediterranean countries, the Middle East, Central Asia, India, 
Southern China, and the Far East, as well as countries along the north coast of Africa and in 
South America (Galanello and Origa 2010). Alpha-thalassemia, including Hemoglobin H (Hb 
H) disease, is particularly common in China and Southeast Asia (Vichinsky 2010). In addition, 
there are a significant number of thalassemia variants that are characterized not only by 
impaired synthesis of β- or α-globin, but also by the presence of abnormal hemoglobins that 
are produced as a result of point mutations within the globin genes. Hemoglobin E (HbE) β-
thalassemia is the most common variant of β-thalassemia in Asia (Vichinsky 2007). Due to 
immigration patterns, patients with alpha and beta thalassemia may be found in  many 
countries outside of the endemic regions. 
The clinical picture of thalassemia may be mild (e.g. β-thalassemia minor), moderate (non- 
transfusion dependent thalassemia [NTDT]) or severe (e.g. β-thalassemia major). Patients 
with thalassemia minor are asymptomatic, while patients with thalassemia major present with 
severe anemia early in life requiring regular blood transfusions and chelation therapy to 
prevent or reverse transfusional iron overload. Patients with NTDT, e.g. β-thalassemia 
intermedia, HbE β-thalassemia, and HbH disease (α-thalassemia), have milder anemia 
compared to thalassemia major and therefore, they require no or only occasional blood 
transfusions. Nonetheless, NTDT patients develop clinically relevant iron overload, mainly 
due to increased intestinal absorption of iron driven by anemia due to ineffective 
erythropoiesis (Pippard 1979, Pootrakul 1988). 
Excess iron deposition, especially in the liver, heart and endocrine organs, results in 
progressive tissue damage and organ failure, and is linked to iron-related promotion of free 
hydroxyl radical formation. Iron overload in NTDT may lead to the various clinical 
complications some of which are also seen in transfusional iron overload, namely liver 
cirrhosis and endocrine dysfunction. Studies show that NTDT patients have a risk of iron 
overload-related complications, such as abnormal liver function, metabolic (diabetes mellitus) 
and endocrine disorders, above certain thresholds of LIC and serum ferritin (Musallam 2013). 
In addition, the risk of some complications increases with age (Taher 2010). 
Serum ferritin (SF) has been traditionally used to assess transfusional iron overload with a 
well-established correlation to liver iron concentration (LIC), a more direct measurement of 
liver tissue iron. However, serum ferritin levels have been reported to underestimate LIC in 
patients with NTDT as compared to regularly transfused patients (Origa 2007, Pakbaz 2007, 
Taher 2008, Musallam 2011, Taher-TIF NTDT Guidelines 2013). Magnetic resonance 


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imaging (MRI) is a sensitive and specific tool for non-invasively assessing hepatic iron 
overload ( It has recently been approved by device regulatory authorities in USA, Europe and 
Australia. Results from the Exjade registration study, Study No. ICL670A0107, confirm that 
this method accurately measures LIC (Nick 2003). 
NTDT patients with iron overload cannot be phlebotomized due to anemia and therefore, 
treatment with iron chelators is the only possibility to decrease or maintain body iron load in 
these patients. The use of iron chelators, such as deferoxamine and deferiprone, has been 
reported in thalassemia intermedia patients (Olivieri 1992, Rombos 2000, Pootrakul 2003)  
and in patients with Hb H disease (Chan 2006). Apart from reduced SF and LIC, these studies 
showed improvement in hematological and iron metabolism parameters, such as hemoglobin, 
erythropoietin (Pootrakul 2003) and labile plasma iron (LPI) (Pootrakul 2003); the latter is a 
component of non-transferrin bound iron (NTBI) which reflects the presence of potentially 
toxic free iron in the plasma. However, neither deferoxamine nor deferiprone have been 
systematically investigated, as those studies were either case reports or small non-randomized 
trials. 
Published small, uncontrolled trials showed that NTDT patients with chronic iron overload 
could be treated with deferasirox (starting doses of 10-20 mg/kg/day with further escalation). 
The safety profile of deferasirox remained unchanged in this population (Ladis 2009, 
Voskaridou 2009). Study [ICL670E2209] (THALASSA), the first randomized, placebo- 
controlled study of iron chelation therapy in NTDT, confirmed that these patients may have 
substantial iron burden as demonstrated by high baseline LIC with moderately elevated levels 
of SF. The THALASSA study demonstrated that deferasirox at starting doses of 5 and 10 
mg/kg/day, escalated to 10 and 20 mg/kg/day, compared to placebo, significantly reduced LIC 
and SF. Both doses had a similar frequency of overall adverse events (AEs) (Taher 2012). 
Notably, the reduction in LIC was dose-dependent and consistent across patient subgroups, 
including baseline iron overload and underlying NTDT syndromes (Taher 2013). The 2 
additional 1-year extensions demonstrated that continued treatment with deferasirox at 
appropriate doses resulted in a progressive reduction in iron overload, highlighting the value 
of long-term chelation therapy (Taher 2013). Furthermore, there were no unexpected safety 
findings and the deferasirox safety profile remained consistent as patients approached near- 
normal body iron levels at the chelation interruption target LIC <3 mg Fe/g dw (Taher 2014). 
The continuously accumulating data on the risk of morbidities associated with iron overload, 
as well as the safety and efficacy of deferasirox, will further confirm the favorable benefit-risk 
profile of deferasirox in patients with transfusional iron overload and in those with NTDT. 
 
1.2 
Introduction to investigational treatment(s) and other study 
treatment(s) 
To date, deferasirox has been approved in over 100 countries worldwide, including the 28 
Member States of the European Union (EU), and the US. 
Deferasirox is registered in the following indications: 
• For the treatment of chronic iron overload due to blood transfusions (transfusional 
hemosiderosis) in adult and pediatric patients (aged 2 years and over) at doses up to 40 
mg/kg/day. 


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• For the treatment of chronic iron overload in patients with NTDT syndromes aged 10 
years and older with LIC ≥5 mg Fe/g d and SF >300 ng/mL at doses of up to 20 
mg/kg/day. 
Detailed information on preclinical and clinical evaluation of deferasirox is provided in the 
current [Investigator 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 must be 
dispersed in water, orange juice or apple juice. A bioavailability study indicates that 
absorption is highly variable when deferasirox is taken together with food. Therefore, it is 
recommended that deferasirox is taken once daily, on an empty stomach, at least 30 minutes 
prior to a meal and no less than 2 hours after the last food intake, consistently at the same time 
of the day. 
 
1.2.1 
Overview of deferasirox 
Deferasirox (ICL670, Exjade®) is an N-substituted bis-hydroxyphenyl-triazole, a 
representative of a new class of tridentate iron chelators (Lattmann 2001, Nick 2003), 
indicated for the treatment of chronic iron overload due to blood transfusions (transfusional 
hemosiderosis) in adult and pediatric patients (aged two years and over) at doses up to 40 
mg/kg/day. It is also indicated for the treatment of chronic iron overload in patients with 
NTDT syndromes aged 10 years and older at doses up to 20 mg/kg/day. Exjade is available as 
a dispersible tablet containing 125, 250, or 500 mg of deferasirox as active substance. 
 
1.2.1.1 
Non-clinical experience 
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). Preclinical studies also revealed that deferasirox 
did not affect fertility and it is neither teratogenic nor carcinogenic. 
 
1.2.1.2 
Clinical experience 
As of 31st of October 2013, the estimated cumulative exposure from post-marketing 
experience was 201,562 patient-treatment years. From 1 November 2012 to 31 October 2013, 
estimated exposure from marketing experience was 40,548 patient-treatment years. In 
addition, over 7098 subjects received deferasirox in clinical trials up to 31 October 2013. 
The efficacy and safety of deferasirox has been evaluated in a large prospective clinical trials 
program that has generated long-term data in patients with transfusional iron overload with a 
variety of transfusion-dependent anemias; this information has recently expanded to also 
include patients with NTDT. Moreover, the data accumulated have characterized the safety 
profile of deferasirox across all age groups and for a wide range of transfusion-dependent and 
independent anemias, including β-thalassemia, sickle cell disease, MDS and NTDT indicating 
that the vast majority of adverse events are mild-to-moderate in severity and manageable with 
dose adjustments or interruptions. 


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Clinical studies have shown deferasirox to effectively chelate iron in patients with 
transfusional iron overload due to a variety of transfusion-dependent anemias, as 
demonstrated by decreases in LIC, SF and cardiac iron (MRI T2*) (Nick 2003, Cappellini 
2006, Vichinsky 2007, Porter 2008, Cappellini 2010, Pennell 2012, Pennell 2014). Long-term 
studies (up to 5 years) in patients aged ≥ 2 have demonstrated that deferasirox administered at 
doses of 10- 40 mg/kg/day effectively reduces or maintains total body iron, as assessed by SF 
or LIC (Cappellini 2011).Deferasirox also has been shown to be associated with improvement 
in liver pathology, as evidenced by biopsy-assessed Ishtak fibrosis staging and necro- 
inflammatory scores (Deugnier 2011) and improvement in hematopoietic parameters in MDS 
patients using the International Working Group 2006 criteria (Gattermann 2012, List 2012, 
Angelucci 2014). Improvements in hematopoietic parameters were also seen in patients with 
Aplastic Anemia (Lee et al 2013). 
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). 
Deferasirox has demonstrated acceptable safety and tolerability in adult and pediatric patients 
with transfusional iron overload (Piga 2005, Cappellini 2006, Vichinsky 2007). The most 
frequent reactions reported during chronic treatment with deferasirox in adult and pediatric 
patients included gastrointestinal disturbances in about 26% of patients (mainly nausea, 
vomiting, diarrhea, or abdominal pain), and skin rash in approximately 7% of patients. These 
reactions were dose-dependent, mostly mild to moderate, generally transient and most 
resolved even if treatment was continued. In addition, there have been rare reports of upper 
gastrointestinal hemorrhages and ulcerations, primarily from clinical trials, in patients 
receiving deferasirox. There have been occasional post-marketing reports of leukocytoclastic 
vasculitis, urticaria, erythema multiforme, and hypersensitivity reactions (anaphylaxis and 
angioedema). Detailed information on the safety evaluation of deferasirox is provided in the 
current [Investigator Brochure]. Mild, non-progressive increases in serum creatinine, mostly 
within the normal range, occurred in approximately 36% of patients. These were dose- 
dependent, often resolved spontaneously and some were alleviated by reducing the dose. Rare 
cases of acute renal failure, mostly serum creatinine increases ≥ 2 x ULN have been reported 
following the prescription use of deferasirox; these were usually reversible after treatment 
interruption. 
Elevations of liver transaminases were reported as an adverse reaction in approximately 2% of 
patients. These were not dose dependent and most of these patients had elevated levels prior 
to receiving deferasirox due to a high background incidence of chronic viral hepatitis and of 
liver damage secondary to chronic iron overload. Elevations of transaminases > 10 x ULN, 
suggestive of hepatitis, were uncommon (0.3%). There have been post-marketing reports of 
hepatic failure, mostly in patients with severe baseline liver disease. 
Reports of cytopenias have mostly been in patients with pre-existing blood disorders which 
are frequently associated with failure of the bone marrow to produce sufficient amounts of 
blood cells. 
As with other iron chelator therapies, high frequency hearing loss and lenticular opacities 
(early cataracts) have been uncommonly observed in patients treated with deferasirox. 


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The risk of toxicity of deferasirox may be increased when inappropriately high doses are 
prescribed to patients with a low iron burden or with SF levels that are only slightly elevated. 
Detailed information regarding the correlation of toxicities and PK parameters (drug 
concentrations, Cmax) is provided in the current [Investigators’ Brochure]. 
A study of deferasirox was conducted in NTDT patients. Study No ICL670E2209, the 
THALASSA study, was a prospective, randomized, double-blind, placebo controlled trial of 
deferasirox with starting doses of 5 and 10 mg/kg/day in patients with NTDT. 
The primary objective of this trial was to compare the efficacy of the two treatment groups of 
deferasirox based on the change in LIC (R2 MRI) from baseline after one year of treatment 
compared to placebo treated patients. One hundred and sixty-six patients with thalassemia 
intermedia (n=95), α-thalassemia (n=22) or HbE/ β-thalassemia (n=49) were randomized to 
starting deferasirox doses of 5 mg/kg/day (n=55) or matching placebo (n=28) and 10 
mg/kg/day (n=55) or matching placebo (n=28). The average actual deferasirox dose (mean ± 
SD) was 5.6 ± 1.4 and 11.5 ± 2.9 mg/kg/day, respectively. The primary objective of this trial 
was met. After one year of treatment with deferasirox, LIC significantly decreased by –1.95 
mg Fe/g dw (95% CI: –2.94, –0.96; BL: 13.11) and –3.80 mg Fe/g dw (95% CI: –4.76, – 2.85; 
BL: 14.56) in the deferasirox 5 and 10 mg/kg/day groups, respectively, compared with an 
increase of 0.38 mg Fe/g dw (95% CI: –0.59, 1.34; BL: 15.94) in the placebo; the difference 
between deferasirox 5 and 10 mg/kg/day groups vs placebo was significant (–2.33 mg Fe/g 
dw, P=0.001 and –4.18 mg Fe/g dw, P<0.001, respectively). After one year of treatment, the 
percentage of patients with LIC decrease ≥3 mg Fe/g dw from baseline was greater in the 
deferasirox 5 and 10 mg/kg/day cohorts (32.7% and 56.4%) compared to placebo (10.7%). In 
addition, more patients in deferasirox 5 and 10 mg/kg/day cohorts achieved LIC reduction 
≥30% from baseline (25.5% and 49.1%) compared to placebo (1.8%). The significant 
difference in the change in LIC from baseline between the 5 and 10 mg/kg/day group, -1.95 vs 
-3.80, p=0.009, justifies the starting dose of 10 mg/kg/day in this trial. 
Mean SF significantly decreased at one year: –121 ng/mL (95% CI: –203, –38) and –222 
ng/mL (95% CI: –304, –140) for deferasirox 5 and 10 mg/kg/day groups while there was an 
increase in the placebo (115 ng/mL: 95% CI: 33, 196); difference vs placebo was significant 
(–235 ng/mL, P<0.001 and –337 ng/mL, P<0.001 for deferasirox 5 and 10 mg/kg/day, 
respectively). 
Overall AE rates were 80.4, 76.4 and 78.2% in the placebo, deferasirox 5 and 10 mg/kg/day 
groups; respectively. The most common investigator-assessed drug-related AEs in the overall 
placebo  (n=56), deferasirox 5 and 10  mg/kg/day groups, respectively, were  nausea (7.1,  5.5 
and 7.3%), rash (1.8, 3.6 and 9.1%), diarrhea (1.8, 0 and 9.1%), headache (3.6, 3.6 and 1.8%) 
and upper abdominal pain (0, 3.6 and 1.8%). Serious AEs were reported in 14.3, 12.7 and 
16.4% of patients in the placebo, deferasirox 5 and 10 mg/kg/day groups, respectively. Three 
(5.5%) deferasirox-treated patients (deferasirox 10 mg/kg/day) had 2 consecutive serum 
creatinine level increases >33% above baseline and >upper limit of normal (ULN). One 
patient in the placebo group had an ALT increase >5 x ULN and >2 x baseline and 2 patients 
had an AST increase to >5 xULN and > 2 x baseline, 1 in the deferasirox 10 mg/kg/day and 1 
in the placebo group (Taher 2012). 


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Therefore, in patients with NTDT and iron overload, deferasirox at starting doses of 5 and 10 
mg/kg/day with dose escalation up to 20 mg/kg/day reduced iron overload, as evidenced by 
significant decreases in LIC and SF and with an overall safety profile comparable to placebo 
(Taher 2012). The reduction in LIC was shown to be dose-dependent since the reduction in 
LIC by average actual dose showed that patients who received deferasirox >12.5–≤17.5 
mg/kg/day achieved the greatest LIC decrease, followed by the ≥7.5–≤12.5 mg/kg/day 
subgroup and the >0–<7.5 mg/kg/day subgroup. Patients who had their dose doubled to 20 
mg/kg/day achieved greater reductions in LIC compared with patients who remained on the 
10 mg/kg/day starting dose (Taher et al. 2013). Continued treatment with deferasirox at 
appropriate doses for up to 2 years resulted in a progressive reduction in iron overload; mean 
change −7.14 mg Fe/g dry weight (dw) (mean dose 9.8±3.6 mg/kg/day; Taher 2013). 
For patients receiving deferasirox for up to 2 years, approximately 40% and 16 % reached  
LIC <5 and <3 mg Fe/g dw, respectively, with more patients reaching these targets during the 
second year. The safety profile remained consistent as patients achieved near-normal body 
iron burdens with no clinically relevant differences in renal and hepatic laboratory parameters 
measured close to the time of LIC <3 compared with measurements near the previous LIC 
assessment (Taher 2014) 
Therefore, the continuously accumulating and available data to date confirm the favorable 
benefit-risk profile of deferasirox in patients with transfusional iron overload and in those 
with NTDT. 
In summary, deferasirox is a once-daily oral iron chelator that has been approved for treating 
transfusional and non-transfusional iron overload, with demonstrated efficacy in the reduction 
or maintenance of body iron stores and an acceptable safety profile 
 
2 
Rationale 
2.1 
Study rationale and purpose 
The purpose of this study is to provide further assessment of the long-term efficacy and safety 
of deferasirox in NTDT patients with iron overload (LIC ≥ 5 mg Fe/g liver dw and SF ≥ 300 
ng/mL) after the closure of the THALASSA trial. In addition, pharmacokinetic (PK), 
endocrine function, quality of life and resource utilization assessments will be included in the 
patient evaluations, as these were not conducted in THALASSA. Also, the patient population 
will be slightly broadened to include patients treated with hydroxyurea, erythropoietin and 
butyrate. 
Liver iron content (LIC) will be estimated throughout the study by the use of a magnetic 
resonance imaging technique called R2 MRI, which is currently the most reliable non- 
invasive method for this purpose. This method was also utilized in the THALASSA trial. 
Dose adjustments throughout the trial will be based upon LIC assessments. The correlation 
between LIC and SF will be further studied to better understand the situations where the 
management of iron overload in NTDT can be performed using solely SF levels. 
At the time the THALASSA protocol was written, iron chelation in this population was not 
well understood. The results from THALASSA have demonstrated that more aggressive 
chelation should be initiated earlier in the course of treatment (see Section 2.3). 


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2.2 
Rationale for the study design 
An open-label, single-arm study design and five year treatment period will be implemented in 
this trial, as the results from the double-blind, randomized THALASSA Study have already 
demonstrated the efficacy of deferasirox in this patient population when compared to placebo. 
After 52 weeks of treatment with deferasirox, LIC significantly decreased by –1.95 mg Fe/g 
dw (95% CI: –2.94, –0.96; BL: 13.11) and –3.80 mg Fe/g dw (95% CI: –4.76, – 2.85; BL: 
14.56) in the deferasirox 5 and 10 mg/kg/day groups, respectively, compared with an increase 
of 0.38 mg Fe/g dw (95% CI: –0.59, 1.34; BL: 15.94) in the placebo; the difference between 
deferasirox 5 and 10 mg/kg/day groups vs placebo was significant (–2.33 mg Fe/g dw, 
P=0.001 and –4.18 mg Fe/g dw, P<0.001, respectively). 
The four week duration of the Screening Period will be implemented to adequately assess trial 
eligibility. The extended duration of the study is to provide follow-up for all patients up to  
five years and generate long-term efficacy and safety data. 
 
2.3 
Rationale for dose and regimen selection 
The treatment regimens of deferasirox (starting dose of 10 mg/kg/day with dose escalation at 
week 4 and adjustments according to LIC response up to 30 mg/kg/day) have been chosen 
based on the results of the THALASSA study. The starting dose regimen of 10 mg/kg/day 
demonstrated significantly better efficacy in reducing LIC over one year when compared to 
the starting dose regimen of 5 mg/kg/day (mean absolute change: -3.80 vs -1.95 mg/g dw, 
p=0.009) along with similar safety parameters. Furthermore, 47.3% of patients in the 5 
mg/kg/day arm, and 45.5% of patients in the 10 mg/kg/day arm required dose increases; some 
of which were up to 20 mg/kg/day. Nevertheless, at week 52, LIC levels were reduced from 
13.11 to 11.56 and from 14.56 to 10.58 mg/g dw in the 5 and 10 mg/kg/day arms; respectively. 
Thus, indicating a need to determine if a faster dose escalation of deferasirox will achieve a 
quick reduction of the iron burden in these patients with high baseline iron burden. 
All patients will receive an initial treatment of 10 mg/kg/day for 4 weeks. After 4 weeks, dose 
escalations in increments of 5 or 10 mg/kg/day will be considered, according to the patient’s 
severity of baseline liver iron concentration. After 24 weeks of treatment, and approximately 
every six months thereafter (for up to five years), additional dosage adjustments will be 
considered in accordance with the patient’s response provided there are no safety or 
tolerability issues while patients are on their individualized dosage regimens. Response will 
be determined via the change in LIC (see Section 6.1.1) and the maximum dose of deferasirox 
will be 30 mg/kg/day. Results from THALASSA also demonstrated 38% of the patients 
assigned to the 10 mg/kg/day group who had baseline LICs >15 mg/g dw showed a rate of 
LIC decrease of 3.8 mg/g dw per year; thus, demonstrating a need for more aggressive 
chelation treatment in this population to 20 and 30 mg/kg/day, as these patients are at risk of 
liver fibrosis and cirrhosis. 
 
2.4 
Rationale for choice of combination drugs 
Not applicable. 


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2.5 
Rationale for choice of comparators drugs 
Not applicable 
 
 
3 
Objectives and endpoints 
Primary objective 
To assess the efficacy of deferasirox in patients with NTDT based on change in LIC from 
baseline after 52 weeks of treatment. 


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Secondary objectives 
• Assess response rates in patients with baseline LIC values >15 mg Fe/g dw defined as 
proportion of patients achieving an LIC <5 mg Fe/g dw and time to achieving LIC <5 mg 
Fe/g/dw 
• Assess long-term efficacy and safety of treatment to target LIC of 3 mg Fe/g dw followed 
by one or more treatment holidays until the LIC is ≥5 mg Fe/g dw 
• To evaluate the impact of deferasirox on adult Quality of Life (QoL) using the Medical 
Outcomes Study Short Form–36 (SF-36) (in patients >18 years of age) 
• To evaluate the impact of deferasirox on pediatric QoL using the Pediatric Quality of Life 
questionnaire (in patients ≤ 18 years of age) 
• To evaluate the efficacy of deferasirox based on change in LIC from baseline over time 
(approximately six month intervals) To assess the correlation of change in SF and LIC at 
baseline and end of study (EOS) 
• To assess the efficacy of deferasirox based on change in LIC from baseline after 52 weeks 
of treatment by NTDT syndrome 
• To assess the efficacy of deferasirox based on change in SF from baseline over time 
• To evaluate the safety of deferasirox doses up to 30 mg/kg/day 
• To assess the efficacy of deferasirox on endocrine function based on change from baseline 
over time of the following parameters: 
• Gonad: total and free testosterone (males), luteinizing hormone (LH) and follicle 
stimulating hormone (FSH) (females) 
• Thyroid: thyroid stimulating hormone (TSH), total and free T4, total and free T3 
• Pancreas: insulin, insulin resistance, fasting plasma glucose (FPG) 
• Adrenal gland: cortisol 
• To conduct pharmacokinetic analysis in a subset of patients 
Objectives and related endpoints are described in Table 3-1 below. 


