Conditions: Transfusion-dependent Thalassemia Non-transfusion-dependent Thalassemia
Keywords: thalassemia TDT transfusion-dependent non-transfusion-dependent NTDT
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 148
Healthy volunteers: no

Brief summary:
Study to evaluate patient preference of deferasirox film-coated tablet (FCT) or deferasirox dispersible tablet (DT) in patient with transfusion - dependent thalassemia or non-transfusion -dependent thalassemia as measured by preference questionnaire at Week 48

Detailed description:
This was an open-label, multicenter, single arm, phase II study aimed at collecting data on preference for iron chelation therapy in patients with transfusion-dependent thalassemia (TDT) or non-transfusion-dependent thalassemia (NTDT) throughout a 48 week treatment period. Participants who were either chelator-naïve, or who were previously treated with iron chelators (excluding deferasirox) for at least 6 months continuously, were eligible to participate in this study.

The study was divided into 2 phases:

1. Core Phase:

   * Screening phase which lasted for a maximum of 4 weeks to determine patient eligibility followed by
   * Period 1: Participants were treated with deferasirox DT from Baseline visit Day 1 to Week 24
   * Period 2: Participants were treated with deferasirox FCT from Week 25 to Week 48:

   At the discretion of the investigator, patients could switch from deferasirox DT to deferasirox FCT at any time during Period 1 of the Core phase, and vice versa, from deferasirox FCT to deferasirox DT at any time during Period 2 of the Core phase. Re-switching treatments was not allowed within each period.
2. Extension Phase:

Participants could continue deferasirox FCT formulation as per the judgment of the investigator, through an extension phase for a maximum of 48 weeks months from the last dose of deferasirox FCT received at the end of period 2 in the Core Phase or until one of the end of study criteria defined is met, whichever came first. Participation in the extension phase was optional.

The end of study was defined as the earliest occurrence of one of the following:

* The patient reached Week 96 in the Extension phase.
* Deferasirox FCT was locally reimbursed for this indication (only applicable for the Extension phase)
* Another clinical study or post-trial access program became available that could continue to provide deferasirox FCT in this patient population and all patients ongoing were eligible to be transferred to that clinical study.

Arms:
arm 1: Participants were treated with deferasirox DT followed by deferasirox FCT (core phase). Those who entered the extension phase were treated with deferasirox FCT

Interventions: intervention 1: Deferasirox dispersable tablet (DT) intervention 2: Deferasirox film coated tablet (FCT)
Intervention descriptions: intervention 1: Deferasirox DT was provided as 125 mg, 250 mg, 500 mg dispersible tablets for oral use. The strengths provided in an individual country could differ and reflected the strengths available commercially in each country.

For iron chelation naive participants, the starting dose on Baseline Day 1 was 20 mg/kg/day in TDT and 10 mg/kg/day in NTDT.

For iron chelation (deferoxamine and/or deferiprone) pre-treated participants, the starting dose was equivalent to the dose of deferoxamine received (for participants pre-treated with deferoxamine) and based on their serum ferritin levels (for participants pre-treated with deferiprone).

Participants took deferasirox DT once daily for 24 weeks (core phase). The required number of deferasirox DT tablets were to be dispersed with gentle stirring in a glass of water. intervention 2: Deferasirox FCT was provided as 90 mg, 180 mg, 360 mg film coated tablets for oral use. The FCT starting dose on Week 25 was 14 mg/kg/day in TDT and 7 mg/kg/day in NTDT.

Participants took deferasirox FCT once daily for 24 weeks during the core phase and up to 48 weeks during the extension phase. For patients with difficulties in swallowing deferasirox FCT, it was allowed to crush the film-coated tablets and administer the study drug by sprinkling the full dose on soft food (like yogurt or apple puree).

Protocol document:
Prot_000.pdf: 
Clinical Development
ICL670, DEFERASIROX
Oncology Clinical Protocol CICL670FIC05 / NCT02993224
Open-label, multicenter, single arm, phase II study 
assessing treatment patient preference for new deferasirox 
formulation (film-coated tablet) compared to the reference 
deferasirox dispersible tablet formulation 
Authors
 
Document type
Amended Protocol Version (Clean)
EUDRACT number
2016‐002282‐61
Version number
01 (incorporating amendment 01)
Development phase
II
Document status
Final
Release date
12-Feb-2019
Property of Novartis
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis
Template version 14-July-2016


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Protocol No. CICL670FIC05
Table of contents
Table of contents .................................................................................................................2
List of tables ........................................................................................................................6
List of abbreviations............................................................................................................7
Glossary of terms.................................................................................................................9
Protocol summary:.............................................................................................................10
Amendment 1 (12-Feb-2019)............................................................................................14
1
Background........................................................................................................................16
1.1
Overview of disease pathogenesis, epidemiology and current treatment..............16
1.2
Introduction to investigational treatment(s) and other study treatment(s).............17
1.2.1
Overview of deferasirox dispersible tablet: ..........................................17
1.2.2
Overview of deferasirox film-coated tablet ..........................................19
2
Rationale............................................................................................................................20
2.1
Study rationale and purpose...................................................................................20
2.2
Rationale for the study design ...............................................................................20
2.3
Rationale for dose and regimen selection..............................................................20
2.4
Rationale for choice of combination drugs............................................................21
2.5
Rationale for choice of comparators drugs............................................................21
3
Objectives and endpoints...................................................................................................21
4
Study design ......................................................................................................................24
4.1
Description of study design ...................................................................................24
4.2
Switching of treatments.........................................................................................25
4.3
Timing of interim analyses ....................................................................................26
4.4
Definition of end of study......................................................................................26
4.5
Definition of patient completed.............................................................................26
4.6
Definition of early study termination ....................................................................26
5
Population..........................................................................................................................26
5.1
Patient population..................................................................................................26
5.2
Inclusion criteria ....................................................................................................27
5.3
Exclusion criteria...................................................................................................27
6
Treatment...........................................................................................................................29
6.1
Study treatment......................................................................................................29
6.1.1
Dosing regimen.....................................................................................29
6.1.2
Ancillary treatments..............................................................................32
6.1.3
Rescue medication ................................................................................32
6.1.4
Treatment duration................................................................................32


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6.2
Dose modifications................................................................................................32
6.2.1
Dose modification and dose delay ........................................................32
6.2.2
Treatment interruption and treatment discontinuation..........................35
6.2.3
Follow-up for toxicities.........................................................................36
6.3
Prior and Concomitant medications.......................................................................36
6.3.1
Permitted concomitant therapy .............................................................36
6.3.2
Prohibited concomitant therapy ............................................................37
6.4
Patient numbering, treatment assignment..............................................................37
6.4.1
Patient numbering .................................................................................37
6.4.2
Treatment assignment ...........................................................................37
6.4.3
Treatment blinding................................................................................37
6.5
Study drug preparation and dispensation...............................................................37
6.5.1
Study treatment packaging and labeling ...............................................38
6.5.2
Drug supply and storage........................................................................38
6.5.3
Study drug compliance and accountability ...........................................38
6.5.4
Disposal and destruction .......................................................................39
7
Visit schedule and assessments .........................................................................................39
7.1
Study flow and visit schedule................................................................................39
7.1.1
Screening...............................................................................................48
7.1.2
Treatment period...................................................................................49
7.1.3
Study Evaluation Completion visit including premature withdrawal...50
7.1.4
Follow up period ...................................................................................51
7.2
Assessment types...................................................................................................52
7.2.1
Efficacy assessments.............................................................................52
7.2.2
Safety and tolerability assessments.......................................................52
7.2.3
Other assessments .................................................................................56
7.3
Patient reported outcomes......................................................................................56
7.3.1
Preference Questionnaire ......................................................................56
7.3.2
mSICT – patients greater or equal to 10 years old................................57
7.3.3
Observer Reported mSICT – patients less than 10 years old................58
7.3.4
GI Symptoms – patients greater or equal to 10 years old .....................59
7.3.5
Observer Reported GI Symptoms – patients less than 10 years old .....59
7.3.6
Palatability – patients greater or equal to 10 years old .........................59
7.3.7
Observer Reported Palatability – patients less than 10 years old .........60
8
Safety monitoring and reporting........................................................................................61
8.1
Adverse events.......................................................................................................61


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8.1.1
Definitions and reporting ......................................................................61
8.1.2
Laboratory test abnormalities................................................................62
8.2
Serious adverse events...........................................................................................62
8.2.1
Definitions.............................................................................................62
8.2.2
Reporting...............................................................................................63
8.3
Emergency unblinding of treatment assignment ...................................................63
8.4
Pregnancies............................................................................................................64
8.5
Warnings and precautions......................................................................................64
8.6
Data Monitoring Committee..................................................................................64
8.7
Steering Committee ...............................................................................................64
9
Data collection and management.......................................................................................64
9.1
Data confidentiality ...............................................................................................64
9.2
Site monitoring ......................................................................................................65
9.3
Data collection.......................................................................................................65
9.4
Database management and quality control............................................................66
10 Statistical methods and data analysis ................................................................................66
10.1
Analysis sets ..........................................................................................................66
10.2
Patient demographics/other baseline characteristics .............................................67
10.2.1
Demographics and baseline characteristics...........................................67
10.2.2
Medical history......................................................................................67
10.3
Treatments (study treatment, concomitant therapies, compliance) .......................68
10.3.1
Study Treatment....................................................................................68
10.3.2
Prior and concomitant medication ........................................................68
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.......................70
10.4.4
Supportive and Sensitivity analyses......................................................70
10.5
Secondary objectives .............................................................................................70
10.5.1
Key secondary objective(s)...................................................................70
10.5.2
Other secondary efficacy objectives .....................................................70
10.5.3
Safety objectives ...................................................................................72
10.5.4
Pharmacokinetics ..................................................................................75
10.5.5
Biomarkers............................................................................................75
10.5.6
Patient-reported outcomes.....................................................................75
10.6
Exploratory objectives...........................................................................................77


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10.7
Interim analysis......................................................................................................77
10.8
Sample size calculation..........................................................................................77
10.9
Power for analysis of key secondary variables......................................................77
11 Ethical considerations and administrative procedures ......................................................78
11.1
Regulatory and ethical compliance........................................................................78
11.2
Responsibilities of the investigator and IRB/IEC/REB.........................................78
11.3
Informed consent procedures.................................................................................78
11.4
Discontinuation of the study..................................................................................79
11.5
Publication of study protocol and results...............................................................79
11.6
Study documentation, record keeping and retention of documents.......................79
11.7
Confidentiality of study documents and patient records .......................................80
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
14 Appendices ........................................................................................................................83
14.1
Dosing tables (Deferasirox DT, Deferasirox FCT) ...............................................83
14.2
Examples of light meal ..........................................................................................96
14.3
Algorithm for Preference questionnaire completion .............................................98


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List of tables
Table 3-1
Objectives and related endpoints ..........................................................22
Table 6-1
Equivalent FCT starting dose at Week 25.............................................29
Table 6-2
Dose and treatment schedule.................................................................31
Table 6-3
Daily dose of study drug based on serum ferritin level ........................31
Table 7-1
Visit Evaluation Schedule - Core Phase................................................40
Table 7-2
Visit Evaluation Schedule - Extension Phase .......................................44
Table 7-3
Equivalent dose to be used: Deferasirox DT vs Deferasirox FCT........49
Table 7-4
Central Clinical laboratory parameters collection plan........................54
Table 7-5
Scoring Matrix ......................................................................................60
Table 10-1
Definition of notable/extended ranges for laboratory test.....................74
Table 10-2
Definition of notable ranges for vital signs and weight ........................75
Table 14-1
Deferasirox DT dosing table for 5 mg/kg/day ......................................83
Table 14-2
Deferasirox DT dosing table for 10 mg/kg/day ....................................83
Table 14-3
Deferasirox DT dosing table for 15 mg/kg/day ....................................84
Table 14-4
Deferasirox DT dosing table for 20 mg/kg/day ....................................84
Table 14-5
Deferasirox DT dosing table for 25 mg/kg/day ....................................85
Table 14-6
Deferasirox DT dosing table for 30 mg/kg/day ....................................85
Table 14-7
Deferasirox DT dosing table for 35 mg/kg/day ....................................87
Table 14-8
Deferasirox DT dosing table for 40 mg/kg/day ....................................88
Table 14-9
Deferasirox FCT dosing table for 3.5 mg/kg/day .................................89
Table 14-10
Deferasirox FCT dosing table for 7 mg/kg/day ....................................89
Table 14-11
Deferasirox FCT dosing table for 10.5 mg/kg/day ...............................89
Table 14-12
Deferasirox FCT dosing table for 14 mg/kg/day ..................................90
Table 14-13
Deferasirox FCT dosing table for 17.5 mg/kg/day ...............................90
Table 14-14
Deferasirox FCT dosing table for 21 mg/kg/day ..................................91
Table 14-15
Deferasirox FCT dosing table for 24.5 mg/kg/day ...............................92
Table 14-16
Deferasirox FCT dosing table for 28 mg/kg/day ..................................93
Table 14-17
Dose Regimen based on Serum Ferritin level.......................................94
Table 14-18
Patients pre-treated with Deferoxamine................................................95


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List of abbreviations
AE
Adverse Event
AML
Acute Myeloid Leukemia
ALT
Alanine aminotransferase/glutamic pyruvic transaminase/GPT
AST
Aspartate aminotransferase/glutamic oxaloacetic transaminase/GOT
AUClast 
The AUC from time zero to the last measurable concentration sampling time 
(tlast) (mass x time x volume-1) after single dose 
AUCtau
The AUC calculated to the end of a dosing interval (tau) at steady-state (amount 
x time x volume-1)
b.i.d.
bis in diem/twice a day
C2hr
Post-dose 2 hr plasma concentration
Cmax
The maximum (peak) observed plasma, blood, serum, or other body fluid drug 
concentration after single dose administration (mass x volume-1)
CRO
Contract Research Organization
Ctrough
Pre-dose plasma concentration
CSR
Clinical study report
DFO
Deferoxamine
DFP
Deferiprone
DS&E
Drug Safety and Epidemiology
DT 
Dispersible Tablet
eCRF
Electronic Case Report/Record Form
ECG
Electrocardiogram
EOS
End Of Study 
i.v.
intravenous(ly)
FAS
Full Analysis Set
FCT 
Film-coated tablet
GI 
Gastrointestinal
ICH
International Conference on Harmonization
ICT
Iron chelation therapy
IEC
Independent Ethics Committee
IO
Iron Overload
IPSS-R
Revised International Prognostic Scoring System
IRB
Institutional Review Board
IRT
Interactive Response Technology that includes Interactive Voice Response 
System and Interactive Web Response System
LC-MS/MS
Liquid Chromatography-Mass Spectrometry/Mass Spectrometry
LIC
Liver Iron Concentration
MDS
Myelodysplastic syndrome
o.d.
omnia die/once a day
NCCN
National Comprehensive Cancer Network
NOAELs
No-adverse-effect-levels
PAS
PK Anaylisis Set
p.o.
per os/by mouth/orally
PHI
Protected Health Information


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PRO
Patient Reported Outcome
RAP
The Report and Analysis Plan (RAP) is a regulatory document which provides 
evidence of preplanned analyses
RBC
Red Blood Cell
REB
Research Ethics Board
SAE
Serious Adverse Event
SEC
Study Evaluation Completion
SOP
Standard Operating Procedure
QoL
Quality of Life
VES
Visit Evaluation Schedule


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Glossary of terms
Assessment
A procedure used to generate data required by the study
Dose level
The dose of drug given to the patient (total daily or weekly etc.). 
Enrollment
Point/time of patient entry into the study; the point at which informed 
consent must be obtained (i.e. prior to starting any of the procedures 
described in the protocol)
Investigational drug
The study treatment whose properties are being tested in the study; this 
definition is consistent with US CFR 21 Section 312.3 and is synonymous 
with “investigational new drug.”
Investigational treatment
Drug whose properties are being tested in the study as well as their 
associated placebo and active treatment controls (when applicable). This 
also includes approved drugs used outside of their indication/approved 
dosage, or that are tested in a fixed combination. Investigational treatment 
generally does not include other study treatments administered as 
concomitant background therapy required or allowed by the protocol when 
used in within approved indication/dosage
Medication number
A unique identifier on the label of each study treatment package which is 
linked to one of the treatment groups of a study
Patient Number (Patient No.) 
A unique identifying number assigned to each patient 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.
Personal Data
Subject information collected by the Investigator that is transferred to 
Novartis for the purpose of the clinical trial. This data includes subject 
identifier information, study information and biological samples.
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, except End of Treatment scheduled 
assessments.
Stop study participation
Point/time at which the patient came in for a final evaluation visit  (study 
evaluation schedule) 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
Variable
Identifier used in the data analysis; derived directly or indirectly from data 
collected using specified assessments at specified timepoints
Withdrawal of consent
Withdrawal of consent from the study occurs only when a subject does not 
want to participate in the study any longer, and does not allow any further 
collection of personal data


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Protocol summary: 
Protocol Number
CICL670FIC05
Title
Open-label, multicenter, single arm, phase II study assessing treatment 
patient preference for new deferasirox formulation (film-coated tablet) 
compared to the reference deferasirox dispersible tablet formulation
Brief title
Study to assess patient preference of deferasirox DT (dispersible tablet) or 
deferasirox FCT (film-coated tablet) in thalassemia patients.
Sponsor and 
Clinical Phase
Novartis Phase II
Investigation type
Drug
Study type
Interventional 
Purpose and 
rationale
The purpose of the present study is to:

evaluate patient’s preference of deferasirox DT or deferasirox FCT 
formulations in patients with transfusion-dependent thalassemia or non-
transfusion-dependent thalassemia as measured by preference 
questionnaire at Week 48

evaluate patient’s preference of deferasirox DT or deferasirox FCT 
formulations or previous iron chelation in patients with transfusion-
dependent thalassemia or non- transfusion-dependent thalassemia as 
measured by preference questionnaire at Week 4, Week 24 and Week 28.

evaluate patient’s palatability, GI symptom and satisfaction of deferasirox 
DT or deferasirox FCT formulations or previous iron chelation in patients 
with transfusion-dependent thalassemia or non- transfusion-dependent 
thalassemia as measured by PRO questionnaire at Screening Visit, Week 
4, Week 24, Week 28 and Week 48.

evaluate any difference of preference and other assessments between 
each subgroup, i.e., patients with transfusion-dependent or non-
transfusion-dependent thalassemia.

evaluate the overall safety of deferasirox DT compared with deferasirox 
FCT formulations in patients with transfusion-dependent thalassemia or 
non- transfusion-dependent thalassemia as measured by frequency and 
severity of adverse events and changes in laboratory values of interest 
during deferasirox FCT (Week 25 to 48) compared with deferasirox DT 
(Baseline day 1 to 24)

assess compliance based on pill-countevaluate efficacy of deferasirox 
(both DT and FCT) in decreasing serum ferritin levels
Primary Objective

To evaluate patient preference of deferasirox FCT or deferasirox DT in 
patient with transfusion –dependent thalassemia or non-transfusion –
dependent thalassemia as measured by preference questionnaire at 
Week 48
Secondary 
Objectives

To evaluate patient’s palatability, GI symptom and satisfaction of 
deferasirox FCT or deferasirox DT or previous iron chelation based on
Patient Reported Outcomes (PRO)

To evaluate patient preference of deferasirox FCT or deferasirox DT or
previous iron chelation 

To evaluate the reason behind preference for deferasirox FCT versus 
deferasirox DT


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
To evaluate the effect of deferasirox FCT compared with deferasirox DT 
on patient compliance using pill count

To evaluate the overall safety of deferasirox FCT compared with 
deferasirox DT

To evaluate efficacy of deferasirox (both formulations DT and FCT) in 
decreasing serum ferritin levels
Study design
This is a an open-label, multicenter, single arm, phase II study aimed at 
collecting data on preference for iron chelation therapy in patients with 
transfusion-dependent thalassemia (TDT) or non-transfusion-dependent 
thalassemia (NTDT) throughout a 48 week treatment period.
The study is divided into 2 phases:
-
Core Phase:

Screening period (visit number 1): which last up to 4 weeks to 
determine the patient eligibility, followed by,

Period 1: from Baseline visit Day 1  to Week 24: 

TDT patients: Deferasirox DT starting at 20 mg/Kg/day to maximum 
dose: 40 mg/Kg/day

NTDT patients: Deferasirox DT starting at 10 mg/Kg/day to maximum 
dose: 20 mg/Kg/day

Period 2: from Week 25 to Week 48: 

TDT patients: Deferasirox FCT starting at 14 mg/Kg/day to 
maximum dose: 28 mg/Kg/day

NTDT patients: Deferasirox FCT starting at 7 mg/Kg/day to 
maximum dose: 14 mg/Kg/day
-
Extension Phase:

Deferasirox FCT: from Week 49 until Study Evaluation Completion 
(SEC - visit number 777) or until at least one of the End of Study 
criterion is met, whichever comes first:

TDT patients: Deferasirox FCT starting at 14 mg/Kg/day to 
maximum dose: 28 mg/Kg/day

NTDT patients: Deferasirox FCT starting at 7 mg/Kg/day to 
maximum dose: 14 mg/Kg/day.
Population
Approximately 145 patients aged ≥ 2 years, male or female with transfusion-
dependent thalassemia or non-transfusion-dependent thalassemia requiring 
chelation therapy due to iron overload will be included in this study. Patients 
may have been previously treated with iron chelators for at least 6 months 
(other than Deferasirox) or be chelation naïve. In the case of a pre-treated 
patient, the patient must be continuously treated by other chelators for at least 
6 months.
The investigator or designee must ensure that only patients who meet all the 
following inclusion and none of the exclusion criteria are offered treatment in 
the study.
Key Inclusion 
criteria

Written informed consent/assent must be provided. For pediatric patients, 
consent will be obtained from parent(s) or legal patient’s representative. 

Male and female patient aged ≥ 2 years

Deferasirox naïve patient or chelation naive patient or treated by other 
chelators for at least 6 months continuously, such as:

Deferiprone/ DFP 


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
Deferoxamine /DFO

Combination (DFO + DFP)

Subject is willing to discontinue current iron chelation therapy at least 5
days prior to the day 1 and for the duration of the study

Patients with transfusion-dependent thalassemia with transfusional iron 
overload as shown by:

a serum ferritin level of > 1000 ng/ml at screening and if available, 
LIC > 3 mg Fe/g dw within 6 months prior to screening

Patients with non-transfusion-dependent thalassemia with iron 
overload as shown by:

a serum ferritin level of ≥ 800 ng/ml at screening and if available, LIC 
≥ 5 mg Fe/g dw within 6 months prior to screening.
Key Exclusion 
criteria

Male and female patient aged < 2 years

Creatinine clearance below the contraindication limit in the locally 
approved prescribing information. 

Serum creatinine level > 1.5 x ULN (upper limit of normal)

AST (SGOT) / ALT (SGPT) > 5xULN, unless LIC is confirmed as >10 mg 
Fe/dw within 6 months prior to screening visit.

Significant proteinuria as indicated by a urinary protein/creatinine ratio > 
0.5 mg/mg in a non-first void urine sample.

Patients with significant impaired gastrointestinal (GI) function or GI 
disease that may significantly alter the absorption of oral deferasirox (e.g. 
ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, 
malabsorption syndrome, or small bowel resection).

Clinical or laboratory evidence of active Hepatitis B (HBsAg in the 
absence of HBsAb) or Hepatitis C (HCV Ab positive with HCV RNA 
positive).

Patients participating in another clinical trial or receiving an investigational 
drug
Investigational 
and reference 
therapy
Deferasirox (ICL670) dispersible tablets as per label (Exjade®)
Deferasirox (ICL670) film- coated tablets as per label 
Efficacy 
assessments
Efficacy of Deferasirox DT and FCT will be evaluated based on changes in 
Serum ferritin levels from Day 1 baseline 
Safety 
assessments

Safety will be monitored by assessing the following parameters:

Adverse events and in particular specific gastrointestinal events, up to 
at least 30 days following last dose of study drug

Hematology, blood chemistry (including renal and hepatic parameters) 
and urinalysis

Vitals signs,

Physical examinations

Ocular examinations

Auditory examinations

Chest X-Ray

ECGs
Other 
assessments

The study will include four Patient Reported Outcome (PRO) 
measurements: patient preference questionnaire, patient palatability 


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questionnaires, GI symptoms and the mSITC (modified Satisfaction with 
iron chelation therapy) questionnaires

The compliance will be measured by pill count
Data analyses

The primary analysis is based on patient preference of FCT over DT at 
Week 48, based on preference questionnaire. 

The null hypothesis is that there is no difference in the proportion of 
patients preferring FCT or DT at Week 48. The alternative hypothesis is 
that there is a difference in the proportion of patients preferring FCT or DT 
at Week 48. 

The primary analysis will be tested based on McNemar’s test and Odd’s 
Ratio (OR) and 95% Confidence Interval (CI) will also be provided for 
comparing the proportions of preferences over FCT and DT.
Key words
New formulation, deferasirox, chelation, iron overload, compliance, 
satisfaction, palatability, PRO, preference, safety


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Amendment 1 (12-Feb-2019)
Amendment rationale
The purpose of this amendment is to provide additional clarity to the study Investigators in 
relation to dosing of deferasirox for patients with non-transfusion dependent thalassemia 
(NTDT), those patients changing therapy from deferiprone, and those patients with body weight 
lower than 20 kg; to provide additional guidance in relation to the ocular and auditory 
assessments; to revise the underlying assumptions used to calculate the sample size of the study; 
to clarify the inclusion criterion that relates to prior therapy; to correct inconsistencies and typos; 
and to update withdrawal of consent language. 
At the time of this amendment, 132 patients have been enrolled in the study.
The protocol has been amended to provide clearer guidance on dose titration and delineate more 
clearly the maximum permitted dose of deferasirox for patients with non-transfusion dependent 
thalassemia. In general, these patients require lower doses of iron chelation therapy than patients 
with transfusion dependent thalassemia and therefore additional guidance in relation to 
deferasirox dosing specifically for this patient group was required. The results of the THETIS 
study [Taher AT et al, 2016] demonstrated that doses of up to 30 mg/kg/day of deferasirox in 
patients with NTDT was effective (at week 52, mean LIC ± SD decreased signiﬁcantly from 
15.13 ± 10.72 mg Fe/g dw at baseline to 8.46 ± 6.25 mg Fe/g dw [absolute change from baseline, 
−6.68 ± 7.02 mg Fe/g dw [95% CI: −7.91, −5.45]; P b 0.0001]). In addition, the safety profile 
of deferasirox in this study was consistent with the already established one. The THETIS study 
based dose adjustments on Liver Iron Concentration [LIC] results. In this trial, dose adjustments 
are based on serum ferritin levels. The relationship between LIC and serum ferritin in patients 
with NTDT and the derivation of  corresponding clinically relevant thresholds were established 
by Taher AT et al [2015] using data from the THALASSA trial. These thresholds have been 
implemented in this amendment.
Table 14-16, which guided Investigators on the dose of deferasirox patients who had received 
prior deferiprone should be initiated on, has been removed due to a lack of supporting evidence. 
Rather, the starting dose of deferasirox will henceforth be based on the patient’s serum ferritin 
level, consistent with clinical practice and the dosing guidance throughout the protocol. An 
additional change made in Appendix 14 was the inclusion of dosing guidance for children 
weighing less than 20 kg.
The minimum requirements for ocular and auditory assessments in pediatric patients have been 
clarified based on queries raised by the participating Investigators to ensure the consistency of 
required safety information. 
Recently, additional analyses regarding patient preference with respect to deferasirox DT and 
deferasirox FCT from the ECLIPSE study have been published (Taher AT et al, 2018). In the 
ECLIPSE study, patients only received one formulation of deferasirox (either DT or FCT). 
Patients were asked to complete a preference questionnaire that included all possible 
formulations of iron chelation therapy. The preference for the FCT formulation ranged between 
41-60% of patients, the preference for DT ranged between <5 – 18% and no preference 
(excluding missing assessments) did not exceed 10%. Based on this recent data, the assumptions 
underlying the sample size of this study have been updated, resulting in a reduction in the 


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number of patients required to enrol in the study (25 fewer) without impacting the power of the 
study.
The final substantial clarification made in this amendment is to specify that all patients must be 
deferasirox naive rather than Exjade naive given the availability of generic formulations of 
deferasirox in many of the countries participating in the study.
As of October 22, 2018, 92 patients have been enrolled in this trial.Protocol changes: The main
changes in this amendment are:

Clarify inclusion criteria number 3, by replacing Exjade naïve patient with Deferasirox 
naïve patient

Clarify requirements for ocular and auditory assessments

Add the withdrawal of informed consent section

Provide additional dosing guidance for patients who have been treated with deferiprone

Provide additional dosing guidance for NTDT patients

Update Appendix 14.1: Deferasirox DT and FCT dosing table starting from a body 
weight of 10 kg

Revise the sample size calculation

Correct inconsistencies, typographical and other errors detected in the protocol

Add Appendix 14.3 Algorithm for Preference questionnaire completion
IRBs/IECs
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 
amended protocol.