 
 
 
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Table 3-1 
Objectives and related endpoints 
Objective 
Endpoint 
Analysis 
Primary 
Assess the efficacy of deferasirox in liver iron removal after 52 weeks 
of treatment 
Secondary 
Change in LIC from baseline after 52 weeks of treatment 
Refer to Section 10.4 
Assess response rates in subset of patients with baseline LIC >15 mg 
Fe/g dw 
Proportion of patients with baseline LIC>15 achieving LIC <5 mg 
Fe/g dw and time to achieving LIC <5 mg Fe/g dw 
Refer to Section 10.5.1 
Assess long-term efficacy of treatment to a target LIC of 3 mg Fe/g dw 
Time from target LIC 3 mg Fe/g dw to the first LIC ≥5 mg Fe/g dw in 
the follow up period 
Evaluate the impact of deferasirox on adult QoL 
Change in health-related outcomes using Medical Outcomes Study 
Form 36 (SF 36) 
Evaluate the impact of deferasirox on pediatric QoL 
Change in health-related outcomes using the Pediatric Quality of 
Life questionnaire 
Refer to Section 10.5.2 
Refer to Section 10.5.7 
Refer to Section 10.5.8 
Evaluate the efficacy of deferasirox in liver iron removal 
Change in LIC from baseline 
Refer to Section 10.5.3 
Assess the correlation of change in SF and LIC 
SF vs LIC at baseline and EOS 
Refer to Section 10.5.6 
Confirm the efficacy of deferasirox in liver iron removal in NTDT 
syndrome 
Change in LIC from baseline after 52 weeks of treatment by 
underlying NTDT syndrome 
Refer to Section 10.5.4 
Assess the efficacy of deferasirox in decreasing SF after 52 weeks of 
treatment 
Change in SF from baseline after 52 weeks of treatment 
Refer to Section 10.5.5 
 
 
Evaluate the safety of deferasirox doses up to 30 mg/kg/day dose 
Safety parameters, labs, adverse events (AEs) 
Refer to Section 10.5.10 
 
 
Assess the efficacy of deferasirox in endocrine function 
Change from baseline during treatment period in total and free 
testosterone (males), LH and FSH (females), TSH, total and free T4, 
total and free T3, fasting plasma glucose, insulin, insulin resistance, 
and cortisol. 
Conduct PK analysis in a subgroup of patients 
PK parameters (AUC, Cmax, tmax and trough levels) during the 
study period 
Refer to Section 10.5.9 
 
 
 
Refer to Section 10.5.11 
 


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4 
Study design 
4.1 
Description of study design 
This open label, single-arm, multi-center study to evaluate the efficacy and safety of 
deferasirox in NTDT patients with iron overload will include the following phases: 
Screening (4 weeks) to determine patient eligibility 
Open label treatment with deferasirox: 
• Starting dose 10 mg/kg/day for 4 weeks; 
• At Week 4, dose adjustments according to baseline LIC: 
• 20 mg/kg/day for patients with baseline LIC > 15 mg Fe/g dw 
• 15 mg/kg/day for patients with baseline LIC > 7 but ≤ 15 mg Fe/g dw 
• Dose will remain at 10 mg/kg/day for patients with baseline LIC ≥ 5 but ≤ 7 mg Fe/g 
dw 
• Approximately every 6 months, starting at Week 24, dose adjustments according to LIC: 
• Increase dose by 5-10 mg/kg/day, if LIC > 15 mg Fe/g dw, maximum of 30 
mg/kg/day 
• May increase dose by 5 mg/kg/day if LIC >7 but ≤ 15 mg Fe/g dw, maximum of 20 
mg/kg/day 
• Same dose if LIC is ≥3 but ≤ 7 mg Fe/g dw, maximum of 10 mg/kg/day 
The maximum dose of deferasirox throughout the study will be 30 mg/kg/day. 
If LIC measurement is <3 mg Fe/g dw or SF is <300 ng/mL, treatment will be interrupted. 
Patients who have interrupted study treatment during the first year of the study due to LIC <3 
mg Fe/g dw or SF <300 ng/mL will continue the monthly visit schedule. Patients who have 
treatment interruption due to LIC <3 mg Fe/g dw or SF<300 ng/mL after 52 weeks, will 
complete scheduled visit one month post-interruption and then be followed every three 
months. 
Study treatment will restart at the previous effective dose when LIC ≥5 mg Fe/g dw and SF ≥ 
300 ng/mL (maximum of 10 mg/kg/day). Once on treatment, patients will be followed 
monthly. 
See Figure 4-1, for study design schematic. 


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Open label, all patients treated with 
10 mg/kg/day deferasirox 
(4 weeks) 
Screening Phase 
(28 days) 
 
 
Figure 4-1 
Study Design 
 
Dose adjustments after 4 weeks of treatment according to baseline LIC 
 
Approximately 117 patients will be enrolled. Treatment duration will be five years. 
Pharmacokinetic analysis will be conducted in a subset of 20 patients from selected participating 
centers. 
 
4.2 
Timing of interim analyses and design adaptations 
No formal interim analysis based on primary endpoint will be performed. 
Some basic safety annual analyses will be performed for PSUR (Periodic Safety Update 
Report). 
 
4.3 
Definition of end of the study 
Patients will be followed up to five years. Completion of this study as a whole will occur after 
the last visit of the last patient of the study and upon the availability and accuracy verification 
of the last data point required for final statistical analysis. 
 
4.4 
Early study termination 
The study can be terminated at any time for any reason by Novartis. Should this be necessary, 
the patient should be seen as soon as possible. The site will contact the patient, schedule a 
final visit and provide instruction to discontinue study drug administration. The same 
assessments must be performed as described in Section 7 for a prematurely withdrawn patient. 
The investigator may be informed of additional procedures to be followed in order to ensure 
that adequate consideration is given to the protection of the patient’s interests. The 
5< Baseline LIC < 7 mg Fe/g dw 
10 mg/kg/day 
Baseline LIC>15 mg Fe/g dw 
20 mg/kg/day 
Dose adjustments at Week 24 and approximately every 6 months thereafter according to LIC 
• Increase dose by 5-10 mg/kg/day, if LIC > 15 mg/g dw (maximum of 30mg/kg/day) 
• May increase dose by 5 mg/kg/day if LIC > 7 and < 15 mg Fe/g dw (maximum of 20mg/kg/day) 
• Same dose if LIC is > 3 and < 7 mg Fe/g dw (maximum of 10 mg/kg/day) 
• Treatment will be stopped if LIC < 3 mg Fe/g dw or SF is < 300 ng/mL 
The maximum dose of deferasirox throughout the study will be 30 mg/kg/day 
7< Baseline LIC < 15 mg Fe/g dw 
15 mg/kg/day 


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investigator will be responsible for informing IRBs and/or ECs of the early termination of the 
trial. 
 
5 
Population 
5.1 
Patient population 
Approximately 117 patients will be enrolled in this trial. 
The investigator or designee must ensure that only patients who meet all the following 
inclusion and none of the exclusion criteria are offered enrollment in the study. 
5.2 
Inclusion criteria 
Patients eligible for inclusion in this study must meet all of the following criteria: 
• Male or female aged ≥ 10 years with non-transfusion-dependent congenital or chronic 
anemias inclusive of beta-thalassemia intermedia, HbE beta-thalassemia or alpha- 
thalassemia intermedia (HbH disease) 
• LIC ≥ 5 mg Fe/g dw measured by R2 MRI at screening 
• Serum ferritin ≥ 300 ng/mL at screening (two consecutive values at least 14 days apart 
from each other) 
• Written informed consent obtained prior to any screening procedures 
5.3 
Exclusion criteria 
Patients eligible for this study must not meet any of the following criteria: 
• Patients diagnosed with HbS-beta Thalassemia 
• Anticipated regular transfusion program during the study. Patients having a sporadic 
transfusion (e.g. in case of infection) during the course of the study will not be excluded 
• Any blood transfusion 6 months prior to study start 
• Patients unable to undergo study assessments including MRI, e.g. who are claustrophobic 
to MRI, have a cardiac pacemaker, ferromagnetic metal implants other than those 
approved as safe for use in MR scanners (Example: some types of aneurysm clips, 
shrapnel), and patients who are obese (exceeding the equipment limits) 
• Significant proteinuria as indicated by a urine protein/urine creatinine ratio > 1.0 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) 
• Creatinine clearance ≤ 40 ml/min on two measurements during visit 1 and visit 2 
• Serum creatinine > ULN on two measurements during visit 1 and visit 2 
• ALT >5 x ULN at visit 1 and visit 2 
• Clinical evidence of active hepatitis B (positive HBsAg with negative HBsAb) or 
hepatitis C (positive HCV antibody and detectable HCV RNA with ALT above the normal 
range) (Note: Hepatitis B carriers will be allowed to enter the trial.) 
• Known diagnosis of cirrhosis (confirmed by biopsy if available) 


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• A history of clinically relevant ocular and/or auditory toxicity related to iron chelation 
therapy 
• History of positive HIV serology (ELISA or Western blot) 
• Presence of a surgical or medical condition that might significantly alter the absorption, 
distribution, metabolism or excretion of the study drug 
• Patients with active inflammatory diseases that interferes with the accurate measurement 
of serum ferritin 
• 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.) 
• Patients participating in another clinical trial or receiving a systemic investigational drug 
within the past 4 weeks or topical investigational drug within the past 7 days of screening 
• History of non-compliance with medical regimens or patients who are considered 
potentially unreliable and/or not cooperative, unwilling or unable to comply with the 
protocol 
• History of hypersensitivity to any of the study drug or excipients 
• Significant medical condition interfering with the ability to partake in this study (e.g. 
systemic uncontrolled hypertension, unstable cardiac disease not controlled by standard 
medical therapy, systemic disease (cardiovascular, renal, hepatic, etc.) 
• History of drug or alcohol abuse within the 12 months prior to enrollment 
Women of child-bearing potential 
Women of child-bearing potential, defined as all women physiologically capable of becoming 
pregnant, including female adolescents who are menarchal or who become menarchal during 
the study, unless they are using effective methods of contraception during dosing of study 
treatment. 
Effective contraception methods include: 
1. Total abstinence: When this is in line with the preferred and usual lifestyle of the patient. 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) 
and withdrawal are not acceptable methods of contraception. 
2. Female sterilization: have had surgical bilateral oophorectomy (with or without 
hysterectomy) or tubal ligation at least six weeks prior to study. In case of oophorectomy 
alone, only when the reproductive status of the woman has been confirmed by follow up 
hormone level assessment. 
3. Male partner sterilization (at least 6 months prior to screening). For female study subjects, 
the vasectomized male partner must be the sole partner for that patient. 
4. Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault 
caps) with spermicidal foam/gel/film/cream/ vaginal suppository. 
5. Placement of an intrauterine device (IUD) or intrauterine system (IUS). 
Women are considered to be not of child bearing potential if they have had 12 months of 
natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, 


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history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without 
hysterectomy) or tubal ligation at least six weeks ago. In the case of oophorectomy alone, 
only when the reproductive status of the patient has been confirmed by follow up hormone 
level assessment is she considered not of child bearing potential. 
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. 
 
5.4 
Exclusion criteria for pediatric patients 
• A patient’s weight of at least 20 kg is required to allow dosing of 5 mg/kg with one tablet 
of 125 mg 
 
6 
Treatment 
6.1 
Investigational treatment, other study treatment, supportive 
treatment 
The investigational study drug used in this trial is deferasirox [ICL670, Exjade®]. Deferasirox 
will be initially administered by oral daily dosing of 10 mg/kg/day. After four weeks, the dose 
of deferasirox may be adjusted according to baseline LIC assessment; further dose 
adjustments may occur approximately every 6 months (starting at Week 24), up to five years, 
based upon LIC measurement (see Section 6.1.1). 
Deferasirox [ICL670, Exjade®] will be provided as 125 mg, 250 mg, and 500 mg dispersible 
tablets packaged, labeled and supplied to the local Country Pharma Organizations, which will 
further distribute them to the study centers. Study medication will be open label. 
Immediately before dispensing the package to the patient, investigator staff will detach the 
tear-off part of the label from the packaging and affix it to the source document (Drug Label 
Form) containing patient’s unique number. 
 
Definition of terms: 
• Study drug: 
deferasirox (ICL670, Exjade®) 125mg, 250mg and 500mg tablets for oral use 
• Study treatment: 
Starting dose: 10 mg/kg/day p.o. deferasirox 
 
6.1.1 
Dosing regimen 
The starting dose of deferasirox for all patients will be 10 mg/kg/day for 4 weeks. 
• After 4 weeks, the dose of deferasirox will be adjusted according to baseline LIC 
measurements: 
• 20 mg/kg/day for patients with baseline LIC > 15 mg Fe/g dw 
• 15 mg/kg/day for patients with baseline LIC > 7 but ≤ 15 mg Fe/g dw 
• Dose will remain at 10 mg/kg/day for patients with baseline LIC ≥ 5 but ≤ 7 mg Fe/g 
dw 


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• Approximately every 6 months (starting at Week 24), the dose of deferasirox will be 
further adjusted, according to the following LIC measurements: 
• Increase dose by 5-10 mg/kg/day if LIC is > 15 mg Fe/g dw, maximum of 30 
mg/kg/day 
• May increase dose by 5 mg/kg/day if LIC is > 7 but ≤ 15 mg Fe/g dw, maximum of 
20 mg/kg/day. Same dose if LIC is ≥3 but ≤7 mg Fe/g dw, maximum of 10 mg/kg/day 
Patients who have been dose escalated will be monitored every week for four weeks after the 
escalation, to assess serum creatinine. Serum transaminases, bilirubin, and alkaline 
phosphatase will be assessed two weeks following dose escalation. This may be conducted at 
the local lab. After these periods (if they are applicable), the patient will visit the study center 
according to the monthly visit schedule. 
If LIC measurement is < 3 mg Fe/g dw or SF is < 300 ng/mL, treatment will be interrupted. 
Patients will continue with visits during the period of treatment interruption and study 
treatment will restart at the previous effective dose when LIC ≥5 mg Fe/g dw and SF is ≥300 
ng/mL (maximum of 10 mg/kg/day). 
Dose adjustments based on safety issues are allowed in the study at any time. Investigator can 
reduce or interrupt study treatment and recommendations for such dose adjustments are 
described in Section 6.4. 
The maximum dose of deferasirox throughout the study will be 30 mg/kg/day. 
 
Study Drug Administration 
The patient will be instructed how to prepare his/her daily dose from the three tablet strengths 
of deferasirox [ICL670, Exjade®] available (125 mg, 250 mg, 500 mg). The dose will be 
assigned based on the patient’s weight (see Table 6-1 through to Table 6-6). Given the 
available strengths of deferasirox tablets, the patient’s daily dose will be rounded to the 
nearest whole tablet size (relative to a 125 mg tablet). 
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 deferasirox. 
At regular site visits the investigator or pharmacist will dispense to the patient and/or the legal 
guardian, an appropriate number of deferasirox bottles (see Table 6-1 through to Table 6-6) 
from a choice of 125 mg, 250 mg, 500 mg strengths, based on the patient’s calculated daily 
dose. Date and visit number must be recorded onto the trial drug label when dispensing the 
drug. The number of tablets of each strength dispensed will be recorded in the study drug 
dosing log. All deferasirox bottles (opened and unopened) returned by the patient will be 
counted and the sum entered into the study drug dosing log by the investigator or pharmacist 
at the study site. 
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. 


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Patient Information 
The investigator must instruct the patient to take the study drug exactly as prescribed. All 
dosages prescribed and dispensed to the patient and all dose changes during the study must be 
recorded on the Dosage Administration Record electronic case report form (eCRF). 
Deferasirox must be taken orally, once daily, on an empty stomach, at least 30 minutes before 
food and no less than 2 hours after the last food intake, preferable at the same time each day. 
The tablets are dispersed by stirring in a glass of water or orange or apple juice (100 ml to 200 
ml) until a fine suspension is obtained. For daily doses less than 1 g, the tablets should be 
dispersed in at least 100 ml, and for daily doses from 1 g to 3 g, the tablets should  be 
dispersed in at least 200 ml. Following full disintegration of the tablets, the liquid should be 
consumed promptly. Any residue in the glass and/or on the stirrer must be dispersed in 
additional liquid and swallowed. 
The individual daily dose of deferasirox will be determined by the investigator and the 
amount of tablets corresponding to this dose will be calculated based on the patient’s body 
weight (see Table 6-1 through to Table 6-6). 
 
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. 
When the patient has signed the informed consent form, the patient is assigned a patient 
number by the investigator. At each site, the first patient is assigned patient number 1, and 
subsequent patients are assigned consecutive numbers (e.g., the second patient is assigned 
patient number 2, the third patient is assigned patient number 3). The assigned patient number 
should be entered in the field labeled “Subject ID” on the electronic data capture (EDC) data 
entry screen. 
Once assigned to a patient, the patient number will not be reused. If the patient fails to be 
enrolled, the patient is deemed a screen failure. In addition, the Screening Log will be 
completed for these patients. 
Re-screened patients will be provided a new patient number. 
 
Deferasirox dosing tables and guidance 
 
Table 6-1 
Deferasirox dosing table for 5 mg/kg/day 
 
Pt Weight in kg 
Closest Dose 
125 mg 
250 mg 
500 mg 
20 - 37.5 
125 
1 
37.6 - 62.5 
250 
1 
62.6 - 87.5 
375 
3 
87.6 - 112.5 
500 
1 
112.6 - 137.5 
625 
1 
1 


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Table 6-2 
Deferasirox dosing table for 10 mg/kg/day 
 
Pt Weight in kg 
Closest Dose 
125 mg 
250 mg 
500 mg 
20 - 31.3 
250 
2 
31.4 - 43.8 
375 
3 
43.9 - 56.3 
500 
1 
56.4 - 68.8 
625 
1 
1 
68.9 - 81.3 
750 
1 
1 
81.4 - 93.8 
875 
3 
1 
93.9 - 106.3 
1000 
2 
106.4 - 118.8 
1125 
1 
2 
Table 6-3 
Deferasirox dosing table for 15 mg/kg/day 
Pt Weight in Kg 
Closest Dose 
125 mg 
250 mg 
500 mg 
20 - 20.8 
250 
2 
20.9 - 29.2 
375 
3 
29.3 - 37.5 
500 
1 
37.6 - 45.8 
625 
1 
1 
45.9 - 54.2 
750 
1 
1 
54.3 - 62.5 
875 
3 
1 
62.6 - 70.8 
1000 
2 
70.9 - 79.2 
1125 
1 
2 
79.3 - 87.5 
1250 
1 
2 
87.6 - 95.8 
1375 
3 
2 
95.9 - 104.2 
1500 
3 
104.3 - 112.5 
1625 
1 
3 
112.6 - 120.8 
1750 
1 
3 
Table 6-4 
Deferasirox dosing table for 20 mg/kg/day 
Pt Weight in Kg 
Closest dose 
125 mg 
250 mg 
500 mg 
20.0 - 21.9 
375 
3 
22.0 - 28.1 
500 
1 
28.2 - 34.4 
625 
1 
1 
34.5 - 40.6 
750 
1 
1 
40.7 - 46.9 
875 
3 
1 
47.0 - 53.1 
1000 
2 
53.2 - 59.4 
1125 
1 
2 
59.5 - 65.6 
1250 
1 
2 
65.7 - 71.9 
1375 
3 
2 
72.0 - 78.1 
1500 
3 
78.2 - 84.4 
1625 
1 
3 
84.5 - 90.6 
1750 
1 
3 
90.7 - 96.9 
1875 
3 
3 
97.0 - 103.1 
2000 
4 
103.2 - 109.4 
2125 
1 
4 
109.5 - 115.6 
2250 
1 
4 
115.7 - 121.9 
2375 
3 
4 


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Table 6-5 
Deferasirox dosing table for 25 mg/kg/day 
 
Pt Weight in Kg 
Closest dose 
125 mg 
250 mg 
500 mg 
20.0 - 22.5 
500 
1 
22.6 - 27.5 
625 
1 
1 
27.6 - 32.5 
750 
2 
1 
32.6 - 37.5 
875 
3 
1 
37.6 - 42.5 
1000 
2 
42.6 - 47.5 
1125 
1 
2 
47.6 - 52.5 
1250 
1 
2 
52.6 - 57.5 
1375 
3 
2 
57.6 - 62.5 
1500 
3 
62.6 - 67.5 
1625 
1 
3 
67.6 - 72.5 
1750 
1 
3 
72.6 - 77.5 
1875 
3 
3 
77.6 - 82.5 
2000 
4 
82.6 - 87.5 
2125 
1 
4 
87.6 - 92.5 
2250 
1 
4 
92.6 - 97.5 
2375 
3 
4 
97.6 - 102.5 
2500 
5 
102.6 - 107.5 
2625 
1 
5 
107.6 - 112.5 
2750 
1 
5 
112.6 - 117.5 
2875 
3 
5 
117.6 - 122.5 
3000 
6 
Table 6-6 
Deferasirox dosing table for 30 mg/kg/day 
Pt Weight in Kg 
Closest Dose 
125mg 
250 mg 
500 mg 
20.0 - 22.9 
625 
1 
1 
23.0 - 27.1 
750 
1 
1 
27.2 - 31.3 
875 
3 
1 
31.4 - 35.4 
1000 
2 
35.5 - 39.6 
1125 
1 
2 
39.7 - 43.8 
1250 
1 
2 
43.9 - 47.9 
1375 
3 
2 
48.0 - 52.1 
1500 
3 
52.2 - 56.3 
1625 
1 
3 
56.4 - 60.4 
1750 
1 
3 
60.5 - 64.6 
1875 
3 
3 
64.7 - 68.8 
2000 
4 
68.9 - 72.9 
2125 
1 
4 
73.0 - 77.1 
2250 
1 
4 
77.2 - 81.3 
2375 
3 
4 
81.4 - 85.4 
2500 
5 
85.5 - 89.6 
2625 
1 
5 
89.7 - 93.8 
2750 
1 
5 
93.9 - 97.9 
2875 
3 
5 
98.0 - 102.1 
3000 
6 
102.2 - 106.3 
3125 
1 
6 


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Pt Weight in Kg 
Closest Dose 
125mg 
250 mg 
500 mg 
106.4 - 110.4 
3250 
1 
6 
110.5 - 114.6 
3375 
3 
6 
114.7 - 118.8 
3500 
7 
 
6.2 
Ancillary treatments 
Any additional therapy used to treat NTDT during this trial (e.g. therapy with hydroxyurea, 
erythropoietin, butyrate) will be permitted. Except for the study medication, no other iron 
chelation therapy will be administered while the patient is enrolled in the trial. 
 
6.3 
Concomitant medications 
Use of the following treatments is NOT allowed after the start of study drug: 
• Other investigational drugs 
• Aluminum containing antacid therapies should be avoided because they may bind to 
deferasirox 
• The concomitant use of deferasirox with potent UGT inducers (e.g. rifampicin, phenytoin, 
phenobarbital, ritonavir) may result in a decrease in deferasirox efficacy. 
• The concomitant use of deferasirox with bile acid sequestrants (e.g., cholestyramine, 
colesevelam, colestipol) may result in a decrease in deferasirox efficacy. 
• 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. 
• Any iron chelation therapy other than the study drug 
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/days have not been associated with adverse 
consequences. 
• 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 metabolised 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. 
A sporadic transfusion depending on the patient’s condition (e.g. in case of infection) during 
the course of the study is allowed and will be recorded in the Transfusions eCRF. 


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The investigator must instruct the patient to notify the study site about any new medications 
(including over-the-counter products) he/she takes after the start of the study drug. All 
medications (other than study drug) and significant non-drug therapies (including physical 
therapy and blood transfusions) administered after the patient starts treatment with study drug 
must be listed on the Concomitant medications/Significant non-drug therapies after start of 
study drug eCRF. 
 
6.4 
Guidelines for continuation of treatment 
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. These changes must be 
recorded on the dosage administration record eCRF. 
The majority of dose adjustments are covered in Section 6.4.1 to Section 6.4.11, below. For 
all cases where a dose adjustment is considered necessary but is not covered in the following 
sections, the investigator will send a written request to Novartis. The request must justify the 
dose change and provide all the supportive clinical and laboratory information for complete 
evaluation by Novartis. Any dose adjustment for reasons not included in this section needs to 
be authorized by Novartis. A written reply will be promptly sent back to the investigator by 
Novartis. 
 
6.4.1 
Change in patient weight 
The dose of study drug will be adapted using Table 6-1 through to Table 6-6 according to the 
patient’s body weight throughout the course of the study. 
6.4.2 
Change in serum ferritin 
If the serum ferritin level decreases to < 300 ng/mL at any visit, study drug will be held and 
the LIC will be assessed by R2 MRI. If repeat serum ferritin is < 300 ng/mL, treatment with 
the study drug will be interrupted. Repeat serum ferritin may be done locally, within two 
weeks of scheduled visit. If LIC is ≥ 5 mg Fe/g dw and repeat serum ferritin is ≥ 300 ng/mL, 
study drug treatment will be restarted at the same dose. Study drug will be held until LIC is 
≥ 5 mg Fe/g dw and serum ferritin is ≥ 300 ng/mL. Study drug treatment will be restarted at 
the same dose (maximum restart dose of 10 mg/kg/day). The investigator will record this 
change on the dosage administration record eCRF and will notify Novartis at the time such a 
dose interruption is made, in order to facilitate optimal safety monitoring. 
 
6.4.3 
Change in liver iron content (LIC) as determined by liver MRI 
See Section 6.1.1 Dosing regimen. 
 
6.4.4 
Serum creatinine and Creatinine clearance 
Serum creatinine and creatinine clearance will be assessed at Weeks -4 and -2 before initiating 
therapy and should be monitored during the study as indicated in Table 7-2. 
During the treatment period, patients who develop an increase in serum creatinine ≥ 33% 
above their baseline value (average of visit 1 and 2) resulting in a serum creatinine above the 


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upper limit of normal, on two consecutive occasions, the dose of the study drug will be 
reduced to: 
• 15 mg/kg if the patient takes 30 mg/kg/day, 
• 10 mg/kg if the patient takes 15-20 mg/kg/day, 
• 5 mg/kg if patient takes 10 mg/kg/day, 
• study drug held if patient takes 5 mg/kg/day of deferasirox 
until serum creatinine returns to below the ULN. 
In case of a single increase in serum creatinine, the assessment will be repeated in 2 weeks. 
If after a dose reduction, a progressive increase in serum creatinine beyond the ULN is 
observed, a treatment interruption is recommended. 
After an interruption, if serum creatinine falls below the age appropriate upper limit of normal 
range on two consecutive visits, it is recommended to resume therapy at 5 mg/kg/day, and 
after 1 month, if the serum creatinine increase does not recur, study medication can be 
doubled at one month intervals in order to return to the initial dose. 
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. 
Deferasirox therapy should be discontinued in case serum creatinine increases > 2 times the 
age-appropriate ULN or if creatinine clearance decreases < 40 mL/min. 
 
6.4.5 
Increased urinary proteinuria/creatinine ratio 
Deferasirox must be temporarily discontinued if the urinary protein/creatinine ratio increases 
to > 1.0 (mg/mg) in two consecutive second-void urine samples separated by a period of at 
least 48 hours. Deferasirox can be resumed at the same dose once the urinary 
protein/creatinine ratio is ≤ 0.5 (mg/mg) in two consecutive urine samples, separated by a 
period of at least 48 hours. If proteinuria of this same magnitude recurs, deferasirox must be 
discontinued again and then resumed at 50% of the dose once the urinary protein/creatinine 
ratio is ≤ 0.5 (mg/mg) in two consecutive urine samples separated by a period of at least 48 
hours. Dose adjustment will be based on central laboratory results. 
In case of a single increase of the urinary protein/creatinine ratio, the assessment must be 
repeated in two weeks. 
 
6.4.6 
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. 
 
6.4.7 
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 


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persists for >1 week, or worsens, treatment with study drug will be interrupted. After the rash 
resolves, study drug should be restarted. Resume deferasirox at 50% of the patient’s dose. If 
the rash does not recur, increase back to 100% of the patient’s dose after 2 weeks. If the rash 
recurs, contact Novartis. 
For severe cases (defined as those causing distressing symptoms, particularly those which 
require the administration of systemic steroids for symptom relief) treatment with study drug 
must be stopped until resolution of the rash. If necessary, a brief course of oral steroids may 
be given. After the rash resolves, study drug should be restarted. Resume deferasirox at 50% 
of the patient’s dose. If the rash does not recur, increase dose by 5 mg/kg increments every 2 
weeks until 100% of the patient’s last dose is achieved. If the rash recurs, study treatment 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. 
6.4.8 
Gastrointestinal disturbances 
Patients with gastrointestinal symptoms or patients who are unable to tolerate deferasirox may 
(in this order): 
• In the first instance try changing the timing of administration from morning to evening (30 
minutes before taking food), 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. after 
first contacting Novartis. Once the symptoms resolve, b.i.d should be switched to o.d. 
 
6.4.9 
Hepatic impairment 
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 
increments 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. 
 
6.4.10 
Elevated liver function tests 
If there is a persistent and progressive increase in serum transaminase levels that cannot be 
attributed to other causes, deferasirox should be interrupted. Once the cause of the liver 
function test abnormalities has been identified or after a return to normal levels, cautious re- 
initiation of deferasirox treatment at a lower dose followed by gradual dose escalation may be 
considered. In cases of a second rise in serum transaminase levels, the investigator must 
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6.4.11 
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 (including fundoscopy) 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. 
 
6.4.12 
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 must 
be discontinued and appropriate medical intervention instituted. 
 
6.4.13 
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 must be 
monitored regularly. Dose interruption of treatment with deferasirox should be considered in 
patients who develop unexplained cytopenia. Reintroduction of therapy with deferasirox may 
be considered, once the cause of the cytopenia has been identified. 
 
6.4.14 
Follow-up for study drug modifications 
Patients, whose treatment is modified, interrupted or permanently discontinued due to an 
adverse event 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. 
 
6.5 
Treatment duration 
The duration of treatment will be five years. 
 
6.5.1 
Study drug discontinuation 
Patients who discontinue study drug entirely before completing the study must be scheduled 
for a visit as soon as possible, at which time all of the assessments listed for the final visit will 
be performed. The End of Treatment eCRF must be completed, documenting the date and 
reason for stopping the study drug. Any safety finding that leads to discontinuation of study 
drug must be captured on the Adverse Event eCRF. 
All patients who discontinue study drug, including those who refuse to return for a final visit, 
will be contacted by the investigational site for safety evaluations during the 30 days 
following the last dose of study drug. 
If patients refuse to return for these visits or are unable to do so, the investigator or  a 
delegated person must make every effort to contact them or a knowledgeable informant by 


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telephone. However, patients are considered to be withdrawn from the study if it is clear that 
the patient will not return for these assessments. 
 
6.5.2 
Premature patient withdrawal / End of treatment 
Patients may voluntarily withdraw from the study or be dropped from it at the discretion of  
the investigator at any time. Patients who are pregnant, withdraw consent, died, fail to meet 
eligibility criteria, or are unwilling to comply with procedures as outlined in the  study 
protocol must be withdrawn from the study. 
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 End of Treatment eCRF. Patients may be withdrawn from the study 
prematurely for one of the following reasons: 
• Adverse event(s) 
• Abnormal laboratory value(s) 
• Abnormal test procedure result(s) 
• Protocol violation 
• Lost to follow-up 
• Administrative problems 
All unused/remaining study drugs must be returned by the patient withdrawn from study and 
must be accounted for. 
If the patient fails to return, every effort should be made to contact the patient or a knowledgeable 
informant to determine the patient’s current health status. Attempts to contact the patient should 
be documented in the source documents. 
 
6.6 
Dose escalation guidelines (Phase 1 studies only) 
Not applicable. 
 
6.6.1 
Study drug compliance and accountability 
 
6.6.1.1 
Study drug compliance 
Compliance will be assessed by the investigator and/or study personnel at each patient visit 
and information provided by the patient and/or caregiver will be captured in the Drug 
Accountability Form. This information must be captured in the source document at each 
patient visit. 
 
6.6.1.2 
Study drug accountability 
The investigator or designee must maintain an accurate record of the shipment and dispensing 
of study treatment in a drug accountability ledger. Drug accountability will be noted by the 
field monitor during site visits and at the completion of the study. Patients will be asked to 
return all unused study treatment and packaging on a regular basis, at the end of the study or 
at the time of study treatment discontinuation. 


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At study close-out, and, as appropriate during the course of the study, the investigator will 
return all used and unused study treatment, packaging, drug labels, and a copy of the 
completed drug accountability ledger to the Novartis monitor or to the Novartis address 
provided in the investigator folder at each site. 
 
6.6.2 
Disposal and destruction 
The drug supply can be destroyed at the local Novartis facility, Drug Supply group or third 
party, as appropriate. Study drug supply may only be destroyed at the site if permitted by local 
regulations and authorized by Novartis in a prior agreement. 
 
7 
Visit schedule and assessments 
7.1 
Study flow and visit schedule 
Written informed consent must be obtained before any study specific medical procedures are 
performed. 
Patients will attend the study site at all visits to perform the scheduled assessments on the 
designated day, or as close as possible. 
Table 7-1 and Table 7-2 list all of the assessments conducted during the Screening Period and 
Treatment Period, and indicate the visits when the assessments are to be performed with an 
“X”. All data obtained from these assessments must be supported in the patient’s source 
documentation. The tables also indicate which assessments produce data to be entered into the 
database (D) or remain in source documents (S) (“Category” column). The Reference column 
in the table indicates the section in this document where further information may be obtained 
regarding the assessment. 


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Table 7-1 
Visit evaluation schedule 
 
Category 
Reference 
Screening 
260 weeks study period 
1-week periods 
4-week periods 
between visits 
EoT 
24, 
25, 
26, 
27, 
52, 
53, 
54, 
55, 
76, 
77, 
78, 
79, 
28-48, 56-72, 80-100, 
1 
104, 
105, 
106, 
107, 
Week 
- 4 
- 2 
ay 
1 
2 
3 
4 
5 
6 
7 
8 
12 
16 
20 
128, 
129, 
130, 
131, 
108-124, 132-152, 
260 
D
156, 
157, 
158, 
159, 
160-176, 184-204, 
180, 
181, 
182, 
183, 
212-228, 236-256 
208, 
209, 
210, 
211, 
232 
233 
234 
235 
15, 
16, 
17, 
18, 
25, 
26, 
27, 
28, 
34, 
35, 
36, 
37, 
19-24, 29-33, 38-43, 
44, 
45, 
46, 
47, 
48-52, 57-62, 
Visit no. 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
53, 
54, 
55, 
56, 
777 
63, 
64, 
65, 
66, 
67-71, 76-81, 
72, 
73, 
74, 
75, 
86-90, 95-100 
82, 
83, 
84, 
85, 
91 
92 
93 
94 
Demography/ 
Informed 
Consent 
D 
7.1.2.3 
X 
Inclusion / 
exclusion 
Relevant 
medical history 
/ current 
medical 
conditions 
Transfusion 
history 
Iron chelation 
therapy history 
Diagnosis of 
NTDT 
S 
7.1.2.3 
X 
D 
7.1.2.3 
X 
D 
7.1.2.3 
X 
D 
7.1.2.3 
X 
D 
7.1.2.3 
X 
X 
X 
X 
X 
X 


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Screening 
 
260 weeks study period 
1-week periods 
4-week periods 
EoT 
between visits 
 
 
 
 
Week 
- 4 
- 2 
 
 
 
 
1 
2 
3 
4 
5 
6 
7 
8 
12 
16 
20 
24, 
52, 
76, 
104, 
128, 
156, 
180, 
208, 
232 
15, 
25, 
34, 
44, 
25, 
53, 
77, 
105, 
129, 
157, 
181, 
209, 
233 
16, 
26, 
35, 
45, 
26, 
54, 
78, 
106, 
130, 
158, 
182, 
210, 
234 
17, 
27, 
36, 
46, 
27, 
55, 
79, 
107, 
131, 
159, 
183, 
211, 
235 
18, 
28, 
37, 
47, 
 
 
 
28-48, 56-72, 80-100, 
108-124, 132-152, 
160-176, 184-204, 
212-228, 236-256 
 
 
 
 
 
19-24, 29-33, 38-43, 
 
 
 
 
260 
Visit no. 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
53, 
63, 
72, 
82, 
91 
54, 
64, 
73, 
83, 
92 
55, 
65, 
74, 
84, 
93 
56, 
66, 
75, 
85, 
94 
48-52, 57-62, 
67-71, 76-81, 
86-90, 95-100 
777 
Height 
Adult 
D 
7.2.2.3 
X* 
X  
(W52, 
104, 
X 
156, 
208) 
Height 
Pediatric 
D 
7.2.2.3 
X* 
X 
X 
Weight 
D 
7.2.2.3 
X* 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical 
examination 
S 
7.2.2.1 
X 
X 
X 
X 
ECG 
D 
7.2.2.6 
X 
Ocular exam 
D 
7.2.2.4 
X 
X  
(W52, 
104, 
X 
156, 
208) 
X  
(W52, 
104, 
X 
156, 
208) 
Category 
Reference 
Day 1 


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Category 
Reference 
Screening 
260 weeks study period 
1-week periods 
4-week periods 
between visits 
EoT 
Week 
- 4 
- 2 
Day 1 
1 
2 
3 
4 
5 
6 
7 
8 
12 
16 
20 
24, 
52, 
76, 
104, 
128, 
156, 
180, 
208, 
232 
25, 
53, 
77, 
105, 
129, 
157, 
181, 
209, 
233 
26, 
54, 
78, 
106, 
130, 
158, 
182, 
210, 
234 
27, 
55, 
79, 
107, 
131, 
159, 
183, 
211, 
235 
28-48, 56-72, 80-100, 
108-124, 132-152, 
160-176, 184-204, 
212-228, 236-256 
260 
Visit no. 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15, 
25, 
34, 
44, 
53, 
63, 
72, 
82, 
91 
16, 
26, 
35, 
45, 
54, 
64, 
73, 
83, 
92 
17, 
27, 
36, 
46, 
55, 
65, 
74, 
84, 
93 
18, 
28, 
37, 
47, 
56, 
66, 
75, 
85, 
94 
19-24, 29-33, 38-43, 
48-52, 57-62, 
67-71, 76-81, 
86-90, 95-100 
777 
Audiometry 
D 
7.2.2.4 
X 
X  
(W52, 
104, 
156, 
208) 
X 
LIC by MRI 
D 
7.2.1.1 
X* 
X 
X 
QoL: 
SF-36 (adults) 
or Peds QL 
(children) 
D 
7.2.5.1 
X 
X  
(W52, 
104, 
156) 
Prior/ 
concomitant 
medications 
D 
6.3 
X 
X 
X 
Continuous 
Transfusions 
D 
7.2.5.2 
X 
X 
X 
Continuous 
Adverse 
events 
D 
8.1 
X 
X 
X 
Continuous 


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Category 
Reference 
Screening 
260 weeks study period 
1-week periods 
4-week periods 
between visits 
EoT 
Week 
- 4 
- 2 
Day 1 
1 
2 
3 
4 
5 
6 
7 
8 
12 
16 
20 
24, 
52, 
76, 
104, 
128, 
156, 
180, 
208, 
232 
25, 
53, 
77, 
105, 
129, 
157, 
181, 
209, 
233 
26, 
54, 
78, 
106, 
130, 
158, 
182, 
210, 
234 
27, 
55, 
79, 
107, 
131, 
159, 
183, 
211, 
235 
28-48, 56-72, 80-100, 
108-124, 132-152, 
160-176, 184-204, 
212-228, 236-256 
260 
Visit no. 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15, 
25, 
34, 
44, 
53, 
63, 
72, 
82, 
91 
16, 
26, 
35, 
45, 
54, 
64, 
73, 
83, 
92 
17, 
27, 
36, 
46, 
55, 
65, 
74, 
84, 
93 
18, 
28, 
37, 
47, 
56, 
66, 
75, 
85, 
94 
19-24, 29-33, 38-43, 
48-52, 57-62, 
67-71, 76-81, 
86-90, 95-100 
777 
Drug 
compliance 
D 
6.6.1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dose 
administration 
record 
D 
6.1.1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dose 
adjustment 
D 
6.4 
X 
X 
Study 
completion 
D 
7.1.5 
X 
Visit numbers highlighted in gray in the table above indicate visits conducted for assessments that may be performed locally (after dose initiation and dose escalations). 
* Vital signs, height, weight and LIC assessment during screening should be performed at Visit 1 or at Visit 2 


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Table 7-2 
Laboratory assessment schedule 
Category 
Reference 
Screening 
260 weeks study period 
1-week periods 
4-week period 
between visits 
EoT 
Week 
- 4 
- 2 
Day 1 
1 
2 
3 
4 
5 
6 
7 
8 
12 
16 
20 
24, 
52, 
76, 
104, 
128, 
156, 
180, 
208, 
232 
25, 
53, 
77, 
105, 
129, 
157, 
181, 
209, 
233 
26, 
54, 
78, 
106, 
130, 
158, 
182, 
210, 
234 
27, 
55, 
79, 
107, 
131, 
159, 
183, 
211, 
235 
28-48, 56-72, 80-100, 
108-124; 132-152, 
160-176, 184-204, 
212-228, 236-256 
260 
Visit no. 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15, 
25, 
34, 
44, 
53, 
63, 
72, 
82, 
91 
16, 
26, 
35, 
45, 
54, 
64, 
73, 
83, 
92 
17, 
27, 
36, 
46, 
55, 
65, 
74, 
84, 
93 
18, 
28, 
37, 
47, 
56, 
66, 
75, 
85, 
94 
19-24, 29-33, 38-43, 
48-52, 57-62, 
67-71, 76-81, 
86-90, 95-100 
777 
Hematology 
D 
7.1.2.3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Biochemistry 
D 
7.2.2.5.2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hepatitis Viral 
D 
7.2.2.5.5 
X 
Serum Ferritin 
D 
7.2.1.2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum 
creatinine 
D 
7.2.2.5.2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum 
transaminases, 
bilirubin, and 
alkaline 
phosphatase 
D 
7.2.2.5.2 
X 
X 
X 
Creatinine 
D 
7.2.2.5.2 
X 
 
X 
X 
X 
X 
X 


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Category 
Reference 
Screening 
260 weeks study period 
1-week periods 
4-week period 
between visits 
EoT 
Week 
- 4 
- 2 
Day 1 
1 
2 
3 
4 
5 
6 
7 
8 
12 
16 
20 
24, 
52, 
76, 
104, 
128, 
156, 
180, 
208, 
232 
25, 
53, 
77, 
105, 
129, 
157, 
181, 
209, 
233 
26, 
54, 
78, 
106, 
130, 
158, 
182, 
210, 
234 
27, 
55, 
79, 
107, 
131, 
159, 
183, 
211, 
235 
28-48, 56-72, 80-100, 
108-124; 132-152, 
160-176, 184-204, 
212-228, 236-256 
260 
Visit no. 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15, 
25, 
34, 
44, 
53, 
63, 
72, 
82, 
91 
16, 
26, 
35, 
45, 
54, 
64, 
73, 
83, 
92 
17, 
27, 
36, 
46, 
55, 
65, 
74, 
84, 
93 
18, 
28, 
37, 
47, 
56, 
66, 
75, 
85, 
94 
19-24, 29-33, 38-43, 
48-52, 57-62, 
67-71, 76-81, 
86-90, 95-100 
777 
Urinary protein 
/creatinine 
ratio 
D 
7.2.2.5.3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
D 
7.2.2.5.3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum 
pregnancy 
test * 
D 
7.2.2.5.4 
X 
Urinary 
pregnancy 
test * 
D 
7.2.2.5.4 
X 
Insulin 
D 
7.2.1.3 
X 
X 
X 
X (W36, 64, 88, 116, 
140, 168, 192, 220, 
244) 
X 
TSH, Total & 
Free T3, Total 
& Free T4 
D 
7.1.2.3 
X 
X 
X 
X (W36, 64, 88, 116, 
140, 168, 192, 220, 
244) 
X 


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Category 
Reference 
Screening 
260 weeks study period 
1-week periods 
4-week period 
between visits 
EoT 
Week 
- 4 
- 2 
Day 1 
1 
2 
3 
4 
5 
6 
7 
8 
12 
16 
20 
24, 
52, 
76, 
104, 
128, 
156, 
180, 
208, 
232 
25, 
53, 
77, 
105, 
129, 
157, 
181, 
209, 
233 
26, 
54, 
78, 
106, 
130, 
158, 
182, 
210, 
234 
27, 
55, 
79, 
107, 
131, 
159, 
183, 
211, 
235 
28-48, 56-72, 80-100, 
108-124; 132-152, 
160-176, 184-204, 
212-228, 236-256 
260 
Visit no. 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15, 
25, 
34, 
44, 
53, 
63, 
72, 
82, 
91 
16, 
26, 
35, 
45, 
54, 
64, 
73, 
83, 
92 
17, 
27, 
36, 
46, 
55, 
65, 
74, 
84, 
93 
18, 
28, 
37, 
47, 
56, 
66, 
75, 
85, 
94 
19-24, 29-33, 38-43, 
48-52, 57-62, 
67-71, 76-81, 
86-90, 95-100 
777 
Males: Total & 
free 
testosterone 
Females: LH & 
FSH 
D 
7.2.1.3 
X 
X 
X 
X (W36, 64, 88, 116, 
140, 168, 192, 220, 
244) 
X 
Cortisol 
D 
7.2.1.3 
X 
X 
X 
X (W36, 64, 88, 116, 
140, 168, 192, 220, 
244) 
X 
PK (subgroup) 
D 
7.2.5.1 
X 
X 
X 
(W24) 
Visit numbers highlighted in gray in the table above indicate visits conducted for assessments that may be performed locally. After dose initiation and escalation occurs, 
the patient will have weekly assessments of serum creatinine. Assessments for serum transaminases, bilirubin, and alkaline phosphatase will be completed 2 weeks 
following dose initiation and escalation. 
Blood samples for deferasirox pharmacokinetic assessment will be collected at pre-dose (0 hour), and at 2, and 4 hours at Week 4 (Visit 7). Trough blood samples will be 
taken at Week 12 (Visit 12) and Week 24 (Visit 15). 
* 
For female patients capable of becoming pregnant serum pregnancy testing should be done within 72 hours prior to treatment start and urine testing at the end of 
treatment visit (see Section 7.2.2.5.4) 


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7.1.1 
Pre-screening assessments 
Not applicable. 
 
7.1.2 
Screening 
Prior to commencement of the screening examination, the patient must have given full 
informed consent and have completed the study Informed Consent form. Once this has been 
signed and dated by the patient, the Investigator should perform the assessments to ensure full 
eligibility for trial participation. The Screening Period will be 4 weeks and will consist of two 
visits, visit 1 and visit 2. Laboratory assessments (hematology, blood biochemistry, serum 
ferritin, and urinalysis) collected at visit 1 and visit 2, must be at least 14 days apart from each 
other. LIC will be conducted at visit 1 or 2. The full list of assessments to be performed  
during the screening period (week -4 to week -1) is detailed in Table 7-1 and Table 7-2. Two 
screening visits are needed to perform key safety parameters prior to the first dose 
administration. All data obtained from these assessments must be supported in the patient’s 
source documentation. Women of child-bearing potential must have a negative serum 
pregnancy test ≤ 72 hours prior to initiating treatment. Please see Table 7-1 and Table 7-2 for 
the Screening Period assessments. 
Should the 4-week screening period be exceeded due to delays in scheduling exams as 
outlined in the protocol (such as ocular exams, audiometry testing, MRI, etc) this delay will 
not be considered a protocol deviation and all laboratory assessments outlined in Visit 1 must 
be repeated. 
Re-screening is permissible on a case-by-case basis. Please contact Novartis for guidance and 
refer to Section 7.1.2.2 for information on data to be collected on screening failures. 
For patients being re-screened there is no need to re-assess LIC if the last assessment was 
performed within the last 3 months. 
 