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1
Background
1.1
Overview of disease pathogenesis, epidemiology and current 
treatment
Chronic iron overload represents a serious complication of potentially lifesaving blood 
transfusions which are the mainstay of therapy in transfusion-dependent anemias. Since humans 
have no mechanism for the active elimination of iron from the body, excess iron received via 
transfusions deposits in various tissues of the body, particularly the liver, heart and endocrine 
organs, leading to end-organ dysfunction and eventually organ failure. Indeed, organ failure 
due to chronic iron overload represents the major cause of death in patients with β-thalassemia 
major who receive blood transfusion regularly without appropriate chelation therapy 
(Cappellini et al, 2006).
Overview β-thalassemia
Beta-thalassemias are a group of hereditary blood disorders characterized by anomalies in the 
synthesis of the beta chains of hemoglobin resulting in variable phenotypes ranging from severe 
anemia to clinically asymptomatic individuals.  
Beta-thalassemia is prevalent in the Mediterranean basin, 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. 
The total annual incidence of symptomatic individuals is estimated at 1 in 100,000 throughout 
the world and 1 in 10,000 people in the European Union. However accurate data on carrier rates 
in many populations are lacking. 
Three main phenotypic forms have been described: thalassemia major, thalassemia intermedia 
and thalassemia minor with β-thalassemia major being the most severe form of the disease. 
Individuals with β-thalassemia major usually present within the first two years of life with 
severe anemia requiring regular red blood cell (RBC) transfusions. Findings in untreated or 
poorly transfused patients with thalassemia major are growth retardation, pallor, jaundice, poor 
musculature, hepatosplenomegaly, development of masses from extramedullary hematopoiesis, 
and skeletal changes that result from expansion of the bone marrow. If left untreated, 80% of 
β-thalassemia major patients die within the first 5 years of life due to anemia-related conditions. 
As such, transfusion therapy remains the mainstay of treatment in β-thalassemia major patients. 
Regular transfusion therapy leads to iron overload with iron-related complications including 
endocrine such as growth retardation, failure of sexual maturation, diabetes mellitus; cardiac 
such as dilated myocardiopathy; and liver including fibrosis and cirrhosis. 
The therapeutic concept of iron chelation has been established with more than 50 years of 
clinical experience with Desferal®, deferoxamine mesylate, (DFO). However, poor oral 
bioavailability and short plasma half-life (t1/2) has necessitated its application as slow 
subcutaneous (s.c.) or intravenous (i.v.) infusion. Iron-chelation therapy with DFO is extremely 
demanding however, and many patients experience considerable discomfort from
administration of the drug, as well as a significant negative impact on their Quality of Life (QoL) 
(Arboretti et al, 2001) thus resulting in poor compliance. The lack of compliance with DFO 


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administration in patients who have serious blood disorders has necessitated recognition for the 
need of an effective iron chelator which can be given via the more convenient oral route. 
Compliance with iron chelation therapy (ICT) mainly influences frequency and severity of iron 
overload-related complications (Galanello et al Origa 2010) with demonstrated improvement in 
organ dysfunction and survival in patients compliant with therapy (Gabutti et al 1996)
Transfusions and oral iron chelation therapy have dramatically improved the quality of life for 
patients with severe anemias. Previously a rapidly fatal disease in early childhood, β-
thalassemia is now a chronic disease compatible with a prolonged life expectancy. Today, life 
expectancy varies between 25 and 55 years, depending on patient compliance with medical 
treatment, particularly iron chelation (Cappellini MD 2008)
1.2
Introduction to investigational treatment(s) and other study 
treatment(s)
1.2.1
Overview of deferasirox dispersible tablet:
The orally available tridentate iron chelator deferasirox (company research code ICL670) was 
first approved for the treatment of chronic iron overload due to blood transfusions in adults and 
pediatric patients aged 2 years and older in the United States in November 2005 and is currently 
approved for this indication in more than 100 countries. Deferasirox has also been approved in 
more than 60 countries for the treatment of chronic iron overload in patients with non-
transfusion dependent thalassemia aged 10 years and older. 
Deferasirox dispersible tablet (DT) is currently marketed as Exjade® in three dosing strengths 
(125, 250, and 500 mg) and is dosed based on body weight. The currently approved dose range 
is up to 40 mg/kg/day; the approved starting dose is 20 mg/kg/day. Initial daily doses of 10 or 
30 mg/kg may be considered depending on treatment aim and transfusion intensity. Deferasirox 
DT is to be taken once daily on an empty stomach, at least 30 minutes before the next meal. 
Administration requires dispersion of the tablets in a glass of water, orange juice or apple juice, 
which takes approximately 3 minutes. 
1.2.1.1
Non-clinical experience
Deferasirox is an N-substituted bis-hydroxyphenyl-triazole, a class of tridentate iron chelators. 
It is available as a dispersible tablet containing 125, 250, or 500 mg of drug substance. In certain 
countries, deferasirox is available as dispersible tablet containing 100 or 400 mg of drug 
substance. In addition, new formulations, such as swallowable film-coated tablets containing 
90, 180 or 360 mg of drug substance and as oral granules corresponding to an amount equivalent 
to 90, 180 and 360 mg of drug substance, have also been produced.
The potent, specific ability of deferasirox to mobilize and promote the excretion of tissue iron 
has been demonstrated in animal models; it was twice as effective as parenteral deferoxamine 
(Desferal®, DFO) and 5-fold more effective than deferiprone (Ferriprox®) in iron-loaded rats, 
and more than 10-fold as effective as deferiprone at equimolar doses in iron-loaded marmosets.
Deferasirox has been tested in vitro and in vivo in animal toxicology, carcinogenicity, and safety 
pharmacology studies. The compound was generally well tolerated and prohibitive toxicities 


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were not observed in rodent (rat) and non-rodent (marmoset) species. Many of the observed 
effects, particularly to the kidney, are considered to be a result of iron deprivation. No-adverse-
effect-levels (NOAELs) in 4-week studies were 10mg/kg in rats (standard diet) and 65 and 130 
mg/kg in male and female marmosets, respectively. The NOAELs in chronic studies were 30 
mg/kg in rats (diet supplemented with iron) and 40 mg/kg in marmosets. Deferasirox had no 
effect on animal fertility and is not teratogenic. In rats and transgenic mice, no relevant 
carcinogenic potential has been observed.
1.2.1.2
Clinical experience
Orally administered deferasirox is rapidly and well absorbed in mice, rats, marmosets and dogs 
and metabolism is mainly by glucuronidation. Deferasirox and its iron complex are highly 
bound (>98%) to plasma proteins, and distribution is mainly intravascular. Key elimination 
processes are hepatic metabolism and hepato-biliary elimination ultimately into the feces. 
Mrp2-mediated active transport processes may be involved in the excretion of deferasirox and 
metabolites. No notable retention of 14C radioactivity was observed in the tissues of rats 
following [14C] deferasirox administration. The placental barrier was passed only to a low 
extent; however, because deferasirox and/or its metabolites can be transferred into milk, women 
are advised not to breast feed.
In β-thalassemia patients, peak plasma concentrations of deferasirox were achieved with a 
median Tmax at between 1-4 hours at steady state and the mean terminal elimination half-life 
was in the range of 7-16 hours which support once daily administration. Following oral 
administration, the steady-state PK of deferasirox was dose-proportional over the dose range of 
10-40 mg/kg (dispersible tablets). Clinical studies demonstrated a dose-dependent increase in 
iron excretion.
Metabolism is primarily by glucuronidation and elimination is mainly via the biliary/fecal route.
In clinical drug-drug interaction studies, deferasirox inhibited metabolism of the CYP2C8 
substrate, repaglinide, and CYP1A2 substrate theophylline. No inhibitory effect on the CY3A4 
substrate midazolam was observed. The potent inducer of UGT and CYP isoenzymes, 
rifampicin led to a marked decrease of deferasirox exposure in humans. The absence of a drug 
interaction with digoxin was confirmed in humans.
Deferasirox dispersible tablet facilitates administration of the appropriate quantity of drug 
substance to pediatric and adult patients. Bioavailability studies with deferasirox dispersible 
tablets indicated that absorption is increased with food, and this is dependent on the fat content 
and the timing of food intake. Deferasirox dispersible tablet was taken on an empty stomach at 
least 30 minutes prior to food in clinical studies; this is also the recommendation in the label.
Deferasirox bioavailability was increased with the newly developed formulations (film-coated 
tablet and granule); therefore, equivalent deferasirox AUC was achieved at a lower dose with 
the new formulations (e.g., 1080 mg film-coated tablets vs. 1080 mg granules vs. 1500 mg 
dispersible tablets) although Cmax was higher with the new formulations compared to the current 
formulation (dispersible tablets). The absence of a substantial food effect with the new 
formulations allowed patients to take the drug either on an empty stomach or with a light meal 
[ICL670F2101].


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Results of a retrospective exposure-response analysis suggested that safety and efficacy of 
deferasirox are largely driven by overall exposure (AUC) and changes in Cmax are unlikely to 
result in worsening renal laboratory values.
1.2.2
Overview of deferasirox film-coated tablet
Based on the chronic nature of chelation therapy and the importance of patient compliance, an 
improved deferasirox formulation for oral administration is being developed (company research 
code ICL670). The film-coated tablet (FCT) to be used in this study contains the same active 
substance but has been strength-adjusted to achieve comparable exposure to the currently 
approved dispersible tablet. The film-coated tablet (FCT) will be available in three dose 
strengths (90 mg, 180 mg and 360 mg) and is dosed based on body weight. The film-coated 
tablets can be taken with or without a light meal.
Deferasirox film-coated tablet (FCT) is already marketed in some countries like USA or Canada, 
as Jadenu®.
Pharmacokinetics 
Deferasirox film-coated tablets are a strength-adjusted formulation of deferasirox with higher 
bioavailability compared to the Exjade® dispersible tablet formulation. After strength-
adjustment, the film-coated tablet formulation (360 mg strength) was equivalent to Exjade®
dispersible tablets (500 mg strength) with respect to the mean area under the plasma 
concentration time curve (AUC) under fasting conditions [74]. The Cmax was increased by 30% 
(90% CI: 20.3% - 40.0%); however a clinical exposure/response analysis has revealed no 
evidence of clinically relevant effects of such an increase.
Absorption 
Deferasirox (dispersible tablet formulation) is absorbed following oral administration with a 
median time to maximum plasma concentration (tmax) of about 1.5 to 4 hours. The absolute 
bioavailability (AUC) of deferasirox (dispersible tablet formulation) was about 70% compared 
to an intravenous dose. The absolute bioavailability of the film-coated tablet formulation has 
not been determined. Bioavailability of deferasirox film-coated tablets was 36% greater than 
that with Exjade® dispersible tablets. 
A food-effect study involving administration of the film-coated tablets to healthy volunteers 
under fasting conditions and with a low-fat (fat content <10% of calories) or high-fat (fat 
content >50% of calories) meal indicated that the AUC and Cmax were slightly decreased after 
a low-fat meal (by 11% and 16%, respectively). After a high-fat meal, AUC and Cmax were 
increased (by 18% and 29%, respectively). The increases in Cmax due to the change in 
formulation and due to the effect of a high-fat meal may be additive and therefore, it is 
recommended that Deferasirox FCT should be taken either on an empty stomach or with a light 
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2
Rationale
2.1
Study rationale and purpose
The availability of deferasirox DT (Exjade®) as a once-daily oral chelation treatment provided 
patients with a treatment that was a significant improvement over parenteral deferoxamine 
therapy. This was confirmed in studies that measured satisfaction and quality of life of oral vs. 
parenteral chelation (Cappellini et al 2007, Osborne et al 2007)
Novartis has developed a film-coated tablet (FCT) with the same active substance as deferasirox 
DT but with modified excipients. 
After strength-adjustment, the new formulation was shown to achieve the same overall exposure 
(AUClast and AUCinf) as the currently approved dispersible tablet formulation in a single-dose 
healthy volunteer study [ICL670F2102]; the peak serum concentrations (Cmax) were 
approximately 30% higher. In addition, a food effect study [ICL670F2103] indicated that the 
FCT can be taken with a light meal (the current deferasirox DT has to be taken on an empty 
stomach, at least 30 mins before a meal). 
The purpose of the present study is fully described on Table 3-1.
2.2
Rationale for the study design
This is an open-label, multicenter, single arm, phase II study which will enroll patients with 
transfusion-dependent thalassemia and non-transfusion-dependent thalassemia. 
Patient preference is the primary objective of this study and will be addressed by measuring the 
proportion of patient claimed preference of deferasirox FCT over deferasirox DT assessed by a 
preference questionnaire at Week 48
Patients previously treated with iron chelators for at least 6 months continuously (excluding
deferasirox) or who are chelator naïve will be eligible to participate in this study. 
The study consists of two phases. The treatment duration for the core phase of 48 weeks is 
considered sufficient to assess the patient preference, safety, compliance and PRO profiles of 
the two formulations. Previous studies of pediatric and adolescent patients have demonstrated 
differences in iron chelation medication compliance within this time period (Jordan 2012, 
Alvarez 2009). The extension phase permits patients to continue receiving deferasirox FCT for 
a maximum of 12 months after completion of the core phase, or until one of the end of study 
criterion is met, whichever comes first.
Patient preference for different ICTs, satisfaction, palatability and GI symptoms will be 
assessed via validated questionnaires; overall safety, efficacy of deferasirox (both DT and FCT)
and pill count will be assessed as secondary objectives. The subgroups of interest are the 
patients with transfusion-dependent or non-transfusion-dependent thalassemia, as well as 
ethnicity.
2.3
Rationale for dose and regimen selection
Deferasirox is available in three dosing strengths: 125, 250 and 500 mg for dispersible tablets 
and 90, 180 and 360 mg for film-coated tablets.  


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For each patient, the dose is calculated by the physician based on the patient’s weight, and then 
rounded up or down to the nearest tablet configuration, which can result in a variance between 
the calculated and actual dose of up to 15%. This dosing paradigm is consistent with how 
deferasirox DT (Exjade®) has been developed with regard to safety and efficacy.
All Deferasirox naïve patient or chelation naive patients or patients who have been treated by 
other chelators such as Deferiprone(DFP) / Deferoxamine (DFO) or Combination (DFO + DFP)
for at least 6 months continuously, at the study entry will use a starting dose of:
-
Deferasirox DT of 20 mg/kg/day in transfusion-dependent thalassemia (TDT) 
-
Deferasirox DT of 10 mg/kg/day in non-transfusion-dependent thalassemia (NTDT),
The equivalent FCT starting dose is:
-
Deferasirox FCT of 14 mg/kg/day in transfusion-dependent thalassemia (TDT) 
-
Deferasirox FCT of 7 mg/kg/day in non-transfusion-dependent thalassemia (NTDT).
For patients with difficulties in swallowing Deferasirox FCT, it is allowed to crush the film-
coated tablets. It should be administered by sprinkling the full dose on soft food like yogurt or 
apple sauce (apple puree). For further instructions, refer to the Appendix 14.
Dose adjustments are permitted as follows:
-
Patients receiving the DT formulation: ± 5-10 mg/kg/day; maximum daily dose: 40 
mg/kg/day for TDT patients; 20 mg/kg/day for NTDT patients
-
Patients receiving the FCT formulation: ± 3.5-7 mg/kg/day; maximum daily dose: 28 
mg/kg/day for TDT patients; 14 mg/kg/day for NTDT patients.
For ICT naïve patients at study entry the dose can be adjusted after 4 weeks of study treatment 
and for ICT pre-treated patients, the dose should be adjusted if necessary every 3 months based 
on serum ferritin levels 
2.4
Rationale for choice of combination drugs 
Not applicable
2.5
Rationale for choice of comparators drugs 
Not applicable
3
Objectives and endpoints
Objectives and related endpoints are described in Table 3-1 below.


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Table 3-1
Objectives and related endpoints
Objective
Endpoint
Analysis
Primary
Refer to Section 10.4
To evaluate patient preference between
deferasirox FCT and deferasirox DT
Proportion of patient claimed preference of deferasirox FCT over 
deferasirox DT as measured by preference questionnaire at Week 
48
Secondary
Refer to Section 10.5.1
To evaluate patient preference of deferasirox 
FCT or deferasirox DT or previous iron chelation
Proportion of patient claimed preference of deferasirox FCT, 
deferasirox DT, and previous iron chelation as measured by 
preference questionnaire at Week 28
To evaluate patient preference of deferasirox 
DT or previous iron chelation 
Proportion of patient claimed preference of deferasirox DT, over 
previous iron chelation as measured by preference questionnaire at 
Week 4 and Week 24
To evaluate the reason behind preference for 
deferasirox FCT or deferasirox DT
Proportion of preference reasons for deferasirox FCT over 
deferasirox DT as measured by preference questionnaire at Week 
28 and Week 48
To evaluate the effect of deferasirox FCT
compared with deferasirox DT on patient 
compliance using pill count
Relative consumed pill count during deferasirox FCT (Week 25 to 
48) compared with deferasirox DT (Baseline day 1 to Week 24)
To evaluate the effect of deferasirox FCT 
compared with deferasirox DT or previous iron 
chelation on patient palatability using PRO
Absolute and relative change in domain scores of palatability
questionnaire over time during deferasirox FCT (Week 28 to 48) 
compared with deferasirox DT (Week 4 to 24) or previous iron 
chelation (Screening)
To evaluate the effect of deferasirox FCT 
compared with deferasirox DT or previous iron 
chelation on patient satisfaction using PRO
Absolute and relative change in domain scores of SICT 
questionnaire over time during deferasirox FCT (Week 28 to 48) 
compared with deferasirox DT (Week 4 to 24) or previous iron 
chelation (Screening)
To evaluate the effect of deferasirox FCT 
compared with deferasirox DT or previous iron 
chelation on patient GI symptom using PRO
Absolute and relative change in domain scores of SICT 
questionnaire over time during deferasirox FCT (Week 28 to 48) 
compared with deferasirox DT (Week 4 to 24) or previous iron 
chelation (Screening)
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Objective
Endpoint
Analysis
To evaluate the overall safety of deferasirox 
FCT compared with deferasirox DT
Overall safety, as measured by frequency and severity of adverse 
events and changes in laboratory values of interest during 
deferasirox FCT (Week 25 to 48) compared with deferasirox DT 
(Baseline day 1 to Week 24)
To evaluate efficacy of deferasirox (both DT and 
FCT) in decreasing serum ferritin levels
Absolute and relative change from baseline (Day 1) in serum ferritin 
on monthly basis 
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4
Study design
4.1
Description of study design
This is an open-label, multicenter, single arm, phase II study aimed at collecting data on 
preference for iron chelation therapy in patients with transfusion-dependent thalassemia (TDT) 
or non-transfusion-dependent thalassemia (NTDT) throughout a 48 week treatment period.
It is a pre-requisite for the patient to provide written consent for participation in this study. This 
must be in place prior to performing any study-related procedures or assessments, including 
those described at the screening visit (please refer to Table 7-1 and Table 7-2 
Patients will undergo up to 4 weeks of screening and if deemed eligible, will receive deferasirox 
dispersible tablet (DT) formulation for 24 weeks. At the completion of 24 weeks patients will 
be transitioned on Week 25 to an equivalent dose of the deferasirox film coated tablet (FCT) 
formulation and continue treatment until Week 48 (EOT of Core Phase). 
Patients can then continue deferasirox FCT formulation as per the judgment of the investigator,
through an extension phase for a maximum of 12 months from the last dose of deferasirox FCT 
received at the end of period 2 in the Core Phase. 
If one of the end of study criterion is met at any time during the study, the patient must 
discontinue from the study and should complete the Study Evaluation Completion (SEC - visit 
number 777). Please refer to Section 4.4 .
Patients must be followed up for 30 days after the last dose of study drug for safety evaluation 
(safety follow up visit).
-
Core Phase: 

Screening phase which lasts for a maximum of 4 weeks to determine patient 
eligibility followed by

Baseline visit (day 1)

Period 1: deferasirox DT as 20-40 mg/kg/day dose regimen of dispersible tablet 
formulation for 24 weeks followed by

Period 2: deferasirox FCT as 14-28 mg/kg/day dose regimen of film- coated tablet for 
24 weeks.
-
Extension Phase:
Deferasirox FCT as 14-28 mg/kg/day dose regimen of film-coated tablet.
-
PRO Validation Sub-study:

Patients in Egypt and Thailand may participate in this optional sub-study [sub-study 
protocol will only be submitted in the participating countries]
Participation in the extension phase is optional. Please refer to Section 4.4 for EOS criteria.
Study treatment should be administered by the patient once per day. Patients will return to the 
site every 2 weeks until Week 4 (V4) and then every 4 weeks for study medication and study 
assessments as specified in -Table 7-1 and Table 7-2.


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Serious adverse events, regardless of causality, occurring after the subject has provided consent 
until 30 days following the last administration of study treatment must be reported to the 
Novartis drug safety team within 24 hours of the investigator learning of its occurrence.
Patients who discontinue study treatment early before completing the study (regardless if the 
discontinuation occurs at core or extension phase) should be scheduled for a visit as soon as 
possible, at which time all of the assessments listed for SEC (visit 777) must be performed.
Figure 4-1
Study design
4.2
Switching of treatments
At the discretion of the investigator, patients can switch from deferasirox DT to deferasirox 
FCT at any time during Period 1 of the Core phase, and vice versa, from deferasirox FCT to 
deferasirox DT at any time during Period 2 of the Core phase.
This change and the rationale of the switch must be recorded in the CRF. Also the investigator 
must provide the preference questionnaire to the patient at the immediate next visit and then 
keep following the schedule of questionnaires pre-planned on Table 7-1 and Table 7-2 (for 
example; if the investigator decides to switch from deferasirox DT to deferasirox FCT at Week 
12, the preference questionnaire must be provided to the patient on the next visit, Week 16, and 
the rest of the preference questionnaires as per regular schedule: Week 24, Week 28 and Week 
48). Please refer to 14 Appendices for further information on preference questionnaire 
completion.
The investigator can decide in the best interest of the patient to switch from one formulation to 
the other with the agreement of the patient if an adverse event (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) grade ≥ 2 (GI symptoms, skin 
rash, laboratory abnormalities) occurred with deferasirox DT or deferasirox FCT.
Re-switching treatments is not allowed within each period in this study, which means that a 
patient cannot switch from Deferasirox DT to Deferasirox FCT and the switch back to 
Deferasirox DT, and viceversa (Deferasirox FCT to Deferasirox DT, and then back to 
Deferasirox FCT).  


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4.3
Timing of interim analyses
One interim analysis is planned in this study.An interim analysis will be performed when all 
enrolled patients complete Week 48 (Visit 15) to assess the patient preference after 6 months 
with deferasirox FCT treatment in comparison to deferasirox DT.
Refer to Section 2.2 and Section 10
4.4
Definition of end of study
All patients must remain within the study until Week 48 (last visit on Core Phase) unless one 
of the criteria defined in Section 7.1.3 (definition of premature patient withdrawal) is met, in 
which case, the patient must discontinue from the study and complete the Study Evaluation 
Completion Visit (SEC - visit number 777) within 7 days of discontinuing treatment. A patient 
will be considered as having “completed the study” if all the visits have been performed from 
Screening (visit number 1) to Week 48 (visit number 15).
The end of study is defined as the earliest occurrence of one of the following:
-
The patient has reached Week 96 at Extension phase.
-
Deferasirox FCT is locally reimbursed for this indication (only applicable in Extension 
phase)
-
Another clinical study or post-trial access program becomes available that can continue to 
provide deferasirox FCT in this patient population and all patients ongoing are eligible to 
be transferred to that clinical study
The investigator will be responsible for informing IRBs and/or EC.
Patients will perform a safety follow up visit 30 days after the last dose of study drug. 
4.5
Definition of patient completed
A patient will be considered as having “completed the study” if the patient has completed the 
core phase of the study, i.e., Week 48.”
4.6
Definition of early study termination
The study can be terminated at any time for any reason by Novartis. Should this be necessary, 
the patient should be seen as soon as possible and the same assessments should be performed 
as described in Section 7 for a prematurely withdrawn patient. The investigator may be 
informed of additional procedures to be followed in order to ensure that adequate consideration 
is given to the protection of the patient’s interests. The investigator will be responsible for 
informing IRBs and/or ECs of the early termination of the trial.
5
Population
5.1
Patient population
Approximately 145 patients aged ≥ 2 years, male or female with transfusion-dependent 
thalassemia or non-transfusion-dependent thalassemia requiring chelation therapy due to iron 


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overload will be included in this study. Patients may have been previously treated with iron 
chelators (excluding deferasirox) for at least 6 months or be chelation naïve.
The investigator or designee must ensure that only patients who meet all the following inclusion 
and none of the exclusion criteria are offered treatment in the study.
5.2
Inclusion criteria
Patients eligible for inclusion in this study have to meet all of the following criteria:
1. Prior to any screening procedures being performed, written informed consent/assent must 
be provided. For pediatric patients, consent will be obtained from the parent(s) or the
patient’s legal representative. Investigators will also obtain assent of patients according to 
local, regional or national guidelines.
2. Male and female patients aged ≥2 years
3. Deferasirox naïve patient or a chelation naive patient or a patient treated by other chelators 
for at least 6 months continuously, such as:
a. Deferiprone (DFP)
b. Deferoxamine (DFO)
c. Combination (DFO + DFP)
4. Subject is willing to discontinue current iron chelation therapy at least 5 days prior to the 
Study day 1 and for the duration of the study
5. Patients with transfusion-dependent thalassemia (independent of underlying condition) 
with transfusional iron overload as shown by:

a serum ferritin level of > 1000 ng/ml at screening and if available, LIC > 3 mg Fe/g 
dw within 6 months prior to screening
6. Patients with non-transfusion-dependent thalassemia with iron overload as shown by:

a serum ferritin level of ≥ 800 ng/ml at screening  and if available, LIC ≥ 5 mg Fe/g 
dw within 6 months prior to screening
5.3
Exclusion criteria
Patients eligible for this study must not meet any of the following criteria:
1. Creatinine clearance below the contraindication limit in the locally approved prescribing 
information. 
2. Serum creatinine level > 1.5 x ULN (upper limit of normal) 
3. AST (SGOT) /ALT (SGPT) > 5 x ULN, unless LIC confirmed as >10 mg Fe/dw within 6 
months prior to screening visit.
4. Significant proteinuria as indicated by a urinary protein/creatinine ratio > 0.5 mg/mg in a 
non-first void urine sample.
5. Patients with significant impaired gastrointestinal (GI) function or GI disease that may 
significantly alter the absorption of oral deferasirox (e.g. ulcerative diseases, uncontrolled 
nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection).
6. Clinical or laboratory evidence of active Hepatitis B or Hepatitis C (HBsAg in the absence 
of HBsAb OR HCV Ab positive with HCV RNA positive).


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7. Patients with psychiatric or addictive disorders which prevent them from giving their 
informed consent or undergoing any of the treatment options or patients unwilling or unable 
to comply with the protocol.
8. Patients with a known history of HIV seropositivity (Elisa or Western blot).
9. History of malignancy of any organ system, treated or untreated, within the past 5 years 
whether or not there is evidence of local recurrence or metastases, with the exception of 
localized basal cell carcinoma of the skin.
10. Patients participating in another clinical trial or receiving an investigational drug. Patients 
who have recently completed treatment with an investigational product must have ceased 
this treatment for at least five times the half-life of the investigational product.
11. History of hypersensitivity to any of the study drug or excipients.
12. 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.).
13. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using effective methods of contraception during dosing 
of study treatment. Effective contraception methods include:

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.

Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy) or tubal ligation at least six weeks before taking study treatment. In 
case of oophorectomy alone, only when the reproductive status of the woman has 
been confirmed by follow up hormone level assessment.

Male sterilization (at least 6 months prior to screening). For female patients on the 
study, the vasectomized male partner should be the sole partner for that patient.

Barrier methods of contraception: Condom or Occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/ vaginal suppository.

Placement of an intrauterine device (IUD) or intrauterine system (IUS).

Please note that deferasirox may reduce the efficacy of hormonal contraception thus it 
is recommended to use alternative methods of contraception as described above.
14. Women are considered post-menopausal and not of child bearing potential if they have had 
12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. 
age appropriate, history of vasomotor symptoms) 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 woman has been 
confirmed by follow up hormone level assessment is she considered not of child bearing
potential. 
15. Sexually active males unless they use a condom during intercourse while taking drug and 
for 28 days after stopping study medication and should not father a child in this period. A 
condom is required to be used also by vasectomized men in order to prevent delivery of the 
drug via seminal fluid.


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For prohibited medication please refer to Section 6.3.2.
Eligibility criteria must be reviewed prior any study treatment is given.
6
Treatment
6.1
Study treatment
The sponsor will provide the following open label study medication:

Deferasirox DT will be provided as 125 mg, 250 mg and 500 mg dispersible tablets for 
oral use.