7.1.2.1 
Eligibility screening 
Patient eligibility will be confirmed by the site monitor during the monitoring visit. 
 
7.1.2.2 
Information to be collected on screening failures 
Patients who sign an informed consent but fail to be started on treatment for any reason will 
be considered a screen failure. The reason for not being started on treatment will be entered  
on the Screening Log and each patient’s demographic information will be on the Demography 
CRF. 
Patients who screen failed because one of the following criteria did not allow their inclusion 
in the study can be screened once again for re-eligibility 3 months later: 
• If their LIC value was between 4.5 mg Fe/g dw and < 5 mg Fe/g dw 
• If their serum ferritin was below 300 ng/mL at screening 
• If their ALT was above 5 times ULN 


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7.1.2.3 
Patient demographics and other baseline characteristics 
At Visits 1 and/or 2, data will be collected on patient characteristics including demographic 
information (age, sex, ethnicity, etc.) and other background or relevant medical history/ 
current medical condition, transfusion history, disease history and diagnosis, prior chelation 
therapy, presence of spleen, serum pregnancy test. 
Other assessments conducted for the purpose of determining study eligibility include LIC by 
R2 MRI, serum ferritin, urine protein/creatinine ratio, creatinine clearance, serum creatinine, 
ALT, AST, hepatitis B, ECG, ocular exam, and audiometry. 
 
7.1.3 
Run-in period 
Not applicable. 
 
7.1.4 
Treatment period 
The Treatment Period will be five years. Visit frequency is every four weeks, while patient is 
receiving study drug. Following initiation of treatment and after dose escalation, patients will 
be monitored weekly for four weeks to assess serum creatinine. Serum transaminases, 
bilirubin, and alkaline phosphatase should be assessed 2 weeks following dose initiation or 
escalation. This is indicated as a shaded “X” in the Visit Schedule, Table 7-2. After these 
periods (if they are applicable), the patient will visit the study center according to the monthly 
visit schedule. 
A patient whose treatment is modified, interrupted or permanently discontinued due to an 
adverse event or abnormal laboratory value, must be followed at least once a week for 4 
weeks. In addition, patients who re-start treatment must perform weekly visits for 4 weeks 
including assessments of vital signs, physical examination, hematology parameters, blood 
chemistry and urinalysis. 
Patients will attend the study site at all visits to perform the scheduled assessments on the 
designated day, or as close as possible. 
PK samples will be collected from 20 patients during the visits indicated in Table 7-2. 
For details of assessments, refer to Table 7-1 and Table 7-2. 
7.1.5 
End of treatment visit, including premature withdrawal and study 
discontinuation visit 
Patients who discontinue study treatment before completing the study must be scheduled for a 
visit as soon as possible, at which time all of the assessments listed for the final visit will be 
performed. An End of Treatment eCRF page must be completed, giving the date and reason 
for stopping the study treatment. At a minimum, all patients who discontinue study treatment, 
including those who refuse to return for a final visit, will be contacted for safety evaluations 
during the 30 days following the last dose of study treatment. 
If a patient discontinues study treatment, but continues study assessments, the patient remains 
on study until such time as he/she completes protocol criteria for ending  study assessments. 
At that time, the reason for study completion must be recorded on the Study Completion 
eCRF. 


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For criteria for premature withdrawal refer to Section 7.1.5.1. 
End of treatment/Premature withdrawal visit is not considered as the end of the study. 
 
7.1.5.1 
Criteria for premature patient withdrawal 
Patients may voluntarily withdraw from the study or be dropped from it at the discretion of 
the investigator at any time. Patients must be withdrawn from the study if any of the following 
occur: 
• Pregnancy 
• Discovery of patient ineligibility 
• Study compliance problems. 
7.1.6 
Follow up period 
All patients who discontinue study treatment before completing the study must have safety 
evaluations for 30 days after the last dose of study treatment. 
Patients lost to follow up must be recorded as such on the CRF. For patients who are lost to 
follow-up, the investigator must show "due diligence" by documenting in the source 
documents steps taken to contact the patient, e.g., dates of telephone calls, registered letters, 
etc. 
 
7.2 
Assessment types 
7.2.1 
Efficacy assessments 
 
7.2.1.1 
Liver iron content (LIC) assessment by MRI 
Change in LIC from baseline after 52 weeks of treatment with study drug will be used as 
primary efficacy parameter. And, change in LIC from baseline after approximately six month 
intervals of treatment with study drug will be used as a secondary efficacy parameter. 
LIC will be measured at Screening Visits 1 or 2, Visit 15 (week 24), Visit 25 (week 52), and 
approximately every six months thereafter (weeks 76, 104, 128, 156, 180, 208, 232, and 260) 
using a validated R2 MRI technique. All patients enrolled in the study will have MRI scans 
using a specific sequence. Raw image data will be analyzed centrally to determine the 
patient’s LIC value. The result of the measurement will be provided to the sites by the central 
laboratory. 
 
7.2.1.2 
Serum ferritin assessment 
The assessment of the change in serum ferritin from baseline over five years of treatment with 
study drug will be used as a secondary efficacy parameter. 
Serum ferritin levels will be measured at Screening Visits 1 and 2, Visit 3 and every 4 weeks 
there after by a central laboratory. Results will be provided to the sites within 24 hours after 
receiving samples by the central laboratory. Baseline serum ferritin will be calculated from  
the mean of the two values measured at Visit 1 and Visit 2, but with a minimum time lag of 
14 days between these two assessments. 


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7.2.1.3 
Endocrine function laboratory parameters 
The assessment of endocrine function during the treatment period will be used as a secondary 
efficacy parameter. Blood samples collected at Visit 3 (baseline), Visit 12 (week 12), Visit 15 
(week 24), Visit 21 (week 36), Visit 25 (week 52), and approximately every three months 
thereafter (weeks 64, 76, 88, 104, 116, 128, 140, 156, 168, 180, 192, 208, 220, 232, 244 and 
260) for analysis of insulin, TSH, total and free T3, total and free T4, total and free 
testosterone (males), LH and FSH (females), and cortisol. Insulin resistance will be calculated 
using the Homeostatic Model Assessment (HOMA). 
 
7.2.2 
Safety and tolerability assessments 
Safety will be monitored by assessing physical examination, vital signs, laboratory 
evaluations, ECG as well as the collecting of the adverse events at every visit. For details on 
AE collection and reporting, refer to Section 8. 
 
7.2.2.1 
Physical examination 
A physical examination will be performed at Screening Visit 1, Baseline Visit 3, Visit 15 
(week 24), Visit 25 (week 52), and approximately every six months thereafter (weeks 76, 104, 
128, 156, 180, 208, 232, and 260). The physical examination at Visit 3 will serve as the 
Baseline physical examination for the entire study. The exam will entail an examination of 
general appearance, skin, neck (including thyroid), eyes, ears, nose, throat, lungs, heart, 
abdomen, back, lymph nodes, extremities and nervous system. 
Information about the physical examination must be present in the source documentation at 
the study site. 
Significant findings that are present prior to the start of study drug must be included in the 
Relevant Medical History/Current Medical Conditions page on the patient’s CRF. Significant 
findings made after the start of study drug which meet the definition of an Adverse Event 
must be recorded on the Adverse Event page of the patient’s CRF. 
 
7.2.2.2 
Vital signs 
Vital signs include blood pressure and pulse measurements and will be measured at Screening 
Visit 1 or Visit 2, and at all study visits thereafter. After the patient has been sitting for five 
minutes, with back supported and both feet placed on the floor, systolic and diastolic blood 
pressure will be measured three times using an automated validated device, e.g. OMRON, 
with an appropriately sized cuff. The repeat sitting measurements will be made at 1 - 2 minute 
intervals and the mean of the three measurements will be used. In case the cuff sizes available 
are not large enough for the patient’s arm circumference, a sphygmomanometer with an 
appropriately sized cuff may be used. 
 
7.2.2.3 
Height and weight 
All subjects will have standing height measured at Screening Visit 1 or Visit 2. Pediatric 
patients will also have their height measured at Visits 15, 25, 34, 44, 53, 63, 72, 82, 91, and 
End of Treatment. Adult patients will have height measured yearly (Visits 25, 44, 63, 82 and 


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End of Treatment). Height will be measured in centimeters. This height measurement must be 
captured in the eCRF. 
Body weight will be recorded for all patients at screening (Visit 1 or Visit 2), then at 4 week 
intervals and captured on the eCRF. Body weight will be measured to the nearest 0.1 kilogram. 
Weight must be measured while the patient is wearing ordinary clothing without shoes. 
 
7.2.2.4 
Auditory and ocular examination 
Patients will undergo auditory and ocular examinations at screening and weeks 52, 104, 156, 
208, 260 and at unscheduled visits (if needed). 
The auditory examination includes the following assessments: 
• Comprehensive audiometry threshold examination 
• Speech recognition 
The ophthalmologic examination includes the following assessments: 
• Visual acuity test 
• Tonometry 
• Slit lamp exam of anterior segment 
• Slit lamp exam of the lens 
• Fundoscopic and retinal examination 
Information about the audiometry and ocular examinations must be present in the source 
documentation at study site. Significant findings of the audiometry and ocular examinations 
that meet the definition of an AE must be recorded in the adverse event summary page of the 
case report form. 
 
7.2.2.5 
Laboratory evaluations 
A central laboratory will be used for analysis of all specimens collected. Details on the 
collections, shipment of samples and reporting of results by the central laboratory are 
provided to investigators in the [Laboratory Manual]. 
 
7.2.2.5.1 Hematology 
Hematology samples will be collected at Screening Visits 1 and 2, Visit 3 and then at 4 week 
intervals, thereafter, as described in the [Laboratory Manual]. Safety laboratory parameters 
monitored during the study will include hemoglobin, hematocrit, white blood cell (WBC) 
count with differential, platelet count, red blood cell (RBC) count, mean corpuscular volume 
(MCV), ANC and reticulocyte count. All hematology samples must be taken before blood 
transfusion and then be sent to the central laboratory. 
 
7.2.2.5.2 Clinical chemistry 
Clinical chemistry samples will be collected at Screening Visits 1 and 2, Visit 3 and then at 4 
week intervals, thereafter, as described in the [Laboratory Manual]. Parameters to be 
measured will include: albumin, alkaline phosphatase, total/fractionated bilirubin, calcium, 
chloride, creatinine, gamma-glutamyl transpeptidase (GGT), fasting glucose, inorganic 


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phosphorus, potassium, total protein, ALT/SGPT, AST/SGOT, sodium, C-reactive protein, 
uric acid, lactase dehydrogenase (LDH), urea (BUN). 
In accordance with the deferasirox label, serum creatinine, creatinine clearance, and 
ALT/SGPT must be assessed in duplicate before the initiation of therapy to establish a reliable 
pretreatment baseline. 
In addition, serum creatinine will be measured weekly for the first four weeks of study drug 
administration at Visits 4, 5, 6, and weekly after any dose escalations for a duration of four 
weeks. Serum transaminases, bilirubin, and alkaline phosphatase will be measured two weeks 
after initiation of treatment or any dose escalations. See Section 6.1.1 These assessments after 
initiation of treatment and dose escalations may be conducted at a local lab. 
Creatinine clearance will be estimated in adults using the Cockcroft-Gault equation and in 
pediatric patients using the Schwartz formula. This estimate will be provided at each monthly 
visit and at EOT. 
 
7.2.2.5.3 Urinalysis 
Urinalysis samples will be collected at Screening Visits 1 and 2, Visit 3 and every week  
during the first four weeks and then every four weeks thereafter. A midstream, second voided 
morning urine sample will be obtained. Specific gravity, pH, blood, glucose, protein, bilirubin, 
ketones, and leukocyte esterase will be assessed. Microscopic analysis will be performed only 
in case of positive dipstick. Dipsticks will be supplied by the central lab. 
At Screening Visits 1 and 2, a urine sample (at least 15 ml) will be collected and sent to the 
central laboratory for urinary protein/creatinine ratio to assess the eligibility of the patient. In 
addition, urine samples for urinary protein/creatinine ratios will be collected at Visit 3 and 
then at 4 week intervals, thereafter, as described in the [Laboratory Manual]. First morning 
void samples must not be used for this analysis. Significant proteinuria is indicated by a 
urinary protein/creatinine ratio > 0.1 mg/mg. 
For patients who develop proteinuria or a worsening of pre-existing proteinuria (assessed by a 
dipstick) at any visit, urine samples must be collected and urine protein assessed by the central 
laboratory. 
 
7.2.2.5.4 Pregnancy and assessments of fertility 
All female patients capable of becoming pregnant will have a pregnancy test (serum β-HCG) 
at Screening Visit 2. The results of the test must be available prior to initiating treatment with 
any study medication. Women of child-bearing potential must have a negative serum 
pregnancy test ≤ 72 hours prior to initiating treatment. Positive pregnancy tests will exclude a 
patient from participating in this trial. 
During the treatment period, urine pregnancy testing will be performed locally if menses are 
delayed for more than 7 days in a female patient capable of becoming pregnant. A urinary 
pregnancy test will also be performed at the end of treatment visit. 
Study drug must be discontinued in patients who become pregnant during the trial. See 
Section 8.4 for procedures to report pregnancy. 


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7.2.2.5.5 Hepatitis Viral tests 
Hepatitis Viral testing consists of the following items: Hepatitis B Surface Antibody (Anti- 
HBs), Hepatitis C Antibody (Anti-HCV), Hepatitis B surface Antigen (HBsAg), Qualitative 
w/confirmation, HCV PCR (Quantitative). Hepatitis Viral testing will be conducted at 
Screening Visit 1 to assess trial eligibility. 
 
7.2.2.6 
Cardiac assessments 
 
7.2.2.6.1 Electrocardiogram (ECG) 
A standard 12 lead ECG will be performed at Screening and annually throughout the study 
(weeks 52, 104, 156, 208, and 260). Interpretation of the tracing must be made by a qualified 
physician and documented on the ECG CRF page. Each ECG tracing must be labeled with the 
study number, patient initials (where regulations permit), patient number, date, and kept in the 
source documents at the study site. Clinically significant abnormalities present when the 
patient signed the Informed Consent form must be reported on the Medical History CRF page. 
Clinically significant findings must be discussed with the Novartis Medical Monitor prior to 
enrolling the patient in the study. New or worsened clinically significant findings occurring 
after informed consent must be recorded on the Adverse Events CRF page. 
 
7.2.3 
Pharmacokinetics 
Pharmacokinetic (PK) blood sampling will be performed in 20 study patients at specified time 
points (as shown in Table 7-2) at Visits 7, 12 and 15 (weeks 4, 12, and 24). These visits will 
be scheduled in the morning in order to allow the patient to withhold the dose until the pre- 
dose/trough PK sample is collected just prior to administration of the dose (approximately 24 
hours after the previous dose). The patient must be on treatment without dose adjustment or 
treatment interruption (for any reason) for at least 4 consecutive days prior to scheduled PK 
sampling visit. If there has been a dosage change or interruption within 4 days of the visit, no 
PK blood samples should be collected, and an appropriate comment has to be made on the PK 
CRF page. 
Thirty (30) minutes after the pre-dose/trough PK sampling is performed and the dose is 
administered, the patient may consume a standard breakfast. The patient may alternatively 
consume a light breakfast 2 hours prior to the pre-dose/trough PK sampling. 
PK blood samples will be taken by either direct venipuncture or an indwelling cannula 
inserted in a forearm vein or anticubital vein to determine plasma concentrations of 
deferasirox and its iron complex. Plasma concentrations of deferasirox and its iron complex 
will be presented in tabular format. AUCtau, Cmax, and tmax may be derived from plasma 
concentration-time profiles (week 4 only) using WinNonlin® (Pharsight, Mountain View, 
CA). 
Multi-center participation in the PK sub-group will be optional. A total of 20 patients will 
participate in the PK analysis. Pediatric patients will not participate in the PK subgroup. 


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7.2.3.1 
Pharmacokinetic blood collection and sample processing 
Three (3) mL blood samples will be collected at each sampling time into a Vacutainer™ tube 
containing lithium heparin. Immediately after each tube of blood is drawn, it must be inverted 
gently several times to ensure the mixing of tube contents with the anticoagulant (avoiding 
prolonged contact with the rubber stopper). Samples must be cooled immediately by placing 
the tube upright in a test tube rack sitting in an ice-water bath until placed in the centrifuge. 
Within 30 minutes of sample draw, the samples are centrifuged at about 5°C for 15 minutes at 
2000 g (to be adapted according to the radius of the centrifuge). Within 10 minutes after 
centrifugation, the upper plasma sample will be transferred into two separate 2 mL, tapered, 
polypropylene screw-cap tubes (Sarstedt #72.693 or equivalent without a skirted base) labeled 
as A and B. Each tube must have at least 0.5 mL of plasma and these will be stored frozen at - 
70°C +/- 15°C within 60 min of collection. 
Each sample will be given a unique sample number as indicated in Table 7-3. The exact clock 
time of dosing, as well as actual sample collection date and time must be captured on the PK 
CRF pages. Issues with obtaining samples will be noted in the comments field of the 
documents. 
 
Table 7-3 
Pharmacokinetic Log 
 
Visit 
Week 
Time 
PK collection No. 
PK sample No. 
Sample volume 
7 
4 
Pre-dose/0 h 
1 
1 
3 mL 
7 
4 
2 h post-dose 
1 
2 
3 mL 
7 
4 
4 h post-dose 
1 
3 
3 mL 
12 
12 
Pre-dose/0 h 
2 
4 
3 mL 
15 
24 
Pre-dose/0 h 
3 
5 
3 mL 
 
7.2.3.2 
PK sample handling and shipping 
All deferasirox samples must be labeled and frozen upon collection at -70°C +/- 15°C and  
kept frozen thereafter. All samples must be carefully packed in suitable packing material 
containing sufficient dry ice to keep them frozen during shipment. Include a list of all samples, 
including the study number, date, subject number and time of sampling. Clearly indicate if 
there are any missing samples. Samples will be sent to 
 China, for 
analysis. 
 
7.2.3.3 
PK analytical method 
Deferasirox and its iron complex in plasma will be measured by 
 China. 
Plasma concentrations of deferasirox and its iron complex will be determined by a validated 
liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay with a lower limit of 
quantitation of 0.670 µmol/L for deferasirox and 0.314 for its iron complex using 100 µL of 
plasma. 
 


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7.2.5 
Other assessments 
 
7.2.5.1 
Health-related Quality of Life 
Health-related Quality of Life will be assessed at Visits 3, 25, 44 and 63 (Day 1 and weeks 52, 
104 and 156). The objective of the health economic component of the study is to evaluate the 
change in patient reported outcomes (PROs) using the SF-36 in adult patients and the PedsQL 
in pediatric patients. 
 
SF-36 
The Medical Outcomes Study Short Form 36 (SF-36) is a self-administered questionnaire for 
adults (greater than 18 years of age) and contains 36 items which measure eight dimensions: 
Physical functioning (10 items), Role limitation due to physical health problems (4 items), 
Bodily pain (2 items), General health perceptions (5 items), Vitality (4 items), Social 
functioning (2 items), Role limitations due to emotional problems (3 items) and General 
mental health (5 items). There is an additional single item giving information on health  
change over the past year. Item scores for each dimension are coded, summed and  
transformed to a scale from 0 (worst possible health state measured by the questionnaire) to 
100 (best possible health state). The higher values indicate a better evaluation of health. Two 
summary scores of physical and mental health can also be calculated and scoring is norm- 
based, with normative values at 50 and no floor or ceilings. The SF-36 is well-documented in 
terms of reliability and validity in all available language versions (Ware and Sherbourne 
1992). The SF-36 has a 4 week recall period. The questionnaire will be scored as per the 
instructions of the developers of the SF-36. In addition, the SF-6D, a utility measure of health 
states, can be derived from the SF-36 and the scoring for the SF-6D utility values will also be 
assessed using the scoring methods from the developers. 


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PedsQL 4.0 
The PedsQL™ is a modular approach to measuring health-related quality of life (HRQOL) in 
children and adolescents. This will be administered to children between the ages of 13 to 18 
years. The approach includes both a child self-report and parent proxy-report. The 23-item 
PedsQL™ Generic Core Scales encompass the essential core domains for pediatric HRQOL 
measurement: 1) Physical Functioning (8 items), 2) Emotional Functioning (5 items), 3) 
Social Functioning (5 items), and 4) School Functioning (5 items). The Generic Core Scales 
are designed to enable comparisons across patient and healthy populations. 
Internal consistency reliability of the PedsQL™ was excellent, with alphas for the generic 
core scales in both self- and proxy-report greater than the 0.70 standard, and alphas for the full 
23-item scale approaching 0.90 for self- and proxy-report. Missing data were minimal. Item 
response distributions were across the full scale range, with no floor effects, and minimal 
ceiling effects. 
The validity of the PedsQL™ Generic Core Scales was demonstrated through known groups 
comparisons, and correlations with other measures of disease burden. The PedsQL™ self- and 
proxy-report distinguished between children with and without a chronic health condition, and 
within the group of children with a chronic condition, between those who did or did not have 
an overnight hospital visit in the last 12 months. Further, both child self-report and parent 
proxy-report correlated significantly with the number of days the child was too ill to pursue 
normal activities, needed someone to care for him or her, missed school in the last month, the 
number of days the parent missed from work in the last month, and parent-report of problems 
pursuing their normal work routine and concentrating at work. The PedsQL™ Generic Core 
Scales are also responsive to clinical change, as demonstrated in field trials. 
 
7.2.5.2 
Transfusion requirements 
Transfusions (i.e. number and volume (ml) of PBRC and platelets administered during the 
course of the study) will be recorded in the appropriate transfusion eCRF. 
 
8 
Safety monitoring and reporting 
8.1 
Adverse events 
8.1.1 
Definitions and reporting 
An adverse event is defined as the appearance of (or worsening of any pre-existing) 
undesirable sign(s), symptom(s), or medical condition(s) that occur after patient’s signed 
informed consent has been obtained. Abnormal laboratory values or test  results occurring 
after informed consent constitute adverse events only if they induce clinical signs or 
symptoms, are considered clinically significant, require therapy (e.g., hematologic 
abnormality that requires transfusion or hematological stem cell support), or require changes 
in study medication(s). 
Adverse events that begin or worsen after informed consent must be recorded in the Adverse 
Events CRF. Conditions that were already present at the time of informed consent must be 
recorded in the Medical History CRF. Adverse event monitoring must be continued for at 


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least 30 days following the last dose of study treatment. Adverse events (including lab 
abnormalities that constitute AEs) should be described using a diagnosis whenever possible, 
rather than individual underlying signs and symptoms. When a clear diagnosis cannot be 
identified, each sign or symptom must be reported as a separate Adverse Event. 
Severity of adverse events will be assessed as mild, moderate, or severe. Information about 
deaths will be collected though a Death form. 
The occurrence of adverse events must be sought by non-directive questioning of the patient 
(subject) during the screening process after signing informed consent and at each visit during 
the study. Adverse events also may be detected when they are volunteered by the patient 
(subject) during the screening process or between visits, or through physical examination, 
laboratory test, or other assessments. As far as possible, each adverse event must be evaluated 
to determine: 
1. The severity grade (mild, moderate, or severe) 
2. Its duration (Start and end dates) 
3. Its relationship to the study treatment (Reasonable possibility that AE is related: No, Yes) 
4. Action taken with respect to study or investigational treatment for the adverse event (none, 
study treatment dose adjusted, study treatment temporarily interrupted, study treatment 
permanently discontinued, unknown, not applicable) 
5. Whether concomitant medication or non-drug therapy was taken for the adverse event (No, 
Yes) 
6. Outcome of the adverse event (not recovered/not resolved, recovered/resolved, 
recovering/resolving, recovered/resolved with sequalae (an after effect of the adverse 
event), fatal, unknown) 
7. Whether it is serious (No, Yes) (a serious adverse event is defined as in Section 8.2.1) 
All adverse events must be treated appropriately. If a concomitant medication or non-drug 
therapy/intervention is given, this action must be recorded on the Adverse Event CRF. 
Once an adverse event is detected, it must be followed until its resolution or until it is judged 
to be permanent, and assessment must be made at each visit (or more frequently, if necessary) 
of any changes in severity, the suspected relationship to the study treatment, the interventions 
required to treat it, and the outcome. 
 
8.1.2 
Laboratory test abnormalities 
 
8.1.2.1 
Definitions and reporting 
Laboratory abnormalities that constitute an Adverse event in their own right (are considered 
clinically significant, induce clinical signs or symptoms, require concomitant therapy or 
require changes in study treatment), must be recorded on the Adverse Events CRF. Whenever 
possible, a diagnosis, rather than a symptom should be provided (e.g. anemia instead of low 
hemoglobin). Laboratory abnormalities that meet the criteria for Adverse Events must be 
followed until they have returned to normal or an adequate explanation of the abnormality is 
found. When an abnormal laboratory or test result corresponds to a sign/symptom of an 
already reported adverse event, it is not necessary to separately record the lab/test result as an 
additional event. 


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Laboratory abnormalities, that do not meet the definition of an adverse event, should not be 
reported as adverse events. A severe event does not automatically indicate a SAE unless it 
meets the definition of serious as defined below and/or as per investigator’s discretion. A dose 
hold of study medication for the lab abnormality may be required by the protocol and is still, 
by definition, an adverse event. 
 
8.1.3 
Adverse events of special interest 
See Section 6.4.1 through to Section 6.4.13. 
 
8.2 
Serious adverse events 
8.2.1 
Definitions 
Serious adverse event (SAE) is defined as one of the following: 
• Is fatal or life-threatening 
• Results in persistent or significant disability/incapacity 
• Constitutes a congenital anomaly/birth defect 
• Is medically significant, i.e., defined as an event that jeopardizes the patient or may 
require medical or surgical intervention to prevent one of the outcomes listed above 
• Requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 
• Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition (specify what this includes) 
• 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 a 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 
 
8.2.2 
Reporting 
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the 
patient has provided informed consent and until at least 30 days after the patient has stopped 
study treatment must be reported to Novartis within 24 hours of learning of its occurrence. 
Any SAEs experienced after this 30 days period should only be reported to Novartis if the 
investigator suspects a causal relationship to the study treatment. Recurrent episodes, 
complications, or progression of the initial SAE must be reported as follow-up to the original 
episode within 24 hours of the investigator receiving the follow-up information. An SAE 
occurring at a different time interval or otherwise considered completely unrelated to a 
previously reported one must be reported separately as a new event. 
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form. The investigator must assess and record the relationship of each SAE to each specific 
study treatment (if there is more than one study treatment), complete the SAE Report Form in 


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English, and send the completed, signed form by fax within 24 hours to the oncology Novartis 
Drug Safety and Epidemiology (DS&E) department. 
The telephone and telefax number of the contact persons in the local department of Drug 
Safety and Epidemiology (DS&E), specific to the site, are listed in the investigator folder 
provided to each site. The original copy of the SAE Report Form and the fax confirmation 
sheet must be kept with the case report form documentation at the study site. 
Follow-up information is sent to the same contact(s) to 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 must be reported as a follow-up to that event regardless of 
when it occurs. The follow-up information must 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. 
 
8.3 
Emergency unblinding of treatment assignment 
Not applicable, this is an open-label treatment study. 
 
8.4 
Pregnancies 
To ensure patient safety, each pregnancy in a patient on study treatment must be reported to 
Novartis within 24 hours of learning of its occurrence. The pregnancy should be followed up 
to determine outcome, including spontaneous or voluntary termination, details of the birth, 
and the presence or absence of any birth defects, congenital abnormalities, or maternal and/or 
newborn complications. 
Pregnancy must be recorded on a Clinical Study Pregnancy Form and reported by the 
investigator to the oncology Novartis Drug Safety and Epidemiology (DS&E) department. 
Pregnancy follow-up must be recorded on the same form and must 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. 
 
8.5 
Warnings and precautions 
No evidence available at the time of the approval of this study protocol indicated that special 
warnings or precautions were appropriate, other than those noted in the provided [Investigator 
Brochure]. Additional safety information collected between IB updates will be communicated 
in the form of Investigator Notifications. This information will be included in the patient 
informed consent and should be discussed with the patient during the study as needed. 
 
8.6 
Data Monitoring Committee 
Not applicable. 
 
8.7 
Steering Committee 
The steering committee (SC) will be established comprising investigators participating in the 
trial, i.e. not being Novartis representatives from the Clinical Trial Team. 


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The SC will ensure transparent management of the study according to the protocol through 
recommending and approving modifications as circumstances require. The SC will review 
protocol amendments as appropriate. Together with the clinical trial team, the SC will also 
develop recommendations for publications of study results including authorship rules. The 
details of the role of the Steering Committee will be defined in a Steering Committee charter. 
 
9 
Data collection and management 
9.1 
Data confidentiality 
Information about study subjects will be kept confidential and managed under the applicable 
laws and regulations. Those regulations require a signed subject authorization informing the 
subject of the following: 
• What protected health information (PHI) will be collected from subjects in this study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• The rights of a research subject to revoke their authorization for use of their PHI. 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization. For subjects that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect at least vital status (i.e. that the subject is alive) 
at the end of their scheduled study period. 
The data collection system for this study uses built-in security features to encrypt all data for 
transmission in both directions, preventing unauthorized access to confidential participant 
information. Access to the system will be controlled by a sequence of individually assigned 
user identification codes and passwords, made available only to authorized personnel who 
have completed prerequisite training. 
Prior to entering key sensitive personally identifiable information (Subject Initials and exact 
Date of Birth), the system will prompt site to verify that this data is allowed to be collected. If 
the site indicates that country rules or ethics committee standards do not permit collection of 
these items, the system will not solicit Subject Initials. Year of birth will be solicited (in the 
place of exact date of birth) to establish that the subject satisfies protocol age requirements 
and to enable appropriate age-related normal ranges to be used in assessing laboratory test 
results. 
 
9.2 
Site monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, Novartis 
personnel (or designated CRO) will review the protocol and CRFs with the investigators and 
their staff. During the study, the field monitor will visit the site regularly to check the 
completeness of patient records, the accuracy of entries on the CRFs, the adherence to the 
protocol to Good Clinical Practice, the progress of enrollment, and to ensure that study 
treatment is being stored, dispensed, and accounted for according to specifications. Key study 
personnel must be available to assist the field monitor during these visits. 


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The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information recorded on CRFs must be traceable to source documents in the 
patient's file. The investigator must also keep the original signed informed consent form (a 
signed copy is given to the patient). 
The investigator must give the monitor access to all relevant source documents to confirm 
their consistency with the CRF entries. Novartis monitoring standards require full verification 
for the presence of informed consent, adherence to the inclusion/exclusion criteria and 
documentation of SAEs. Additional checks of the consistency of the source data with the 
CRFs are performed according to the study-specific monitoring plan. 
 
9.3 
Data collection 
For studies using Electronic Data Capture (EDC), the designated investigator staff will enter 
the data required by the protocol into the Electronic Case Report Forms (eCRF). The eCRFs 
have been built using fully validated secure web-enabled software that conforms to 21 CFR 
Part 11 requirements, Investigator site staff will not be given access to the EDC system until 
they have been trained. Automatic validation programs check for data discrepancies in the 
eCRFs and, allow modification or verification of the entered data by the investigator staff. 
The Principal Investigator is responsible for assuring that the data entered into eCRF is 
complete, accurate, and that entry and updates are performed in a timely manner. 
9.4 
Database management and quality control 
For studies using eCRFs, Novartis personnel (or designated CRO) will review the data entered 
by investigational staff for completeness and accuracy. Electronic data queries stating the 
nature of the problem and requesting clarification will be created for discrepancies and 
missing values and sent to the investigational site via the EDC system. Designated 
investigator site staff are required to respond promptly to queries and to make any necessary 
changes to the data. 
Concomitant treatments entered into the database will be coded using the WHO Drug 
Reference List, which employs the Anatomical Therapeutic Chemical classification system. 
Medical history/current medical conditions and adverse events will be coded using the 
Medical dictionary for regulatory activities (MedDRA) terminology. 
Samples and/or data will be processed centrally and the results will be sent electronically to 
Novartis (or a designated CRO). 
At the conclusion of the study, the occurrence of any emergency code breaks will be 
determined after return of all code break reports and unused drug supplies to Novartis 
personnel (or designated CRO). The occurrence of any protocol violations will be determined. 
After these actions have been completed and the data has been verified to be complete and 
accurate, the database will be declared locked. Authorization is required prior to making any 
database changes to locked data, by joint written agreement between the Global Head of 
Biostatistics and Data Management and the Global Head of Clinical Development. 


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For EDC studies, after final database lock, the investigator will receive a CD-ROM or paper 
copies of the patient data for archiving at the investigational site. 
 
10 
Statistical methods and data analysis 
This is an open label, single arm, multi-center, efficacy and safety study of deferasirox in iron 
overloaded patients with non-transfusion dependent thalassemia. 
Data from all centers participating in this study will be aggregated to have an adequate  
number of patients for the analyses. 
Standard descriptive analyses will include: 
• Frequencies and percentages for categorical data; 
• n, mean, standard deviation, minimum, median, 25th and 75th percentiles and maximum for 
continuous data. 
In order to optimize consistency within project, statistical methods considered are similar to 
companion study CICL670E2209 (NTDT patients). 
Two analyses will be performed as follows: 
• A one-year-analysis which will include assessments and events within treatment Year- 1. 
• A final analysis when the study is completed and the last patient enrolled has completed 
last study visit or discontinued. 
Additional information for analysis methods will be available in RAP documentation. In 
addition to the overall population analysis, it is anticipated that statistical analysis will be 
performed according to subgroup Chinese/non-Chinese patients. 
 
10.1 
Analysis sets 
10.1.1 
Full Analysis Set 
The Full Analysis Set (FAS) consists of all patients who were assigned at least one dose of 
study drug. The FAS will be used for all efficacy analyses. 
 
10.1.2 
Safety Set 
The Safety Set consists of all patients who received at least one dose of study drug. 
 
10.1.3 
Pharmacokinetic analysis set 
The pharmacokinetic analysis set (PAS) consists of all patients from FAS set who have 
evaluable pharmacokinetic (PK) data. 
 
10.2 
Patient demographics/other baseline characteristics 
Demographic and other baseline data (including disease characteristics) will be summarized 
descriptively for the FAS. 


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10.3 
Treatments (study treatment, concomitant therapies, compliance) 
Duration of study drug exposure as well as average and cumulative planned (mg/kg/day) and 
prescribed treatment regimens (mg/kg/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. 
Compliance based on prescribed amount of study medication versus amount of medication 
taken based on dispensed and returned amount of study medication will be summarized. 
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will also be provided. 
Results will be summarized for the safety set. 
 
10.4 
Primary objective 
To assess the efficacy of deferasirox in patients with non-transfusion-dependent thalassemia 
based on absolute change in LIC from baseline after 52 weeks of treatment. As in previous 
studies within patients with transfusional iron overload, a normal distribution will be assumed 
for LIC absolute change. Handling of missing values is described in Section 10.4.3. 
 
10.4.1 
Variable 
The primary efficacy variable is the absolute change in LIC measured by MRI from baseline 
after 52 weeks of treatment. 
10.4.2 
Statistical hypothesis, model, and method of analysis 
Absolute change in LIC from baseline after 52 weeks of treatment will be analyzed using the 
FAS set. Null hypothesis (change from baseline at week 52 equal to 0) will be tested against 
alternative hypothesis using 2-sided one sample t-test with 5% type I error rate. 
LIC values for baseline, week 24, week 52 and absolute changes from baseline will be 
provided. 
10.4.3 
Handling of missing values/censoring/discontinuations 
In case of missing week 52 LIC the last available post-baseline LIC value before week 52 will 
be used instead in the calculation of the primary endpoint (Last-observation carried forward 
principle). Patients without any post-baseline LIC will have a missing value and will not be 
included in the analysis. 
 
10.4.4 
Supportive analyses 
To further assess the absolute change and relative change in LIC from baseline at week 52,  
the descriptive statistics will be provided for: 
• The proportion of patients with an LIC decrease by at least 3 mg Fe/g dw from baseline at 
week 52; 
• The proportion of patients with an LIC decrease by at least 30% from baseline at week 52 


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10.4.5 
One-year and Final analysis 
At Week 52, the time defined for the primary objective, the one-year analysis will be 
performed. The primary objective and additional objectives performed in the one-year 
analysis are listed in Table 10-1. 
The analyses supporting objectives not included in the one-year analysis and the objectives 
with assessments beyond treatment Year-1 will be performed at the completion of this study 
(details in Table 10-1). 
The primary objective and the PK data will only be analyzed in the one-year analysis. 
 
Table 10-1 One-year analysis and Final analysis 
Objective 
Endpoint 
Performed in the 
One-year 
Analysis? 
Performed in the 
Final Analysis? 
Primary 
Assess the efficacy of 
deferasirox in liver iron removal 
after 52 weeks of treatment 
Secondary 
Assess response rates in 
subset of patients with baseline 
LIC≥15 mg Fe/g dw 
 
Assess long-term efficacy of 
treatment to a target LIC of 3 
mg Fe/g dw 
Evaluate the impact of 
deferasirox on adult QoL 
 
Evaluate the impact of 
deferasirox on pediatric QoL 
 
Change in LIC from baseline after 
52 weeks of treatment 
 
 
Proportion of patients with 
baseline LIC>15 achieving LIC <5 
mg Fe/g dw and time to achieving 
LIC <5 mg Fe/g dw 
Time from target LIC 3 mg Fe/g 
dw to the first LIC ≥5 mg Fe/g dw 
in the follow up period 
Change in health-related 
outcomes using Medical 
Outcomes Study Form 36 (SF 36) 
Change in health-related 
outcomes using the Pediatric 
Quality of Life questionnaire 
 
Yes1 
No2 
 
 
No 
Yes 
 
 
 
No 
Yes 
 
 
No 
Yes 
 
 
No 
Yes 
Evaluate the efficacy of 
deferasirox in liver iron removal 
Assess the correlation of 
change in SF and LIC 
Change in LIC from baseline 
Yes1 
Yes 
 
SF vs LIC at baseline and EOS 
Yes1 
Yes 
Confirm the efficacy of 
deferasirox in liver iron removal 
in NTDT syndrome 
Assess the efficacy of 
deferasirox in decreasing SF 
after 52 weeks of treatment 
Evaluate the safety of 
deferasirox doses up to 30 
mg/kg/day dose 
Assess the efficacy of 
deferasirox in endocrine 
function 
Change in LIC from baseline after 
52 weeks of treatment by 
underlying NTDT syndrome 
Change in SF from baseline after 
52 weeks of treatment 
 
Safety parameters, labs, adverse 
events (AEs) 
 
Change from baseline during 
treatment period in total and free 
testosterone (males), LH and FSH 
(females), TSH, total and free T4, 
total and free T3, fasting plasma 
glucose, insulin, insulin 
resistance, and cortisol. 
Yes1 
No2 
 
Yes1 
No2 
 
Yes1 
Yes 
 
Yes1 
Yes 
 
 


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Objective 
Endpoint 
Performed in the 
One-year 
Analysis? 
Performed in the 
Final Analysis? 
Conduct PK analysis in a 
subgroup of patients 
 
Safety 
All safety objectives will be 
performed. 
PK parameters (AUC, Cmax, 
Tmax and trough levels) during 
the study period 
 
All safety events and 
assessments will be included 
Yes1 
No2 
 
 
Yes1 
Yes 
 
1 Endpoint analysis conducted in the One-year analysis will be presented in the One-year study report 
2 Endpoint analysis conducted in the One-year analysis will be used and presented in the final analysis 
 
 
10.5 
Secondary objectives 
10.5.1 
Response analysis in patients with baseline LIC greater than 15 mg 
Fe/g dw 
The proportion of patients with baseline LIC>15 mg Fe/g dw achieving an LIC <5 mg Fe/g 
dw during the study will be presented with a 95% confidence interval. The normal 
approximation will be used for the distribution, i.e. the confidence interval will be calculated 
as follows (Agresti and Coull 1998, formula (2)): 
100*(p + z0.9752/2n +/- z0.975*sqrt((p(1-p) + z0.9752/4n)/n) / (1 + z0.9752/n) 
Where p denotes the proportion, n the corresponding number of values, z0.975 the 97.5% 
quantile of the standard normal distribution, and sqrt the square root function (see also Brown, 
Cai, DasGupta, 2001). 
Time to the first LIC <5 mg Fe/g dw among patients with baseline LIC >15 mg Fe/g dw will 
be analyzed based on the Kaplan-Meier method. Kaplan-Meier curves for time to first LIC<5 
mg Fe/ g dw and the medians along with 95% confidence intervals will be presented. 
 
10.5.2 
Long-term efficacy of treatment to target LIC of 3 mg Fe/g dw followed 
by one or more treatment holidays until the LIC is greater or equal 5 
mg Fe/g dw 
Time from the target LIC <3 mg Fe/g dw to the first LIC ≥5 mg Fe/g dw in the follow-up 
period will be analyzed by using the Kaplan-Meier method. Kaplan-Meier curves for time to 
first LIC ≥5 mg Fe/g dw and the medians along with 95% confidence intervals will be 
presented. 
 
10.5.3 
Absolute change in LIC measured by MRI from baseline over time 
Absolute changes from baseline LIC at all scheduled LIC evaluation weeks will be analyzed 
in an analogous way as described in Section 10.4.2. Patients without any LIC post-baseline 
value at or prior to the scheduled LIC evaluation week will have missing values and will not 
be included in the analyses for the scheduled weeks. 


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Descriptive statistics and box plots will be provided for: 
• LIC at baseline, at all scheduled LIC evaluation weeks (24, 52, 76, 104, 128, 156, 180, 
208, 232, 260) and for last available LIC measurement; 
• Absolute change from baseline LIC at all scheduled LIC evaluation weeks (24, 52, 76, 104, 
128, 156, 180, 208, 232, 260) and for last available LIC measurement 
 
10.5.4 
Absolute change in LIC measured by MRI from baseline by NTDT 
syndrome 
Absolute change from baseline LIC at all scheduled LIC evaluation weeks (24, 52, 76, 104, 
128, 156, 180, 208, 232, and 260) by NTDT syndrome (beta-thalassemia intermedia, HbE 
beta-thalassemia or alpha-thalassemia intermedia (HbH disease)) will be analyzed in an 
analogous way as described in Section 10.4.2. 
Very small subgroups are expected and therefore no inferential statistics will be provided. 
 
10.5.5 
Absolute change in serum ferritin from baseline over time 
Descriptive statistics will be provided for serum ferritin (including absolute change from 
baseline) by visit up to week 260. 
In order to reduce variability of serum ferritin values, patient-wise average will be defined per 
quarter: 
• baseline serum ferritin as average of all available ferritin values from screening to last 
sample prior to first intake of study medication 
• end of quarter is defined as average of available ferritin values from visit corresponding to 
end of quarter, visit prior, and visit after 
(e.g. end of first quarter includes average ferritin values from Visits 11, 12, and 13). 
Similarly to analysis by visit, descriptive statistics will be provided for serum ferritin 
(including absolute change from baseline) by quarter up to week 260. 
Absolute change from baseline at week 52 will be tested using a 2-sided one sample t-test. P- 
values will be considered as exploratory with no multiplicity considerations. 
10.5.6 
Correlation between serum ferritin and LIC at baseline and EOS 
The following regression analyses will be performed without imputing any missing data: 
• baseline serum ferritin versus baseline LIC, serum ferritin at 2nd quarter versus LIC at 
week 24, serum ferritin at 4th quarter versus LIC at week 52 
• serum ferritin change from baseline at 2nd quarter versus change from baseline in LIC at 
week 24 
• serum ferritin change from baseline at 4th quarter versus change from baseline in LIC at 
week 52 
• serum ferritin change from baseline at week 260 versus change from baseline in LIC at 
week 260 


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10.5.7 
Medical Outcomes Study Short Form-36 (SF-36) 
See Section 7.2.5.1 for details on PROs. 
Descriptive statistics will be provided for all items and PCS/MCS summary scores (including 
absolute change from baseline) by visit (baseline, week 52, 104, and 156). 
Absolute change from baseline at week 52, 104, and 156 will be tested as exploratory using a 
2-sided one sample t-test. 
Additional information for PRO analysis methods will be available in RAP documentation. P- 
values will be considered as exploratory with no multiplicity considerations. 
10.5.8 
Pediatric Quality of Life Questionnaire 
See Section 7.2.5.1 for details on PROs. 
Descriptive statistics will be provided for all domains scores (including absolute change from 
baseline) by visit (baseline, week 52, 104, and 156). 
Absolute change from baseline at week 52, 104, and 156 will be tested as exploratory using a 
2-sided one sample t-test. 
Additional information for PRO analysis methods will be available in RAP documentation. P- 
values will be considered as exploratory with no multiplicity considerations. 
10.5.9 
Endocrine function 
Endocrine function parameters are: total and free testosterone (males), LH and FSH (females), 
TSH, total and free T4, total and free T3, fasting plasma glucose, insulin, insulin resistance, 
and cortisol). 
Descriptive statistics will be provided for all parameters (including absolute change from 
baseline) by visit up to week 260. 
 
10.5.10 Safety objectives 
 
10.5.10.1 Analysis set and grouping for the analyses 
For all safety analyses, the safety set will be used. 
 
10.5.10.2 Adverse events (AEs) 
Summary tables for adverse events (AEs) have to include only AEs that started or worsened 
during the on-treatment period, the treatment-emergent AEs. However, all safety data 
(including those from the pre and post-treatment periods) will be listed and those collected 
during the pre-treatment and post-treatment period are to be flagged. 
The incidence of treatment-emergent adverse events (new or worsening from baseline) will be 
summarized by system organ class and or preferred term, severity, type of adverse event, 
relation to study treatment. Deaths reportable as SAEs and non-fatal serious adverse events 
will be listed by patient and tabulated by type of adverse event. 


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Additionally, AEs with suspected relationship to study drug, requiring dose adjustment, 
leading to drug interruption/discontinuation will be specifically tabulated and listed. 
 