The strengths provided in an individual country may differ and will reflect the strengths 
available commercially in each country

Deferasirox FCT will be provided as 90 mg, 180 mg and 360 mg film-coated tablets for 
oral use.  
Once a patient meets one of the end of study criterion (see Section 4.4), he/she will be 
discontinued from the study, a SEC visit will be completed and will be followed up for safety 
purposes 30 days after the last dose of study drug. If the patient is to continue on Deferasirox 
FCT after discontinuing from the study, this will be using commercially available deferasirox 
FCT (Jadenu®) as 90 mg, 180 mg and 360 mg film-coated tablets for oral use.
For this study, the terms “investigational drug”, “study drug” and “study treatment” refer to 
deferasirox FCT as well as deferasirox DT.
6.1.1
Dosing regimen
Having completed the screening period (including the 5-day wash-out period for patients 
previously treated with Deferiprone/DFP or Deferoxamine/DFO), eligible patients will start the 
core phase and be switched on the Day 1 visit to deferasirox DT for 24 weeks followed by 
deferasirox FCT for 24 weeks duration. Upon completion of Week 48 (Core Phase), the patient 
can still be treated with deferasirox FCT for a maximum of another 48 weeks or until one of the 
end of study criteria defined is met, whichever comes first.
The starting dose on Baseline Day 1 would be as following:
-
Deferasirox DT of 20 mg/kg/day in transfusion-dependent thalassemia (TDT)
-
Deferasirox DT of 10 mg/kg/day in non- transfusion-dependent thalassemia (NTDT),
Table 6-1
Equivalent FCT starting dose at Week 25
Equivalent dose to be used
Deferasirox DT (mg/kg/day)
Deferasirox FCT (mg/kg/day)
5
3.5
10
7
15
10.5
20
14
25
17.5
30
21


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Equivalent dose to be used
Deferasirox DT (mg/kg/day)
Deferasirox FCT (mg/kg/day)
35
24.5
40
28
All iron chelation pre-treated patients who had received treatment with deferoxamine (DFO) 
and deferiprone (DFP) will be initiated on deferasirox DT. The dose of deferiprone will be 
determined by their serum ferritin and the dose of deferoxamine by using the equivalent 
deferasirox DT dose (see Appendix 14.2). 
Dose adjustment for better treatment effects, based on serum ferritin levels and investigator’s 
judgment, will be allowed for ICT naïve patients after 4 weeks of study treatment and for ICT 
pre-treated patients every 3 months. The dose adjustments will be performed in steps of 5-10 
mg/kg/day for deferasirox DT or in steps of 3.5-7 mg/kg/day for deferasirox FCT. 
For each patient the daily dose is calculated by the physician based on the patient’s actual body 
weight, and then rounded up or down to the nearest whole tablet according to the available 
strengths of deferasirox tablets (125 mg, 250 mg and 500 mg for the DT and 90 mg, 180 mg 
and 360 mg for the FCT, see Appendix 14.1). 
The investigator should instruct the patient (or legal patient’s representative in the case of 
pediatric patients) to take the study drug as prescribed. All doses planned and prescribed to the 
patient and all dose changes including reasons for change during the study must be recorded in 
the eCRF. 
During the regular study visits, the investigator or pharmacist will dispense to the patient or the
patient’s legal representative, an appropriate number of deferasirox tablets depending on the 
patients calculated dose. The number of tablets of each strength dispensed will be recorded in 
the Subject IMP dispensing and accountability log. Each time the deferasirox study drug is 
dispensed to the patient and/or legal patient’s representative, the investigator will provide 
detailed instructions on how to prepare and administer the dose. Patients or the patient’s legal 
representative will be instructed to take/administer the assigned amount of study drug and will 
be obliged to return all unused study medication every 4 weeks. Study medication returned by 
the patient or the patient’s legal representative will be counted and unused study medication 
will be recorded by the investigator or pharmacist involved in the study. Drug accountability 
will be verified by the field monitor during site visits and at the completion of the trial.
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 patient 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 for study drug will be described on the medication label.
Patients on deferasirox DT period will take the deferasirox DT every day (not later than 12:00 
PM) on an empty stomach, at least 30 minutes before the next meal. The patient will disperse 
the required number of deferasirox DT in a glass of water, apple juice or orange juice. Gentle 
stirring should be applied and continued until the tablets are fully disintegrated, which takes 
approximately 1 to 3 minutes. Immediately, after full disintegration of the tablets, the entire 
content of the glass should be swallowed. 


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Patients on deferasirox FCT will swallow the required number of deferasirox FCT every day 
(not later than 12:00 PM) with or without a light meal. For patients with difficulties in 
swallowing Deferasirox FCT, it is allowed to crush the film-coated tablets. They should be 
administered by sprinkling the full dose on soft food like yogurt or apple sauce (apple puree).
All patients should take their deferasirox dose (DT or FCT) before 12:00 PM (noon).
Dose adjustments based on safety are allowed at any time point in the study and will be in 
increments of 5-10 mg/kg/day for deferasirox DT or 3.5-7 mg/kg/day for deferasirox FCT. Dose 
adjustments based on efficacy are permitted. For ICT naïve patients at study entry dose 
adjustments are allowed after 4 weeks of study treatment based on serum ferritin levels and 
investigator’s judgement. For ICT pre-treated patients, the dose of deferasirox should be 
adjusted if necessary every 3 months based on the trends in serum ferritin and investigator’s 
judgement.  For more details please refer to Table 6.2 – Dose of study drug based on serum 
ferritin level.
Table 6-2
Dose and treatment schedule
Study 
treatments
Pharmaceutical 
form and route 
of administration
Starting 
Dose*
(weeks 1-4)
Dose 
adjustment
(after week 4)
Max dose
Frequency 
and/or 
Regimen
Deferasirox 
DT – TDT 
patients
Dispersible 
tablets, p.o.
20 mg/kg/day
+ 5 - 10 
mg/kg/day
40 
mg/kg/day
Once daily
Deferasirox 
DT – NTDT 
patients
Dispersible 
tablets, p.o.
10 mg/kg/day
+ 5 - 10 
mg/kg/day
20
mg/kg/day
Once daily
Deferasirox 
FCT – TDT 
patients
Film-coated 
tablets, p.o.
14mg/kg/day
+ 3.5 - 7 
mg/kg/day
28 
mg/kg/day
Once daily
Deferasirox 
FCT – NTDT 
patients
Film-coated 
tablets, p.o.
7 mg/kg/day
+ 3.5 - 7 
mg/kg/day
14
mg/kg/day
Once daily
*Iron chelation naïve patients. All iron chelation pre-treated patients see Section 6.1.1 and Appendix 
14.2 for guidance.
Table 6-3
Daily dose of study drug based on serum ferritin level 
Dose Regimen of Drug for TDT patients
Serum ferritin level
20 mg/Kg Deferasirox DT 
14 mg/Kg Deferasirox FCT
1000-1500 ng/ml
30 mg/Kg Deferasirox DT 
21 mg/Kg Deferasirox FCT
>1500-2000 ng/ml
40 mg/Kg Deferasirox DT 
28 mg/Kg Deferasirox FCT
>2000 ng/ml
Dose Regimen of Drug for NTDT patients
Serum ferritin level
5 mg/Kg Deferasirox DT 
3.5 mg/Kg Deferasirox FCT
300-799 ng/ml
10 mg/Kg Deferasirox DT 
800-2000 ng/ml


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Dose Regimen of Drug for TDT patients
Serum ferritin level
7 mg/Kg Deferasirox FCT
20 mg/Kg Deferasirox DT 
14 mg/Kg Deferasirox FCT
>2000 – 4000 ng/ml
30mg/Kg Deferasirox DT
21mg/Kg Deferasirox FCT
>4000ng/mL
Serum ferritin level will be measured monthly to evaluate the study drug response
6.1.2
Ancillary treatments
Not applicable
6.1.3
Rescue medication
Not applicable
6.1.4
Treatment duration
The planned treatment duration of the core phase is 48 weeks and the planned treatment period
for the extension phase is another 48 weeks. 
The total duration of the study is approximately 104 weeks (including the Screening, Treatment, 
Study Evaluation Completion and Safety Follow-up visits).
6.2
Dose modifications 
6.2.1
Dose modification and dose delay
For patients who are unable to tolerate the protocol-specified dosing schedule, dose reductions 
are permitted in order to keep the patient on study drug. These changes must be recorded on the 
dosage administration record in the eCRF.
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.
6.2.1.1
Change in patient’s weight
The dose of study medication will be adapted using the Dosing Table (provided in Appendix 
14.1) during the study in case the change (increase or decrease) in body weight exceeds 10% of 
the body weight compared to Visit 2 or the last dose adjustment due to a change in the patient’s 
body weight. 
6.2.1.2
Elevations in serum creatinine
Serum creatinine should be monitored during the study as stated in the Table 7-1 and Table 7-
2.


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In case of a single clinically relevant increase in serum creatinine, the assessment will be 
repeated at the next visit, or as clinically indicated.
Deferasirox dose reduction by 10 mg/kg/day for the DT formulation and by 7 mg/kg/day for 
the FCT formulation should be performed if there is a rise in serum creatinine by 33% above 
baseline value resulting in a serum creatinine above the ULN on two consecutive visits (a 
minimum of 7 days apart).
If after a dose reduction, a progressive increase in serum creatinine beyond the ULN is observed, 
a treatment interruption is recommended.
After a treatment 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 50% of the last 
dose, and after 1 month, if the serum creatinine increase does not recur, study medication can 
be returned to 100% of the last dose (including body weight adjustment if required).
6.2.1.3
Changes in Serum Ferritin
Serum ferritin should be monitored monthly during the study as stated in the Visit Evaluation 
Schedule Table 7-1 and Table 7-2. 
For ICT pre-treated patients, the dose of deferasirox DT should be adjusted if necessary every 
3 months based on the trends in serum ferritin and investigator’s judgement. Table 6.2 provides 
additional guidance on suggested doses.
Dose adjustments should be made in steps of 5-10 mg/kg/day for deferasirox DT and of 3.5-7 
mg/kg/day for deferasirox FCT and are to be tailored to the individual patient’s response and 
therapeutic goals (maintenance or reduction of iron burden). 
For TDT patients not adequately controlled with:

Deferasirox DT doses of 30 mg/kg/day, doses of up to 40 mg/kg/day may be considered.  
Doses above 40 mg/kg/day are not permitted. 

Deferasirox FCT doses of 21 mg/kg/day, doses of up to 28 mg/kg/day may be considered. 
Doses above 28 mg/kg/day are not permitted. 
For NTDT patients not adequately controlled with:

Deferasirox DT doses of 15 mg/kg/day, doses of up to 20 mg/kg/day may be considered.  
Doses above 20 mg/kg/day are not permitted. 

Deferasirox FCT doses of 10.5 mg/kg/day, doses of up to 14 mg/kg/day may be 
considered. Doses above 14 mg/kg/day are not permitted. 
In patients whose serum ferritin level has reached the target (usually between 500 and 1000 
ng/mL for TDT patients or between 300-800 ng/mL for NTDT patients), dose reductions in 
steps of 5-10 mg/kg/day for deferasirox DT and of 3.5-7 mg/kg/day for deferasirox FCT should 
be considered to maintain serum ferritin levels within the target range. 
If serum ferritin falls below 500 ng/mL for TDT patients and 300 ng/mL for NTDT patients, an 
interruption of study treatment should be considered until serum ferritin rises above 500 ng/mL
or 300 ng/mL respectively. 


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6.2.1.4
Changes in urine protein/creatinine ratio
Proteinuria should be monitored during the study as stated in Table 7-1 and Table 7-2.
In case of a single increase of the urinary protein/creatinine ratio the assessment should repeated 
at the next visit.
Deferasirox dose reduction by 50% should be performed if the urinary protein/creatinine ratio 
increases to > 0.5 mg/mg in two consecutive second-void urine samples (a minimum of 48h 
apart), if all other causes of proteinuria have been excluded.
Deferasirox must be temporarily interrupted if the urinary protein/creatinine ratio increases to > 
1.0 mg/mg in two consecutive second-void urine samples (a minimum of 48h apart).
Should proteinuria persist, study treatment may be discontinued if the investigator believes it is 
in the best interest of the patient. Novartis may be contacted by the investigator to discuss dosing 
options if the investigator so desires.
Dose adjustment will be based on local laboratory results.
6.2.1.5
Skin Rash
For skin rash of mild/moderate severity (defined as those causing minimal symptoms which 
require no or minimal supportive treatment), study drug should be continued without dose 
adjustment. The skin rash may resolve spontaneously without further intervention.
If the rash persists for >1 week or becomes more severe, treatment with study drug will be 
interrupted. After the rash resolves, resume study drug at 50% of patient’s last dose. If the rash 
does not recur, increase the dose back to 100% of the patient’s last dose after 2 weeks.
For a severe rash (distressing symptoms requiring discontinuation and/or systemic steroids), 
discontinue treatment until resolution of rash. Once the rash has resolved, resume at 50% of the 
patient’s last dose. If necessary, a brief course of oral steroids may be given concurrently with 
resumption of study drug. If the rash does not recur, increase by steps of 5 mg/kg/day for 
deferasirox DT and of 3.5 mg/kg/day for deferasirox FCT every 2 weeks until 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.
6.2.1.6
Increased liver enzyme levels (ALT/AST)
If there is a persistent and progressive increase in serum transaminase levels that cannot be 
attributed to other causes, deferasirox (FCT or DT) 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 should 
contact Novartis.


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6.2.1.7
Dose modification criteria for auditory (decreased hearing) and ocular 
(lens opacities) disturbances
Auditory (decreased hearing) and ocular (lens opacities) disturbances have been reported with 
deferasirox treatment. Auditory and ophthalmic testing (including fundoscopy) must be 
performed before the start of deferasirox treatment and at regular intervals thereafter (every 12 
months). If disturbances are noted, dose reduction or interruption may be considered and a 
repeated testing performed as per investigator’s judgement.
6.2.1.8
Dose modification criteria for hypersensitivity reactions
Cases of serious hypersensitivity reactions (such as anaphylaxis and angioedema) have been 
reported in patients receiving deferasirox, with the onset of the reaction occurring in the 
majority of cases within the first month of treatment. If reactions are severe, deferasirox should 
be discontinued and appropriate medical intervention instituted.
6.2.1.9
Dose modification criteria for cytopenias
There have been post-marketing reports (both spontaneous and from clinical trials) of 
cytopenias in patients treated with deferasirox. Most of these patients had pre-existing 
hematological disorders that are frequently associated with bone marrow failure. The 
relationship of these episodes to treatment with deferasirox is uncertain. In line with the 
standard clinical management of such hematological disorders, blood counts should be 
monitored regularly. Dose interruption of treatment with deferasirox should be considered in 
patients who develop unexplained cytopenia. Reintroduction of therapy with deferasirox may 
be considered (as per investigator decision), once the cause of the cytopenia has been identified.
6.2.1.10 Gastrointestinal disturbances
Some basic recommendations, based on practical experience, can be made to guide physicians 
in managing patients who experience diarrhea.
At the first sign of diarrhea, consider anti-diarrheal medication such as loperamide.
Remind patient to discontinue any laxative preparations or stool softeners they may be taking.
Eat small, frequent meals. Determine if the patient is lactose intolerant. Deferasirox DT contains 
lactose in the formulation so supplemental lactase may benefit the patient. As a reminder, the 
deferasirox FCT does not contain lactose. Remind the patient to drink 8 to 10 glasses of clear 
liquid per day. Suggest that the patient take their deferasirox DT with water, not with orange 
juice or apple juice until the diarrhea resolves.
Novartis may be contacted by the investigator to discuss dosing options if the investigator so 
desires. 
6.2.2
Treatment interruption and treatment discontinuation
Patients who permanently discontinue study drug before completing the study should be 
scheduled for an End of Treatment visit (SEC – visit number 777) within 7 days from the last 
dose, at which time all of the assessments listed for the End of treatment (SEC – visit number 
777) visit will be performed. The Study Evaluation Completion eCRF page  must be completed, 


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documenting the date and reason for stopping study treatment. Any safety finding that leads to 
discontinuation of study drug should be captured on the AE eCRF.
All patients who discontinue study drug, including those who refuse to return for an End of 
treatment visit (SEC), will be contacted by the investigational site for safety evaluations 30 days 
after the last dose of study drug.
Patients who discontinue study drug should be considered withdrawn from the study after the 
final visit assessments are performed or when it is clear that the patient will not return for these 
assessments.
All patients must be followed for AEs and SAEs for 30 days after the last dose of study 
treatment. Patients lost to follow up should be recorded as such on the eCRF. For patients who 
are lost to follow-up, the investigator should show “due diligence” by documenting in the source 
documents steps taken to contact the patient, e.g., dates of telephone calls, registered letters, etc.
The investigator can decide in the best interest of the patient to switch from one formulation to 
the other with the agreement of the patient if an adverse event grade ≥ 2 (GI symptoms, skin 
rash, laboratory abnormalities) occurred with deferasirox DT or deferasirox FCT.
6.2.3
Follow-up for toxicities
Patients whose treatment is interrupted or permanently discontinued due to an adverse event or 
abnormal laboratory value must be followed at least for 4 weeks, from the last treatment dose 
received or until the adverse event is resolved or the laboratory value is considered to be 
clinically insignificant.
6.3
Prior and Concomitant medications 
The patient must be told to notify the investigational site about any prior and/or new 
medications he/she takes after the start of the study drug. All medications (other than study drug) 
and significant non-drug therapies (including physical therapy, herbal/natural medications and 
blood transfusions) administered during the study must be listed on the Concomitant 
Medications eCRF
6.3.1
Permitted concomitant therapy
The concomitant administration of deferasirox and Vitamin C has not been formally studied. 
Doses of Vitamin C up to 200 mg/day have not been associated with adverse consequences.
Use of the following treatments as part of the routine clinical care for the patients was allowed:

Patients are able to continue blood transfusions during the study protocol according to the
regimen that they had been receiving prior to enrollment that could allow maintaining a 
hemoglobin level > 9g/dL.

Caution must be exercised in patients who are taking study drug in combination with the 
following drugs:

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


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
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 metabolized through CYP2C8 (e.g repaglinide, 
paclitaxel)
6.3.2
Prohibited concomitant therapy

Aluminium 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 

Any iron chelation therapy other than the study drug
6.4
Patient numbering, treatment assignment 
6.4.1
Patient numbering
Each patient is identified in the study by a Patient Number (Patient No.), that is assigned when 
the patient is first enrolled for screening and is retained as the primary identifier for the patient
throughout his/her entire participation in the trial. The Patient No. consists of the Center 
Number (Center No.) (as assigned by Novartis to the investigative site) with a sequential patient 
number suffixed to it, so that each patient is numbered uniquely across the entire database. Upon 
signing the informed consent form, the patient is assigned to the next sequential Patient No. 
Once assigned, the Patient No. must not be reused for any other patient. If the patient fails to 
start the treatment for any reason, the reason will be entered into the Screening Log.
Re-screening is not allowed in the study.
6.4.2
Treatment assignment
This is an open label study. Patients will be assigned as described in (Section 4.1 and Section 
6.1)
All patients who fulfill all inclusion/exclusion criteria and complete the core phase, are eligible 
to roll over to the extension phase and receive the FCT formulation until one of the End of 
Study criteria is met (Section 4.4).
6.4.3
Treatment blinding
Not applicable as this is an open label study.
6.5
Study drug preparation and dispensation
The investigator or responsible site personnel must instruct the patient or caregiver to take the 
study drugs as per protocol. Study drug(s) will be dispensed to the patient by authorized site 
personnel only. 


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All dosages prescribed to the patient and all dose changes during the study must be recorded on 
the Dosage Administration Record eCRF.
6.5.1
Study treatment packaging and labeling
Site personnel will add the patient number on the medication label. Immediately before 
dispensing the package to the patient, site personnel will detach the outer part of the label from 
the packaging and affix it to the Subject IMP dispensing and accountability log for that patient’s 
unique patient number.
Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the drug.
6.5.2
Drug supply and storage
Study treatments must be received by designated personnel at the study site, handled and stored 
safely and properly, and kept in a secured location to which only the investigator and designated 
site personnel have access. Upon receipt, the study treatment should be stored according to the 
instructions specified on the drug labels. 
6.5.3
Study drug compliance and accountability
6.5.3.1
Study drug compliance
Compliance will be assessed by the investigator and/or study personnel at each patient visit and 
information provided by the patient and/or caregiver will be captured in the source documents
at each patient visit and Subject IMP dispensing and accountability log.. Patient compliance 
with study treatment will be evaluated using the pill count.
6.5.3.2
Study drug accountability
The investigator or designee must maintain an accurate record of the shipment and dispensing 
of study treatment in Site IMP Inventory and Reconciliation Log. Drug accountability will be 
verified 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.
At study close-out, and, as appropriate during the course of the study, the investigator will return 
all used and unused study treatment, packaging, drug labels, and a copy of the completed drug 
accountability log to the Novartis monitor so the final drug reconciliation can be documented 
accordingly.
Information on study drug will be collected on the Dose Administration Record (DAR) eCRF 
and will include the planned dose (mg/kg/day), reason for the dose change or dose delay, start 
date and end date.
Details are described in the monitoring plan.


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6.5.4
Disposal and destruction
The study drug supply can be destroyed at the local Novartis facility, third party or at site level
only if permitted by local regulations and authorized by Novartis in a prior agreement, as 
appropriate.
7
Visit schedule and assessments
7.1
Study flow and visit schedule
Table 7-1 and Table 7-2 list all of the assessments and indicate with an “X”, the visits when 
they are performed. All data obtained from these assessments must be supported in the patient’s 
source documentation. 
No CRF will be used as a source document. 
Patients should be seen for all visits to perform the scheduled assessments on the designated 
day, or as close to it as possible, i.e., not exceeding ± 2 days for all assessments scheduled in 
Visits 1 to 7 and ± 7 days for all other visits till Visit 26. Study visits must be anchored 
(calculated) based on the baseline visit. 
All Baseline assessments indicated in Table 7-1 and Table 7-2 must be completed prior to 
initiating Deferasirox DT treatment. 
Study evaluation completion (SEC / Visit 777) should be performed as follows:
-
For discontinuers or completers of the core phase, who do not roll over to the extension 
phase, SEC has to done within 7 days of discontinuing treatment.
-
For completers of the extension phase, the SEC needs to be performed after receiving 96 
weeks of treatment. The Study Evaluation Completion (777) and W96 visit will occur on 
the same visit and same date.
In this clinical trial, a week is 7 calendar days. 
All data obtained from these assessments must be supported in the patient’s source
documentation. The table indicates which data are entered into the database (D) or remain in 
source documents only (S) (column category).


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Table 7-1
Visit Evaluation Schedule - Core Phase
Category
Protocol 
Section 
7.2
Screening
Baseline
CORE PHASE treatment4
Visit Number
1
212
3
4
5
6
7
8
9
10
11
12
13
14
156
Study Week
Up to 
28days 
prior to 
Baseline
D1
W2
W4 
(M1)
W8 
(M2)
W12 
(M3)
W16 
(M4)
W20 
(M5)
W24 
(M6)
W28(M7)
W32 
(M8)
W36 
(M9)
W40 
(M10)
W44 
(M11)
W48 
(M12)
Informed consent
(D)
7.1.1
X
Inclusion/ exclusion 
criteria
(D)
7.1.1.1
X
X
History of disease
(D)
7.1.1.3
X
Demography13
(D)
7.1.1.3
X
Relevant medical 
history/current medical 
conditions
(D)
7.1.1.3
X
Prior chelation therapy1
(D)
7.1.1.3
X
Transfusion/RBC History
(D)
7.1.1.3
X
X
Transfusions received
(D)
7.1.2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical exam
(S)
7.2.2.1
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Weight
(D)
7.2.2.3
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Height
(D)
7.2.2.3
X
X
Vital signs
(D)
7.2.2.2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Ocular exam
(D)
7.2.2.5
X
X
Audiometry
(D)
7.2.2.5
X
X


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Category
Protocol 
Section 
7.2
Screening
Baseline
CORE PHASE treatment4
Visit Number
1
212
3
4
5
6
7
8
9
10
11
12
13
14
156
Study Week
Up to 
28days 
prior to 
Baseline
D1
W2
W4 
(M1)
W8 
(M2)
W12 
(M3)
W16 
(M4)
W20 
(M5)
W24 
(M6)
W28(M7)
W32 
(M8)
W36 
(M9)
W40 
(M10)
W44 
(M11)
W48 
(M12)
ECG
(D)
7.2.2.7.1
X
X
Chest X-ray (if clinically 
indicated)
(D)
7.2.2.4
X
X
Prior and Concomitant 
medications
(D)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse events
(D)
7.2.2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory assessments-
Blood
Hematology
(D)
7.2.2.6.1
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Biochemistry
(D)
7.2.2.6.2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum ferritin
(D)
7.2.1
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum creatinine
(D)
7.2.2.6.2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Creatinine clearance
(D)
7.2.2.6.2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hepatitis testing
(D)
7.2.2.6.5
X
X
Serum pregnancy test3
(D)
7.2.2.6.4
X
X
Laboratory assessments-
Urine
Urine dipstick
(D)
7.2.2.6.3
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Microscopic urine
(D)
7.2.2.6.3
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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Protocol No. CICL670FIC05
Category
Protocol 
Section 
7.2
Screening
Baseline
CORE PHASE treatment4
Visit Number
1
212
3
4
5
6
7
8
9
10
11
12
13
14
156
Study Week
Up to 
28days 
prior to 
Baseline
D1
W2
W4 
(M1)
W8 
(M2)
W12 
(M3)
W16 
(M4)
W20 
(M5)
W24 
(M6)
W28(M7)
W32 
(M8)
W36 
(M9)
W40 
(M10)
W44 
(M11)
W48 
(M12)
Proteinuria (urine protein/ 
creatinine ratio)
(D)
7.2.2.6.3
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine pregnancy test
(D)
7.2.2.6.4
X
Other assessments
Deferasirox DT drug 
administration
(D)
X
X
X
X
X
X
X
X
Deferasirox FCT drug 
administration
(D)
X
X
X
X
X
X
Dispensed/ returned 
DT/FCT count
(D)
7.2.4
X
X
X
X
X
X
X
X5
X
X
X
X
X
X
PRO7,8
Preference 
(D)
X
X
X
X
SICT
(D)
X9,10
X
X
X
X
GI symptoms
(D)
X9,10
X
X
X
X
Palatability
(D)
X9,10, 11
X
X
X
X
End of Core Phase
X
1 Includes 5-day washout period from previous iron chelation therapy.
2 Study Evaluation Completion visit will be undertaken for all patients completing the study or discontinuing earlier for any reason.  Please refer to Section 7 (except for 
further information.
3 A serum pregnancy test can also be carried out at any time if deemed necessary by the investigator.


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4 The study will last until one of the patient withdrawal criteria is met (Section 7.1.3.1). At that time, the patient needs to complete the Study Evaluation Completion (SEC /
777) visit, and then FUP visit 30 days after last dose of study drug.
5 Last dose of deferasirox DT will be dispensed on Week 24, and taken by the patient until Week 24 day 7. At the Week 24 visit, the site will also dispense deferasirox 
FCT. The patient will take the first dose on Week 25 day 1.
6 Week 48 Visit (visit number 15) is a combined visit as it is the last visit of the Core Phase and the Baseline visit for the extension phase
7 If the patient switches treatment, the investigator must provide the preference questionnaire to the patient in the immediate next visit. Please refer to Appendix 14.3 for 
further information.
8 “PROs” include observer reports for patients 2-9 years old
9 Palatability, satisfaction and GI symptoms questionnaires will be provided to the patient on Screening (visit number 1), during the 5 days of wash-out period from 
previous iron chelators therapies
10 Completion of PRO questionnaires at screening visit for ICT naïve patient or patients who did not take any ICT treatment within the 6 months prior to screening is not 
required
11 Completion of palatability questionnaires at screening visit for patients who received Deferoxamine as prior chelation therapy is not required
12 All Baseline assessments indicated in Table 7-1 and Table 7-2 must be completed prior to initiating Deferasirox DT treatment. 
13 The investigators will have to re-assess, every 6 months, the childbearing potential of female patients aged 13 and older who are pre-menarche at the time of enrolling 
in the study.  Once patient is able to bear children, they will need to undergo a urine pregnancy test in the next consecutive visit and then follow the VES for the urine and 
serum pregnancy tests. 