10.5.10.3 Laboratory abnormalities 
All laboratory values will be converted into SI units and the severity grade calculated using 
the low/normal/high classifications based on laboratory normal ranges, and for selected 
parameters (see Table 10-2 below) by notable/extended ranges. 
The following summaries will be generated separately for hematology, biochemistry and 
urinary laboratory tests: 
• shift tables using normal/notable/extended ranges to compare baseline to the worst on- 
treatment value 
• listing of all laboratory data with values flagged to show the corresponding 
normal/notable/extended ranges (see Table 10-2 below). 
For each hematology/iron metabolism parameter, observed values (and changes from baseline) 
averaged at baseline, after first intake of study medication to day 30, day 31 to day 90, and per 
subsequent quarter will be summarized by descriptive (n, mean, standard deviation, minimum, 
lower quartile, median, upper quartile and maximum). 
In addition to the above mentioned tables and listings, other exploratory analyses, for example 
figures plotting time course of raw or change in laboratory tests over time or box plots might 
be specified in the RAP. 
 
Table 10-2 
Definition of notable/extended ranges for laboratory tests 
 
Laboratory test 
Criteria for notable ranges 
Platelet count 
< 100 x 109/L (extended range <50×109/L) 
Absolute neutrophils 
< 1.5 x 109/L (extended range <0.5×109/L) 
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 at two consecutive 
measurements at least 7 days apart) 
Urinary protein/urinary creatinine 
ratio 
>= 1.0 (mg/mg) at two consecutive measurements at least 7 days apart 
SGOT/ALT and SGPT/AST 
>5 x ULN and 2 x baseline (extended range >10×ULN and 
>2×baseline value) 
Creatinine clearance will be estimated using the Cockcroft-Gault equation and the Schwartz 
formula (for pediatric population) and will be displayed using relative change from baseline 
by categories. 
 
10.5.10.4 Other safety data 
Data from electrocardiogram, vital signs, ocular and auditory examination will be listed and 
summarized (e.g., by investigator’s overall interpretation) as appropriate. 
Any significant findings after start of study will be documented as adverse events and 
reported as such. 


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10.5.10.5 Tolerability 
Incidence of grouped gastro-intestinal adverse events (defined by MedDRA terms to be 
specified in the more detailed RAP document) will be presented as well as Kaplan-Meier 
curves for time to first occurrence of such AEs. 
 
10.5.11 Pharmacokinetics 
PAS will be used in all pharmacokinetic data analysis and PK summary statistics. The 
pharmacokinetic parameters, AUCtau, Cmax and Tmax (week 4 data only) may be 
determined using non-compartmental method(s) for deferasirox and its iron complex. 
Biofluid concentrations will be expressed in mass per volume units. All concentrations below 
the limit of quantitation or missing data will be reported as such in the concentration data 
listings. Concentrations below the limit of quantitation will be treated as zero in summary 
statistics. 
Descriptive statistics of all pharmacokinetic data and parameters will include arithmetic and 
geometric mean, median, SD, and CV, geometric CV, minimum and maximum. Zero 
concentrations will not be included in the geometric mean calculation. Since tmax is generally 
evaluated by a nonparametric method, median values and ranges will be given for this 
parameter. 
 
10.5.11.1 Data handling principles 
Missing concentration values will be reported as is in data listings. Concentration values 
below Lower Limit of Quantitation (LLOQ, BLLOQ) will be handled as zero, excluded in 
summary statistics, and reported as is in data listings. 
 
 
10.5.13 Resource utilization 
Not applicable. 
 
10.5.14 Patient-reported outcomes 
Not applicable. 
 


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10.7 
Interim analysis 
No formal interim analysis based on primary endpoint will be performed. 
Some basic safety annual analyses will be performed for PSUR (Periodic Safety Update 
Report). 
 
10.8 
Sample size calculation 
Sample size is based on results from [ICL670A2209] (THALASSA) study, which was a 
prospective, double-blind, placebo controlled trial of deferasirox in starting doses of 5 and 10 
mg/kg/day in patients with NTDT. 
166 patients with randomized to starting doses of 5 mg (n=55) or matching placebo (n=28) 
and 10 mg (n=55) or matching placebo (n=28). 
See in table below results for absolute change in LIC for this study: 
 
Table 10-3 
Absolute change in LIC (mg Fe/ g dw), Full Analysis Set 
 
Time point Value| 
ICL670 
5.mg/kg 
(N=55) 
ICL670 
10.mg/kg 
(N=55) 
Placebo 
(N=56) 
Baseline Value 
N 
55 
55 
55 
Mean 
13.11 
14.56 
15.94 
SD 
7.290 
7.921 
10.845 
Week.52.Value 
N 
51 
54 
54 
Mean 
11.56 
10.58 
16.38 
SD 
7.928 
7.667 
10.606 
Absolute.change.from.baseline 
N 
51 
54 
54 
Mean 
-1.85 
-3.78 
0.26 
SD 
3.078 
4.150 
3.501 
Note: Absolute change from baseline: value at timepoint – baseline value. Summary only includes patients with a 
value both at baseline and at considered timepoint. Source: [Table 14.2-1.9 from the ICL670A2209 trial] (29-Sep- 
2011 CSR). 
The population of patients planned to be enrolled in this study will cover a broader type of 
patients (e.g. including patients treated with hydroxyurea, erythropoietin and butyrate) and 


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from multiple countries. This is likely to lead to more heterogeneity and thus to an increased 
variability compared to the one observed in the [ICL670A2209] study. 
Assuming a true SD as high as 6 mg Fe and a drop-out rate of 20%, a sample size of 117 
patients is required to obtain 90% power to detect a LIC absolute change of at least 2 mg Fe at 
Week 52 from the baseline value and using a paired t-test at 0.05 two-sided significance level. 
Table below provides number of patients required according to different scenarios that ensure 
80% power in case of lower true SD than expected (the others hypotheses remaining same): 
 
 
SD (mg Fe/g dw) 
4.5 
5 
5.5 
Power (%) 
80 
80 
80 
n patients 
51 
63 
75 
Sample size has been computed using PASS 2008. 
 
10.9 
Power for analysis of key secondary variables 
Not applicable. 
 
11 
Ethical considerations and administrative procedures 
11.1 
Regulatory and ethical compliance 
This clinical study was designed, shall be implemented and reported in accordance with the 
ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC and US Code of Federal Regulations 
Title 21), and with the ethical principles laid down in the Declaration of Helsinki. 
 
11.2 
Responsibilities of the investigator and IRB/IEC/REB 
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly constituted Institutional Review Board/Independent Ethics Committee/Research 
Ethics Board (IRB/IEC/REB) before study start. 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. 
 
11.3 
Informed consent procedures 
Eligible patients must 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 must be informed 
about the study to the extent possible given his/her understanding. If the patient is capable of 


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doing so, he/she must 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 must be documented in the patient source 
documents. The date when a subject’s Informed Consent was actually obtained will be 
captured in their CRFs. 
Novartis will provide investigators in a separate document with a proposed informed consent 
form (ICF) that is considered appropriate for this study and complies with the ICH GCP 
guideline and regulatory requirements. Any changes to this ICF suggested by the investigator 
must be agreed to by Novartis before submission to the IRB/IEC/REB, and a copy of the 
approved version must be provided to the Novartis monitor after IRB/IEC/REB approval. 
Women of child bearing potential must be informed that taking the study medication may 
involve unknown risks to the fetus if pregnancy were to occur during the study and agree that 
in order to participate in the study they must adhere to the contraception requirement for the 
duration of the study. If there is any question that the patient will not reliably comply, they 
should not be entered in the study. 
 
 
11.4 
Discontinuation of the study 
Novartis reserves the right to discontinue this study under the conditions specified in the 
clinical study agreement. Specific conditions for terminating the study are  outlined  in  
Section 4.4. 
 
11.5 
Publication of study protocol and results 
Novartis assures that the key design elements of this protocol will be posted in a publicly 
accessible database such as clinicaltrials.gov. 
Two study reports will be prepared, reporting on the one-year and the final analysis, 
respectively. 
In addition, upon study completion and finalization of the study report the results of this study 
will be either submitted for publication and/or posted in a publicly accessible database of 
clinical study results. 


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11.6 
Study documentation, record keeping and retention of 
documents 
Each participating site will maintain appropriate medical and research records for this trial, in 
compliance with Section 4.9 of the ICH E6 GCP, and regulatory and institutional 
requirements for the protection of confidentiality of subjects. As part of participating in a 
Novartis-sponsored study, each site will permit authorized representatives of the sponsor(s) 
and regulatory agencies to examine (and when required by applicable law, to copy) clinical 
records for the purposes of quality assurance reviews, audits and evaluation of the study 
safety and progress. 
Source data are all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. 
Examples of these original documents and data records include, but are not limited to, hospital 
records, clinical and office charts, laboratory notes, memoranda, subjects’ diaries  or 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies or transcriptions certified after verification as being accurate and complete, 
microfiches, photographic negatives, microfilm or magnetic media, x-rays, and subject files 
and records kept at the pharmacy, at the laboratories, and medico-technical departments 
involved in the clinical trial. 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site Principal Investigator. The study case report form (CRF) is the primary data collection 
instrument for the study. The investigator must ensure the accuracy, completeness, legibility, 
and timeliness of the data reported in the CRFs and all other required reports. Data reported 
on the CRF, that are derived from source documents, must be consistent with the source 
documents or the discrepancies must be explained. All data requested on the CRF must be 
recorded. Any missing data must be explained. Any change or correction to a paper CRF must 
be dated, initialed, and explained (if necessary) and must not obscure the original entry. For 
electronic CRFs an audit trail will be maintained by the system. The investigator must retain 
records of the changes and corrections to paper CRFs. 
The investigator/institution must maintain the trial documents as specified in Essential 
Documents for the Conduct of a Clinical Trial (ICH E6 Section 8) and as required by 
applicable regulations and/or guidelines. The investigator/institution must take measures to 
prevent accidental or premature destruction of these documents. 
Essential documents (written and electronic) must be retained for a period of not less than 
fifteen (15) years from the completion of the Clinical Trial unless Sponsor provides written 
permission to dispose of them or, requires their retention for an additional period of time 
because of applicable laws, regulations and/or guidelines 
 
11.7 
Confidentiality of study documents and patient records 
The investigator must ensure anonymity of the patients; patients must not be identified by 
names in any documents submitted to Novartis. Signed informed consent forms and patient 
enrollment log must be kept strictly confidential to enable patient identification at the site. 


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11.8 
Audits and inspections 
Source data/documents must be available to inspections by Novartis or designee or Health 
Authorities. 
 
11.9 
Financial disclosures 
Financial disclosures must be provided by study personnel who is directly involved in the 
treatment or evaluation of patients at the site - prior to study start. 
 
12 
Protocol adherence 
Investigators ascertain they will apply due diligence to avoid protocol deviations. Under no 
circumstances should the investigator contact Novartis or its agents, if any, monitoring the 
study to request approval of a protocol deviation, as no authorized deviations are permitted. If 
the investigator feels a protocol deviation would improve the conduct of the study this must  
be considered a protocol amendment, and unless such an amendment is agreed upon by 
Novartis and approved by the IRB/IEC/REB it cannot be implemented. All significant 
protocol deviations will be recorded and reported in the CSR. 
 
12.1 
Amendments to the protocol 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, Health Authorities where required, and the IRB/IEC/REB. 
Only amendments that are required for patient safety may be implemented prior to 
IRB/IEC/REB approval. Notwithstanding the need for approval of formal protocol 
amendments, the investigator is expected to take any immediate action required for the safety 
of any patient included in this study, even if this action represents a deviation from the 
protocol. In such cases, Novartis must be notified of this action and the IRB/IEC/REB at the 
study site must be informed within 10 working days. 


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13 
References (available upon request) 
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binomial proportions. The American Statistician. May 1998 Vol.52, No. 2, 119-126. 
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patients with myelodysplastic syndromes: safety, efficacy, and beyond (GIMEMA MDS0306 
Trial) Eur. J. of Haematology. 92 (527–536) 
 
Brown LD, Cai TT, DasGupta A (2001). Interval estimation for a binomial population. 
Statistical Science. 2001, Vol. 16, No. 2, 101-133. 
Cappellini MD1, Porter J, El-Beshlawy A, et al. (2010) Tailoring iron chelation by iron intake 
and serum ferritin: the prospective EPIC study of deferasirox in 1744 patients with 
transfusion-dependent anemias. Haematologica. 95(4):557-66 
Cappellini MD, Bejaoui M, Agaoglu L, et al (2011) Iron chelation with deferasirox in adult 
and pediatric patients with thalassemia major: efficacy and safety during 5 years’ follow-up. 
Blood. 118(18): 884-93. 
Chan JC, Chim CS, Ooi CG, et al. (2006). Use of the oral chelator deferiprone in the 
treatment of iron overload in patients with Hb H disease. Br J Haematol. 133(2):198-205. 
Clark PR and St Pierre TG (2000). Quantitative mapping of transverse relativity (1/T(2)) in 
hepatic iron overload: a single spin-echo imaging methodology. Magn Reson Imaging. 
18(4):431-8. 
Deugnier Y, Turlin B, Ropert M, et al (2011) Improvement in liver pathology of patients with 
beta-thalassemia treated with deferasirox for at least 3 years. Gastroenterology. 141(4): 1201- 
11. Erratum im: Gastroenterology 142(1): 186. 
 
 
 
Galanello R and Origa R (2010). Beta-thalassemia. Orphanet J Rare Dis; 5:11 
Gattermann N, Finelli C, Della Porta M, et al. (2012) Hematologic responses to deferasirox 
therapy in transfusion-dependent patients with myelodysplastic syndromes. Haematologica. 
97(9):1364-1371. 
Ladis V, Berdoussi H, Kattamis A. Treatment with deferasirox for non-transfusional iron 
overload in patients with thalassemia intermedia. Abstract, EHA Berlin 2009. 
Lee JW, Yoon SS, Shen ZX, et al (2013) Hematologic responses in patients with aplastic 
anemia treated with deferasirox: a post hoc analysis from the EPIC study. Haematologica. 
98(7): 1045-8. 


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List AF, Baer MR, Steensma DP, et al (2012) Deferasirox reduces serum ferritin and labile 
plasma iron in RBC transfusion-dependent patients with myelodysplastic syndrome. J Clin 
Oncol. 30(17): 2134-9 
Musallam KM, Khoury B, Abi-Habib R, Bazzi L, Succar J, et al. (2011) Health-related 
quality of life in adults with transfusion-independent thalassaemia intermedia compared to 
regularly transfused thalassaemia major: new insights. Eur J Haematol. 87(1): 73-79. 
Musallam KM et al. (2011) Elevated liver iron concentration is a marker of increased 
morbidity in patients with β thalassemia intermedia. Haematologica. 96:1605–1612 
Mussallam KM (2011) Iron-Chelating Therapy for Transfusional Iron Overload. N Engl. J 
Med. 364;15 
Musallam KM, Cappellini MD, Taher AT. (2013) Evaluation of the 5 mg/g liver iron 
concentration threshold and its association with morbidity in patients with β-thalassemia 
intermedia. Blood Cells, Molecules and Diseases. 51: 35–38 
Nick H, Acklin P, Lattmann R, et al. (2003). Development of tridentate iron chelators: from 
desferrithiocin to ICL670. Curr Med Chem. 10(12):1065-76. 
Olivieri NF, Koren G, Matsui D, et al. (1992). Reduction of tissue iron stores and 
normalization of serum ferritin during treatment with the oral iron chelator L1 in thalassemia 
intermedia. Blood 79(10):2741-8. 
Origa R, Galanello R, Ganz T, et al. (2007). Liver iron concentrations and urinary hepcidin in 
beta-thalassemia. Haematologica; 92(5):583-8. 
Pakbaz Z, Fischer R, Fung E, et al. (2007). Serum ferritin underestimates liver iron 
concentration in transfusion independent thalassemia patients as compared to regularly 
transfused thalassemia and sickle cell patients. Pediatr Blood Cancer; 49(3):329-32. 
Pennell DJ, Porter JB, Cappellini MD, et al (2012) Deferasirox for up to 3 years lead to 
continued improvement of myocardial T2* in patients with beta-thalassemia major. 
Haematologica. 97 (6): 842 – 8. 
Pennell DJ, Porter JB, Piga A, et al. (2014) 1-year randomized controlled trial of deferasirox 
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123(10):1447-1454. 
Pippard MJ, Callender ST, Warner GT, et al. (1979). Iron absorption and loading in beta- 
thalassaemia intermedia. Lancet. 2(8147):819-21. 
Pootrakul P, Huebers HA, Finch CA, et al. (1988). Iron metabolism in thalassemia. Birth 
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Pootrakul P, Sirankapracha P, Sankote J, et al. (2003). Clinical trial of deferiprone iron 
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122(2):305-10. 
Rombos Y, Tzanetea R, Konstantopoulos K, et al. (2000). Chelation therapy in patients with 
thalassemia using the orally active iron chelator deferiprone (L1). Haematologica. 85(2):115-7. 


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St Pierre TG, Clark PR, Chua-Anusorn W, et al (2005). Noninvasive measurement and 
imaging of liver iron concentrations using proton magnetic resonance. Blood. 105:855-61. 
Taher AT, El Rassi F, Isma’eel H et al. (2008) Correlation of liver iron concentration 
determined by R2 magnetic resonance imaging with serum ferritin in patients with 
thalassemia intermedia. Haematologica. 93:1584-1586. 
Taher AT, Musallam KM, Karimi M, El-Beshlawy A, Belhoul K, et al. (2010). Overview on 
practices in thalassemia intermedia management aiming for lowering complication rates 
across a region of endemicity: the OPTIMAL CARE study. Blood. 115(10): 1886-1892. 
Taher AT et al. (2010) Magnetic resonance evaluation of hepatic and myocardial iron 
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transfused thalassemia major patients. Am J Hematol. 85:288–290. 
Taher AT, Porter JB, Viprakasit V, et al (2012) Deferasirox reduces iron overload 
significantly in nontransfusion-dependent thalassemia: 1-year results from a prospective, 
randomized, double-blind, placebo-controlled study. Blood. 120(5):970-7. 
Taher AT, Porter JB, Viprakasit V, et al (2013) Deferasirox effectively reduces iron overload 
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THALASSA study. Ann Hematol. 92(11):1485-93. 
Taher AT, Porter JB, Viprakasit V, et al. (2013). Deferasirox demonstrates a dose-dependent 
reduction in liver iron concentration and consistent efficacy across subgroups of non- 
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Taher AT, Vichinsky E, Mussalam K, et al. (2013) Guidelines for the management of non 
transfusion dependent thalassemia (NTDT). Thalassemia International Federation; publication 
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Taher AT1, Porter JB, Viprakasit V, et al. (2014) Approaching low liver iron burden in 
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approaches to screening, diagnosis, and therapy. Ann NY Acad Sci. 1202: 180-7. 
Voskaridou E, Konstantinidiou M, Doskou M, et al. (2009). Treatment with Deferasirox 
effectively decreases iron burden in patients with thalassemia intermedia. Abstract, EHA 
Berlin 2009. 
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Conceptual framework and item selection. Medical Care. 30(6):473-83.Blood. 115(10): 1886- 
1892. 

SAP_000.pdf: 
Clinical Development
ICL670/ Deferasirox /Exjade®
Study number: CICL670E2419 / NCT01709838
An open label, multi-center, efficacy and safety study of 
deferasirox in iron overloaded patients with non-
transfusion dependent thalassemia (THETIS)
Statistical Analysis Plan (SAP) – Final Analysis
Author:
 
Document type:
SAP Documentation Amendment 1
Document status:
Final
Release date:
23-Jan-2019
Number of pages:
29
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
SAP - Final CSR Amendment 1
CICL670E2419
Document History – Changes compared to previous final version of SAP
Date
Time 
point
Reason for 
update
Outcome for update
Section and title 
impacted 
(Current)
17-
Oct-
2018
Prior 
to 
DB 
lock
Creation of 
final 
version
N/A - First version
NA
dd-
Mmm-
2019
Creation of 
amendment 
1
Added 
clarification 
for
primary 
endpoint
Section 2.5.1
Added sodium, C-reactive protein, uric 
acid, lactase dehydrogenase (LDH), 
urea (BUN)
laboratory parameters 
which were missed in the previous 
version
Section 2.7.3 


Novartis
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SAP - Final CSR Amendment 1
CICL670E2419
Table of contents
Table of contents .................................................................................................................3
List of abbreviations............................................................................................................4
1
Introduction .........................................................................................................................6
1.1
Study design.............................................................................................................6
1.2
Study objectives and endpoints ...............................................................................7
2
Statistical methods...............................................................................................................8
2.1
Data analysis general information ...........................................................................8
2.1.1
General definitions..................................................................................9
2.2
Analysis sets ..........................................................................................................13
2.2.1
Subgroup of interest ..............................................................................13
2.3
Patient disposition, demographics and other baseline characteristics ...................13
2.4
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................14
2.4.1
Study treatment / compliance................................................................14
2.4.2
Prior, concomitant and post therapies...................................................15
2.5
Analysis of the primary objective..........................................................................15
2.5.1
Primary endpoint...................................................................................15
2.6
Analysis of secondary efficacy objective(s)..........................................................16
2.6.1
Secondary endpoints .............................................................................16
2.7
Safety analyses.......................................................................................................20
2.7.1
Adverse events (AEs)............................................................................20
2.7.2
Deaths....................................................................................................20
2.7.3
Laboratory data .....................................................................................21
2.7.4
Other safety data ...................................................................................22
2.8
Pharmacokinetic endpoints....................................................................................24
25
2.10
Interim analysis......................................................................................................25
3
Sample size calculation .....................................................................................................25
4
Change to protocol specified analyses ..............................................................................26
5
Appendix ...........................................................................................................................26
5.1
Imputation rules.....................................................................................................26
5.2
Laboratory parameters derivations ........................................................................28
6
Reference...........................................................................................................................29


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Page 4
SAP - Final CSR Amendment 1
CICL670E2419
List of abbreviations
AE
Adverse event
ALT/SGPT
Alanine aminotransferase/serum glutamic pyruvic transaminase
AST/SGOT
Aspartate aminotransferase/serum glutamic oxaloacetic transaminase
AUC
Area Under the Curve
BUN
Blood Urea Nitrogen
Cmax
Maximum (peak) observed plasma concentration after single dose administration
CSR
Clinical Study report
CTCAE
Common Terminology Criteria for Adverse Events
DMC
Data Monitoring Committee 
dw
Dry weight
ECG
Electrocardiogram
eCRF
Electronic Case Report/Record Form
EOS
End of study
FAS
Full Analysis Set
FE
Iron
FSH
Follicle stimulating hormone
GGT
Gamma glutamyl transferase
HbE
Hemoglobin E
HbH
Hemoglobin H
LDH
lactase dehydrogenase
LH
Luteinizing hormone
LIC
Liver iron content
LPLV
Last patient last visit
MedDRA
Medical Dictionary for Drug Regulatory Affairs
MRI
Magnetic resonance imaging
NTDT
Non-transfusion-dependent thalassemia
o.d.
Once Daily
OS
Overall Survival
PedsQLTM
Pediatric Quality of Life InventoryTM
PFS
Progression-Free Survival
PK
Pharmacokinetics
PPS
Per-Protocol Set
PRO
Patient-reported Outcomes
qd
Qua’que di’e / once a day
QoL
Quality of Life
RAP
Report and Analysis Process
RECIST
Response Evaluation Criteria in Solid Tumors 
SAE
Serious adverse event


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SAP
Statistical Analysis Plan
SD
Standard deviation
SF
Serum ferritin
SF-36
Medical Outcomes study short form-36
SF-6D
Short-Form Six-Dimension
SOC
System Organ Class
THALASSA
Novartis Study CICL670E2209
TFLs
Tables, Figures, Listings
Tmax
Time to reach maximum (peak) plasma concentration after single dose 
administration
TSH
Thyroid stimulating hormone
WHO
World Health Organization