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Table 7-2
Visit Evaluation Schedule - Extension Phase
Category
Protocol 
Section 
7.2
Baseline EXT
EXTENSION PHASE treatment4
Study 
Evaluation 
Completion2
Safety 
Follow 
up
Visit Number
155
16
17
18
19
20
21
22
23
24
25
26
777
501
Study Week
W48 
(M12)
W52 
(M13)
W56 
(M14)
W60 
(M15)
W64 
(M16)
W68 
(M17)
W72 
(M18)
W76 
(M19)
W80 
(M20)
W84 
(M21)
W88 
(M22)
W92 
(M23)
W96 (M24)
30 days 
after 
last 
dose of 
study 
drug 
received 
Informed 
consent
(D)
7.1.1
Inclusion/ 
exclusion criteria
(D)
7.1.1.1
History of 
disease
(D)
7.1.1.3
Demography
(D)
7.1.1.3
Relevant medical 
history/current 
medical 
conditions
(D)
7.1.1.3
Prior chelation 
therapy1
(D)
7.1.1.3
Transfusion/RBC 
History
(D)
7.1.1.3
Transfusions 
received
(D)
7.1.2
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical exam
(S)
7.2.2.1
X
X
X
X
X
X
X
X
X
X
X
X
X
Weight
(D)
7.2.2.3
X
X
X
X
X
X
X
X
X
X
X
X
X
Height
(D)
7.2.2.3
X


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Category
Protocol 
Section 
7.2
Baseline EXT
EXTENSION PHASE treatment4
Study 
Evaluation 
Completion2
Safety 
Follow 
up
Visit Number
155
16
17
18
19
20
21
22
23
24
25
26
777
501
Study Week
W48 
(M12)
W52 
(M13)
W56 
(M14)
W60 
(M15)
W64 
(M16)
W68 
(M17)
W72 
(M18)
W76 
(M19)
W80 
(M20)
W84 
(M21)
W88 
(M22)
W92 
(M23)
W96 (M24)
30 days 
after 
last 
dose of 
study 
drug 
received 
Vital signs
(D)
7.2.2.2
X
X
X
X
X
X
X
X
X
X
X
X
X
Ocular exam
(D)
7.2.2.5
X
Audiometry
(D)
7.2.2.5
X
ECG
(D)
7.2.2.7.1
X
Chest X-ray (if 
clinically 
indicated)
(D)
7.2.2.4
X
Prior and 
Concomitant 
medications
(D)
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse events
(D)
7.2.2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory 
assessments-
Blood
Hematology
(D)
7.2.2.6.1
X
X
X
X
X
X
X
X
X
X
X
X
X
Biochemistry
(D)
7.2.2.6.2
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum ferritin
(D)
7.2.1
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum creatinine
(D)
7.2.2.6.2
X
X
X
X
X
X
X
X
X
X
X
X
X
Creatinine 
clearance
(D)
7.2.2.6.2
X
X
X
X
X
X
X
X
X
X
X
X
X


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Category
Protocol 
Section 
7.2
Baseline EXT
EXTENSION PHASE treatment4
Study 
Evaluation 
Completion2
Safety 
Follow 
up
Visit Number
155
16
17
18
19
20
21
22
23
24
25
26
777
501
Study Week
W48 
(M12)
W52 
(M13)
W56 
(M14)
W60 
(M15)
W64 
(M16)
W68 
(M17)
W72 
(M18)
W76 
(M19)
W80 
(M20)
W84 
(M21)
W88 
(M22)
W92 
(M23)
W96 (M24)
30 days 
after 
last 
dose of 
study 
drug 
received 
Serum/ urine
pregnancy test3, 6
(D)
7.2.2.6.4
X
Laboratory 
assessments-
Urine
Urine dipstick
(D)
7.2.2.6.3
X
X
X
X
X
X
X
X
X
X
X
X
X
Microscopic 
urine
(D)
7.2.2.6.3
X
X
X
X
X
X
X
X
X
X
X
X
X
Proteinuria (urine 
protein/ 
creatinine ratio)
(D)
7.2.2.6.3
X
X
X
X
X
X
X
X
X
X
X
X
X
Other 
assessments
Deferasirox FCT 
drug 
administration
(D)
X
X
X
X
X
X
X
X
X
X
X
X
-
Dispensed/ 
returned FCT 
count
(D)
7.2.4
X
X
X
X
X
X
X
X
X
X
X
X
X
1 Includes 5-day washout period from previous iron chelation therapy.
2 Study Evaluation Completion visit will be undertaken for all patients completing the study or discontinuing earlier for any reason. Please refer to Section 7.1 for further 
information.


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3 A serum pregnancy test can also be carried out at any time if deemed necessary by the investigator.
4 The study will last until one of the EOS criteria is met (Section 4.4). At that time, the patient needs to complete the Study Evaluation Completion (SEC) visit, and then 
FUP visit 30 days after last dose of study drug.
5 Week 48 Visit (visit number 15) is a combined visit as it’s being identified as the last visit of the Core Phase and the Baseline visit for the extension phase (if none of the 
End Of Study criteria is met)
6The investigators will have to re-assess, every 6 months, the childbearing potential of female patients aged 13 and older who are pre-menarche at the time of enrolling in 
the study. Once a patient is able to bear children, they will need to undergo a urine pregnancy test at the next consecutive visit and then follow the VES for the urine and 
serum pregnancy tests thereafter. 


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7.1.1
Screening
Prior to commencement of the screening examination, the patient must have given full informed 
consent and have completed the study Informed Consent form. Once this has been signed and 
dated by the patient or the patient’s legal representative, then the investigator can undertake the 
required assessments to confirm the patient’s eligibility for the study.
Ocular and Audiometry examinations must be performed at screening. In the case that the 
examination(s) had already been performed 6 months prior to screening, then the examination(s) 
do not need to be repeated. The examination(s) can be performed at any time at the investigators 
discretion if symptomatically/clinically indicated.
Serum ferritin, serum creatinine and proteinuria (urine protein/ creatinine ratio) will be 
measured during the screening visit for eligibility criteria. 
The serum ferritin samples should be obtained in the absence of known infection.
Pregnancy test will be required only for females with child bearing potential.
The full list of assessments to be performed during the screening period (including the 5-day 
wash out period for patients previously treated with deferiprone (DFP) or deferoxamine (DFO)) 
is detailed in Table 7-1. 
See Section 7.1.1.2 to get information on how to process screen failures.
Patients that do not meet the eligibility criteria are not allowed to be re-screened.
7.1.1.1
Eligibility screening
Following registration for screening, patient eligibility will be checked once all screening 
procedures are completed, and before study drug is provided to the patient.
7.1.1.2
Information to be collected on screening failures
Patients who sign an informed consent but fail to be started on treatment for any reason will be 
considered a screen failure. The reason for not being started on treatment will be entered on the 
Screening Log. 
The demographic information, informed consent, inclusion/exclusion evaluation and Screening 
log pages in the eCRF must also be completed for Screen Failure patients. No other data will 
be entered into the clinical database for patients who are screen failures, unless the patient 
experienced a Serious Adverse Event (SAE) during the Screening Phase (see Section 8 for SAE 
reporting details).
7.1.1.3
Patient demographics and other baseline characteristics
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, prior chelation history, serum pregnancy test, vital signs at 
Screening visit. 


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To determine eligibility to be enrolled into the study, patients will also undergo assessments as 
per the inclusion and exclusion criteria which include hematology and biochemistry evaluations, 
hepatitis viral evaluation, serum ferritin, serum creatinine and creatinine clearance, a known 
history of HIV positive test result (ELISA or Western blot) which is documented in the source 
documents, active Hepatitis B and/or C, serum pregnancy test and urinalysis.
Other assessments include chest x-ray (if clinically indicated), ocular exam, audiometry and 
ECG.
Specifics are given on Table 7-1 and Table 7-2. Patients who meet all the inclusion/exclusion 
criteria at screening will be admitted for baseline evaluations. All baseline results for safety 
evaluations must be available prior to dosing on Day 1.
At baseline visit (day 1), a verification of eligibility will be performed prior to performing any 
baseline assessments and administering the study drug.
7.1.2
Treatment period
The duration of core phase treatment is 48 weeks. Patient visits will occur every 2 weeks during 
the first month of treatment and then every 4 weeks thereafter until Visit 777 (SEC). 
Having completed the screening period (including the 5-day wash out period for patients 
previously treated with deferiprone (DFO) or deferoxamine (DFP)), patients who are eligible 
will be enrolled to receive deferasirox DT during 24 weeks then switch to deferasirox FCT for 
24 weeks. Daily dose is calculated by the physician based on the patient’s actual body weight. 
At the start of treatment, iron chelation naïve patients will receive deferasirox DT 10 mg/kg 
(NTDT patients) or 20 mg/kg (TDT patients) once daily then will transition to the equivalent 
FCT dose as outlined in the following table.
Table 7-3
Equivalent dose to be used: Deferasirox DT vs Deferasirox FCT
Equivalent dose to be used
Deferasirox DT (mg/kg/day)
Deferasirox FCT (mg/kg/day)
5
3.5
10
7
15
10.5
20
14
25
17.5
30
21
35
24.5
40
28
All iron chelation pre-treated patients will follow the below guidance:
Patients who were taking deferoxamine (DFO), will need to take the deferosirox DT equivalent 
deferasirox. For deferiprone (DFP) the dose of deferosirox DT will be based on their serum 
ferritin. Please refer to Table 6-2.


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At the Week 48 visit, patients will roll over to the extension phase in the case that none of the 
End of Study criteria is met at that time. The patient will receive deferasirox FCT following the 
same dose regulations and adjustments as per the core phase.
The treatment period of the extension study is approximately 52 weeks (including treatment 
period (48 weeks), Study Evaluation Completion and 4 weeks Safety Follow-up visits)
For details on study design and dose adjustments, see Section 4 and Section 6.3.
For details of assessments, see Table 7-1 and Table 7-2. 
7.1.3
Study Evaluation Completion visit including premature withdrawal
At the time patients discontinue study treatment; a visit should be scheduled at which time all 
of the assessments listed for the Study Evaluation Completion (SEC) visit will be performed. 
A Study Evaluation Completion eCRF page should be completed, giving the date and reason 
for stopping the study treatment, within 7 days following the last dose of 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 30 days after the last dose of 
study treatment.
Patients who discontinue study treatment should be considered withdrawn from the study after 
the SEC visit assessments are performed or when it is clear that the patient will not return for 
these assessments.
If a study withdrawal occurs, or if the patient fails to return for visits, the investigator must 
determine the primary reason for a patient’s premature withdrawal from the study and record 
this information on the Study Evaluation Completion eCRF page.
Patients who complete the extension phase will have to complete the SEC after receiving 96 
weeks of treatment. The Study Evaluation Completion (777) and W96 visit will occur on the 
same visit and same date.
For criteria for premature withdrawal refer to Section 7.1.3.1. For criteria on End of Study refer 
to Section 4.3.
7.1.3.1
Criteria for premature patient withdrawal
Patients may voluntarily withdraw from the study or be dropped from it at the discretion of the 
investigator/Sponsor at any time. Patients may be withdrawn from the study if any of the 
following occur unless the investigator decides in the best interest of the patient to switch from 
deferasirox DT to deferasirox FCT:

Pregnancy (not applicable for the switch)

Unwillingness to comply with procedures as outlined in the study protocol, including 
unwillingness to comply with the prescribed study treatment

Discovery of patient ineligibility (not applicable for the switch)

Intake of prohibited medications (not applicable for the switch)

Adverse event(s)

Abnormal lab value(s)


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
Unsatisfactory therapeutic effect

Protocol violation (not applicable for the switch)

Subject withdrew consent (not applicable for the switch)

Lost to follow-up (not applicable for the switch)

Administrative problems (not applicable for the switch)

Death (not applicable for the switch)

Decision of the Sponsor

Unacceptable toxicity in the opinion of the investigator/Sponsor
If such withdrawal occurs, or if the patient fails to return for visits, the investigator must 
determine the primary reason for a patient’s premature withdrawal from the study and record 
this information on the Study Evaluation Completion eCRF.
7.1.3.2
Withdrawal of informed consent section
Subjects may voluntarily withdraw consent to participate in the study for any reason at any time. 
Withdrawal of consent occurs only when a subject:

Does not want to participate in the study anymore, and

Does not allow further collection of personal data
In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the subject’s decision to withdraw his/her consent and 
record this information. 
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing. 
Further attempts to contact the subject are not allowed unless safety findings require 
communicating or follow-up.
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the subject’s study withdrawal should be made as detailed in the 
assessment table. 
Novartis (sponsor) will continue to keep and use collected study information (including any 
data resulting from the analysis of a subject’s samples until their time of withdrawal) according 
to applicable law.
All biological samples not yet analyzed at the time of withdrawal will no longer be used, unless 
permitted by applicable law. They will be stored according to applicable legal requirements.
7.1.4
Follow up period
All patients must have a safety evaluation 30 days after the last dose of study treatment 
(regardless if that situation occurs during core or extension phase).
For patients who are lost to follow-up, the investigator should show "due diligence" by 
documenting in the source documents steps taken to contact the patient, e.g., dates of telephone 
calls, registered letters, etc.


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7.2
Assessment types
7.2.1
Efficacy assessments
Serum ferritin testing will be performed in both phases every month. The baseline serum ferritin 
value will be defined during the screening period.
7.2.2
Safety and tolerability assessments
Safety will be monitored by assessing physical examination, vital signs, height and weight, 
ECG, Chest X-ray, Ocular and Auditory examinations, laboratory evaluations as well as 
collecting of the adverse events at every visit. For details on AE collection and reporting, refer 
to Section 8 (in the core and extension phase).
7.2.2.1
Physical examination
A physical examination will be performed at all study visits (refer to Table 7-1 and Table 7-2). 
The physical examination on Day 1, 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 were present prior to the signing of informed consent must be included 
in the Medical History page on the patient’s eCRF. Significant new findings that begin or 
worsen after informed consent must be recorded on the Adverse Event page of the patient’s 
eCRF. 
7.2.2.2
Vital signs
Vital signs include blood pressure and pulse measurements and will be measured at all study 
visits (including SEC). 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.
Young children may be placed on their parent’s / caregivers’ lap for the measurement of the 
vital signs.
7.2.2.3
Height and weight
Height in centimeters (cm) and body weight (to the nearest 0.1 kilogram (kg) in indoor clothing, 
but without shoes will be measured. For specifications refer to Table 7-1 and Table 7-2.


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7.2.2.4
Chest x-ray section
Chest x-ray will be performed at screening visit (if clinically indicated). If any chest x-ray has 
been performed 3 months prior to study entry the last available result will be collected. 
7.2.2.5
Auditory and ocular examination
Patients will undergo auditory and ocular examinations at screening, Week 48 and at 
unscheduled visits (if needed). For specifications refer to Table 7-1 and Table 7-2
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

Funduscopic 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.
Please follow the guidance below for children aged 2 to 5. It can also be applied for children 
aged 5 to 7 who cannot complete the aforementioned ocular tests:

Sedation is not requested nor required. 

The ophthalmologist of each site must decide what is age-appropriate ocular testing 
without the use of sedation.  If any aspect of the ocular testing listed above cannot be 
completed, please document this in the CRF (which assessments and the reason). 

Once the site has determined which assessment can be performed for a given patient in the 
screening visit, then these assessments must be repeated consistently at subsequent visits

It is critical to collect the visual acuity results.   Please collect ‘best corrected’ visual 
acuity for all patients (for example: do with glasses if done with glasses before).  

The preferred method of collection for tonometry is applanation tonometry.  If not 
possible, then do an age-appropriate procure (without sedation). 
For children aged 2 to 5 and older who do not cooperate, speech audiometry should be 
performed. If not possible, then the speech recognition test will be suffice. 
7.2.2.6
Laboratory evaluations
All analyses will be performed by the local lab. Please refer to Table 7-4 for detailed laboratory 
parameters.


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Table 7-4
Central Clinical laboratory parameters collection plan
Test Category
Test Name
Hematology
Hematocrit, Hemoglobin, MCH, MCHC, MCV, Platelets, Red blood cells, 
White blood cells (WBC) count with differential (Basophils, Eosinophils, 
Lymphocytes, Monocytes, Neutrophils), RBC Morphology 
Biochemistry
Albumin, Alkaline phosphatase, ALT (SGPT), AST (SGOT), Bicarbonate, 
Calcium, Chloride, Creatinine, Creatine kinase, glucose, inorganic 
phosphorus, potassium; sodium Direct Bilirubin, Indirect Bilirubin, Total 
Bilirubin, Total Cholesterol, LDL, HDL, Lactate dehydrogenase (LDH), Total 
Protein, Triglycerides, Blood Urea Nitrogen (BUN) or Urea, Uric Acid, C-
reactive protein (CRP)
Urinalysis
Microscopic Panel (Red Blood Cells, White Blood Cells, Casts, Crystals, 
Bacteria, Epithelial cells)
Macroscopic Panel (Dipstick) ( Bilirubin, Blood, Glucose, Ketones, Leukocytes 
esterase, Nitrite, pH, Protein, Specific Gravity, Urobilinogen)
Hepatitis markers
HbsAg, HbsAb, HCV Ab, HCV RNA, PCR (quantitative)
Additional tests
Serum ferritin, creatinine clearance, urine protein/creatinine ratio, serum 
pregnancy test, urine pregnancy test
7.2.2.6.1 Hematology
Hematology samples will be collected as described in Table 7-1 and Table 7-2, following local 
standard practice. 
Safety laboratory parameters monitored during the study will include hematocrit, hemoglobin, 
MCH, MCHC, MCV, platelets, red blood cells, white blood cells (WBC) count with differential 
(basophils, eosinophils, lymphocytes, monocytes, neutrophils), RBC Morphology  
7.2.2.6.2 Clinical chemistry
Clinical chemistry samples will be collected as described in Table 7-1 and Table 7-2 following 
local standard practice. 
Parameters to be measured will include: albumin, alkaline phosphatase, ALT (SGPT), AST 
(SGOT), bicarbonate, calcium, chloride, serum creatinine, creatine kinase, glucose, inorganic 
phosphorus, potassium, sodium, total bilirubin (direct and indirect bilirubin only required if 
total bilirubin is > 1.5 ULN) total cholesterol, LDL, HDL, lactate dehydrogenase (LDH), total 
protein, triglycerides, blood urea nitrogen (BUN) or urea, uric acid, C-reactive protein (CRP).
In addition, serum creatinine will be measured every 2 weeks during the first four weeks after 
first study drug administration and then monthly. Refer to Table 7-1 and Table 7-2 for specifics. 
Creatinine clearance will be estimated using the Cockcroft-Gault equation for adult patients and 
Schwartz formula for pediatric patients. This estimate will be provided each time serum 
creatinine is collected. The formula should be consistently used throughout the study for a 
particular patient. 
Use the following reference source for calculation of creatinine clearance:

https//reference.medscape.com/calculator/creatinine-clearance-cockcroft-gault

http//wwwusers.med.cornell.edu/~spon/picu/calc/crclsch2.htm


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Serum ferritin test will also be performed at the screening visit to assess the eligibility of the 
patient. Serum ferritin testing will also be performed as described on Table 7-1 and Table 7-2.
7.2.2.6.3 Urinalysis
Urinalysis samples will be collected as described on Table 7-1 and Table 7-2, following local 
standard practice. 
A midstream, second voided morning urine sample will be obtained. Bilirubin, blood, glucose, 
ketones, leukocytes esterase, nitrite, pH, protein, specific gravity, urobilinogen will be assessed. 
Microscopic analysis will be performed only in case of positive dipstick.
At the screening visit, a urine sample (at least 15 ml) will be collected for urinary 
protein/creatinine ratio to assess the eligibility of the patient. First morning void samples must 
not be used for this analysis. 
For patients who develop proteinuria or a worsening of pre-existing proteinuria (assessed by a 
dipstick) at any visit, please refer to Section 6.2.1.4. Threshold values for proteinuria should 
be provided.
7.2.2.6.4 Pregnancy and assessments of fertility
All female patients capable of becoming pregnant will have a pregnancy test (serum β-HCG) at 
the screening visit and visit 15. An urine pregnancy text will be performed as described in Table 
7-1 and Table 7-2. The results of the test must be available prior to initiating treatment with any 
study medication. Positive pregnancy tests will exclude a patient from participating in this trial.
Pregnancy must be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the local Novartis Clinical Safety & Epidemiology Department. Pregnancy 
follow-up must be recorded on the same form and must include an assessment of the possible 
relationship to the Novartis study drug of any pregnancy outcome. Any SAE experienced during 
pregnancy must be reported on the SAE Report Form. 
7.2.2.6.5 Hepatitis Viral tests
Hepatitis viral testing consists of the following items: Hepatitis B surface Antigen (HBsAg), 
Hepatitis B Surface Antibody (Anti-HBs), Hepatitis C Antibody (Anti-HCV), HCV PCR 
(Quantitative). Hepatitis viral testing will be conducted at Screening Visit 1 to assess trial 
eligibility and visit 15.
7.2.2.7
Cardiac assessments 
7.2.2.7.1 Electrocardiogram (ECG)
A standard 12 lead ECG will be performed

at screening visit

week 48
Interpretation of the tracing must be made by a qualified physician and documented on the ECG 
eCRF page. Each ECG tracing should be labeled with the study number, patient number, date, 
and kept in the source documents at the study site. Clinically significant abnormalities present 


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when the patient signed informed consent should be reported on the Medical History eCRF 
page. Clinically significant findings must be discussed with Novartis 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 eCRF page.
7.2.3
Other assessments
Patient compliance with study treatment will be evaluated using pill count. 
Pill count will be measured as per assessments mentioned in Table 7-1 and Table 7-2. The 
number of tablets of study medication of each strength (125 mg, 250 mg and 500 mg for the 
DT and 90 mg, 180 mg and 360 mg for the FCT) dispensed will be recorded during the study 
in the source documents using a subject IMP dispensing log and accountability log and in the 
Drug Accountability eCRF. Empty bottles and unused medication will be returned by the 
patient to the study site. Unused study medication tablets will be counted and recorded by the 
investigator/pharmacist/study staff involved in the study.
7.3
Patient reported outcomes
Please see guidance below on PRO completion:

In case of treatment switch, the investigator must provide the preference questionnaire to 
the patient at the immediate next visit and then keep following the schedule of 
questionnaires pre-planned on Table 7-1 and Table 7-2.  Please refer to Appendix 14.3 for 
further information.

Completion of PRO questionnaires at screening visit for ICT naïve patient or patients who 
did not take any ICT treatment within the 6 months prior to screening visit is not required 
as patient never took any ICT thus they cannot answer to the questionnaire related to 
palatability, satisfaction and AEs to ICT.

Completion of palatability questionnaires at screening visit for patients who received 
Deferoxamine as prior chelation therapy is not required
In case the patient’s parents/legal representative and/or the patient are illiterate, the nurse / study 
coordinator should read each question and the response options to the parent / legal 
representative. The answer provided verbally by the parent / legal representative can be 
recorded on the PRO questionnaire by the nurse / study coordinator. In this case, the nurse/ 
study coordinator must not prompt or in any way try to help the parent / legal representative 
select an answer. This process needs to be carefully document in the source notes.
7.3.1
Preference Questionnaire
The preference questionnaire is a four item questionnaire. There are four separate versions 
depending on the week(s) that the questionnaire is administered.
For week 48 (primary endpoint) the first item asks the patients (or parents of young patients
from 2 to 9 years old) which medicine they are currently taking with the response options: 
“Tablet to dissolve in liquid”, “Film coated tablet ”, “Sprinkle powder on food” and “I don’t 
know”.  The second item asks which of the medicines did the patient “Like best” with the same 
response options as that of the first item. Finally, the third item asks the patient why he/she 
preferred the medicine they chose.


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For week 28 the first item asks patients to choose from the following medicines: “Tablet to 
dissolve in liquid”, “Film coated tablet (taken once a day)”, “Tablet (taken 3 times a day)”, 
“Sprinkle powder on food”, “Injection” and “I don’t know”. The second items remain the same 
asking which medicine the patients like the best (out of the above response options). Similarly 
the third item remains the same.
For weeks 4 and 24 the first item asks patients to choose from the following medicines: “Tablet 
to dissolve in liquid”, “Tablet (taken 3 times a day)”, “Injection” and “I don’t know”. The 
second items remain the same asking which medicine the patients like the best (out of the above 
response options). Similarly the third item remains the same.
The following preference attributes are provided:

Taste

Aftertaste (taste left in your mouth after you swallow)

Convenience (it’s not a problem to take your medicine - administration)

Number of pills

No/Less side effects

Can correctly prepare the medicine

Easier to remember to take the medicine

Number of times you have to take the medicine

No/Less pain on the injection site

Gain my personal time with family and friends

Other____________________
The questionnaire is administered at week 4, week 24, week 28 and week 48. No total score is 
calculated on the preference questionnaire.  Each item will be scored as the proportion of 
patients who select each response option.  
7.3.2
mSICT – patients greater or equal to 10 years old
The Modified SICT (mSICT) questionnaire consists of 15 items that represent 3 domains; 
Adherence, Preference and Concerns.
The adherence domain consists of 7 items, 6 of which are measured using a 5 point response 
scale. 
Items 4, 5 and 6 use the response format 1 “Never””, 2 “Rarely” 3 “Sometimes” 4 ” Most of the 
time”, 3 “Sometimes”, 4 ”Rarely”, and 5 “Never;  Item 8 uses the response format 1 “Very 
easy”, 2 “Easy”, 3 “Neither easy nor hard”, 4 “Hard” and 5 “Very hard”; Items 9 and 10 use the 
response format 1 “Very bothered”, 2 “Quite bothered”, 3 “Moderately bothered”, 4 “A little
bothered” and 5 “Not bothered at all”. An Adherence domain score will be calculated by 
summing these 6 items and as a result a higher score will indicate worse adherence. 
Item 7 captures the reasons that the patient did not always take their medication as instructed 
and is only asked for patients who, at Item 6, indicated that they did not “Always” take their 
medication as instructed. These patients are instructed to choose all reasons that apply. Each 
response category will be coded as a binary item, for example taste will be an item with the 


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response format 0 “Not endorsed”, 1 “Endorsed”. For the “other” option, if there is a common 
response (>10%) it will be included as an additional binary response category in the analysis, 
otherwise other will be treated as Other 0 “Not endorsed”, 1 “Endorsed”.  This item will be 
used as a standalone item to better understand the overall Adherence domain. 
Satisfaction/preference domain consists of 3 items, 2 assess the patients’ satisfaction with the 
medication and are measured using a 5 point response scale with the response format: 1 “Very 
satisfied”, 2 “Satisfied”, 3 “Neither satisfied nor dissatisfied”, 4 “Dissatisfied”, 5 “Very 
dissatisfied”.  A Satisfaction domain score will be calculated by summing these two items. 
Higher scores will indicate worse satisfaction.  
The third item asks the patients to assess which medication for iron overload they prefer; this 
item will be used as a standalone item in the clinical trial. 
Concerns domain consists of 3 items to address any concerns and worries the patient has with 
their medication. All 3 items are measured on a 5 point response scale with the response format 
1 “Always”, 2 “Most of the time”, 3 “Sometimes”, 4 “Rarely” and 5 “Never”. A Concerns 
domain score will be calculated by summing these 3 items. Higher scores will indicate fewer 
concerns. 
Two additional items (items 14 and 15) will also be scored as standalone items. Item 14 asks 
patients to choose attributes pertaining to why they chose to prefer a certain medication. Item 
15 asks patients to “rank order” the medicines they have taken.
Adherence, satisfaction/preference and concerns domain scores and items will be summarized 
using standard descriptive statistics (Screening, week 4, week 24, week 28 and week 48).
7.3.3
Observer Reported mSICT – patients less than 10 years old
Similar to the mSICT for patients greater than 10 years old, an observer reported mSICT will 
be administered to those patients who are 2-9 years old.  Parents or caregivers of these patients 
will complete the mSICT for behaviors that are observed. The items are similar to the original 
mSICT however item 15 (the ranking exercise) is not included.  In addition, there are 7 items 
asking the parent to respond from their perspective regarding:

Feeling worried

How often medication was given for iron over load

Thinking to stop giving medication for iron overload

Following the doctor’s instructions

Reasons why not always giving medication

Ease of administrating medication

Bothered by time it took to administer medication
Adherence, satisfaction/preference and concerns domain scores (which are the same as above) 
and items will be summarized using standard descriptive statistics (Screening, week 4, week 24, 
week 28 and week 48).


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7.3.4
GI Symptoms – patients greater or equal to 10 years old
The GI symptom questionnaire consists of 6 items, 5 of which are scored using a 0 – 10 rating 
scale with item appropriate end anchors to rate the symptom, for example Pain in your belly 0 
= no pain and 10 = worst pain, with the numbers 1-9 labeled in between. The sixth item assesses 
bowel movement frequency during the past 24 hours, using 7 response options 0 = 0 (none), 1 
= 1, 2 = 2, 3 = 3, 4 = 4, 5 = 5 – 10 and 6 = 11 or more. 
A GI summary score will be created using the 10 point response scale items (5 items), Item 6 
will be excluded from the calculation of the GI symptom summary score and used in the analysis 
as a standalone item. Overall, higher scores on the GI symptom diary items and the summary 
score will indicate worse symptoms.
Weekly GI diary symptoms summary scores as well as item 6 (bowel movement) will be 
summarized using descriptive statistics at Screening, week 4, week 24, week 28 and week 48.
7.3.5
Observer Reported GI Symptoms – patients less than 10 years old
An observer GI symptoms questionnaire will be administered to those patients who are 2-9 
years old.  All items will be completed by the parents of the patients.  All items are the same 
and the scoring algorithm remains the same.
Weekly GI diary symptoms summary scores as well as item 6 (bowel movement) will be 
summarized using descriptive statistics at Screening, week 4, week 24, week 28 and week 48.
7.3.6
Palatability – patients greater or equal to 10 years old
The palatability questionnaire consists of 4 items. Two items measure the taste and aftertaste of 
the medication and are scored on a 5 point response scale with the response format 1 “Very 
good”, 2 “Good”, 3 “Neither good nor bad”, 4 “Bad” and 5 “Very bad”. The aftertaste item 
offers an additional response option of “no aftertaste”. This response option will be recoded 
such that all patients have a response, for example, patients who choose this option will be 
coded 0 and patients who rated the aftertaste will be coded 1. This will result in binary (yes/no) 
aftertaste item. 
The remaining palatability items refer to whether the medication was taken (i.e., swallowed or 
vomited) and how the patient perceived the amount of medication to be taken. 
A summary of Items 1, 3 and 4 leading to the palatability summary score will be constructed 
using the following rules:
Recode Item 1  
“Very good”, “Good” & “Not good or bad” =1
“Bad” & “Very bad” = 2
Recode Item 2
“Swallowed ALL of the medicine” =1
“Spat out SOME of the medicine” & “Spat out ALL of the medicine” & “Swallowed none” =2
“Vomited within 30 minutes after swallowing the medicine” = 3
Recode Item 3  
“Not enough liquid” & “Too much liquid” = 1
“Just enough liquid” = 2


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No missing data will be imputed when calculating the palatability summary score. 
The Table 7-5 presents the Items 1, 3 and 4 scoring matrix leading to the palatability summary 
score:
Table 7-5
Scoring Matrix
Palatability 
Score
Item1 – taste 
Item3 – what 
happened
Item4 – amount 
Definition
0
Bad & Very bad; 2
Vomited < 30 min; 3
Not enough & too 
much; 1
Worst 
palatability
1 
Bad & Very bad; 2
Vomited < 30 min; 3
Just enough: 2
1
2
Bad & Very bad; 2
Spat some/ all out; 2
Not enough & too 
much; 1
2
3
Bad & Very bad; 2
Spat some/ all out; 2
Just enough: 2
3
4
Bad & Very bad; 2
Swallowed all: 1
Just enough: 2
4
5
Bad & Very bad; 2
Swallowed all: 1
Not enough & too 
much; 1
5
6
V. good, Good & Not 
good/bad; 1
Vomited < 30 min; 3
Not enough & too 
much; 1
6
7
V. good, Good & Not 
good/bad; 1
Vomited < 30 min; 3
Just enough: 2
7
8
V. good, Good & Not 
good/bad; 1
Spat some/ all out; 2
Not enough & too 
much; 1
8
9
V. good, Good & Not 
good/bad; 1
Spat some/ all out; 2
Just enough: 2
9
10
V. good, Good & Not 
good/bad; 1
Swallowed all: 1
Not enough & too 
much; 1
10
11
V. good, Good & Not 
good/bad; 1
Swallowed all:  1
Just enough: 2
Best 
palatability
The palatability summary score will be summarized using descriptive statistics by treatment
arm and week (Screening, week 4, week 24, week 28 and week 48).
7.3.7
Observer Reported Palatability – patients less than 10 years old
An observer palatability questionnaire will be administered to those patients who are 2-9 years 
old.  All items will be completed by the parents of the patients.  All items are the same and the 
scoring algorithm remains the same as outlined in Section 7.3.6.
The palatability summary score will be summarized using descriptive statistics by treatment
arm and week (Screening, week 4, week 24, week 28 and week 48).


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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).
Except for screening failures, adverse events that begin or worsen after informed consent should 
be recorded in the Adverse Events eCRF. Conditions that were already present at the time of 
informed consent should be recorded in the Relevant Medical History/Current Medical 
Conditions eCRF page. Adverse event monitoring should be continued for at least 30 days (or 
5 half-lives, whichever is longer) following the last dose of study treatment. Adverse events 
(including lab abnormalities that constitute AEs) should be described using a diagnosis 
whenever possible, rather than individual underlying signs and symptoms. When a clear 
diagnosis cannot be identified, each sign or symptom should be reported as a separate Adverse 
Event.
Severity of adverse events will be assessed as mild, moderate, or severe. Information about 
deaths will be collected though an SEC form.
The occurrence of adverse events should be sought by non-directive questioning of the patient 
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 during the 
screening process or between visits, or through physical examination, laboratory test, or other 
assessments. As far as possible, each adverse event should be evaluated to determine:
1. The severity grade (mild, moderate, or severe)
2. Its duration (Start and end dates or Ongoing at End of Study )
3. Its relationship to the study treatment (Reasonable possibility that AE is related: suspected 
vs non-suspected)
4. Action taken with respect to study or investigational treatment (none, dose adjusted, 
temporarily interrupted, permanently discontinued, unknown, not applicable)
5. Whether medication or therapy was given (no concomitant medication/non-drug therapy, 
concomitant medication/non-drug therapy)
6. Whether it is serious, where a serious adverse event (SAE) is defined as in Section 8.2.1
All adverse events should be treated appropriately. If a concomitant medication or non-drug 
therapy is given, this action should be recorded on the Adverse Event eCRF.
Once an adverse event is detected, it should be followed until its resolution or until it is judged 
to be permanent, and assessment should be made at each visit (or more frequently, if necessary) 


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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 by investigator, induce clinical signs or symptoms, require concomitant 
therapy or require changes in study treatment), should be recorded on the Adverse Events eCRF. 
Whenever possible, a diagnosis, rather than a symptom should be provided (e.g. anemia instead 
of low hemoglobin). Laboratory abnormalities that meet the criteria for Adverse Events should 
be followed until they have returned to normal or an adequate explanation of the abnormality 
is found. When an abnormal laboratory or test result corresponds to a sign/symptom of an 
already reported adverse event, it is not necessary to separately record the lab/test result as an 
additional event.
Laboratory abnormalities, that do not meet the definition of an adverse event, should not be 
reported as adverse events. A severe event does not automatically indicate a SAE unless it meets 
the definition of serious as defined below and/or as per investigator’s discretion. A dose hold 
or medication for the lab abnormality may be required by the protocol in which case the lab 
abnormality would still, by definition, be an adverse event and must be reported as such.
8.2
Serious adverse events
8.2.1
Definitions
Serious adverse event (SAE) is defined as one of the following:

Is fatal or life-threatening

Results in persistent or significant disability/incapacity

Constitutes a congenital anomaly/birth defect

Is medically significant, i.e., defined as an event that jeopardizes the patient or may 
require medical or surgical intervention to prevent one of the outcomes listed above

Requires inpatient hospitalization or prolongation of existing hospitalization, 

Note that hospitalizations for the following reasons should not be reported as serious 
adverse events:

Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 

Elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent

Social reasons and respite care in the absence of any deterioration in the patient’s general 
condition

Note that treatment on an emergency outpatient basis that does not result in hospital 
admission and involves an event not fulfilling any of the definitions of a SAE given above 
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8.2.2
Reporting
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the 
patient has provided informed consent and until at least 30 days after the patient has stopped 
study treatment must be reported to Novartis within 24 hours of learning of its occurrence. 
Any SAEs experienced after this 30 days period should only be reported to Novartis if the 
investigator suspects a causal relationship to the study treatment. Recurrent episodes, 
complications, or progression of the initial SAE must be reported as follow-up to the original 
episode within 24 hours of the investigator receiving the follow-up information. An SAE 
occurring at a different time interval or otherwise considered completely unrelated to a 
previously reported one should be reported separately as a new event.
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 
thorough report. The investigator must assess and record the relationship of each SAE to each 
specific study treatment (if there is more than one study treatment), complete the SAE Report 
Form in English, and send the completed, signed form by fax within 24 hours to the oncology 
Novartis Drug Safety and Epidemiology (DS&E) department.
The telephone and telefax number of the contact persons in the local department of Drug Safety 
and Epidemiology (DS&E), specific to the site, are listed in the investigator folder 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 should be reported as a follow-up to that event regardless of 
when it occurs. The follow-up information should describe whether the event has resolved or 
continues, if and how it was treated, whether the blind was broken or not, and whether the 
patient continued or withdrew from study participation.
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the Novartis study treatment, an oncology Novartis 
Drug Safety and Epidemiology (DS&E) department associate may urgently require further 
information from the investigator for Health Authority reporting. Novartis may need to issue 
an Investigator Notification (IN), to inform all investigators involved in any study with the same 
drug that this SAE has been reported. Suspected Unexpected Serious Adverse Reactions 
(SUSARs) will be collected and reported to the competent authorities and relevant ethics 
committees in accordance with Directive 2001/20/EC or as per national regulatory requirements 
in participating countries.
8.3
Emergency unblinding of treatment assignment
Not applicable, this is an open-label treatment study.


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8.4
Pregnancies
To ensure patient safety, each pregnancy occurring while the patient is on study treatment must 
be reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of 
the birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal 
and/or newborn complications.
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the oncology Novartis Drug Safety and Epidemiology Department (DS&E). 
Pregnancy follow-up should be recorded on the same form and should include an assessment 
of the possible relationship to the study treatment any pregnancy outcome. Any SAE 
experienced during pregnancy must be reported on the SAE Report Form.
Pregnancy outcomes must be collected for the female partners of any males who took study 
treatment in this study. Consent to report information regarding these pregnancy outcomes 
should be obtained from the mother.
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 
A Steering Committee (SC), comprising 2 principal investigators from the study, will be formed 
plus two Novartis members (regional medical head and a statistician). The purpose of this study 
management committee is to provide overall guidance regarding the conduct and execution of 
the trial to include (and not limited to) rationale of the study, accrual and contribution to 
scientific input for publications.
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


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
Who will have access to that information and why

Who will use or disclose that information

The rights of a research subject to revoke their authorization for use of their PHI
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization. For subjects that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect follow-up safety information (e.g. has the subject 
experienced any new or worsened AEs) at the end of their scheduled study period.
The data collection system for this study uses built-in security features to encrypt all data for 
transmission in both directions, preventing unauthorized access to confidential participant 
information. Access to the system will be controlled by a sequence of individually assigned 
user identification codes and passwords, made available only to authorized personnel who have 
completed prerequisite training.
9.2
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, Novartis
personnel (or designated CRO) will review the protocol and eCRFs with the investigators and 
their staff. During the study, the field monitor will visit the site regularly to check the 
completeness of patient records, the accuracy of entries on the eCRFs, the adherence to the 
protocol to Good Clinical Practice, the progress of enrollment, and to ensure that study 
treatment is being stored, dispensed, and accounted for according to specifications. Key study 
personnel must be available to assist the field monitor during these visits.
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information recorded on eCRFs 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 eCRF 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 eCRFs 
are performed according to the study-specific monitoring plan.
9.3
Data collection
This study will use 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.


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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
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 staffs are required to 
respond promptly to queries and to make any necessary changes to the data.
Concomitant treatments and prior medications entered into the database will be coded using the 
WHO Drug Reference List, which employs the Anatomical Therapeutic Chemical classification 
system. Medical history/current medical conditions and adverse events will be coded using the 
Medical dictionary for regulatory activities (MedDRA) terminology.
The site staff will transcribe data from the paper questionnaires into the EDC system. 
The occurrence of any protocol deviations 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 and made available for data analysis. Authorization is required prior to making 
any database changes to locked data, by joint written agreement between the Medical Advisor 
or Equivalent, Head of Biostatistics PLSS, Global/ Head Data Sciences PLSS; prior authorizing 
the database un-lock, a CTT meeting will be hosted, to discuss the issues leading to database 
unlock and update. For EDC studies, after database lock, the investigator will receive a CD-
ROM or paper copies of the patient data for archiving at the investigational site.
10
Statistical methods and data analysis
Summary statistics for continuous variables will generally include the number of patients (N), 
minimum, lower quartile, mean, median, upper quartile, and maximum. For categorical or 
binary variables, the number and percent of patients in each category will be presented. P-values 
presented will be 2-sided unless otherwise specified.
Inferential efficacy comparisons will be done on the first 4, 24, 28 and 48 weeks of treatment.
All data analyses will be presented by treatment group (wherever applicable) and by transfusion 
or non-transfusion dependence thalassemia. Efficacy and safety data for the core and extension 
phases will also be presented by the above groups. Patients will be included in more than 1 
treatment group for some analyses (e.g. exposure-adjusted AEs over the entire treatment period).
The analysis will be conducted on all patient data at Week 4, 24, 28, 48, and at the time the trial 
(both phases) ends. Any data analysis carried out independently by the investigator should be 
submitted to Novartis before publication or presentation.
10.1
Analysis sets
The following analysis sets will be used in this trial.


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Enrolled Set
The Enrolled Set comprises of all patients enrolled in this study.
Full Analysis Set
The Full Analysis Set (FAS) comprises all patients to whom study treatment has been assigned 
and who received at least one dose of each study treatment (DT and FCT).  Patients will be 
analyzed according to the treatment they have been assigned to.  
Safety set
The Safety Set includes all patients who received at least one dose of either study treatment (DT 
or FCT), and at least one safety assessment on or after Day 1. 
Patients will be analyzed according to the study treatment received, where treatment received 
is defined as the assigned treatment if the patient took at least one dose of that treatment or the 
first treatment received if the assigned treatment was never received.
Per-Protocol set
The Per-Protocol Set (PPS) consists of a subset of the patients in the FAS who are compliant 
with requirements of the CSP (clinical study protocol) without any major protocol deviation.
The major protocol deviations that will lead to exclusion of patients from the PPS will be
detailed in the SAP.
Pharmacokinetic analysis set
Not applicable
10.2
Patient demographics/other baseline characteristics
10.2.1
Demographics and baseline characteristics
Summary statistics will be presented for continuous demographic and baseline characteristic 
variables the subgroup of interest and for all patients in the Enrolled Set. The number and 
percentage of patients in each category will be presented for categorical variables for each 
treatment group and all patients.
Demographic and baseline disease characteristics will be summarized for the variables listed in 
Section 7.1.1.3.
10.2.2
Medical history
Any significant prior or active medical condition at the time of signing informed consent will 
be coded using the MedDRA dictionary. These medical conditions will be summarized by 
primary system organ class and preferred term.


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10.3
Treatments (study treatment, concomitant therapies, 
compliance)
10.3.1
Study Treatment
The following variables will be summarized descriptively for each study treatment based on the 
Safety Set. Summaries will be presented overall and on prior intake of iron chelation status 
(naïve or pre-treated) and thalassemia transfusion status (transfusion or non-transfusion), 
separately for Core and Extension phases.
The number of medications (pills) received for each dosing regimen; the duration of exposure 
(in weeks) and in categories (<4 weeks, 4-<12 weeks, 12-<24 weeks, >=24 weeks); average 
planned (mg/kg/day) and average actual daily dose; cumulative planned (mg/kg) and 
cumulative total actual dose (mg/kg); percentage of planned dose taken; dose intensity 
(computed as the ratio of actual cumulative dose received and actual duration of exposure); and
relative dose intensity (computed as the ratio of dose intensity and planned dose intensity). 
The number of patients with dose adjustments (reductions, interruption, or permanent 
discontinuation) and the reasons will be summarized for all patients and by treatment group.
Dose adjustments for auditory, hypersensitivity reactions and cytopenias will also be 
summarized.
The number of patients with ‘switching’ from one treatment to another at any treatment period 
along with the reasons of switching will also be summarized.
The duration of exposure is defined as the number of weeks between the start and end of study 
medication. The exposure calculation will be based on the actual date of switch from one 
treatment to another. The end of study medication day is the last day with a non-zero actual 
dose of study medication as recorded on the drug administration pages.
The average daily dose (planned or actual, in mg/kg) is calculated as the mean dose over all 
days between first and last dose, including interim days with zero dose (interruptions). The 
cumulative dose is calculated as the sum over the daily doses of all days between first and last 
dose. The current weight is used when calculating the actual daily dose.
The percentage of planned dose taken is derived as 100 * cumulative actual dose (mg/kg)/ 
cumulative planned dose (mg/kg).
10.3.2
Prior and concomitant medication
Prior and concomitant medications will be summarized in separate tables by treatment group.
Prior medications are defined as treatments taken and stopped prior to first dose of study 
treatment. Any medication given at least once between the day of first dose of randomized study 
treatment and the date of the last study visit will be a concomitant medication, including those 
which were started pre-baseline and continued into the period where study treatment is 
administered. 
Medications will be presented in alphabetical order, by Anatomical Therapeutic Classification
(ATC) codes and grouped by anatomical main group. 


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Tables will show the overall number and percentage of patients receiving at least one treatment 
of a particular ATC code and at least one treatment in a particular anatomical main group.
Significant prior and concomitant non-drug therapies and procedures will be summarized using 
WHO Drug Reference List.
The number and percentage of patients receiving prior iron chelation treatments will be 
presented by treatment group as well as the reasons for stopping their and the total duration of 
exposure to chelation therapies previously.
10.4
Primary objective
The primary objective is to evaluate patient preference of deferasirox DT or deferasirox FCT 
formulations in patients with transfusion-dependent thalassemia or non-transfusion dependent 
thalassemia as measured by the preference questionnaire at Week 48.
10.4.1
Variable
The primary variable is proportion and percentage (%) of patients claimed preference of 
deferasirox FCT over deferasirox DT as measured by preference questionnaire at Week 48.
The analysis of primary variable will be based on the FAS.
10.4.2
Statistical hypothesis, model, and method of analysis
The null hypothesis is that there is no difference in the proportion of patients preferring FCT or 
DT at Week 48. The alternative hypothesis is that there is a difference in the proportion of 
patients preferring FCT or DT at Week 48
Let p.1 denotes the proportion of patients with preference (discordance) or no-preference 
(concordance) of DT and p1. denotes the proportion of patients with preference or no-preference 
of FCT, at Week 48.
In statistical terms, the following hypothesis will be tested for primary objective:
H1: p1. = p.1, versus HA1: p1. ≠p.1
This is equivalent to test: H1: p12 = p21, versus HA1: p12 ≠p21, 
where p12 and p21 denotes the proportion of patients with preference of FCT over DT and vice 
versa.
In other words, 
H1: Deferasirox FCT is not different from deferasirox DT with respect to patient preference at 
Week 48
versus
HA1: Deferasirox FCT is different from deferasirox DT with respect to patient preference at 
Week 48
The primary analyses of testing patient preference of FCT over DT will be conducted via Mc 
Nemar’s test. Both exact and asymptotic p-values will be presented for Mc Nemar’s test for 
matched pairs. 


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Along with p-values, the estimates of proportions of patient preferences and non-preferences 
for each study treatment will also be presented along with 95% CI (if required).
The family-wise error will be set to 2-sided α=5% or 1-sided α=2.5%. 
Please refer to Section 10.8 for sample size calculation.
10.4.3
Handling of missing values/censoring/discontinuations
There will be no imputation for missing data. Wherever appropriate, available data will be 
summarized over specified intervals using suitable summary statistics. Details will be provided 
in SAP. 
10.4.4
Supportive and Sensitivity analyses
Sensitivity analyses and supportive analyses will be conducted in order to provide evidence that 
the results seen from the primary analysis are robust. 
In order to support the Mc Nemar’s test for matched pair, the Odd’s Ratio (OR) of patient 
preference (i.e., OR=p12/p21), 95% confidence interval (CI) and p-values may also be presented, 
if appropriate. Conditional logistic model for matched pair analyses may also be fitted if 
required. 
The above primary analyses will also be performed for each subgroup of stratification factor, 
i.e., on patients with transfusion dependent or non-transfusion dependent thalassemia. Also, the 
primary analyses may be performed based on prior treatment status of iron chelation. 
In case of switching, the primary analyses will be performed separately for patients with or 
without switching before Week 48. Further details will be presented in SAP.
The primary analysis will also be provided for PPS.
10.5
Secondary objectives
The secondary objectives and endpoints are described in protocol Section 3. The analyses will 
be based on FAS population.
10.5.1
Key secondary objective(s)
Not applicable
10.5.2
Other secondary efficacy objectives
The following secondary analyses will be performed:
Patient preference of FCT, DT, and iron chelation at Week 28
Proportion and percentage, % (and 95% CI) of patients with preference and non-preference of 
FCT over DT, FCT over iron chelation, and DT over iron chelation will be summarized 
separately at Week 28. 
Homogeneity test (Cochran’s Q test) may be performed to check the homogeneity of the three 
preferences. Exact and asymptotic p-values of Mc Nemar’s test will also be presented as 
analogous to primary analysis, for each pair of treatment comparison. For comparison of FCT 


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and DT with iron-chelation, only patients who are pre-treated with iron chelation will be 
selected.
Patient preference of DT and iron chelation at Week 4 and Week 24
Proportion and percentage, % (and 95% CI) of patients with preference and non-preference of 
DT over iron chelation will be summarized at Week 4 and Week 24. Exact and asymptotic p-
values of Mc Nemar’s test will also be presented as analogous to primary analysis. Only patients 
who are pre-treated with iron-chelation will be considered.
Reasons of patient preference
The reasons or factors influencing behind patient preference of FCT over DT will be 
summarized at Week 28 and 48. Proportions of patients for selecting each reason will be 
presented for each study treatment. Further summary of reasons behind non-preference of each 
study treatment will also be presented.
Compliance using pill count 
Compliance is measured by pill /tablet count based on amount of medication dispensed, 
returned and reported as lost/wasted by the patient or caregiver. Compliance will be calculated 
for each treatment (FCT: Week 25- Week 48, DT: Baseline day 1 – Week 24) as the ratio of 
total count consumed to total count prescribed, where
total count consumed is derived from cumulative dispensed, returned and lost/wasted counts;

total count prescribed is cumulative prescribed count
Analysis of covariance (ANCOVA) will be performed for comparison between both treatment 
groups (FCT and DT). The ANCOVA model for compliance endpoint will include treatment 
group and age group ((2 to <6 years, 6 to<10 years, 10 to <18 years, and >=18 years) and 
thalassemia transfusion dependence (transfusion and non-transfusion dependent) as factors. 
Least squares estimates, 95% CI and p-value will be presented for each treatment and difference 
between treatments. 
Summary statistics of number of pills (and percentages) will also be presented overall and by 
treatment and subgroups. Refer to Section 10.5.6 for further details.
Serum Ferritin for monthly visits from Day 1 baseline up to Week 48 
Summary statistics of change from baseline (absolute and difference, and 95% CI) will 
presented by treatment and subgroups and difference between treatments. Further details will 
be mentioned in SAP.
Palatability
Refer to PRO Section 10.5.6 for details.
mSICT
Refer to PRO Section 10.5.6 for details.


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GI symptoms 
Refer to PRO Section 10.5.6 for details.
10.5.3
Safety objectives
The overall safety will be measured by frequency and severity of AEs and changes in laboratory 
values of interest during the two treatment period (DT and FCT). The analyses are described 
below in respective sections.
10.5.3.1 Analysis set and grouping for the analyses
For all safety analyses, the Safety set will be used. All listings and tables will be presented by 
treatment group (wherever applicable) and by transfusion or non-transfusion dependence 
thalassemia. The safety analyses will also be presented separately for core and extension phases 
of the study.
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 dose 
of study medication
3. post-treatment period: starting at day 30+1 after last dose of study medication
10.5.3.2 Adverse events (AEs)
Summary tables for adverse events (AEs) will include only AEs that started or worsened during 
the on-treatment period, the treatment-emergent AEs. The AEs will be summarized separately 
and compared for two treatment groups FCT (Week 25 to 48) and DT (Baseline Day 1 to Week 
24).
The incidence of treatment-emergent adverse events (new or worsening from baseline) will be 
summarized by system organ class and or preferred term, severity (based on on mild, moderate, 
severe, life threatening, death), type of adverse event, relation to study treatment. If a patient 
reported more than one AE with the same preferred term, the AE with the greatest severity will 
be presented. If a patient reported more than one AE within the same primary system organ 
class, the patient will be counted only once with the greatest severity at the system organ class 
level, where applicable. 
Serious adverse events, non-serious adverse events and adverse events of special interest (AESI)
which are specific gastrointestinal events during the on-treatment period will be tabulated. 
Separate summaries will be provided for death, SAE, other significant AEs leading to 
discontinuation and AEs leading to dose adjustment (including study treatment discontinuation).
As appropriate, the incidence of AEs will be presented per 100 patient years of exposure. 
All AEs, deaths and serious adverse events (including those from the pre and post-treatment 
periods) will be listed and those collected during the pre-treatment and post-treatment period 
will be flagged.


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A graphical display of relative frequencies within system organ classes and relative risks, as 
appropriate, may be presented is required.
For AEs of special interest, time-to-event analysis will be performed, as appropriate and as 
described in the statistical analysis plan. Results will be tabulated and the Kaplan-Meier 
estimates for the cumulative rate will be plotted.
10.5.3.3 Laboratory abnormalities
The summary of laboratory evaluations will be presented for different groups of laboratory tests 
(hematology, serum chemistry, serum ferritin, serum creatinine, and urinalysis). Descriptive 
summary statistics for the change from baseline to each study visit will be presented. These 
descriptive summaries will be presented by test group, laboratory test and treatment group. 
Change from baseline will only be summarized for patients with both baseline and post-baseline. 
The laboratory evaluations will be summarized separately and compared for two treatment 
groups FCT (Week 25 to 48) and DT (Baseline Day 1 to Week 24). 
For each parameter, the maximum change from baseline within each study period will be 
evaluated analogously. 
In addition, shift tables will be provided for all parameters to compare a patient’s baseline 
laboratory evaluation relative to the visit’s observed value. For the shift tables, the normal 
laboratory ranges will be used to evaluate whether a particular laboratory test value was normal, 
low, or high for each visit value relative to whether or not the baseline value was normal, low, 
or high. These summaries will be presented by laboratory test and treatment group. Shifts will 
be presented by visit as well as for most extreme values post-baseline.
Grading of laboratory values will be assigned programmatically as per NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.3.  The calculation of CTCAE 
grades will be based on the observed laboratory values only, clinical assessments will not be 
taken into account.
CTCAE Grade 0 will be assigned for all non-missing values not graded as 1 or higher. Grade 5 
will not be used.
For laboratory tests where grades are not defined by CTCAE v4.3, results will be categorized 
as low/normal/high based on laboratory normal ranges.
The following summaries will be generated separately for hematology, and biochemistry tests:

Listing of all laboratory data with values flagged to show the corresponding CTCAE v4.3 
grades if applicable and the classifications relative to the laboratory normal ranges (Table 
10-1)

For laboratory tests where grades are defined by CTCAE v4.3

Worst post-baseline CTCAE grade (regardless of the baseline status). Each patient will be 
counted only once for the worst grade observed post-baseline.

Shift tables using CTCAE v4.3 grades to compare baseline to the worst on-treatment value
For laboratory tests where grades are not defined by CTCAE v4.3,

Shift tables using the low/normal/high/ (low and high) 


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
Classification to compare baseline to the worst on-treatment value.
Apart from the above laboratories summaries, summaries of Hepatitis Viral tests will also be 
performed. 
Table 10-1
Definition of notable/extended ranges for laboratory test
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
ALT and AST
>5 x ULN and >2 x baseline value (extended 
range >10×ULN and >2×baseline value)
* Creatinine clearance will be estimated using the Schwartz formula
10.5.3.4 Other safety data
Data from vital signs, body weight, ECG, ocular, and auditory examinations will be listed and 
summarized with descriptive statistics as appropriate separately for the Safety Set. All new or 
worsened abnormalities will be recorded on the AE eCRF page.
ECG
ECG will be performed at baseline and EOT. Abnormalities will be reported together with an 
overall interpretation of the findings. Any abnormalities at baseline will be summarized. At 
EOT, the investigator will flag all abnormalities which are new or worsened since baseline. All 
new or worsened abnormalities will be recorded on the AE eCRF page. All findings of patients 
with new or worsened clinically significant abnormalities will be listed.
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 but will be listed.
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.
A listing will be provided for all vital signs and weight. Notable vital signs and weight values 
are flagged. The criteria for notably abnormal vital signs and weight are displayed in Table 10-
2.


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Table 10-2
Definition of notable ranges for vital signs and weight
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
Auditory, chest x-ray and ocular assessment evaluations
Auditory evaluations, chest x-ray and ocular examinations will be performed at baseline and
at 12 months visit. Any abnormalities at baseline will be summarized. Abnormalities will be 
reported together with an overall interpretation of the findings. All new or worsened
abnormalities will be recorded on the AE eCRF page. All findings of patients with new or 
worsened clinically significant abnormalities will be listed.
10.5.3.5 Supportive analyses for secondary objectives 
Similar to the supportive analyses for primary objective as mentioned in section 4.4
10.5.3.6
Tolerability
Not applicable
10.5.4
Pharmacokinetics
Not applicable
10.5.5
Biomarkers
Not applicable
10.5.6
Patient-reported outcomes 
The following PROs will be summarized using FAS.
Preference questionnaire
The preference questionnaire is a three item questionnaire. There are three separate versions 
depending on the week(s) that the questionnaire is administered. For week 48 (primary endpoint) 
the first item asks the patients on which medicine they are currently taking with the response 
options: “Tablet to dissolve in liquid”, “Film coated tablet (taken once a day)”, “Sprinkle 
powder on food” or, “I don’t know”.  The second item asks which of the medicines did the 
patient “Like best” with the same response options as that of the first item. Finally, the third 
item asks the patient why he/she preferred the medicine they chose.  
For week 28 the first item asks patients to choose from the following medicines: “Tablet to 
dissolve in liquid”, “Film coated tablet”, “Tablet (taken 3 times a day)”, “Sprinkle powder on 
food”, “Injection” and “I don’t know”. The second items remain the same asking what patients 
like the best (out of the above response options. Similarly the third item remains the same.


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For weeks 4 and 24 the first item asks patients to choose from the following medicines: “Tablet 
to dissolve in liquid”, “Tablet (taken 3 times a day)”, “Injection” and “I don’t know”. The 
second items remain the same asking what patients like the best (out of the above response 
options. Similarly the third item remains the same.
Summaries of the preference questionnaires will be performed at Visits 4, 24, 28 and 48 in Core 
phase of the study and additionally from the data collected at the time of immediate next visit 
based on patients who had treatment switching. 
The analysis of preference data has been explained in protocol Section 10.4 and Section 10.5.2.
Palatability 
The palatability questionnaire consists of 4 items. Two items measure the taste and aftertaste of 
the medication and are scored on a 5 point response scale with the response format 1 “Very 
good”, 2 “Good”, 3 “Neither good nor bad”, 4 “Bad’ and 5 “Very bad”. The remaining 
palatability items refer to whether the medication was taken (i.e., swallowed or vomited) and 
how the patient perceived the amount of medication to be taken. 
For the palatability questionnaire the overall score will be constructed using a scoring matrix 
from the score of items. Standard descriptive analyses including absolute and relative changes 
will be performed for both formulations (DT/FCT) for the overall score at Week 4, Week 24, 
Week 28 and Week 48 and overall score at Screening for iron chelators. The baseline data for 
treatment period 1 and 2 will be Week 4 and Week 24 data respectively, only one assessment 
is observed at Screening period. 
The standard descriptive analyses include: n, mean, standard deviation, minimum, median and 
maximum. The 95% confidence interval for the absolute and relative (or difference) change 
from baseline of the overall score will also be presented for the treatments. In addition to that, 
summaries will also be performed from the data collected at the time of immediate next visit 
based on patients who had treatment switching.
Details about scoring and further analyses will be included in the SAP.
mSICT
The Modified SICT (mSICT) questionnaire consists of 15 items that represent 3 domains; 
Adherence, Preference and Concerns.
For the SICT questionnaire, the score for each domain will be the mean of the score of items 
included in the corresponding domain. Standard descriptive analyses will be performed for both 
formulations (DT/FCT) for each domain score at Week 4, Week 24, Week 28 and Week 48 and 
at Screening for iron chelators. The baseline data for treatment period 1 and 2 will be Week 4 
and Week 24 data respectively, only one assessment is observed at Screening period.
The standard descriptive analyses include: n, mean, standard deviation, minimum, median and 
maximum. The 95% confidence intervals for the absolute and relative (or difference) changes 
from baseline in all domains will be presented for the treatments. In addition to that, summaries 
will also be performed from the data collected at the time of immediate next visit based on 
patients who had treatment switching. .
Details about scoring and further analyses will be included in the SAP.