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1
Introduction
CICL670E2419 is a phase IV open label, multi-center, efficacy and safety study of deferasirox 
in iron overloaded patients with non-transfusion dependent thalassemia. This open-label, 
single-arm, multi-center 5-year study was designed to evaluate the efficacy and safety of 
deferasirox in iron overloaded NTDT patients, at least ten-years-old. A 1-year analysis was 
performed to assess the primary objective and selected secondary objectives. This study 
enrolled 134 patients including 68 Chinese and 66 non-Chinese, with 112 patients still on 
treatment at the time of the 1-year primary analysis.
The primary objective of this one-year analysis was met, confirming activity of deferasirox in 
the NTDT population, as observed in Study ICL670A2209. The absolute change in LIC from 
Baseline to Week 52 was statistically significantly different (Paired T-test, p<0.0001, two-
sided). The absolute mean change in LIC (mg Fe/g dw) from Baseline to Week 52 was -6.68 
(SD 7.018) with a 95% CI (-7.91, -5.45).
Pharmacokinetic analysis was performed on the data from 22 patients at Week 4. Mean (SD)
AUCtau at 10 mg/kg/day was 773 (350) hr×μmol/L and was similar for the Chinese and non-
Chinese groups (770 (405) and 776 (250) hr×μmol/L, respectively). Mean (SD) Cmax was 61
(27) μmol/L and was comparable between these two groups (Chinese 62 (33) μmol/L and non-
Chinese 57 (14) μmol/L).
This analysis plan is written to analyze all data up to last patient last visit (LPLV) and to support 
final CSR. 
1.1
Study design
This open label, single-arm, multi-center study to evaluate the efficacy and safety of deferasirox 
in NTDT patients with iron overload will include the following phases:
Screening (4 weeks) to determine patient eligibility 
Open label treatment with deferasirox:

Starting dose 10 mg/kg/day for 4 weeks;

At Week 4, dose adjustments according to baseline LIC:
o
20 mg/kg/day for patients with baseline LIC > 15 mg Fe/g dw
o
15 mg/kg/day for patients with baseline LIC > 7 but ≤ 15 mg Fe/g dw
o
Dose will remain at 10 mg/kg/day for patients with baseline LIC ≥ 5 but ≤ 7 
mg Fe/g dw

Approximately every 6 months, starting at Week 24, dose adjustments according to 
LIC:
o
Increase dose by 5-10 mg/kg/day, if LIC > 15 mg Fe/g dw, maximum of 30 
mg/kg/day
o
May increase dose by 5 mg/kg/day if LIC >7 but ≤ 15 mg Fe/g dw, maximum 
of 20 mg/kg/day
o
Same dose if LIC is ≥3 but ≤ 7 mg Fe/g dw, maximum of 10 mg/kg/day


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The maximum dose of deferasirox throughout the study will be 30 mg/kg/day.
If LIC measurement is <3 mg Fe/g dw or SF is <300 ng/mL, treatment will be interrupted.
Patients who have interrupted study treatment during the first year of the study due to LIC <3
mg Fe/g dw or SF <300 ng/mL will continue the monthly visit schedule. Patients who have
treatment interruption due to LIC <3 mg Fe/g dw or SF<300 ng/mL after 52 weeks, will
complete scheduled visit one month post-interruption and then be followed every three months.
Study treatment will restart at the previous effective dose when LIC ≥5 mg Fe/g dw and SF ≥
300 ng/mL (maximum of 10 mg/kg/day). Once on treatment, patients will be followed monthly.
Approximately 117 patients were planned to be enrolled. Treatment duration will be 5 years. 
Pharmacokinetic analysis was conducted in a subset of 20 patients from selected participating 
centers.
During the screening phase, patient eligibility was determined, followed by an open-label phase 
with deferasirox up to five years. Completion of this study occurs after the Last Patient Last 
Visit of the study, and upon the availability and accuracy verification of the last data point 
required for final statistical analysis.
No randomization was done in this study. No formal interim analysis based on primary endpoint 
was planned for this study.
1.2
Study objectives and endpoints
The study objectives and endpoints are presented in the following table.
Table 1-1
Objectives and endpoints
Objective
Endpoint
Primary
Assess 
the 
efficacy 
of 
deferasirox in liver iron 
removal after 52 weeks of 
treatment
Change in LIC from baseline after 52 weeks of treatment
Secondary
Assess response rates in 
subset 
of 
patients 
with 
baseline LIC>15 mg Fe/g dw
Proportion of patients with baseline LIC>15 achieving 
LIC<5 mg Fe/g dw and time to achieving LIC <5 mg Fe/g 
dw
Assess long-term efficacy of 
treatment to a target LIC of 3 
mg Fe/g dw
Time from target LIC of 3 mg Fe/g dw to the first LIC ≥5 mg 
Fe/g dw in the follow up period
Evaluate 
the 
impact 
of 
deferasirox on adult QoL
Change in health-related outcomes using Medical Outcomes 
Study Form 36 (SF-36v2)
Evaluate 
the 
impact 
of 
deferasirox on pediatric QoL
Change in health-related outcomes using the Pediatric 
Quality of Life questionnaire (PedsQL™)


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Evaluate the efficacy of 
deferasirox in liver iron 
removal
Change in LIC from baseline
Assess the correlation of 
change in SF and LIC
SF vs LIC at baseline and EOS
Confirm the efficacy of 
deferasirox in liver iron 
removal in NTDT syndrome
Change in LIC from baseline after 52 weeks of treatment by 
underlying NTDT syndrome
Assess 
the 
efficacy 
of 
deferasirox in decreasing SF 
after 52 weeks of treatment
Change in SF from baseline after 52 weeks of treatment
Evaluate 
the 
safety 
of 
deferasirox doses up to 30 
mg/kg/day dose
Safety parameters, labs, adverse events (AEs)
Assess 
the 
efficacy 
of 
Deferasirox 
in 
endocrine 
function
Change from baseline during treatment period in total and 
free testosterone (males), LH and FSH (females), TSH, total 
and free T4, total and free T3, fasting plasma glucose, insulin, 
insulin resistance, and cortisol.
Conduct PK analysis in a 
subgroup of patients
PK parameters (AUC, Cmax, Tmax and trough levels) during 
the study period
Safety
All safety objectives will be 
performed.
All safety events and assessments will be included
2
Statistical methods
2.1
Data analysis general information
Data will be analyzed by Novartis according to the data analysis section 10 of the study protocol 
and its amendments.
All analyses will be performed by using SAS Version 9.2 or higher.
As described in Section 10 of the protocol, in addition to the overall population analysis, 
statistical analysis will be performed according to ethnicity groups: Chinese/non-Chinese 
patients.


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All summaries described below will be performed by ethnicity group and all patients, if not 
otherwise stated.
2.1.1
General definitions
Observation periods for safety analysis
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 30 days after last 
nonzero dose of study medication.
3. post-treatment period: starting at day 30+1 after last dose of study medication.
Safety summaries (tables, figures) include only data that from the pre-treatment period (to
display the baseline status e.g. for ECG) and the on-treatment period, i.e. no data from the post-
treatment period must be included if not otherwise requested from Health Authorities. In
particular, summary tables for adverse events (AEs) have to include only AEs that started or
worsened during the on-treatment period, the so-called treatment-emergent AEs. Similarly,
summary tables and figures only include lab values observed during the on-treatment period.
However, all safety data (including those from the post-treatment period) will be listed and
those collected during the pre-treatment and post-treatment period will be flagged.
The above defined observation periods will be only applicable for safety analysis. In particular, 
all post-baseline values will be used in the analyses of LIC, serum ferritin 
 
 defined in the protocol section 7.2.1 for efficacy assessment.
Study day, last assessment day and baseline
Study day
Since this is an open label study, for all variables (safety or efficacy), study day will be defined 
as the number of days since the date of first dose of study medication. For a particular date on 
or after first dose, it is calculated as:
Study day = Assessment date – Date of first dose of study medication + 1.
Therefore, the date of the first dose of study medication will be Day 1 by definition.
The day before this day will be defined to be Day -1, i.e., there is no Day 0. Study days before
first dose of study medication will be calculated as:
Study day = Assessment date – Date of first dose of study medication.
In the above study day calculation, the date of the first day of study drug will be replaced with 
the study drug assignment date if the patient doesn’t take any study drug.
So if the patient doesn’t take the study drug, Day 1 is the study drug assignment date.
Definition of baseline value
For all variables, the baseline value will be defined to be the last available value prior to or on 
Day 1.


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For serum ferritin the baseline value will be calculated from the mean of values measured prior 
to or on Day 1.
Last assessment day
For the safety assessment, the censoring date will be the last treatment date+30 days. For
example, time to first specific adverse event will be censored at the last treatment date+30 days 
for a patient without the specified adverse event on-treatment.
End of treatment year 1
All data collected at Week 52 visit will be noted as End of treatment year 1
Month definition
Unless otherwise noted (e.g. for the calculation for month of exposure, 1 month = 365.25/12
days), one month will be defined as 30 days, with the exception of month 1 which consisted the 
first 45 days. When multiple values will be present for a month, the average value will be used 
unless otherwise noted. The grouping of each month will be according to the following rules:

If the day is in (1, 30+15] assign to month 1.

If the day is in (30*×x-15, 30*×x+15] assign to month x<12.

If the day is in (345, 378] assign to month 12.
This would allow for a +/- 15 days window for each month.
Quarter definition
Unless otherwise noted, the quarter is defined as shown in the table below:
Visit
Description
First day in 
window
Scheduled day 
in window
Last day in 
window
Quarter
Baseline
-35
1
Week 2
2
14
21
1
Week 4
22
28
42
1
Week 8
43
56
70
1
Week 12
71
84
98
1
Week 16
99
112
126
2
Week 20
127
140
154
2
Week 24
155
168
182
2
Week 28
183
196
210
3
Week 32
211
224
238
3
Week 36
239
252
266
3
Week 40
267
280
294
4


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Visit
Description
First day in 
window
Scheduled day 
in window
Last day in 
window
Quarter
Week 44
295
308
322
4
Week 48
323
336
350
4
Week 52
351
364
378
4
Week 56
379
392
406
5
Week 60
407
420
434
5
Week 64
435
448
462
5
Week 68
463
476
490
6
Week 72
491
504
518
6
Week 76
519
532
546
6
Week 80
547
560
574
7
Week 84
575
588
602
7
Week 88
603
616
630
7
Week 92
631
644
658
8
Week 96
659
672
686
8
Week 100
687
700
714
8
Week 104
715
728
742
8
Week 108
743
756
770
9
Week 112
771
784
798
9
Week 116
799
812
826
9
Week 120
827
840
854
10
Week 124
855
868
882
10
Week 128
883
896
910
10
Week 132
911
924
938
11
Week 136
939
952
966
11
Week 140
967
980
994
11
Week 144
995
1008
1022
12
Week 148
1023
1036
1050
12
Week 152
1051
1064
1078
12
Week 156
1079
1092
1106
12


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Visit
Description
First day in 
window
Scheduled day 
in window
Last day in 
window
Quarter
Week 160
1107
1120
1134
13
Week 164
1135
1148
1162
13
Week 168
1163
1176
1190
13
Week 172
1191
1204
1218
14
Week 176
1219
1232
1246
14
Week 180
1247
1260
1274
14
Week 184
1275
1288
1302
15
Week 188
1303
1316
1330
15
Week 192
1331
1344
1358
15
Week 196
1359
1372
1386
16
Week 200
1387
1400
1414
16
Week 204
1415
1428
1442
16
Week 208
1443
1456
1470
16
Week 212
1471
1484
1498
17
Week 216
1499
1512
1526
17
Week 220
1527
1540
1554
17
Week 224
1555
1568
1582
18
Week 228
1583
1596
1610
18
Week 232
1611
1624
1638
18
Week 236
1639
1652
1666
19
Week 240
1667
1680
1694
19
Week 244
1695
1708
1722
19
Week 248
1723
1736
1750
20
Week 252
1751
1764
1778
20
Week 256
1779
1792
1806
20
Week 260
1807
1820
1834
20


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2.2
Analysis sets
The Full Analysis Set (FAS) consists of all patients who will be assigned at least one dose of
study drug. The FAS will be used for all efficacy analyses.
The Safety Set consists of all patients who will receive at least one dose of study drug.
The pharmacokinetic analysis set (PAS) consists of all patients from FAS set who have
evaluable pharmacokinetic (PK) data. 
The Ethnicity group: The Patients will be grouped based on the ethnicity as Chinese patients,
non-Chinese patients and all patients.
2.2.1
Subgroup of interest
The following subgroups will be considered for further analyses:

Age categories (<18 years and ≥ 18 years)

Baseline LIC categories (≤7, >7 - 15 and >15 mg Fe/g dw)

NTDT diagnosis subtypes (Beta-thalassemia intermedia, HbE Beta-thalassemia, Alpha-
thalassemia intermedia (HbH disease) and Other)

Average actual daily dose (>0 - <7.5, 7.5 - 12.5, >12.5 - 17.5 and >17.5 mg/kg/day)
2.3
Patient disposition, demographics and other baseline 
characteristics
Demographic and baseline characteristics will be summarized by ethnicity group and overall 
for the FAS.
Demographics include age, age group (<18 years, 18-<50 years, 50-<65 years, ≥65 years), 
gender, race. Other baseline characteristics include weight, weight group (<35 kg, 35-<55 kg, 
55- <75 kg, ≥75 kg), main underlying disease, history of blood transfusion (Yes/No), history of 
splenectomy (Yes/No), history of chelation therapy (Yes/No), type of last chelation therapy 
prior to the study, hepatitis B and C status, medical history by MedDRA primary SOC and 
preferred term, clinically significant abnormality in baseline ECG (Yes/No), abnormality in 
baseline audiometric test (Yes/No) and (clinically significant/non-significant), abnormality in 
baseline ocular exam (Yes/No) and (clinically significant/non-significant), baseline LIC, 
baseline LIC group (<5, 5-≤7, >7-15, >15 mg Fe/g dw), baseline serum ferritin, baseline serum 
ferritin group (<300, ≥300-500, >500-1000, >1000-2500, >2500-5000, >5000 ng/mL), baseline 
creatinine, baseline creatinine group (≤upper limit of normal range (ULN), >ULN), baseline 
creatinine clearance, baseline creatinine clearance group (<60, 60-<90, 90-<160, ≥160 mL/min), 
baseline ALT, baseline ALT group (≤ULN, >ULN-5 ×ULN, >5 ×ULN), baseline AST, baseline 
AST group (≤ULN, >ULN-5×ULN, >5 ×ULN), urine protein/creatinine ratio(≤0.2 
mg/mg,>0.2-1 mg/mg, >1 mg/mg).


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2.4
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance)
2.4.1
Study treatment / compliance
The duration of exposure is defined as the number of months between the start and end of study 
medication. One month of exposure corresponded to 365.25/12 days. So the duration of 
exposure in month will be calculated as (study medication end date-study medication start 
date+1)/30.4375.
The following variables will be summarized for the Safety Set : duration of exposure, in months 
and in categories (<3 months, 3-<6 months, 6-<9 months, and so on); average planned 
(mg/kg/day) and average actual daily dose (>0 -<7.5, 7.5 - 12.5, >12.5 - 17.5 and >17.5 
mg/kg/day); cumulative planned (mg/kg) and actually administered dose (mg/kg); percentage 
of planned dose taken (as calculated from DAR); number, mean length, and total length of 
treatment interruptions per patient; duration of treatment excluding interruptions relative to the 
overall follow-up time; frequency of dose change in planned dose by reason as recorded in the 
eCRF.
The total patient-years while on treatment, calculated as the sum of (overall drug exposure) / 
365.25 will be provided by ethnicity group and for all patients.
The average daily dose (planned or actual, in mg/kg) will be calculated as the mean dose over 
all days between first and last dose, including interim days with zero dose (interruptions). The 
cumulative dose (planned or actual, in mg/kg) will be calculated as the sum over the daily doses 
of all days between first and last dose. The current weight of subject will be used when 
calculating the actual daily dose.
The percentage of planned dose taken will be derived as 100 × cumulative actual dose (mg/kg)/
cumulative planned dose (mg/kg).
The overall follow-up time will be the number of days between start of study medication and 
the day before the final visit, both inclusive.
An interruption will be a period of days with a zero actual dose. Only interruptions between 
start and end of study medication will be taken into account. A patient could have multiple 
interruptions during the study.
Dose increase and dose reduction will be summarized at week 4, week 24 and approximately 
every 6 months thereafter. Patient has dose increase at visit if the dose assignment at the visit 
will be higher than the last available one before the visit. Patient has dose decrease or reduction 
at visit if the dose assignment at the visit will be nonzero and lower than the last available one 
before the visit.
Selected efficacy and safety parameters will be summarized by age.
Selected safety data will be summarized by baseline LIC categories
NTDT syndromes or main underlying diseases are Beta-thalassemia intermedia, HbE 
Betathalassemia, Alpha-thalassemia intermedia (HbH disease) or other. LIC will be 
summarized by NTDT syndrome.


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Selected safety parameters will be summarized by average actual daily dose.
Protocol deviations and patient disposition will be summarized by ethnicity group and listed.
2.4.2
Prior, concomitant and post therapies
Prior and concomitant medications and significant non-drug therapies will be summarized 
through frequency tables according to their WHO ATC class and WHO generic term. Prior 
medications will be defined to be drugs taken prior to the first dose of study medication. 
Concomitant medications will be medications taken between the first and last day with study 
medication, excluding medications started on the last day of study medication. Medications 
which started prior to the first dose of study medication and continued thereafter will be counted 
in both summaries.
The number of transfusions and the total RBC transfused during the study (mL/kg) will be 
summarized by ethnicity groups and overall. The amount of RBC transfused denoted the 
amount of RBC contained in the blood, i.e. (amount of blood transfused [mL])×hematocrit  / 
100). For each transfusion, the amount of blood given, expressed in mL, will be divided by the 
last available weight to calculate the amount transfused in mL/kg. For each patient, the total 
RBC transfused over the whole study will be calculated, summing up the amount received at 
each transfusion. Only transfusion dates on or after start of ICL670 will be considered for this 
analysis.
Missing day information for start date of prior chelation therapy or start date of history of blood 
transfusions will be imputed by the 1st of the Month. If the month is missing it will be imputed 
by January.
Time since start of first chelation therapy/blood transfusion = (Screening Visit date – start of 
first chelation/transfusion date + 1)/365.25.
Relevant medical history and current medical conditions will be coded and frequencies 
summarized for patients in the safety analysis set. 
2.5
Analysis of the primary objective
2.5.1
Primary endpoint
The trial is designed to assess the efficacy of deferasirox in patients with non-transfusion
dependent thalassemia based on absolute change in LIC from baseline after one year of 
treatment. The analysis for primary objective was performed at one-year (data cut-off date : 03-
Jan-2015). The study met its primary objective. The primary endpoint, absolute change in LIC 
(mg Fe/g dw) at Week 52 from baseline, was statistically significantly different from 0 (Paired 
T-test p<0.0001, two-sided). The absolute change in LIC at Week 52 from baseline had mean 
(SD) -6.68 (7.018) (mg Fe/g dw) and a 95% confidence interval (-7.91, -5.45) (mg Fe/g dw).
As done in previous studies within patients with transfusional iron overload, a normal 
distribution will be assumed for LIC absolute change.
LIC will be measured at screening (Visit 1), Week 24 (Visit 15) and Week 52 (Visit 25) in 
treatment year 1. The primary efficacy variable will be the absolute change from baseline in 
LIC at Week 52, i.e. the difference of LIC at Week 52 minus LIC at baseline.


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The absolute change in LIC from baseline after one year of treatment will be analyzed using 
the FAS set. 
The following estimates will be provided:

point estimate of the absolute change at Week 52,

the ordinary 2-sided 95% confidence interval,

p-value (descriptive only).
Also, LIC values at Week 52 will be computed with their corresponding 95% CI.
Handling of missing values/censoring/discontinuations
In case of missing LIC at Week 52, the last available post-baseline LIC value before Week 52 
will be used in the calculation of the primary endpoint. Patients without post-baseline LIC at or 
before Week 52 or baseline LIC will be excluded from the analyses.
Supportive analyses
In order to further assess the absolute change and the relative change in LIC from baseline at 
Week 52, the estimates and the 95% confidence intervals will be provided for the following
proportions (In case of missing LIC at Week 52, the last available post-baseline LIC value 
before Week 52 will be used):

The proportion of patients with an LIC decrease by at least 3 mg Fe/g dw from baseline
(LIC decrease >= 3 mg Fe/g dw) at Week 52; i.e., proportion of LIC decrease >=3 mg 
Fe/g dw = subjects with ((baseline LIC – LIC at Week 52)>=3) divided by total number 
of subjects

The proportion of patients with an LIC decrease by at least 30% from baseline (LIC 
decrease >=30%) at week 52. i.e., proportion of LIC decrease >=30% = subjects with 
((100*(Baseline LIC – LIC at Week 52)/Baseline LIC) >=30%)  divided by total number 
of subjects.
2.6
Analysis of secondary efficacy objective(s)
All p-values provided for the secondary efficacy endpoints will be considered as exploratory
only.
2.6.1
Secondary endpoints
2.6.1.1
Response analysis in patients with baseline LIC>15 mg Fe/g dw
Subjects who achieved the target baseline LIC >15 mg Fe/g will be included in this analysis.
The proportion of patients with baseline LIC>15 mg Fe/g dw achieving a post-baseline LIC <5 
mg Fe/g dw during the study will be presented with a 95% confidence interval. The normal
approximation will be used for the distribution, i.e. the confidence interval will be calculated as 
follows (Agresti and Coull 1998):
100*(p + z0.975 2/2n +/- z0.975*sqrt((p(1-p) + z0.975 2/4n)/n) / (1 + z0.975 2/n)


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Where p denotes the proportion, n the corresponding number of values, z0.975 the 97.5% quantile 
of the standard normal distribution, and sqrt the square root function (see also Brown,
Cai, DasGupta, 2001).
Time to the first LIC <5 mg Fe/g dw among patients with baseline LIC >15 mg Fe/g dw will 
be analyzed based on the Kaplan-Meier method. Kaplan-Meier curves for time to first LIC<5 
mg Fe/ g dw and the medians along with 95% confidence intervals will be presented.
If a subject does not achieve a first post-baseline LIC <5 mg Fe/g dw, the day of the last LIC 
assessment during the study will be used in the Kaplan-Meier analyses for censoring.
If  the last assessment date will be incomplete, the earliest possible date will be imputed (first 
of month if day will be missing, first of year if both day and month will be missing). This 
imputation rule will be only used for the derivation of the last assessment day.
2.6.1.2
Long-term efficacy of treatment to target LIC of 3 mg Fe/g dw followed
by one or more treatment holidays until the LIC is greater or equal to 5
mg Fe/g dw
Subjects who achieved the target LIC <3 mg Fe/g will be included in this analysis. Time from 
the target LIC <3 mg Fe/g dw to the first LIC ≥5 mg Fe/g dw in the follow-up period will be 
analyzed by using the Kaplan-Meier method. Kaplan-Meier curves for time to first LIC ≥5 mg 
Fe/g dw and the medians along with 95% confidence intervals will be presented.
If the subject does not have a first LIC ≥5 mg Fe/g dw in the follow-up period, the day of the 
last LIC assessment during the study will be used in the Kaplan-Meier analyses for censoring.
If  the last assessment date will be incomplete, the earliest possible date will be imputed (first 
of month if day will be missing, first of year if both day and month will be missing). This 
imputation rule will be only used for the derivation of the last assessment day.
2.6.1.3
Absolute change in LIC measured by MRI from baseline over time
Absolute changes from baseline LIC at all scheduled LIC evaluation weeks will be analyzed. 
Patients without any LIC post-baseline value at or prior to the scheduled LIC evaluation week 
had missing values and will be not included in the analyses for the scheduled weeks. Descriptive 
statistics and box plots will be provided for:

LIC at baseline, at all scheduled LIC evaluation weeks (24, 52, 76, 104, 128, 156, 180, 
208, 232, 260) and for last available LIC measurement

Absolute change from baseline LIC at all scheduled LIC evaluation weeks (24, 52, 76, 
104, 128, 156, 180, 208, 232, 260) and for last available LIC measurement.
2.6.1.4
Absolute change in LIC measured by MRI from baseline over time by 
underlying disease
Absolute changes from baseline LIC at all scheduled LIC evaluation weeks will be analyzed by 
underlying disease. Patients without any LIC post-baseline value at or prior to the scheduled 
LIC evaluation week had missing values and will be not included in the analyses for the 
scheduled weeks.