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GI symptoms
The GI symptom consists of 6 items, 5 of which are scored using a 0 – 10 rating scale with item 
appropriate end anchors to rate the symptom, The sixth item assesses bowel movement 
frequency during the past 24 hours, using 7 response options. 
The GI symptoms will be summarized as analogous to the above questionnaires. Details about 
scoring and further analyses will be included in the SAP.
10.6
Exploratory objectives
Not applicable
10.7
Interim analysis
One interim analysis is contemplated in this study.
The interim analysis will be performed after all patients complete Week 48 to assess the patient 
preference after 6 months with deferasirox FCT treatment in comparison to deferasirox DT. 
The primary analysis to evaluate the patient preference of FCT over DT will be performed at 
this interim. 
10.8
Sample size calculation
Based on data from the ECLIPSE study [Taher et al, 2018], the following assumptions have 
been made at Week 48, the patient preference for  deferasirox FCT (formulation) is 45% and 
preference for deferasirox DT (formulation) is 25% and no preference to either of the 
formulations is 30%. This means the discordant pairs is 70 % (i.e. 70% preferred one 
formulation over another,45 %) and concordant pairs= 30% (assuming same preference for each 
formulation, 15%).
At least 130 patients are needed at Week 48 to have 80% power to detect the difference of 
patient preference of 20% (i.e., 45% preference of FCT over DT and 25% preference of DT 
over FCT) at a two sided significance level of 0.05 using McNemar's test for matched pairs.
To allow for roughly 10% of subjects with missing measurement, a total of approximately 145
evaluable patients aged >2 years male or female with transfusion-dependent thalassemia or
non-transfusion-dependent thalassemia requiring chelation therapy due to iron overload,  need 
to be enrolled. Patients may have been previously treated with iron chelators (outside 
Deferasirox DT) or be chelation naïve.
EAST 6.0 is used to calculate the sample size.
10.9
Power for analysis of key secondary variables
Not applicable


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11
Ethical considerations and administrative procedures
11.1
Regulatory and ethical compliance
This clinical study was designed, shall be implemented and reported in accordance with the 
ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC and US Code of Federal Regulations 
Title 21), and with the ethical principles laid down in the Declaration of Helsinki.
11.2
Responsibilities of the investigator and IRB/IEC/REB
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly constituted Institutional Review Board/Independent Ethics Committee/Research 
Ethics Board (IRB/IEC/REB) before study start. Prior to study start, the investigator is required 
to sign a protocol signature page confirming his/her agreement to conduct the study in 
accordance with these documents and all of the instructions and procedures found in this 
protocol and to give access to all relevant data and records to Novartis monitors, auditors, 
Novartis Clinical Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs/REBs and regulatory authorities as required.
11.3
Informed consent procedures
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC/REB-approved informed consent or, if incapable of 
doing so, after such consent has been provided by a legally acceptable representative of the 
patient. In cases where the patient’s representative gives consent, the patient should be informed 
about the study to the extent possible given his/her understanding. If the patient is capable of 
doing so, he/she should indicate assent by personally signing and dating the written informed 
consent document or a separate assent form.
Informed consent must be obtained before conducting any study-specific procedures (i.e. all of 
the procedures described in the protocol). The process of obtaining informed consent should be 
documented in the patient source documents. The date when a subject’s Informed Consent was 
actually obtained will be captured in their eCRFs.
Novartis will provide to investigators, in a separate document, a proposed informed consent 
form (ICF) that is considered appropriate for this study and complies with the ICH GCP 
guideline and regulatory requirements. Any changes to this ICF suggested by the investigator
must be agreed to by Novartis before submission to the IRB/IEC/REB and a copy of the 
approved version must be provided to the Novartis monitor after IRB/IEC/REB approval.
Women of child bearing potential should be informed that taking the study medication may 
involve unknown risks to the fetus if pregnancy were to occur during the study and agree that 
in order to participate in the study they must adhere to the contraception requirement for the 
duration of the study. If there is any question that the patient will not reliably comply, they 
should not be entered in the study.


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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. In addition, upon study completion and 
finalization of the study report the results of this study will be either submitted for publication 
and/or posted in a publicly accessible database of clinical study results.
11.6
Study documentation, record keeping and retention of 
documents
Each participating site will maintain appropriate medical and research records for this trial, in 
compliance with Section 4.9 of the ICH E6 GCP, and regulatory and institutional requirements 
for the protection of confidentiality of subjects. As part of participating in a Novartis-sponsored 
study, each site will permit authorized representatives of the sponsor(s) and regulatory agencies 
to examine (and when required by applicable law, to copy) clinical records for the purposes of 
quality assurance reviews, audits and evaluation of the study safety and progress.
Source data are all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Examples 
of these original documents and data records include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, subjects’ diaries or evaluation 
checklists, pharmacy dispensing records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate and complete, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, and subject files and records kept 
at the pharmacy, at the laboratories, and medico-technical departments involved in the clinical 
trial.
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 (eCRF) is the primary data collection 
instrument for the study. The investigator should ensure the accuracy, completeness, legibility, 
and timeliness of the data reported in the eCRFs and all other required reports. Data reported 
on the eCRF, that are derived from source documents, should be consistent with the source 
documents or the discrepancies should be explained. All data requested on the eCRF must be 
recorded. Any missing data must be explained. For electronic CRFs an audit trail will be 
maintained by the system.
The investigator/institution should maintain the trial documents as specified in Essential 
Documents for the Conduct of a Clinical Trial (ICH E6 Section 8) and as required by applicable 
regulations and/or guidelines. The investigator/institution should take measures to prevent 
accidental or premature destruction of these documents.
Essential documents (written and electronic) should be retained for a period of not less than 
fifteen (15) years from the completion of the Clinical Trial unless Sponsor provides written 


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permission to dispose of them or, requires their retention for an additional period of time 
because of applicable laws, regulations and/or guidelines.
11.7
Confidentiality of study documents and patient records
The investigator must ensure anonymity of the patients; patients must not be identified by names 
in any documents submitted to Novartis. Signed informed consent forms and patient enrollment 
log must be kept strictly confidential to enable patient identification at the site.
11.8
Audits and inspections
Source data/documents must be available to inspections by Novartis or designee or Health 
Authorities.
11.9
Financial disclosures
Financial disclosures should be provided by study personnel who are directly involved in the 
treatment or evaluation of patients at the site - prior to study start
12
Protocol adherence
Investigators ascertain they will apply due diligence to avoid protocol deviations. Under no 
circumstances should the investigator contact Novartis or its agents, if any, monitoring the study 
to request approval of a protocol deviation, as no authorized deviations are permitted. If the 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC/REB it cannot be implemented. All significant protocol 
deviations will be recorded and reported in the CSR.
12.1
Amendments to the protocol
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, Health Authorities where required, and the IRB/IEC/REB. Only 
amendments that are required for patient safety may be implemented prior to IRB/IEC/REB 
approval. Notwithstanding the need for approval of formal protocol amendments, the 
investigator is expected to take any immediate action required for the safety of any patient 
included in this study, even if this action represents a deviation from the protocol. In such cases, 
Novartis should be notified of this action and the IRB/IEC at the study site should be informed 
according to local regulations (e.g. UK requires the notification of urgent safety measures 
within 3 days) but not later than 10 working days.


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13
References (available upon request)
Alvarez O, Rodriguez-Cortes H, Robinson N et al (2009) Adherence to deferasirox in children 
and adolescents with sickle cell disease during 1-year of therapy. J Pediatr Hematol 
Oncol;31(10):739-44.
Arboretti R, Tognoni G, Alberti D, et al (2001) Pharmacosurveillance and quality of care of 
thalassaemic patients. A large scale epidemiological survey. Eur J Clin 
Pharmacol;56(12):915-22.
Cappellini MD, Cohen A, Piga A, et al (2006). A Phase III study of deferasirox (ICL670), a 
once-daily oral iron chelator, in patients with β-thalassemia. Blood; 107:3455-62.
Cappellini  MD, Bejaoui  M, Agaoglu L, et al (2007) Prospective evaluation  of patient-
reported outcomes during treatment  with deferasirox or deferoxamine for iron overload  in 
patients  with beta-thalassemia. Clinical Therapeutics; 29 (5):909-17.
Cappellini MD (2008) Long-term efficacy and safety of deferasirox. Blood Rev. Suppl 2:S35-
41.
Galanello R and Origa R (2010). Beta-thalassemia. Orphanet J Rare Dis; 5:11.
Gabutti V and Piga A (1996).  Results of Long-Term Iron-Chelating Therapy. Acta 
Haematologica;95:26-36.
Hanley JA, Lippman-Hand A (1983) If nothing goes wrong, is everything all right? 
Interpreting zero numerators JAMA;249(13):1743-5.
Jaeger M, Aul C, Sohngen D, et al (1992). Iron overload in polytransfused patients with 
MDS: the use of L1 for oral iron chelation. Drugs of Today; 28(Suppl A): 143-47.
Jensen PD, Heickendorff L, Pedersen B, et al (1996). The effect of iron chelation on 
haemopoiesis in MDS patients with transfusional iron overload. Br J Haematol; 94:288-299.
Jensen PD, Jensen FT, Christensen T, et al (2003). Relationship between hepatocellular injury 
and transfusional iron overload prior to and during iron chelation with desferrioxamine: a 
study in adult patients with acquired anemias. Blood; 101:91-96.
Jordan L. B, Vekeman F, Sengupta A et al (2012) Persistence and compliance of 
deferoxamine versus deferasirox in Medicaid patients with sickle-cell disease. Journal of 
Clinical Pharmacy and Therapeutics, 37, 173–181.
Malcovati L, Della Porta MG, Pascutto C,  et al (2005). Prognostic Factors and Life
Expectancy in Myelodysplastic Syndromes Classified Accodring to WHO Criteria: A Basis 
for Clinical Decision Making. Journal of Clinical Oncology; v23,no.30:7594-7603.
[National Comprehensive Cancer Network] NCCN Clinical Practice Guidelines in Oncology 
Myelodysplastic Syndromes. Version 2.2011. Available at: 
http//wwwnccn.org/professionals/physician_gls/pdf/mds.pdf Accessed August 9, 2011. 
Osborne RH, De Abreu Lourenço R, Dalton A, et al (2007) Quality of life related to oral 
versus subcutaneous iron chelation: a time trade-off study. Value Health;10(6):451-6.
Schafer AI, Cheron RG, Dluhy R, et al (1981). Clinical consequences of acquired 
transfusional iron overload in adults. NEJM;304: 319-324.


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Schafer AI, Rabinowe S, Le Boff MS, et al (1985). Long-term efficacy of deferoxamine iron 
chelation therapy in adults with acquired transfusional iron overload. Arch Intern Med; 
145:1217-1221
Taher AT, Porter JB, Viprakasit V et al (2015). Deﬁning serum ferritin thresholds to predict 
clinically relevant liver iron concentrations for guiding deferasirox therapy when MRI is 
unavailable in patients with non-transfusion-dependent thalassaemia. British Journal of 
Haematology; 168:284–290
Taher AT, Cappellini MD, Aydinok Y et al (2016) Optimising iron chelation therapy with 
deferasirox for non-transfusion-dependent thalassaemia patients: 1-year results from the 
THETIS study. Blood Cells, Molecules and Diseases; 57:23–29
Taher AT, Origa R, Perrotta S, et al (2018). Patient-reported outcomes from a randomized 
phase II study of the deferasirox film-coated tablet in patients with transfusion-dependent 
anemias. Health and Quality of Life Outcomes; 16:216


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14
Appendices
14.1
Dosing tables (Deferasirox DT, Deferasirox FCT)
To guide the investigator and/or pharmacist on the number of deferasirox DT or FCT tablets of 
a given strength to prescribe to a given patient, taking into account the patient’s body weight 
and protocol specified dosing scheme described above, a table is provided below. Where the 
calculated dose cannot be constituted by the available tablet strengths, the closest dose is applied. 
Examples illustrating this approach are provided here below: 

For a patient whose body weight is 46 kg, and whose planned deferasirox DT dose is 20 
mg/kg/day, the calculated deferasirox DT daily dose would be 920 mg. So taking into 
account the available strengths of 125, 250 & 500 mg deferasirox DT tablets, the patient 
should receive the closest daily dose of 875 mg which can be easily constituted by taking 
1 x 125 mg + 1 x 250 mg + 1 x 500 mg deferasirox DT tablets = 3 tablets.

For a patient whose body weight is 46 kg, and whose planned deferasirox FCT dose is 14 
mg/kg/day, the calculated deferasirox FCT daily dose would be 644 mg. So taking into 
account the available strengths of 90, 180 & 360 mg deferasirox FCT tablets, the patient 
should receive the closest daily dose of 630 mg which can be easily constituted by taking 
1 x 90 mg + 1 x 180 mg + 1 x 360 mg deferasirox FCT tablets = 3 tablets.
The dosing tables below have been constructed with cut-offs for lower and upper body weights 
being 20 and 143 kg respectively depending on the dose administered. This is taking into 
account that the study will enroll male or female patients ≥ 2 years.
Table 14-1
Deferasirox DT dosing table for 5 mg/kg/day
Pt Weight in kg
Closest Dose
125 mg
250 mg
500 mg
10 – 19.9
Please consult the Novartis Medical Lead for advice
20 – 37.5
125
1
0
0
37.6 - 62.5
250
0
1
0
62.5 - 87.5
375
3
0
0
87.6 - 112.5
500
0
0
1
112.6 - 137.5
625
1
0
1
Table 14-2
Deferasirox DT dosing table for 10 mg/kg/day
Pt Weight in kg
Closest Dose
125 mg
250 mg
500 mg
10 – 19.9
125
1
0
0
20 – 31.3
250
0
1
0
31.4 – 43.8
375
3
0
0
43.9 – 56.3
500
0
0
1
56.4 – 68.8
625
1
0
1
68.9 – 81.3
750
0
1
1
81.4 – 93.8
875
3
0
1


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Pt Weight in kg
Closest Dose
125 mg
250 mg
500 mg
93.9 – 106.3
1000
0
0
2
106.4 – 118.8
1125
1
0
2
Table 14-3
Deferasirox DT dosing table for 15 mg/kg/day
Pt Weight in Kg
Closest Dose
125 mg
250 mg
500 mg
10 – 13.9
125
1
0
0
14 - 20.8
250
0
1
0
20.9 – 29.2
375
3
0
0
29.3 – 37.5
500
0
0
1
37.6 – 45.8
625
1
0
1
45.9 – 54.2
750
0
1
1
54.3 – 62.5
875
3
0
1
62.6 – 70.8
1000
0
0
2
70.9 – 79.2
1125
1
0
2
79.3 – 87.5
1250
0
1
2
87.6 – 95.8
1375
3
0
2
95.9 – 104.2
1500
0
0
3
104.3 – 112.5
1625
1
0
3
112.6 – 120.8
1750
0
1
3
Table 14-4
Deferasirox DT dosing table for 20 mg/kg/day
Pt Weight in Kg
Closest dose
125 mg
250 mg
500 mg
10 – 15.9
250
0
1
0
16.0 – 21.9
375
3
0
0
22.0 – 28.1
500
0
0
1
28.2 – 34.4
625
1
0
1
34.5 – 40.6
750
0
1
1
40.7 – 46.9
875
3
0
1
47.0 – 53.1
1000
0
0
2
53.2 – 59.4
1125
1
0
2
59.5 – 65.6
1250
0
1
2
65.7 – 71.9
1375
3
0
2
72.0 – 78.1
1500
0
0
3
78.2 – 84.4
1625
1
0
3
84.5 – 90.6
1750
0
1
3
90.7 – 96.9
1875
3
0
3
97.0 – 103.1
2000
0
0
4
103.2 – 109.4
2125
1
0
4


Novartis
Confidential
Page 85
Amended Protocol Version 01 (Clean)
Protocol No. CICL670FIC05
Pt Weight in Kg
Closest dose
125 mg
250 mg
500 mg
109.5 – 115.6
2250
0
1
4
115.7 – 121.9
2375
3
0
4
Table 14-5
Deferasirox DT dosing table for 25 mg/kg/day
Pt Weight in Kg
Closest dose
125 mg
250 mg
500 mg
10 – 13.9
250
0
1
0
14.0 – 16.9
375
3
0
0
17..0 – 22.5
500
0
0
1
22.6 – 27.5
625
1
0
1
27.6 – 32.5
750
0
2
1
32.6 – 37.5
875
3
0
1
37.6 – 42.5
1000
0
0
2
42.6 – 47.5
1125
1
0
2
47.6 – 52.5
1250
0
1
2
52.6 – 57.5
1375
3
0
2
57.6 – 62.5
1500
0
0
3
62.6 – 67.5
1625
1
0
3
67.6 – 72.5
1750
0
1
3
72.6 – 77.5
1875
3
0
3
77.6 – 82.5
2000
0
0
4
82.6 – 87.5
2125
1
0
4
87.6 – 92.5
2250
0
1
4
92.6 – 97.5
2375
3
0
4
97.6 – 102.5
2500
0
0
5
102.6 – 107.5
2625
1
0
5
107.6 – 112.5
2750
0
1
5
112.6 – 117.5
2875
3
0
5
117.6 – 122.5
3000
0
0
6
Table 14-6
Deferasirox DT dosing table for 30 mg/kg/day
Pt Weight in Kg
Closest Dose
125mg
250 mg
500 mg
10 – 14.9
375
3
0
0
15.0 – 18.9
500
0
0
1
19..0 – 22.9
625
1
0
1
23.0 – 27.1
750
0
1
1
27.2 – 31.3
875
3
0
1
31.4 – 35.4
1000
0
0
2
35.5 – 39.6
1125
1
0
2


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Page 86
Amended Protocol Version 01 (Clean)
Protocol No. CICL670FIC05
39.7 – 43.8
1250
0
1
1
43.9 – 47.9
1375
3
0
2
48.0 – 52.1
1500
0
0
3
52.2 – 56.3
1625
1
0
3
56.4 – 60.4
1750
0
1
3
60.5 – 64.6
1875
3
0
3
64.7 – 68.8
2000
0
0
4
68.9 – 72.9
2125
1
0
4
73.0 – 77.1
2250
0
1
4
77.2 – 81.3
2375
3
0
4
81.4 – 85.4
2500
0
0
5
85.5 – 89.6
2625
1
0
5
89.7 – 93.8
2750
0
1
5
93.9 – 97.9
2875
3
0
5
98.0 – 102.1
3000
0
0
6
102.2 – 106.3
3125
1
0
6
106.4 – 110.4
3250
0
1
6
110.5 – 114.6
3375
3
0
6
114.7 – 118.8
3500
0
0
7


Novartis
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Page 87
Amended Protocol Version 01 (Clean)
Protocol No. CICL670FIC05
Table 14-7
Deferasirox DT dosing table for 35 mg/kg/day
Pt Weight in Kg
Closest Dose
125 mg
250 mg
500 mg
10 – 13.9
375
3
0
0
14.0-19.9
500
0
0
1
20.0-26.5
875
1
1
1
26.6-30.1
1000
0
0
2
30.2-33.6
1125
1
0
2
33.7-37.2
1250
0
1
2
37.3-40.8
1375
1
1
2
40.9-44.4
1500
3
44.5-47.9
1625
1
3
48.0-51.5
1750
1
3
51.6-55.1
1875
1
1
3
55.2-58.6
2000
4
58.7-62.2
2125
1
4
62.3-65.8
2250
1
4
65.9-69.4
2375
1
1
4
69.5-72.9
2500
5
73.0-76.5
2625
1
5
76.6-80.1
2750
1
5
80.2-83.6
2875
1
1
5
83.7-87.2
3000
6
87.3-90.8
3125
1
6
90.9-94.4
3250
1
6
94.5-97.9
3375
1
1
6
98.0-101.5
3500
7
101.6-105.1
3625
1
7
105.2-108.6
3750
1
7
108.7-11.2
3875
1
1
7
112.3-115.8
4000
8
115.9-119.4
4125
1
8
119.5-122.9
4250
1
8
123.0-126.5
4375
1
1
8
126.6-130.1
4500
9
130.2-133.6
4625
1
9
133.7-137.2
4750
1
9
137.3-140.8
4875
1
1
9
140.9-144.4
5000
10


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Page 88
Amended Protocol Version 01 (Clean)
Protocol No. CICL670FIC05
Table 14-8
Deferasirox DT dosing table for 40 mg/kg/day
Pt Weight in Kg
Closest Dose
125mg
250 mg
500 mg
10.0 – 11.9
375
3
0
0
12.0 – 13.9
500
0
0
1
14.0 – 16.9
625
1
0
1
17.0 – 20.3
750
0
1
1
20.4 – 23.4
875
1
1
1
23.5 – 26.6
1000
0
0
1
26.7 – 29.7
1125
1
0
2
29.8 – 32.8
1250
0
1
2
32.9 – 35.9
1375
1
1
2
36.0 – 39.1
1500
0
0
3
39.2 – 42.2
1625
1
0
3
42.3 – 45.3
1750
0
1
3
45.4 – 45.3
1875
1
1
3
48.5 – 51.6
2000
0
0
4
51.7 – 54.7
2125
1
0
4
54.8 – 57.8
2250
0
1
4
57.9 – 60.9
2375
1
1
4
61.0 – 64.1
2500
0
0
5
64.2 – 67.2
2625
1
0
5
67.3 – 70.3
2750
0
1
5
70.4 – 73.4
2875
1
1
5
73.5 – 76.6
3000
0
0
6
76.7 – 79.7
3125
1
0
6
79.8 – 82.8
3250
0
1
6
82.9 – 85.9
3375
1
1
6
86.0 – 89.1
3500
0
0
7
89.2 – 92.2
3625
1
0
7
92.3 – 95.3
3750
0
1
7
95.4 – 98.4
3875
1
1
7
98.5 – 101.6
4000
0
0
8
101.7 – 104.7
4125
1
0
8
104.8 – 107.8
4250
0
1
8
107.9 – 110.9
4370
1
1
8
111.0 – 114.1
4500
0
0
9


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Page 89
Amended Protocol Version 01 (Clean)
Protocol No. CICL670FIC05
Table 14-9
Deferasirox FCT dosing table for 3.5 mg/kg/day
Pt Weight in kg
Closest Dose 
(mg)
90 mg
180 mg
360 mg
10 – 19.9
Please consult the Novartis Medical Lead for advice
20 - 38
90
1
39 - 64
180
1
65 - 89
270
1
1
90 - 115
360
1
116 - 141
450
1
1
Table 14-10
Deferasirox FCT dosing table for 7 mg/kg/day
Pt Weight in kg
Closest Dose 
(mg)
90 mg
180 mg
360 mg
10 – 19.9
90
1
0
0
20 - 32
180
1
33 - 44
270
1
1
45 - 57
360
1
58 - 70
450
1
1
71 - 83
540
1
1
84 - 96
630
1
1
1
97 - 109
720
2
110 - 122
810
1
2
123 - 134
900
1
2
135 - 147
990
1
1
2
Table 14-11
Deferasirox FCT dosing table for 10.5 mg/kg/day
Pt Weight in kg
Closest Dose 
(mg)
90 mg
180 mg
360 mg
10 – 13.9
90
1
0
0
14 - 21
180
1
22 - 29
270
1
1
30 - 38
360
1
39 - 46
450
1
1
47 - 55
540
1
1
56 - 64
630
1
1
1
65 - 72
720
2
73 - 81
810
1
2
82 - 89
900
1
2
90 - 98
990
1
1
2
99 - 106
1080
3


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Page 90
Amended Protocol Version 01 (Clean)
Protocol No. CICL670FIC05
Pt Weight in kg
Closest Dose 
(mg)
90 mg
180 mg
360 mg
107 - 115
1170
1
3
116 - 124
1260
1
3
125 - 132
1350
1
1
3
133 - 141
1440
4
Table 14-12
Deferasirox FCT dosing table for 14 mg/kg/day
Pt Weight in kg
Closest Dose 
(mg)
90 mg
180 mg
360 mg
10 – 15.9
180
0
1
0
16 - 22
270
1
1
23 - 28
360
1
29 - 35
450
1
1
36 - 41
540
1
1
42 - 47
630
1
1
1
48 - 54
720
2
55 - 60
810
1
2
61 - 67
900
1
2
68 - 73
990
1
1
2
74 - 80
1080
3
81 - 86
1170
1
3
87 - 92
1260
1
3
93 - 99
1350
1
1
3
100 - 105
1440
4
106 - 112
1530
1
4
113 - 118
1620
1
4
119 - 125
1710
1
1
4
126 - 131 
1800
5
132 - 137
1890
1
5
138 - 144
1980
1
5
Table 14-13
Deferasirox FCT dosing table for 17.5 mg/kg/day
Pt Weight in kg
Closest Dose 
(mg)
90 mg
180 mg
360 mg
10 – 17.9
180
0
1
0
18 - 23
360
1
24 - 28
450
1
1
29 - 33 
540
1
1
34 - 38 
630
1
1
1
39 - 43
720
2


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Page 91
Amended Protocol Version 01 (Clean)
Protocol No. CICL670FIC05
Pt Weight in kg
Closest Dose 
(mg)
90 mg
180 mg
360 mg
44 - 48
810
1
2
49 - 53
900
1
2
54 - 59
990
1
1
2
60 - 64
1080
3
65 - 69
1170
1
3
70 - 74
1260
1
3
75 - 79
1350
1
1
3
80 - 84
1440
4
85 - 89
1530
1
4
90 - 95
1620
1
4
96 - 100
1710
1
1
4
101 - 105
1800
5
106 - 110
1890
1
5
111 - 115
1980
1
5
116 - 120 
2070
1
1
5
121 - 125
2160
6
126 - 131
2250
1
6
132 - 136
2340
1
6
137 - 141
2430
1
1
6
Table 14-14
Deferasirox FCT dosing table for 21 mg/kg/day 
Pt Weight in kg
Closest Dose 
(mg)
90 mg
180 mg
360 mg
10 – 13.9
270
1
1
0
14 – 19.9
360
0
0
1
20 - 23
450
1
1
24 - 27
540
1
1
28 - 31
630
1
1
1
32 - 36
720
2
37 - 40
810
1
2
41 - 44
900
1
2
45 - 48
990
1
1
2
49 - 53
1080
3
54 - 57
1170
1
3
58 - 61
1260
1
3
62 - 66
1350
1
1
3
67 - 70
1440
4
71 - 74
1530
1
4
75 - 78
1620
1
4


Novartis
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Page 92
Amended Protocol Version 01 (Clean)
Protocol No. CICL670FIC05
Pt Weight in kg
Closest Dose 
(mg)
90 mg
180 mg
360 mg
79 - 83
1710
1
1
4
84 - 87
1800
5
88 - 91
1890
1
5
92 - 96
1980
1
5
97 - 100
2070
1
1
5
101 - 104
2160
6
105 - 108
2250
1
6
109 - 113
2340
1
6
114 - 117
2430
1
1
6
118 - 121
2520
7
122 - 126
2610
1
7
127 - 130
2700
1
7
131 - 134
2790
1
1
7
135 - 138
2880
8
139 - 143
2970
1
8
Table 14-15
Deferasirox FCT dosing table for 24.5 mg/kg/day 
Pt Weight in kg
Closest Dose 
(mg)
90 mg
180 mg
360 mg
10 – 11.9
270
1
1
0
12 – 15.9
360
0
0
1
16 – 19.9
450
1
0
1
20 - 23
540
1
1
24 - 27
630
1
1
1
28 - 30
720
2
31 - 34
810
1
2
35 - 38
900
1
2
39 - 41
990
1
1
2
42 - 45
1080
3
46 - 49
1170
1
3
50 - 52
1260
1
3
53 - 56
1350
1
1
3
57 - 60
1440
4
61 - 63
1530
1
4
65 - 67
1620
1
4
68 - 71
1710
1
1
4
72 - 74
1800
5
75 - 78
1890
1
5
79 - 82
1980
1
5


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Page 93
Amended Protocol Version 01 (Clean)
Protocol No. CICL670FIC05
Pt Weight in kg
Closest Dose 
(mg)
90 mg
180 mg
360 mg
83 - 85
2070
1
1
5
86 - 89
2160
6
90 - 93
2250
1
6
94 - 97
2340
1
6
98 - 100
2430
1
1
6
101 - 104
2520
7
105 - 108
2610
1
7
109 - 111
2700
1
7
112 - 115
2790
1
1
7
116 - 119
2880
8
120 - 122
2970
1
8
123 - 126
3060
1
8
127 - 130
3150
1
1
8
131 - 133
3240
9
134 - 137
3330
1
9
138 - 141
3420
1
9
Table 14-16
Deferasirox FCT dosing table for 28 mg/kg/day 
Pt Weight in kg
Closest Dose 
(mg)
90 mg
180 mg
360 mg
10 – 11.9
270
1
1
0
12 – 13.9
360
0
0
1
14 – 17.9
450
1
0
1
18 – 19.9
540
0
1
1
21 - 24
630
1
1
1
25 - 27
720
2
28 - 30
810
1
2
31 - 33
900
1
2
34 - 36
990
1
1
2
37 - 40
1080
3
41 - 43
1170
1
3
44 - 46
1260
1
3
47 - 49
1350
1
1
3
50 - 52
1440
4
53 - 56
1530
1
4
57 - 59
1620
1
4
60 - 62
1710
1
1
4
63 - 65
1800
5
66 - 69
1890
1
5


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Page 94
Amended Protocol Version 01 (Clean)
Protocol No. CICL670FIC05
Pt Weight in kg
Closest Dose 
(mg)
90 mg
180 mg
360 mg
70 - 72
1980
1
5
73 - 75
2070
1
1
5
76 - 78
2160
6
79 - 81
2250
1
6
82 - 85
2340
1
6
86 - 88
2430
1
1
6
89 - 91
2520
7
92 - 94
2610
1
7
95 - 97
2700
1
7
98 - 101
2790
1
1
7
102 - 104
2880
8
105 - 107
2970
1
8
108 - 110
3060
1
8
111 - 114
3150
1
1
8
115 - 117
3240
9
118 - 120
3330
1
9
121 - 123
3420
1
9
124 - 126
3510
1
1
9
127 - 130
3600
10
131 - 133
3690
1
10
134 - 136
3780
1
10
137 - 139
3870
1
1
10
140 - 142
3960
11
Equivalent dose guidance
For patients pre-treated with deferoxamine, a starting dose of DT or an equivalent FCT dose
that is numerically half that of the deferoxamine dose (e.g. a patient receiving 40 mg/kg/day of 
deferoxamine for 5 days per week (or equivalent) could be transferred to a starting daily dose 
of 20 mg/kg/day of DT or 14 mg/kg/day of FCT) see Table 14-17. 
For patients pre-treated with deferiprone (DFP), please base the patient’s required dose on their 
serum ferritin level.
Table 14-17
Dose Regimen based on Serum Ferritin level
Dose Regimen of Drug for TDT patients
Serum ferritin level
20 mg/Kg Deferasirox DT 
14 mg/Kg Deferasirox FCT
1000-1500 ng/ml
30 mg/Kg Deferasirox DT 
21 mg/Kg Deferasirox FCT
>1500-2000 ng/ml
40 mg/Kg Deferasirox DT 
28 mg/Kg Deferasirox FCT
>2000 ng/ml


Novartis
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Page 95
Amended Protocol Version 01 (Clean)
Protocol No. CICL670FIC05
Dose Regimen of Drug for NTDT patients
Serum ferritin level
5 mg/Kg Deferasirox DT 
3.5 mg/Kg Deferasirox FCT
300-799 ng/ml
10 mg/Kg Deferasirox DT 
7 mg/Kg Deferasirox FCT
800-2000 ng/ml
20 mg/Kg Deferasirox DT 
14 mg/Kg Deferasirox FCT
>2000- 4000 ng/ml
30 mg/Kg Deferasirox DT
21 mg/Kg Deferasirox FCT
>4000 ng/ml
Please see the table belowfor guidance: 
Table 14-18
Patients pre-treated with Deferoxamine
Previous dose
Equivalent dose to be used
Deferoxamine
(mg/kg/day)
Deferasirox DT (mg/kg/day)
Deferasirox FCT (mg/kg/day)
10
5
3.5
20
10
7
30
15
10.5
40
20
14
50
25
17.5
60
30
21
70
35
24.5
80
40
28


Novartis
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Page 96
Amended Protocol Version 01 (Clean)
Protocol No. CICL670FIC05
14.2
Examples of light meal
Example 1:
amount
kcal
g total 
fats
Wheat Bread or Toast
2 slices
138
2
jams, preserves, all flavors
1 Tablespoon
109
0
banana
medium (7-7 7/8" long)
105
0
orange juice
1 cup
114
0
skim milk
1 cup
83
0
Total:
549
2
Example 2:
amount
kcal
g total 
fats
Pita Bread 
1 medium (5.25" across) pita 
124
1
hummus or deli chicken/turkey
1 Tablespoon humuus or 2 oz meat
27
1
apple
medium (2.75" across)
72
0
salsa, red, cooked
6 Tablespoons
26
0
carrots & celery sticks
4 carrot sticks (3" long) and small 5" 
stalk of celery
14
0
Total:
263-295
2
Example 3:
amount
kcal
g total 
fats
yogurt, fruit, low-fat
6 oz
173
2
banana
medium (7-7 7/8" long)
105
0
orange juice
1 cup
114
0
skim milk
1 cup
83
0
Total:
475
2
Example 4:
amount
kcal
g total 
fats
vegetable chicken noodle soup, 
canned
1 cup
70
2
baked potato, peel not eaten
1 medium (2.25-3" across)
121
0
skim milk
1 cup
83
0
banana
medium (7-7 7/8" long)
105
0
Total:
379
2
Example 5:
egg whites, cooked, no fat added
2 large egg whites
32
0
salsa, red, cooked
6 Tablespoons
26
0
Wheat Bread or Toast
2 slices
138
2
jams, preserves, all flavors
1 Tablespoon
109
0
orange juice
1 cup
114
0


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Page 97
Amended Protocol Version 01 (Clean)
Protocol No. CICL670FIC05
skim milk
1 cup
83
0
Total:
502
2
Example 6:
chicken, boneless, skinless baked
0.5 cup diced
111
2
salsa, red, cooked
6 Tablespoons
26
0
white rice, cooked, no fat added
0.5 cup
102
0
black beans, canned or cooked 
from dry, no fat added
0.5 cup
99
0
skim milk
1 cup
83
0
Total:
421
2


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Page 98
Amended Protocol Version 01 (Clean)
Protocol No. CICL670FIC05
14.3
Algorithm for Preference questionnaire completion
In case of treatment switch during the Core Phase of the study, the investigator must provide 
the preference questionnaire to the patient in the immediate next visit and then keep following 
the schedule of questionnaires pre-planned on Table 7-1 and Table 7-2.
Please see below the preference questionnaire version to be completed, based on treatment 
switch (yes/no) and when it occurred.

Scenario 1 – Patient does NOT switch treatment
STUDY VISIT
QUESTIONNAIRE VERSION
Visit 4 (week 4)
Questionnaire vs. week 4 and 24
Visit 9 (week 24)
Questionnaire vs. week 4 and 24
Visit 10 (week 28)
Questionnaire vs. week 28
Visit 15 (week 48)
Questionnaire vs. week 48

Scenario 2 – Treatment switch happens V3
STUDY VISIT
QUESTIONNAIRE VERSION
Visit 4 (week 4)
Questionnaire vs. week 28
Visit 9 (week 24)
Questionnaire vs. week 28
Visit 10 (week 28)
Questionnaire vs. week 28
Visit 15 (week 48)
Questionnaire vs. week 48

Scenario 3 – Treatment switch happens between Visit 4 to Visit 7 
STUDY VISIT
QUESTIONNAIRE VERSION
Visit 4 (week 4)
Questionnaire vs. week 4 and 24
Unplanned – next study visit 
after treatment switch
Questionnaire vs. week 28
eCRF: Summary page -
Visit 9 (week 24)
Questionnaire vs. week 28
Visit 10 (week 28)
Questionnaire vs. week 28
Visit 15 (week 48)
Questionnaire vs. week 48


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Confidential
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Amended Protocol Version 01 (Clean)
Protocol No. CICL670FIC05

Scenario 4 – Treatment switch happens at visit 8
STUDY VISIT
QUESTIONNAIRE VERSION
Visit 4 (week 4)
Questionnaire vs. week 4 and 24
Visit 9 (week 24)
Questionnaire vs. week 28
Visit 10 (week 28)
Questionnaire vs. week 28
Visit 15 (week 48)
Questionnaire vs. week 48

Scenario 5 – Treatment switch happens at visit 9
STUDY VISIT
QUESTIONNAIRE VERSION
Visit 4 (week 4)
Questionnaire vs. week 4 and 24
Visit 9 (week 24)
Questionnaire vs. week 4 and 24
Visit 10 (week 28)
Questionnaire vs. week 28
Visit 15 (week 48)
Questionnaire vs. week 48

Scenario 6 – Treatment switch happens at visit 10 to 13
STUDY VISIT
QUESTIONNAIRE VERSION
Visit 4 (week 4)
Questionnaire vs. week 4 and 24
Visit 9 (week 24)
Questionnaire vs. week 4 and 24
Visit 10 (week 28)
Questionnaire vs. week 28
Unplanned – next study visit after 
treatment switch
Questionnaire vs. week 48
eCRF: Summary page -
Visit 15 (week 48)
Questionnaire vs. week 48


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Amended Protocol Version 01 (Clean)
Protocol No. CICL670FIC05

Scenario 7 – Treatment switch happens at visit 14
STUDY VISIT
QUESTIONNAIRE VERSION
Visit 4 (week 4)
Questionnaire vs. week 4 and 24
Visit 9 (week 24)
Questionnaire vs. week 4 and 24
Visit 10 (week 28)
Questionnaire vs. week 28
Visit 15 (week 48)
Questionnaire vs. week 48

SAP_001.pdf: 
Clinical Development
ICL670, DEFERASIROX
Oncology Clinical Protocol CICL670FIC05 / NCT02993224
Open-label, multicenter, single arm, phase II study 
assessing treatment patient preference for new deferasirox 
formulation (film-coated tablet) compared to the reference 
deferasirox dispersible tablet formulation 
Statistical Analysis Plan (SAP)
Author:
Trial Statistician, 
Document type:
SAP Documentation
Document status:
Amendment v1.2
Release date:
08-Apr-2021
Number of pages:
43
Property of Novartis
For business use only
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


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Document History – Changes compared to previous final version of SAP
Date
Time 
point
Reason for 
update
Outcome for update
Section and title 
impacted 
(Current)
03-
May-
2017
Prior 
to 
DB 
lock
Creation of 
final 
version
N/A - First version
NA
10-
Jun-
2020
Prior 
to 
DB 
lock
Creation of 
Amendment 
version 1.0
Protocol amended. Modification in 
objectives and some definitions. Sample 
size calculation changed. DRP updated.
Section 
1.2, 
Section 
3, 
appendix
and 
some parts of 
other sections as 
per 
modified 
protocol
04-
Sep-
2020
Prior 
to IA 
DB 
lock
Creation of 
Amendment 
version 1.1

Definition 
of 
enrolled 
set 
changed to show the actual 
scenario

Formula of risk difference added

Section 
2.2

Section
2.8.1
08-
Apr-
2021
Post 
IA 
DB 
lock
Creation of 
addendum 
version 1.0

Changes of analysis in GI 
symptom ObsRO questionnaire 
based on data characteristics 
(data was not available prior to 
DBL and hence change has been 
done post DBL)  

Section 
2.11
08-
Apr-
2021
Prior
DB 
lock
Creation of 
amendment 
1.2

Adding Serum ferritin TDT vs 
NTDT and baseline definition 
for lab assessemnts

Adding figures related analysis 
in PRO section 

Section 
2.8.3 

Section 
2.11


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Table of contents
Table of contents .................................................................................................................3
List of abbreviations............................................................................................................5
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 ..........................................................................................................12
2.2.1
Subgroup of interest ..............................................................................12
2.3
Patient disposition, demographics and other baseline characteristics ...................13
2.3.1
Patient disposition.................................................................................13
2.3.2
Patient demographics ............................................................................13
2.3.3
Patient baseline characteristics..............................................................13
2.4
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................15
2.4.1
Study treatment / compliance................................................................15
2.4.2
Prior, concomitant and post therapies...................................................16
2.5
Analysis of the primary objective..........................................................................16
2.5.1
Primary endpoint...................................................................................16
2.5.2
Statistical hypothesis, model, and method of analysis..........................16
2.5.3
Handling of missing values/censoring/discontinuations.......................17
2.5.4
Supportive analyses...............................................................................17
2.6
Analysis of the key secondary objective ...............................................................18
2.7
Analysis of secondary efficacy objective(s)..........................................................18
2.7.1
Secondary endpoints .............................................................................18
2.7.2
Statistical hypothesis, model, and method of analysis..........................18
2.7.3
Handling of missing values/censoring/discontinuations.......................20
2.8
Safety analyses.......................................................................................................20
2.8.1
Adverse events (AEs)............................................................................20
2.8.2
Deaths....................................................................................................23
2.8.3
Laboratory data .....................................................................................23
2.8.4
Other safety data ...................................................................................24
2.9
Pharmacokinetic endpoints....................................................................................24
2.10
PD and PK/PD analyses.........................................................................................24
2.11
Patient-reported outcomes .....................................................................................24


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2.12
Biomarkers.............................................................................................................28
2.13
Other Exploratory analyses....................................................................................28
2.14
Interim analysis......................................................................................................28
3
Sample size calculation .....................................................................................................29
4
Change to protocol specified analyses ..............................................................................29
5
Appendix ...........................................................................................................................29
5.1
Imputation rules.....................................................................................................29
5.1.1
Study drug.............................................................................................29
5.1.2
AE date imputation ...............................................................................29
5.1.3
Concomitant medication date imputation .............................................30
5.2
AEs coding/grading ...............................................................................................32
5.3
Laboratory parameters derivations ........................................................................33
5.4
Statistical models...................................................................................................33
5.4.1
Primary analysis....................................................................................33
5.4.2
Secondary analysis................................................................................34
5.5
Rule of exclusion criteria of analysis sets..............................................................37
6
Reference...........................................................................................................................43


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List of abbreviations
AE
Adverse event
ATC
Anatomical Therapeutic Classification
CSR
Clinical Study report
CTCAE
Common Terminology Criteria for Adverse Events
DT
Dispersible tablet
FAS
Full Analysis Set
FCT
Film-coated tablet
eCRF
Electronic Case Report Form
MedDRA
Medical Dictionary for Drug Regulatory Affairs
NCI
National Cancer Institute
NTDT
Non-transfusion- dependent thalassemia
PFS
Progression-Free Survival
PK
Pharmacokinetics
PPS
Per-Protocol Set
PRO
Patient-reported Outcomes
RAP
Report and Analysis Process
SAP
Statistical Analysis Plan
SOC
System Organ Class
TDT
Transfusion-dependent thalassemia
TFLs
Tables, Figures, Listings
WHO
World Health Organization


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1
Introduction
This analysis plan module describes the statistical methods which will be used in the Phase II 
clinical study CICL670FIC05.
The main purpose of this document is to provide a summary of the statistical methodology that 
will be used for this clinical study; this includes a detailed description of data summaries. 
Analyses plan in this document refers to the related statistical analysis sections in the clinical 
study report.
The analysis described here will be conducted by Novartis using statistical software SAS®
Version 9.4 according to the Statistical methods and data analysis Section 10 of the study 
protocol which will be available in Appendix 16.1.1 of the CSR. Important information will be 
given in the following sections and further details are provided, as applicable, in the Appendix 
16.1.9 of the CSR.
Unless otherwise specified, the statistical methodologies including the analysis sets, analysis 
models, algorithms and conventions are following the Oncology study protocol CICL670FIC05 
final version.
1.1
Study design
This is an open-label, multicenter, single arm study of deferasirox. This study aims to assess 
treatment patient preference for new deferasirox formulation (film-coated tablet) compared to 
reference deferasirox dispersible tablet formulation in transfusion-dependent thalassemia (TDT) 
and non-transfusion-dependent thalassemia (NTDT) patients throughout a 48 week treatment 
period. 
Patients will undergo up to 4 weeks of screening period and if deemed eligible, will receive 
deferasirox dispersible tablet (DT) formulation for 24 weeks. After completion of 24 weeks 
patients will be transitioned on Week 25 to an equivalent dose of the deferasirox film coated 
tablet (FCT) formulation and continue treatment till Week 48. Completion of Week 48 indicates
“End of Trial” of the Core Phase.
Patients can then continue deferasirox FCT formulation as per the judgment of the investigator, 
through an extension phase for maximum of 12 months counting from last dose of deferasirox 
FCT received at the end of period 2 on Core Phase.
Planned number of patients
It is intended that a total of 145 patients of age ≥ 2 years will be recruited in the study. Patients 
may have been previously treated with iron chelators (other than deferasirox DT) or be 
chelation-naïve.
The overall study design is as follows:

Core phase:

Screening phase which lasts for maximum 4 weeks to determine whether the 
patient is eligible or not and is followed by

Baseline visit (Day 1)


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
Period 1: deferasirox DT as 10-40 mg/kg/day dose regimen of dispersible tablet 
formulation for 24 weeks followed by

Period 2: deferasirox FCT as 7-28 mg/ kg/ day dose regimen of film coated tablet 
for 24 weeks.

Extension Phase:

Deferasirox FCT as 7-28 mg/kg/ day dose regimen of film-coated tablet.
The overall study design is given in the following figure:
Figure 1-1
Study Design
Patients who discontinue study treatment before completing the study should be scheduled for 
a visit as soon as possible, at which time all of the assessments listed for SEC must be performed.
Primary analysis time point
The primary analysis will be performed at Week 48 to evaluate patient preference of deferasirox 
DT vs. deferasirox FCT formulations.
Interim analysis 
The interim analysis will be performed at Week 48 to assess the patient preference after 
6 months with deferasirox FCT treatment in comparison to deferasirox DT.
1.2
Study objectives and endpoints
The objective of the study is to assess patient preference of deferasirox DT or deferasirox FCT 
in thalassemia patient.
Table 1.2.1: Study objectives and related endpoints
Objective
Endpoint
Primary
To evaluate patient preference between 
deferasirox FCT and deferasirox DT
Proportion of patients claimed preference of deferasirox 
FCT over deferasirox DT as measured by preference 
questionnaire at Week 48


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Objective
Endpoint
Secondary
To evaluate patient preference of 
deferasirox FCT or deferasirox DT or 
previous iron chelation
Proportion of patients claimed preference of deferasirox 
FCT, deferasirox DT, and previous iron chelation as 
measured by preference questionnaire at Week 28
To evaluate patient preference of 
deferasirox DT or previous iron 
chelation 
Proportion of patients claimed preference of deferasirox 
DT, over previous iron chelation as measured by 
preference questionnaire at Week 4 and Week 24
To evaluate the reason behind 
preference for deferasirox FCT or 
deferasirox DT
Proportion of preference reasons for deferasirox FCT 
over deferasirox DT as measured by preference 
questionnaire at Week 28 and Week 48
To evaluate the effect of deferasirox 
FCT compared with deferasirox DT on 
patient compliance using pill count
Relative consumed pill count during deferasirox FCT 
(Week 25 to 48) compared with deferasirox DT (Baseline 
day 1 to Week 24)
To evaluate the effect of deferasirox 
FCT compared with deferasirox DT or 
previous iron chelation on patient 
palatability using PRO
Absolute and relative change in domain scores of 
palatability questionnaire over time during deferasirox 
FCT (Week 28 to 48) compared with deferasirox DT 
(Week 4 to 24) or previous iron chelation (Screening)
To evaluate the effect of deferasirox 
FCT compared with deferasirox DT or 
previous iron chelation on patient 
satisfaction using PRO
Absolute and relative change in domain scores of SICT 
questionnaire over time during deferasirox FCT (Week 
28 to 48) compared with deferasirox DT (Week 4 to 24) 
or previous iron chelation (Screening)
To evaluate the effect of deferasirox 
FCT compared with deferasirox DT or 
previous iron chelation on patient GI 
symptom using PRO
Absolute and relative change in domain scores of SICT 
questionnaire over time during deferasirox FCT (Week 
28 to 48) compared with deferasirox DT (Week 4 to 24) 
or previous iron chelation (Screening)
To evaluate the overall safety of 
deferasirox FCT
compared with deferasirox DT
Overall safety, as measured by frequency and severity of 
adverse events and changes in laboratory values of 
interest during deferasirox FCT (Week 25 to 48) 
compared with deferasirox DT (Baseline day 1 to Week 
24)
To evaluate efficacy of deferasirox
( both DT and FCT) in decreasing 
serum ferritin levels
Absolute and relative change from baseline ( Day 1) in  
serum ferritin on monthly basis 
2
Statistical methods
2.1
Data analysis general information
All analysis will be performed by NBS CONEXTS, Novartis.
It is planned that the data from all centers that participate in this study will be used for analysis. 
Analysis datasets and statistical outputs will be produced using the most recent SAS® Version 
9.4 (SAS Institute Inc., Cary, NC, USA), and stored in Novartis global programming & 
statistical environment (GPS).
As the primary endpoint analysis will be performed at Week 48, there will be a database lock 
after all patients have completed Week 48 assessments. The proposed statistical analysis for 
interim analysis is described in Section 2.14. A final database lock will occur when all patients 
have completed the study.


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All summary statistics for continuous variables will include n (number), mean, standard 
deviation (SD), median, lower and upper quartiles (Q1, Q3), minimum, maximum, and, where 
applicable, the estimate and  the 95% confidence intervals (CI) of mean. For categorical 
variables, descriptive statistics will include the number (frequencies) and percentage of patients 
in each category. Summary statistics will also be presented graphically wherever applicable.
If not otherwise specified, p-values and CI will be presented as two-sided. Unless otherwise 
stated, the default level of significance will be set to 5% (two-sided, family-wise type-I-error).
All data analysis will be presented by treatment group, i.e. DFX DT and DFX FCT, iron 
chelation status (naïve or pre-treated) and by thalassemia transfusion status (TDT or NTDT), 
wherever applicable. Efficacy and safety data for the core and extension phases will also be 
presented by the above groups. Since this study also includes pediatric patients, all key safety 
and efficacy endpoints will also be summarized by the age groups as defined in the protocol
and Section 2.2.1. 
The analysis will be conducted on all patients’ data at the specific time-points (Week 4, 24, 28, 
and 48), wherever applicable and at the time the study (both core and extension phases) ends. 
Unless otherwise specified, if there are additional data available for any assessment (for 
example data on unscheduled visit) then the average of the available values will be presented 
under the dedicated visit.
2.1.1
General definitions
Study treatment
In this and subsequent analysis plan module (TFL and PDS), the terms “investigational drug”, 
“study drug” and “study treatment” refers to deferasirox FCT as well as deferasirox DT.
Study treatment start and end date
Study treatment start date is defined as the first date when a non-zero dose of study drug is 
administered and recorded on the Drug Administration Record (DAR) CRF page. Similarly, 
study drug end date is defined as the last date when a non-zero dose of study drug is 
administered and recorded on the DAR CRF page of the study.
End of study
The end of study is defined as the earliest occurrence of one of the following:
-
The patient has reached Week 96 at Extension phase.
-
Deferasirox FCT is locally reimbursed for this indication (only applicable in Extension 
phase)
-
Another clinical study or post-trial access program becomes available that can continue to 
provide deferasirox FCT in this patient population and all patients ongoing are eligible to 
be transferred to that clinical study
The investigator will be responsible for informing IRBs and/or EC.


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Patient completed
A patient is considered as having “completed the study” if the patient has completed the core 
phase of the study, i.e. Week 48.
Study day
Study day will be calculated as (event date – study drug start date + 1 day) for events that 
occurred on or after study drug start date (e.g. visit, lab samples, AEs). For events prior to study 
drug start date (e.g. time of diagnosis), study day will be negative and calculated as (event date 
– study drug start date). Note that study drug start date is study day 1 and the day before study 
drug start date is study day -1 (i.e. no study day 0).
Due to the study drug dosing schedule, one month will be considered as 28 days. However, for 
“time since event” data (e.g. medical history), one month will be considered as 365.25/12 days 
for events that occurred prior to study Day 1. Time from events prior to the start of study drug, 
e.g., time since diagnosis, is calculated as the difference between the start date of study drug 
and the date of prior event. 
Note that, the first dose day is Day 1, and the day before the first dose day is counted as Day -1 
(not Day 0).
Baseline assessment: 
Baseline assessment in general will be defined as the last assessment prior to the start of the 
study treatment which is the assessment taken at Day 1 of study. A baseline value refers to the 
last measurement made prior to administration of first dose of study treatment.
Post baseline assessment:
A post-baseline value refers to a measurement taken after the first dose of study treatment.
Treatment period
The planned treatment duration of the core phase is 48 weeks (24 weeks of DT followed by 
24 weeks of FCT) and the planned treatment period for the extension phase is another 48 weeks
of FCT. 
The total duration of the study is approximately 104 weeks (including the Screening, Treatment 
and Safety Follow-up visits).
Patients will be followed up for safety purposes for 30 days after the last dose of study drug
(regardless if that situation occurs during core or extension phase).
Lost to follow up
The patients whose study completion status is unclear because they fail to appear for study visits 
without stating an intention to withdraw.
Visit window
Visit wise following window period will be used:


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Visit 3 Date of visit should be 14 days from Visit 2 also consider buffer +/-2 days (e.g. 
Timeframe to do the visit is 12 days to 16 days)
Visit 4 Date of visit should be 28 days from Visit 2 also consider buffer +/-2 days (e.g. 
Timeframe to do the visit is 26 days to 30 days)
Visit 5 Date of visit should be 56 days from Visit 2 also consider buffer +/-2 days (e.g. 
Timeframe to do the visit is 54 days to 58 days)
Visit 6 Date of visit should be 84 days from Visit 2 also consider buffer +/-2 days (e.g. 
Timeframe to do the visit is 82 days to 86 days)
Visit 7 Date of visit should be 112 days from Visit 2 also consider buffer +/-2 days (e.g. 
Timeframe to do the visit is 110 days to 114 days)
Visit 8 Date of visit should be 140 days from Visit 2 also consider buffer +/-7 days (e.g. 
Timeframe to do the visit is 133 days to 147 days)
Visit 9 Date of visit should be 168 days from Visit 2 also consider buffer +/-7 days (e.g. 
Timeframe to do the visit is 161 days to 175 days)
Visit 10 Date of visit should be 196 days from Visit 2 also consider buffer +/-7 days (e.g. 
Timeframe to do the visit is 189 days to 203 days)
Visit 11 Date of visit should be 224 days from Visit 2 also consider buffer +/-7 days (e.g. 
Timeframe to do the visit is 217 days to 231 days)
Visit 12 Date of visit should be 252 days from Visit 2 also consider buffer +/-7 days (e.g. 
Timeframe to do the visit is 245 days to 259 days)
Visit 13 Date of visit should be 280 days from Visit 2 also consider buffer +/-7 days (e.g. 
Timeframe to do the visit is 273 days to 287 days)
Visit 14 Date of visit should be 308 days from Visit 2 also consider buffer +/-7 days (e.g. 
Timeframe to do the visit is 301 days to 315 days)
Visit 15 Date of visit should be 336 days from Visit 2 also consider buffer +/-7 days (e.g. 
Timeframe to do the visit is 329 days to 343 days)
Visit 16 Date of visit should be 364 days from Visit 2 also consider buffer +/-7 days (e.g. 
Timeframe to do the visit is 357 days to 371 days)
Visit 17 Date of visit should be 392 days from Visit 2 also consider buffer +/-7 days (e.g. 
Timeframe to do the visit is 385 days to 399 days)
Visit 18 Date of visit should be 420 days from Visit 2 also consider buffer +/-7 days (e.g. 
Timeframe to do the visit is 413 days to 427 days)
Visit 19 Date of visit should be 448 days from Visit 2 also consider buffer +/-7 days (e.g. 
Timeframe to do the visit is 441 days to 455 days)
Visit 20 Date of visit should be 476 days from Visit 2 also consider buffer +/-7 days (e.g. 
Timeframe to do the visit is 469 days to 483 days)
Visit 21 Date of visit should be 504 days from Visit 2 also consider buffer +/-7 days (e.g. 
Timeframe to do the visit is 497 days to 511 days)


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Visit 22 Date of visit should be 532 days from Visit 2 also consider buffer +/-7 days (e.g. 
Timeframe to do the visit is 525 days to 539 days)
Visit 23 Date of visit should be 560 days from Visit 2 also consider buffer +/-7 days (e.g. 
Timeframe to do the visit is 553 days to 567 days)
Visit 24 Date of visit should be 588 days from Visit 2 also consider buffer +/-7 days (e.g. 
Timeframe to do the visit is 581 days to 595 days)
Visit 25 Date of visit should be 616 days from Visit 2 also consider buffer +/-7 days (e.g. 
Timeframe to do the visit is 609 days to 623 days)
Visit 26 Date of visit should be 644 days from Visit 2 also consider buffer +/-7 days (e.g. 
Timeframe to do the visit is 637 days to 651 days)
Visit 777 Date of visit should be 672 days from Visit 2 also consider buffer +/-7 days (e.g. 
Timeframe to do the visit is 665 days to 679 days)
2.2
Analysis sets
The following analysis sets will be used in this study.
Enrolled Set: The Enrolled Set comprises all patients enrolled in this study. Patients who 
discontinued from the study due to ineligibility immediately after Visit 2 are not considered as 
enrolled.
Full Analysis Set (FAS): The Full Analysis Set comprises all patients to whom study treatment 
has been assigned and who received at least one dose of each study treatment (DT and FCT). 
Patients will be analyzed according to the treatment they have been assigned to.
Safety Set (SAF): The Safety Set includes all patients who received at least one dose of either 
study treatment (DT or FCT), and at least one safety assessment on or after Day 1.
Patients will be analyzed according to the study treatment received, where treatment received 
is defined as the assigned treatment if the patient took at least one dose of that treatment or the 
first treatment received if the assigned treatment was never received.
Per-Protocol Set (PPS): The Per-Protocol Set consists of a subset of the patients in FAS who 
are compliant with requirements of the clinical study protocol (CSP) without any major protocol 
deviation.
Any major protocol deviation will lead to exclusion of patients from PPS. The list of PDs is
defined in Section 5.5.
2.2.1
Subgroup of interest
Since this study also includes pediatric patients, all key safety and efficacy analyses will be 
performed separately by age groups: 2-6 years (infant), 7-11 years (child), 12-17 years 
(adolescent), < 18 years (overall of infant, child and adolescent), and ≥18 years (adult). In 
addition, these summaries will be performed on prior intake of iron chelation status (naïve or 
pre-treated) and thalassemia transfusion status (TDT or NTDT).