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Descriptive statistics will be provided for:

LIC at baseline, at all scheduled LIC evaluation weeks (24, 52) and for last available 
LIC measurement in treatment year 1;

Absolute change from baseline LIC at all scheduled LIC evaluation weeks (24, 52) 
and for last available LIC measurement in treatment year 1.
2.6.1.5
Absolute change in SF from baseline over time
Baseline serum ferritin as average of all available ferritin values from screening to last sample 
prior to or on the day of first intake of study medication;
Descriptive statistics and box plots will be provided for:

SF at baseline, quarterly SF up to week 260;

Absolute changes of quarterly SF at quarter 1, 2, …,20 from baseline.
Quarter is defined as average of available ferritin values from visit corresponding to end of 
quarter, visit prior, and visit after (e.g. end of first quarter includes average ferritin values from 
Visits 11, 12, and 13).
Absolute change from baseline at week 52 will be tested using a 2-sided one sample t-test. The 
p-value will be considered as exploratory with no multiplicity considerations.
2.6.1.6
Correlation between serum ferritin and LIC at baseline and EOS
Scatter plots with pearson correlation coefficient and simple linear model will be provided 
without imputing any missing data:

LIC versus serrum ferritin at baseline, Week 24, Week 52, Week 104, Week 156, Week 
208, Week 260

LIC versus serrum ferritin at baseline, Week 24, Week 52, Week 104, Week 156, Week 
208, Week 260 on log scale

Absolute changes in LIC versus absolute changes in serrum ferritin at baseline, Week 
24, Week 52, Week 104, Week 156, Week 208, Week 260
2.6.1.7
Medical Outcomes Study Short Form-36 (SF-36)
The Medical Outcomes Study Short Form 36 (SF-36v2) is a self-administered questionnaire for 
adults (greater than 18 years of age) and contains 36 items which measure eight dimensions: 
Physical functioning (10 items), Role limitation due to physical health problems (4 items), 
Bodily pain (2 items), General health perceptions (5 items), Vitality (4 items), Social 
functioning (2 items), Role limitations due to emotional problems (3 items) and General mental 
health (5 items). There is an additional single item giving information on health change over 
the past year. Item scores for each dimension are coded, summed and transformed to a scale 
from 0 (worst possible health state measured by the questionnaire) to 100 (best possible health 
state). The higher values indicate a better evaluation of health. Two summary scores of physical 
and mental health can also be calculated and scoring is normbased, with normative values at 50 
and no floor or ceilings. In addition, the SF-6D, a utility measure of health states, can be derived 


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from the SF-36 and the scoring for the SF-6D utility values will also be assessed using the 
scoring methods from the developers.
Descriptive statistics will be provided for all dimensions, PCS/MCS summary scores and SF-
6D scores (including absolute change from baseline) by visit (baseline, week 52, 104, and 156).
Absolute change from baseline at week 52, 104, and 156 will be tested as exploratory using a 
2-sided one sample t-test. P-values will be considered as exploratory with no multiplicity 
considerations.
2.6.1.8
Pediatric Quality of Life Questionnaire
The PedsQL™ is a modular approach to measuring health-related quality of life (HRQOL) in 
children and adolescents. This will be administered to children between the ages of 13 to 18 
years. The approach includes both a child self-report and parent proxy-report. The 23-item 
PedsQL™ Generic Core Scales encompass the essential core domains for pediatric HRQOL 
measurement: 1) Physical Functioning (8 items), 2) Emotional Functioning (5 items), 3) Social 
Functioning (5 items), and 4) School Functioning (5 items). The Generic Core Scales are 
designed to enable comparisons across patient and healthy populations.
Scores are transformed on a scale from 0 to 100. Items are reversed scored and linearly 
transformed to a 0-100 scale as follows: 0=100, 1=75, 2=50, 3=25, 4=0.

Score by Domains: If more than 50% of the items in the scale are missing, the scale 
scores should not be computed, 
Mean Score of domain = Sum of the items in the domain over the number of items 
answered in that domain.

Psychosocial Health Summary Score = sum of the items over the number of items 
answered in the Emotional, Social, and School Functioning Scales

Physical Health Summary Score = Physical Functioning Scale Score

Total Score = Sum of all the items over the number of items answered on all the scales. 
If more than 50% of the items in the scale are missing, the Scale Scores should not be computed. 
If 50% or more items are completed: Impute the mean of the completed items in a scale.
Descriptive statistics will be provided for all domains scores (including absolute change from 
baseline) by visit (baseline, week 52, 104, and 156).
Absolute change from baseline at week 52, 104, and 156 will be tested as exploratory using a 
2-sided one sample t-test.
P-values will be considered as exploratory with no multiplicity considerations.
2.6.1.9
Endocrine function
The endocrine function will be assessed using the following parameters: Total and Free 
testosterone (males), LH and FSH (females), TSH, total and free T4, total and free T3, fasting 
plasma glucose, insulin, insulin resistance, and cortisol. Insulin resistance will be derived by 
HOMA method:


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Insulin resistance= fasting Glucose (mmol/L) x fasting Insulin (mU/L) / 22.5
Descriptive statistics will be provided for the values of all parameters and also for their 
corresponding absolute change from baseline by scheduled visits (Week 12, 24, 36, 52, 64, 76, 
88, 104, 116, 128, 140, 156, 168, 180, 192, 208, 220, 232, 244 and 260)
2.7
Safety analyses
All safety analyses will be based on the Safety Set. Post-baseline safety data included values up 
to 30 days after last non-zero dose.
2.7.1
Adverse events (AEs)
AEs and the principal cause of death will be coded using MedDRA 20.1.
All summaries of AEs only included treatment emergent AEs, i.e., AEs which started or 
worsened on or after the day with first study medication intake and not more than 30 days after 
last study medication.
The incidence of AEs (number and percentage of patients with AEs) will be summarized by 
MedDRA primary SOC and preferred term, and separately by preferred term only. These two 
summaries will be generated for all AEs, serious AEs (SAEs), AEs with suspected relationship 
to study medication, SAEs with suspected relationship to study medication, AEs leading to 
discontinuation of study medication, and AEs leading to dose adjustment or interruption. AEs 
will be also summarized by MedDRA primary SOC, preferred term, and maximum severity. 
Non-serious AEs (i.e. excluding SAEs) will be also summarized by primary SOC and preferred 
term.
2.7.1.1
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 latest document has 
to be used (The name of the retrieval document should be “ICL670 AESI_MedDRA 
xx.x_DDMmmYY”, where xx.x is the MedDRA version number. At the time of approval of 
this report analysis plan, the latest retrieval document is “ICL670 AESI_MedDRA 
20.1_08Nov17”). The MedDRA codes will be used to generate the outputs.
For adverse event started before and ended after one-year cutoff date, the end date of the adverse 
event would be set as “missing”, but reported as “Ongoing” in listings.
2.7.2
Deaths
All Deaths and on-treatment deaths will be summarized by MedDRA primary system organ 
class (SOC) and preferred term of the principal cause of death.


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2.7.3
Laboratory data
For safety monitoring, the following laboratory parameters will be assessed during the study:

hematology: hemoglobin, hematocrit, white blood cell (WBC) count with differential, 
platelet count, red blood cell (RBC) count, mean corpuscular volume (MCV), absolute 
Neutrophil Count (ANC) and reticulocyte count

biochemistry: albumin, alkaline phosphatase, total/fractionated bilirubin, calcium, 
chloride, creatinine, gamma-glutamyl transpeptidase (GGT), fasting glucose, inorganic 
phosphorus, potassium, total protein, sodium, C-reactive protein, uric acid, lactase 
dehydrogenase (LDH), urea (BUN), serum glutamic pyruvic transaminase
(SGPT)/alanine aminotransferase (ALT), serum glutamic oxaloacetic transaminase
(SGOT)/aspartate aminotransferase (AST), ,  creatinine clearance, serum creatinine; 

urinalysis (dipstick): urinary protein/creatinine ratio, pH, specific gravity, urine blood, 
urine glucose, urine protein, urine bilirubin, urine ketones, and urine leukocyte esterase.
All hematology and biochemistry laboratory values will be converted into standard international 
(SI) units and categorized according to laboratory normal ranges (low/normal/high). All values 
reported on the same day will be first averaged and then used as the result for that day.
In addition to the laboratory data measured by the central laboratory, creatinine clearance will 
be calculated based on two different formulae (Cockroft-Gault equation, Schwartz formula for 
pediatric population). All results for creatinine clearance presented will be based on the 
Cockroft-Gault/Schwartz formula.
For selected laboratory tests, additional flags for notable ranges as defined in Table 2-1 will be 
generated. Laboratory values assessed more than 30 days after discontinuation of study 
medication will be excluded from the analysis.
Table 2-1
Definition of notable ranges for laboratory tests
Laboratory test
Criteria for notable ranges
Platelet count
< 100 x 109/L (extended range <50×109/L)
Absolute neutrophils
< 1.5 x 109/L (extended range <0.5×109/L)
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 at two consecutive 
measurements at least 7 days apart)
Urinary protein/urinary 
creatinine ratio
> 1.0 (mg/mg) at two consecutive measurements at least 7 days 
apart
SGOT/ALT and 
SGPT/AST
>5 x ULN and 2 x baseline (extended range >10×ULN 
and >2×baseline value)
The number and percentage of patients with post-baseline laboratory results (scheduled and 
unscheduled) meeting the criteria for notable values (see Table 2-1) will be displayed in a 


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frequency table, by quarter A patient with a notably abnormal value of serum creatinine, or 
creatinine clearance will be counted in the period during which the second of the two 
consecutive abnormally high (or low) measurements occurred.
All notable laboratory abnormalities will be listed.

Shift tables will be generated for each hematology and biochemistry test, cross-
tabulating normal/notable/extended ranges baseline laboratory values against worst 
postbaseline values.

Listing of all laboratory data with values flagged to show the corresponding 
normal/notable/extended ranges
Furthermore, observed values and changes from baseline (absolute and relative to baseline) will 
be summarized for each laboratory test with descriptive statistics quarterly (baseline, Quarter 1, 
Quarter 2 etc.). If a time period included more than 1 test result from central lab for serum
creatinine, the average will be analyzed. For others, if a time period included more than 1 test 
result from central or local lab, the average will be analyzed.
Boxplots over time will be generated for selected laboratory test (see Table 2-1). Data will be 
summarized by period and presented at the midpoint of the respective period. If a time period 
included more than 1 test result, the average will be analyzed.
2.7.4
Other safety data
Data from vital signs, body weight, ECG, ocular, and auditory examination will be listed and 
summarized with descriptive statistics as appropriate. Any significant findings after start of 
study will be documented as AEs and reported as such.
2.7.4.1
ECG, audiometric test and ocular examination
ECG, audiometric test, ocular examination and echocardiography will be performed at baseline, 
Week 52 and Week 260. Abnormalities will be reported together with an overall interpretation 
of the findings. Any abnormalities at baseline will be summarized. At Week 260, the 
investigator flagged all abnormalities which will be new or worsened since baseline. All new 
or worsened abnormalities are recorded on the AE CRF page. All findings of patients with new 
or worsened clinically significant abnormalities will be listed.
2.7.4.2
Vital signs
Measurements of vital signs and body weight done more than 30 days after discontinuation of 
study medication will be excluded from the analysis.
The change from baseline in diastolic blood pressure, systolic blood pressure, pulse rate, and 
weight will be summarized by scheduled visit with n, mean, SD, minimum, median, and 
maximum values. Furthermore, the number (%) of patients with notably abnormal vital signs 
or weight will be presented by visit and for time point 'at any time after baseline'.
The criteria for notably abnormal vital signs and weight are displayed in Table 2-2.


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Table 2-2
Definition of notable ranges for vital signs and weight
Parameter
Criteria for notable ranges
Systolic blood 
pressure
≥180 mmHg / ≤90 mmHg with increase / decrease from baseline of 
≥20 mmHg
Diastolic blood 
pressure
≥105 mmHg / ≤50 mmHg with increase / decrease from baseline of 
≥15 mmHg
Pulse rate
≥120 bpm / ≤50 bpm with increase / decrease from baseline of ≥15 
bpm
Weight
≥7% increase or decrease from baseline weight
The vital sign data of patients with notably abnormal vital signs will be listed. Similarly body 
weight data of patients with notably abnormal body weight will be listed.
2.7.4.3
Tolerability
The following GI events (grouped) will be analyzed:

Abdominal pain/ GI pain (preferred terms of Abdominal discomfort, Abdominal pain, 
Abdominal pain lower, Abdominal pain upper, Abdominal tenderness, Epigastric 
discomfort, or Gastrointestinal pain)

Dyspepsia (preferred terms of Dyspepsia)

Diarrhoea (preferred terms of Diarrhoea, Diarrhoea neonatal, or Frequent bowel 
movements)

Constipation (preferred terms of Constipation, Faeces hard, or Infrequent bowel 
movements)

Vomiting (preferred terms of Discoloured vomit, Nausea, Retching, or Vomiting)

Abdominal distension (preferred terms of Abdominal distension)

Oesophagitis (preferred terms of Oesophageal discomfort, Oesophageal irritation, 
Oesophageal mucosa erythema, Oesophageal pain, or Oesophagitis)
These events will be investigated with regards to frequency, time to onset, duration and outcome 
(event end yes/no). For each patient and type of event the following will be determined:

Number of events

Time to first event

Duration of first event
All variables of type 'number of events' will be summarized in frequency tables showing the 
number and percentage of patients with 0, 1, 2, ≥ 3 events, and with descriptive statistics (n, 
mean, SD, minimum, median, maximum, sum). The median time to first event and the median 
duration of first event will be estimated using Kaplan-Meier methods. The analysis of the 
duration of first event only included patients with event. In the analysis of time to first event, 


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patients without event will be considered censored at their last assessment date. In the analysis 
of duration of first event, patients without end of event will be considered censored at their last 
assessment date. Incidences of grouped gastro-intestinal adverse events will be presented.
2.8
Pharmacokinetic endpoints
PAS will be used in all pharmacokinetic data analysis and PK summary statistics. Only patients 
with valid PK samples will be included in PAS.
The following criteria will be used to flag not valid PK samples:
For pre-dose samples (at Week 4, Week 12 and Week 24):
o
PK sample time should be +/- 20% around 24 hrs (or 24 hr +/- 4.8 hr) after the 
previous dose.
o
PK sample time should be prior to dosing time on the PK sampling date.
o
PK sample should be taken at steady state.
o
No vomiting should occur within 4 hours post-dose on the day prior to PK pre-
dose sampling.
o
No vomiting should occur within 4 hours prior to PK pre-dose sampling
For post-dose samples (at Week 4):

Taken at steady state
A second flag will identify those PK samples which are or which are not at steady-state. For a
patient to be at steady state, the study medication should be administered for 4 consecutive days 
before the PK sampling date without any interruption or change in actual daily dose 
administered.
Excluded PK samples will be flagged and listed in the PK data listing. Valid PK samples will 
be considered for the summary statistics. Biofluid concentrations will be expressed in μmol/L. 
All concentrations below the limit of quantitation or missing data will be reported as such in 
the concentration data listings. Concentrations below the limit of quantitation will be treated as 
zero in summary statistics.
Descriptive statistics of all pharmacokinetic data (pre-dose concentration) and PK parameters 
(AUCtau in μmol/L*hr, Cmax in μmol/L and Tmax in hr) will be provided by incident dose (i.e. 
dose administered over the 4 days prior to PK sampling) included arithmetic and geometric 
mean, median, SD, and CV, geometric CV, minimum and maximum. Zero concentrations will 
be not included in the geometric mean calculation. Since Tmax is generally evaluated by a 
nonparametric method, median values and ranges will be given for this parameter.
Scatter plots between PK pre-dose concentrations at Week 4, 12 and 24 and selected PD 
endpoints (SF at Week 4, 12 and 24, LIC at Week 24 – absolute values and relative change from 
baseline) will be presented.


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2.10
Interim analysis
No formal interim analysis based on primary endpoint was planned.
3
Sample size calculation
Sample size is based on results from ICL670A2209 (THALASSA) study, which was a 
prospective, double-blind, placebo controlled trial of deferasirox in starting doses of 5 and 10 
mg/kg/day in patients with NTDT.
166 patients with randomized to starting doses of 5 mg (n=55) or matching placebo (n=28) and 
10 mg (n=55) or matching placebo (n=28).
See in Table 3-1 below results for absolute change in LIC for this study:
Table 3-1
Absolute change in LIC (mg Fe/g dw), Full Analysis Set
Time point Value
ICL670
5.mg/kg
(N=55)
ICL670
10.mg/kg
(N=55)
Placebo
(N=56)
Baseline Value
N
Mean
SD
55
13.11
7.290
55
14.56
7.921
55
15.94
10.845
Baseline Value
N
Mean
SD
51
11.56
7.928
54
10.58
7.667
54
16.38
10.606
Baseline Value
N
Mean
SD
51
-1.85
3.078
54
-3.78
4.150
54
0.26
3.501
Note: Absolute change from baseline: value at timepoint – baseline value. Summary only 
includes patients with a value both at baseline and at considered timepoint. Source: [Table 
14.2-1.9 from the ICL670A2209 trial] (29-Sep-2011 CSR).
The population of patients planned to be enrolled in this study covered a broader type of patients 
(e.g. including patients treated with hydroxyurea, erythropoietin and butyrate) and from 
multiple countries. This will be likely to lead to more heterogeneity and thus to an increased 
variability compared to the one observed in the ICL670A2209 study.
Assuming a true SD as high as 6 mg Fe/g dw and a drop-out rate of 20%, a sample size of 117 
patients will be required to obtain 90% power to detect a LIC absolute change of at least 2 mg 


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Fe/g dw at Week 52 from the baseline value and using a paired t-test at 0.05 two-sided 
significance level.
Table below provides number of patients required according to different scenarios that ensure 
80% power in case of lower true SD than expected (the others hypotheses remaining same):
SD (mg Fe/g dw)
4.5
5
5.5
Power (%)
80
80
80
N patients
51
63
75
Sample size had been computed using PASS 2008.
4
Change to protocol specified analyses
No change from protocol specified analysis was made.
5
Appendix
5.1
Imputation rules
Partially or completely missing AE onset dates and concomitant medication dates will be 
imputed according to the standard Novartis imputation rules as the following:
Date imputation is the creation of a new, complete date from a partial one according to an agreed 
and acceptable algorithm. Missing date for AE will be handled according to STL standard.
A partial date is simply an incomplete date e.g.,
ddOCT2001 the days will be missing from this DDMMMYYYY date
Partial adverse event start dates, if left partial, would ultimately mean the following

It would not be possible to place the adverse event in time.

Therefore the treatment/dosage at the time of the event would be unknown.

Therefore the event could not be reported/summarized appropriately – if at all.
Therefore it will be important to perform date imputation to ensure that as many data events 
will be represented as correctly as possible. Of course partial and/or missing dates should also 
be caught as edit checks and passed back to the investigator for resolution.
There will be no attempt to impute the following

Missing AE start dates

AE start dates missing the year

Partial/missing AE end dates
Table 5-1 explains the abbreviations used.


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Table 5-1
AE/Treatment Date Abbreviations
Day
Month
Year
Partial Adverse Event 
Start Date
<not used>
AEM
AEY
Treatment Start Date
(TRTSTD)
<not used>
TRTM
TRTY
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 the relationship of the AE start 
date to the treatment start date (TRTSTD).
Table 5-2
Imputation Algorithm
AEM MISSING
AEM < TRTM
AEM = TRTM
AEM > 
TRTM
AEY 
MISSING
NC
Uncertain
NC
Uncertain
NC
Uncertain
NC
Uncertain
AEY < TRTY
(B)
Before TRTSTD
(C)
Before TRTSTD
(C)
Before TRTSTD
(C)
Before TRTSTD
AEY = TRTY
(B)
Uncertain
(C)
Before TRTSTD
(B)
Uncertain
(A)
After TRTSTD
AEY > TRTY
(E)
After TRTSTD
(A)
After TRTSTD
(A)
After TRTSTD
(A)
After TRTSTD
The legend to the above table is shown in Table 5-3
Table 5-3
Relationship and Imputation legend
Realtionship
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


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(C)
15MONYYYY
(D)
01JULYYYY
(E)
01JANYYYY
5.2
Laboratory parameters derivations
Percentages in shift tables cross-tabulating baseline versus post-baseline values will be based 
on all patients with a non-missing post-baseline value in the respective treatment group and 
analysis set.
Hepatitis B, C and other
The following preferred terms, in the medical history dataset, will be used to identify patients 
with hepatitis B, hepatitis C or other forms of hepatitis.

Hepatitis B preferred terms: hepatitis B, hepatitis B positive, hepatitis B surface antigen 
positive, hepatitis B virus test positive, hepatitis B e antigen positive, hepatitis B antigen 
positive

Hepatitis C preferred terms: hepatitis C, hepatitis C positive, hepatitis C RNA positive, 
hepatitis C virus test positive

Hepatitis other preferred terms: autoimmune hepatitis, hepatitis non-A non-B, chronic 
hepatitis, hepatitis acute, hepatitis chronic active, hepatitis post transfusion, hepatitis 
viral, hepatitis chronic nos, hepatitis D, hepatitis D antibody positive, hepatitis D antigen 
positive, hepatitis D virus test positive, hepatitis cholestatic, hepatitis chronic persistent, 
granulomatous liver disease, hepatitis
The preferred term list will be discussed with clinicians prior to finalizing outputs.
Creatinine clearance re-calculation
Cockroft Gault formula (≥ 18 years of age)
Male patients: CrCl (mL/min) = (140 - age) × weight/(815 × 0.001 × SCr)
Female patients: CrCl (mL/min) = (140 - age) × weight × 0.85/(815 × 0.001 × SCr).
Schwartz formula (< 18 years of age)
CrCl (mL/min) = (k × height) / (SCr × 0.01131) with

k = 0.55 for children from 1 to 12 years

k = 0.55 for girls ≥ ≥ 13 years

k = 0.70 for boys ≥ ≥ 13 years
Calculation of the amount of RBC transfused
In calculating the amount of RBC transfused, the hematocrit value will be as reported in the
eCRF for each transfusion. If the transfusion record’s hematocrit value is missing, it will be
imputed by the hematocrit value provided by the respective center. If no value is provided by
center, 65% will be imputed.


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If the amount of blood transfused is expressed in Unit, it will be first converted to mL according 
to the average amount of blood per unit as provided by the respective center. In the case of the 
average amount per unit being unknown from a center and the amount is reported in Unit, it 
will be assumed that each unit contains 185 mL of RBC according to ICL670 project standard.
6
Reference
Agresti A., Coull BA (1998). Approximate is better than “Exact” for interval estimation of
binomial proportions. The American Statistician. May 1998 Vol.52, No. 2, 119-126.
Brown LD, Cai TT, Dasgupta A (2001). Interval estimation for a binomial proportion. 
Statistical Science. 2001, Vol. 16, No. 2, 101-133.