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2.3
Patient disposition, demographics and other baseline 
characteristics
Descriptive statistics will be provided for patient disposition, demographics and all baseline 
characteristics including baseline values of main efficacy endpoints. 
Summary statistics will be presented for continuous variables of the subgroup of interest and 
for all patients in the Enrolled Set. The number and percentage of patients in each category will 
be presented for categorical variables for the subgroup of interest and all patients.
Patients with missing data will not be included in the calculation of the percentages.
2.3.1
Patient disposition
The Enrolled Set will be used for the summary and listing of patient disposition. The overall 
number and percentage of patients who were screened, completed (core phase, extension phase) 
and discontinued the study (core phase or extension phase) along with reasons for 
discontinuation will be summarized.
2.3.2
Patient demographics
Summary statistics will be presented for continuous demographic variables by the subgroup of 
interest and for all patients in the Enrolled Set. For categorical variables, number and percentage 
of patients in each category will be presented for subgroup of interest and all patients.
The following demographic variables will be summarized:
Continuous variables:

Age (years)

Height (meter)

Weight (kg)

Body mass index (BMI) = (body weight in kilograms) / (height in meters)2
For BMI, height and body weight used is the last value prior to randomization. If there is 
no weight recorded prior to taking of study drug, BMI will be missing.
Categorical variables

Age group ( 2 years ≤age < 7 years, 7 years ≤age < 12years, 12 years ≤age <
18 years, < 18 years (overall of infant, child and adolescent), and age ≥18 years)

Gender (male, female)

Ethnicity (Hispanic/Latino, Chinese, Indian (Indian subcontinent), Japanese, Other)
2.3.3
Patient baseline characteristics
Summary statistics will be presented for continuous baseline variables by subgroup of interest 
and for all patients in the Enrolled set. For categorical variables, number and percentage of 
patients in each category will be presented for subgroup of interest and all patients. Baseline 
characteristics will be summarized depending on the following histories and tests: 


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
Disease history

Prior chelation therapy

Transfusion history
Baseline disease characteristics will be summarized for the following variables:

Disease history continuous variables
-
Time since diagnosis (months)

Disease history categorical variables
-
Disease type (Transfusion-dependent thalassemia, Non-transfusion-dependent 
thalassemia)
-
Patients who are hematologically stable since the examination (Yes/ No)

Prior chelation therapy continuous variables
-
Time since last iron chelation therapy (from end date)
-
Duration of last iron therapy (days)
-
Average daily dose (DFO) (mg/kg)
-
Average daily dose (DFP) (mg/kg)
-
Average daily dose of DFO or DFP (mg/ kg)
-
Average daily dose 1 (Other) (mg/kg)
-
Average daily dose 2 (Other) (mg/kg)

Prior chelation therapy categorical variables
-
Patients who have received a chelation therapy in at least last 6 months prior to 
start of study drug (Yes/ No), where ‘Yes’ means prior chelation treated and ‘No’ 
means prior chelation naïve. 
-
Medication name (DFO, DFP, DFO and DFP, Other)

Transfusion history continuous variable
-
Total number of transfusion(s) received in last 12 months (units)
-
Time since last transfusion received (days)
-
Number of units last transfused 
       - Platelets
       - PRBC
       - White blood 

Transfusion history categorical variable
-
The subject received blood transfusion prior to study (Yes/ No)
Medical history
Relevant medical history and current medical conditions will be summarized by system organ 
class and preferred term of the MedDRA dictionary. Other relevant baseline information will 
be listed and summarized using descriptive statistics, as appropriate.  


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2.4
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance)
2.4.1
Study treatment / compliance
Study treatment
The following variables will be summarized descriptively for each study treatment period based 
on the Safety Set. Summaries will be presented overall and by age groups and also on prior 
intake of iron chelation status (naïve or pre-treated) and thalassemia transfusion status 
(transfusion or non-transfusion), separately for Core and Extension phases.

The number of medications (pills) received for each dosing regimen

The duration of exposure (in weeks) and in categories (< 4 weeks, 4-< 12 weeks, 
12-< 24 weeks, ≥24 weeks)

Average planned (mg/kg/day) and average actual daily dose (mg/kg/day)

Cumulative planned (mg/kg) and cumulative total actual dose (mg/kg)

Percentage of planned dose taken

Dose intensity (computed as the ratio of actual cumulative dose received and actual 
duration of exposure)

Relative dose intensity (computed as the ratio of dose intensity and planned dose 
intensity)
The number of patients with dose adjustments (increase, reductions, interruption, or permanent 
discontinuation) and the reasons of change and interruption will be summarized for all patients 
and by treatment group. Dose adjustments for auditory, hypersensitivity reactions and 
cytopenias will also be summarized. 
The number of patients with ‘switching’(this is a switch outside the normal switch at the end of 
Week 24) from one treatment to another at any treatment period along with the reasons of 
switching will also be summarized. In case of switching within each treatment period, duration
of exposure will be calculated accordingly as described below.
The duration of exposure is defined as the number of weeks between the start and end of study 
medication. The exposure calculation will be based on the actual date of switch from one 
treatment to another. The end of study medication day is the last day with a non-zero actual 
dose of study medication as recorded on the drug administration pages.
The average daily dose (planned or actual, in mg/kg) is calculated as the mean dose over all 
days between first and last dose, including interim days with zero dose (interruptions). The final 
daily dose is recorded as the last non-zero dose. The cumulative dose is calculated as the sum 
over the daily doses of all days between first and last dose. The current weight is used when 
calculating the actual daily dose.
The percentage of planned dose taken is derived as 100 * cumulative actual dose (mg/kg)/ 
cumulative planned dose (mg/kg).


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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.
Patient compliance with study treatment will be evaluated using the pill count. The details of 
summary of compliance are explained in Section 2.7.2.
2.4.2
Prior, concomitant and post therapies
Prior and concomitant medications will be summarized in separate tables by treatment group.
Prior medications are defined as treatments taken and stopped prior to first dose of study 
treatment. Any medication given at least once between the day of first dose of randomized study 
treatment and the date of the last study visit will be a concomitant medication, including those 
which were started pre-baseline and continued into the period where study treatment is 
administered.
Medications will be presented in alphabetical order, by Anatomical Therapeutic Classification 
(ATC) codes and grouped by anatomical main group. Tables will show the overall number and 
percentage of patients receiving at least one treatment of a particular ATC code and at least one 
treatment in a particular anatomical main group.
Significant prior and concomitant surgeries and procedures will be summarized by primary 
system organ class and MedDRA preferred term.
The number and percentage of patients receiving prior and concomitant medication or therapy 
will be provided by system organ class and preferred term.
Prior or concomitant medication will be identified by comparing recorded or imputed start and
end dates of medication taken to the reference start date. 
2.5
Analysis of the primary objective
The primary objective of the study is to evaluate patient preference of deferasirox FCT or 
deferasirox DT at Week 48.
2.5.1
Primary endpoint
The primary endpoint is the proportion (and percentage, %) of patients who claim preference 
of deferasirox FCT over deferasirox DT as measured by preference questionnaire at Week 48.
The analysis of primary variable will be based on the FAS.
2.5.2
Statistical hypothesis, model, and method of analysis
The null hypothesis is that there is no difference in the proportion of patients preferring FCT or 
DT at Week 48. The alternative hypothesis is that there is a difference in the proportion of 
patients preferring FCT or DT at Week 48.


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Let p.1 denote the proportion of patients with preference (discordance) or no-preference 
(concordance) of DT and p1. denote the proportion of patients with preference or no-preference 
of FCT, at Week 48.
In statistical terms, the following hypothesis will be tested for primary objective:
H1: p1. = p.1, versus HA1: p1. ≠p.1
This is equivalent to test: H1: p12 = p21, versus HA1: p12 ≠p21, 
where p12 and p21 denotes the proportion of patients with preference of FCT over DT and vice 
versa.
In other words, 
H1: Deferasirox FCT is not different from deferasirox DT with respect to patient preference at 
Week 48
versus
HA1: Deferasirox FCT is different from deferasirox DT with respect to patient preference at 
Week 48
The primary analyses of testing patient preference of FCT over DT will be conducted via Mc 
Nemar’s test. Both exact and asymptotic p-values will be presented for Mc Nemar’s test for the 
matched pairs. Along with p-values, the estimates of proportions and percentages (%) of patient 
preferences and non-preferences for each study treatment will also be presented along with 95% 
CI (if required) using Clopper-Pearson method. The Type I error will be set to 2-sided α=5% or 
1-sided α=2.5%. The testing will be done on the patients who have completed question 2 in the 
preference questionnaire.
2.5.3
Handling of missing values/censoring/discontinuations
There will be no imputation for missing data. Wherever appropriate, available data will be 
summarized over specified intervals using suitable summary statistics. 
Patients should be seen for all visits to perform the scheduled assessments on the designated 
day, or as close to it as possible, i.e., not exceeding ± 2 days for all assessments scheduled in 
Visits 1 to 7 and ± 7 days for all other visits till Visit 777. In this clinical study, a week is 
7 calendar days.
2.5.4
Supportive analyses
Sensitivity analyses and supportive analyses will be conducted in order to provide evidence that 
the results seen from the primary analysis are robust. 
In order to support the Mc Nemar’s test for matched pair, the Odd’s Ratio (OR) of patient 
preference (i.e. OR=p12/p21), 95% CI and p-values will also be presented. Conditional logistic 
model for matched pair analyses may also be fitted if feasible. 


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The primary and above supportive analyses will also be performed for each subgroup of the 
baseline factor, i.e. on patients with TDT or NTDT and also on prior treatment status of iron 
chelation (naïve or pre-treated). Additionally, the primary analysis will be performed by age 
groups: 2-6 years (infant), 7-11 years (child), 12-17 years (adolescent), < 18 years (overall of 
infant, child and adolescent), and ≥18 years (adult). No p-values will be presented for subgroup 
analyses.
To identify the impact of preference on switching, the primary analyses will be performed 
separately for patients with or without switching before Week 48.
As a supportive analysis, the primary analysis will also be provided for PPS.
2.6
Analysis of the key secondary objective
Not applicable.
2.7
Analysis of secondary efficacy objective(s)
Refer to Table 1.2.1 of Section 1 for the list of secondary objectives.
2.7.1
Secondary endpoints
All the secondary efficacy evaluation will be performed on FAS population.
Refer to Table 1.2.1 of Section 1 for the list of secondary endpoints.
2.7.2
Statistical hypothesis, model, and method of analysis
No formal hypothesis testing will be conducted for secondary endpoints. 
Patient preference of FCT, DT, and iron chelation at Week 28
The proportion and percentage (%) of patients including 95% CI will be reported separately for
preference and non-preference of FCT over DT, FCT over prior iron chelation, and DT over
prior iron chelation at Week 28. 
Homogeneity tests (including Cochran’s Q test) will also be performed to check the 
homogeneity of the above three preferences. Exact and asymptotic p-values of Mc Nemar’s test 
will also be presented as analogous to primary analysis, for pairwise treatment comparisons. 
The OR of patient preference (i.e. OR=p12/p21), 95% CI and p-values will also be presented for 
pairwise comparisons. For comparisons with iron-chelation, only patients who were pre-treated 
with iron chelation will be selected for pairwise comparisons.
Patient preference of DT and iron chelation at Week 4 and Week 24
The proportion and percentage (%) of patients including 95% CI will be reported separately for
preference and non-preference of DT over iron chelation at Week 4 and Week 24. Exact and 
asymptotic p-values of Mc Nemar’s test will also be presented as analogous to primary analysis, 
described in Section 2.5.2. The OR of patient preference (i.e. OR=p12/p21), 95% CI and p-values 
will also be presented. Only patients who are pre-treated with iron-chelation will be considered.


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Reasons of patient preference
The reasons or factors influencing behind patient preference of FCT over DT will be 
summarized at Week 28 and 48. The number and percentage (%) of patients for selecting each 
reason will be presented for preference of each study treatment. In addition to that, the summary 
of reasons behind non-preference of each study treatment will also be presented.
Similar summaries will also be provided for different preference comparisons at Week 4 and 
24. 
Compliance using pill count 
Compliance is measured by pill/tablet count based on amount of medication dispensed, returned 
and reported as lost/wasted by the patient or caregiver. Compliance will be calculated for each 
treatment (FCT: Week 25- Week 48, DT: Baseline day 1 – Week 24) as the ratio of total count 
consumed to total count prescribed, where total count consumed is derived from cumulative 
dispensed, returned and lost/wasted counts and total count prescribed is the cumulative 
prescribed count.
The prescribed count corresponds to the count prescribed by the investigator for a period that 
the patient should have taken during this period. For each strength (125 mg, 250 mg and 500 mg 
tablets for Deferasirox DT; 90 mg, 180 mg and 360 mg tablets for Deferasirox FCT), the 
prescribed count for a period is calculated from the daily prescribed count at the beginning of 
this period multiplied by the duration (days) of this period. The daily prescribed count is the 
sum of counts prescribed per strength. The duration of a period will be calculated as (end date 
of the period) – (start date of the period) + 1. The following period duration calculation will 
exclude the start day. The total count prescribed is the sum of counts prescribed over all periods.
If a patient does not return the study drug, the compliance will not be calculated.
Analysis of covariance (ANCOVA) will be performed for comparison between both treatment 
groups (FCT and DT). The ANCOVA model for compliance endpoint will include treatment 
group and age group (2 to < 6 years, 6 to < 10 years, 10 to < 18 years, and ≥18 years) and 
thalassemia transfusion dependence (TDT and NTDT) as factors. Least squares estimates, 95% 
CI and p-value will be presented for each treatment and difference between treatments. 
Summary statistics of number of pills (and percentages) will also be presented overall and by 
treatment and subgroups. 
Serum Ferritin for monthly visits from Day 1 baseline up to Week 48 
Summary statistics of change from baseline (absolute and difference, and 95% CI) will be
presented by visit, treatment and subgroups (i.e. by age group, and status of previous iron 
chelators) and difference between treatments. Graphical presentation including mean (and SD) 
change from baseline plots will also be reported for all visits.
Palatability
Refer to PRO section (Section 2.11) for summary details.
mSICT
Refer to PRO section (Section 2.11) for summary details.


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GI symptoms 
Refer to PRO section (Section 2.11) for summary details.
2.7.3
Handling of missing values/censoring/discontinuations
There will be no imputation for missing data. Wherever appropriate, available data will be 
summarized over specified intervals using suitable summary statistics. 
Last observation carried forward can only be applied for serum ferritin levels. 
2.8
Safety analyses
For all safety analyses, the Safety Set (SAF) will be used. All listings and summaries will be 
presented by treatment group (wherever applicable) and by TDT and NTDT. In addition, all 
key safety summaries will be reported separately for all age groups (defined earlier in Section 
2.2.1). The safety analysis will also be presented separately for core and extension phases of
the study.
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 dose 
of study medication.
3. Post-treatment period: starting at day 30+1 after last dose of study medication. 
All serious adverse events (SAEs), non-serious adverse events (AEs) and adverse events of 
special interest (AESI) which are specific gastrointestinal events during the on-treatment period 
will be summarized. 
All data, regardless of observation period, will be listed. Safety assessments starting during the 
pre-treatment or post-treatment period will be flagged in the listings. Safety assessments starting 
prior to study day 1 will appear with negative study day in the listings.
2.8.1
Adverse events (AEs)
Summary tables for AEs will include only AEs that started or worsened during the on-treatment 
period, the treatment-emergent AEs. 
The incidence of treatment-emergent AEs (new or worsening from baseline) will be 
summarized by system organ class and or preferred term, severity (mild, moderate, severe), 
type of adverse event, relation to study treatment. If a patient reported more than one AE with 
the same preferred term, the AE with the greatest severity will be presented. If a patient reported 
more than one AE within the same primary system organ class, the patient will be counted only 
once with the greatest severity at the system organ class level, where applicable.
Severity is captured in CRF as per CTCAE V 4.03 grades. The mapping from CTCAE to 
severity grade is given below:

Grade 1=Mild 

Grade 2= Moderate 


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
Grade 3= Severe 

Grade 4 = Life- threatening

Grade 5= Death related to AE
In this study the grade ≥3 will be considered as severe. 
As appropriate, the incidence of AEs will be presented per 100 patient years of exposure. 
The following adverse event summaries will be produced by treatment for Safety Set:

Adverse events (overall and severe), regardless of study drug relationship by primary 
system organ class and preferred term

Adverse events, regardless of study drug relationship by primary system organ class and 
preferred term and severity 

Adverse events (overall and severe), with suspected study drug relationship by primary 
system organ class and by preferred term 

Serious adverse events (overall and severe), regardless of study drug relationship, by 
primary system organ class and preferred term

Adverse events leading to study drug discontinuation (overall and severe), regardless of 
study drug relationship, by primary system organ class and preferred term

Adverse events requiring dose adjustment or study-drug interruption (overall and severe), 
regardless of study drug relationship, by primary system organ class and preferred term

Adverse events requiring additional therapy (overall and severe), regardless of study drug 
relationship, by primary system organ class and preferred term
The incidences listed above will additionally be summarized by preferred term.

Deaths by primary system organ class and preferred term. 

Non-serious adverse events, regardless of study drug relationship, by primary system 
organ class and preferred term (for clinicaltrials.gov purpose)
An overall summary of type of AEs (e.g. serious, leading to study drug discontinuation, 
requiring dose adjustment and/or interruption) will be presented by treatment (overall and 
severe). This summary as well as the incidence of AEs (overall and severe), regardless of study 
drug relationship, will additionally be provided separately for pediatric and adult patients. AEs 
will be summarized by presenting the number and percentage of patients having at least one 
AE, and having at least one AE by system organ class and/or preferred term, severity, and 
relation to study drug by treatment. A patient with multiple occurrences of an AE will be 
counted only once in the AE category. 
All AEs, deaths and SAEs (including those from the pre and post-treatment periods) will be
summarized and listed and those collected during the pre-treatment and post-treatment period 
will be flagged. Severity of AEs will be assessed as mild, moderate, or severe.
Separate summaries will be provided for deaths, SAEs, other significant AEs leading to 
discontinuation,
and AEs leading to dose adjustment (including study treatment 
discontinuation).


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A graphical display of relative frequencies within system organ classes and risks difference 
=risk in FCT-risk in DT (because if in DT, patient count for some SOC becomes 0, then relative 
risk will be undefined), as appropriate, may be presented by forest plot.
The following formula will be used:
Table 2-1
Contingency Table for Risk*
Treatment
DFX FCT
DFX DT
No of patient with AE 
FCTE
DTE
No of Patient without AE
FCTN
DTN
*separate calculation will be done for each SOC
Risk difference (RD) =

	 −

	 =  −, 
where  =

	 and  =

	
The sampling distribution of RD is approximately normal.
Hence, Standard Error for RD = SE( RD)=
∙	
(	) +
∙	
(	)
                                                                  =
()
	
+
()
	
, 
                                                             where N1=  +  and N2=  + 
95% CI of SE(RD)= RD±1.96×SE(RD)
In plot all results will be presented in percentages (%).
2.8.1.1
Adverse events of special interest / grouping of AEs
Specific groupings of AESI will be considered and the number of patients with at least one 
event in each grouping will be reported. Such groups consist of AEs for which there is a specific 
clinical interest in connection with deferasirox treatment or AEs which are similar in nature 
(although not identical). Note that certain AEs may be reported within multiple groupings.
All AESI groupings are defined through the use of Preferred Terms (PT), High Level Terms 
(HLT), System Organ Classes (SOC), Standardized MedDRA Queries (SMQ), Novartis 
MedDRA Queries (NMQ), or through a combination of these components.
The AESI search table will be used to map reported AEs to the notable AE groupings. The list 
of AESIs may be updated during the course of the study based on accumulating safety data. 
Therefore, the clinical study report will list the AE groupings used and provide a listing of the 
corresponding AESI search table. 
Note that certain AEs may be reported within multiple groupings.
For AESIs, time-to-event analysis will be performed as appropriate. Results will be tabulated 
and the Kaplan-Meier estimates for the cumulative rate will be plotted.


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2.8.2
Deaths
Separate summaries and listings will be provided for deaths for each treatment period (core and 
extension).
2.8.3
Laboratory data
The summary of laboratory evaluations will be presented for different groups of laboratory tests
(hematology, serum chemistry, serum ferritin, serum creatinine, and urinalysis) for different 
treatment periods (core and extension). Descriptive summary statistics for the change from 
baseline to each study visit will be presented. These descriptive summaries will be presented 
by test group, laboratory test and treatment group. Change from baseline will be summarized 
only for the patients who have both baseline and post-baseline assessment. For each parameter, 
maximum change from baseline within each study period will be evaluated analogously.
In addition, shift tables will be provided for all parameters to compare a patient’s baseline 
laboratory evaluation relative to the visit’s observed value. For the shift tables, the normal 
laboratory ranges will be used to evaluate whether a particular laboratory test value was normal, 
low, or high for each visit value relative to whether or not the baseline value was normal, low, 
or high. These summaries will be presented by laboratory test and treatment group. Shifts will 
be presented by visit as well as for most extreme values post-baseline.
Grading of laboratory values will be assigned programmatically as per NCI Common 
Terminology Criteria for Adverse Events (CTCAE).  The calculation of CTCAE grades will be 
based on the observed laboratory values only, clinical assessments will not be taken into account.
CTCAE Grade 0 will be assigned for all non-missing values not graded as 1 or higher. Grade 5 
will not be used.
For laboratory tests where grades are not defined by CTCAE, results will be categorized as 
low/normal/high based on laboratory normal ranges.
The following summaries will be generated separately for hematology and biochemistry tests:

Reporting of all laboratory data with values flagged to show the corresponding CTCAE
grades if applicable and the classifications relative to the laboratory normal ranges (Table 
5.3.1)
For laboratory tests where grades are defined by CTCAE 

Worst post-baseline CTCAE grade (regardless of the baseline status). Each patient will be 
counted only once for the worst grade observed post-baseline.

Shift tables using CTCAE v4.3 grades to compare baseline to the worst on-treatment value
For laboratory tests where grades are not defined by CTCAE

Shift tables using the low/normal/high/ (low and high) 

Classification to compare baseline to the worst on-treatment value. Apart from the above 
laboratories summaries, summaries of Hepatitis Viral tests will also be performed.
In addition, a summary of serum ferritin will be presented by TDT and NTDT patients, by age 
group, and ICT-naive vs. ICT patients by visit.


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For all lab assessments, the baseline of each period will be considered based on the actual 
baseline or start of that particular period, as applicable. Also the baseline data for FCT phase 
will be provided for only the number of patients available in the analysis set at the start of the 
period. 
2.8.4
Other safety data
2.8.4.1
ECG and cardiac imaging data
Abnormalities of ECG parameters will be summarized together with an overall interpretation 
of the findings at screening and end of core phase, i.e. at Week 48. The following quantitative 
variables will be summarized: QTcB interval, QTcF interval, heart rate, PR interval, QT interval, 
QRS duration.
Number and percentage will be provided for the patients who have clinically significant 
abnormalities present.
Summary statistics will be presented for ECG variables at baseline and at end of core phase i.e. 
at Week 48. In addition, shift tables comparing baseline ECG interpretation (normal, abnormal, 
not available, total) with the Week 48 interpretation (normal, abnormal, not available, total) will 
be provided. A listing of all newly occurring or worsening abnormalities will be provided, as 
well as a by subject listing of all quantitative ECG parameters. 
2.8.4.2
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 but will be listed.
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.
A listing will be provided for all vital signs and weight. Notable vital signs and weight values 
are flagged.
2.8.4.3
Auditory, ocular, and chest X-ray interpretation
Auditory, ocular, and chest X-ray overall interpretation will be summarized by normal, 
clinically insignificant abnormality, and clinically significant abnormality, with number and 
percentages.
2.9
Pharmacokinetic endpoints
Not applicable.
2.10
PD and PK/PD analyses
Not applicable.
2.11
Patient-reported outcomes
The following PROs will be summarized using FAS.


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Preference questionnaire
The preference questionnaire is a three item questionnaire. There are three separate versions 
depending on the week(s) that the questionnaire is administered. Week 4 and 24 contains 
preference questions on DT and iron chelators, Week 28 contain questions on all three 
medications and Week 48 on DT and FCT only.
Summaries of the preference questionnaires will be performed at Visits 4, 24, 28 and 48, if data 
is available, in Core phase of the study and additionally from the data collected at the time of 
immediate next visit based on patients who had treatment switching. No total score is calculated 
on the preference questionnaire. Each item will be scored as the proportion of patients who 
select each response option.  
The analysis of preference data has been explained in Section 2.5 and Section 2.7.
Palatability using PRO/ ObsRO questionnaire
The palatability questionnaire consists of 4 items. Two items measure the taste and aftertaste of 
the medication and are scored on a 5 point response scale. The remaining palatability items 
refer to whether the medication was taken (i.e. swallowed or vomited) and how the patient 
perceived the amount of medication to be taken. 
For the palatability questionnaire the overall score will be constructed using a scoring matrix 
from the score of items. Standard descriptive analyses including absolute and relative changes 
will be performed for both formulations (DT/FCT) for the overall score at Week 4, Week 24, 
Week 28 and Week 48 and overall score at Screening for iron chelators. The baseline data for 
treatment period 1 and 2 will be Week 4 and Week 24 data respectively, only one assessment 
is observed at Screening period. The summary will be provided separately for PRO and ObsRO 
patient groups.
The standard descriptive analyses include: n, mean, standard deviation, minimum, median and 
maximum. The 95% CI for the absolute and relative (or difference) change from baseline of the 
overall score will also be presented for the treatments.
mSICT using PRO / ObsRO questionnaire
The Modified SICT (mSICT) questionnaire consists of 15 items for the PRO version and 
22 items for the ObsRO version that represent 3 domains; Adherence, Preference and Concerns.
For the mSICT questionnaire, the score for each domain based on the 15 questions common to 
both the PRO and ObsRO versions, will be the mean of the score of items included in the 
corresponding domain. The additional 7 questions that are included in the ObsRO version will 
be scored as standalone items. Standard descriptive analyses will be performed for both 
formulations (DT/FCT) for each domain score at Week 4, Week 24, Week 28 and Week 48,
and at Screening for iron chelators. The baseline data for treatment period 1 and 2 will be 
Week 4 and Week 24 data respectively, only one assessment is observed at Screening period. 
The summary will be provided separately for PRO and ObsRO patient groups.
Weighted mean of both groups will also be reported to highlight the combined result. Separately 
weighted mean of both the groups for 15 common questions will also be reported. Pooled SD
will be provided only if the data from both the groups follow the same distribution.


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The standard descriptive analyses include: n, mean, SD, minimum, median and maximum. The 
95% CI for the absolute and relative (or difference) changes from baseline in all domains will 
be presented for the treatments.
GI symptoms using PRO / ObsRO questionnaire
The GI symptom PRO consists of 6 items, 5 of which are scored using a 0 – 10 rating scale with 
item-appropriate end anchors to rate the symptom, The sixth item assesses bowel movement 
frequency during the past 24 hours, using 7 response options. 
For GI symptom ObsRO, the following rules (as applicable in this study) are used for coding:
Over the last 2 weeks how often have you been troubled by abdominal pain or abdominal 
cramps? 
0.
Never
1.
Rarely
2.
Sometimes
3.
Often
4.
All the time
Over the last 2 weeks, how much of a problem have you had with bloating? 
0.
No problem
1.
A minor problem
2.
Some problem
3.
A significant problem
4.
A major problem 
In the last 2 weeks, how much of a problem have you had with excessive wind? 
0.
No problem
1.
A minor problem
2.
Some problem
3.
A significant problem
4.
A major problem 
Over the last 2 weeks, on average how often do your bowels move per day? 
0.
Less than once daily
1.
1-2 times per day
2.
3-4 times per day
3.
5-6 times a day 
4.
More than 6 times per day


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In the last 2 weeks, how much of a problem have you had with loose stools? 
0.
No problem
1.
A minor problem
2.
Some problem
3.
A significant problem
4.
A major problem 
How often during the last 2 weeks have you had an urgent need for your bowels to open or a 
sudden need for a toilet? 
0.
Never
1.
Rarely
2.
Sometimes
3.
Often
4.
All the time
How often during the last 2 weeks have you been woken from your sleep to open your bowels?
0.
Never
1.
Rarely
2.
Sometimes
3.
Often
4.
All the time
Over the last 2 weeks, how often do your bowel motions float and require more than one flush?
0.
Never
1.
Rarely
2.
Sometimes
3.
Often
4.
All the time
Over the last 2 weeks, how often have your bowel motions been oily or greasy? 
0.
Never
1.
Rarely
2.
Sometimes
3.
Often
4.
All the time
Over the last 2 weeks, how much of a problem have you had with foul smelling stools?


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0.
No problem
1.
A minor problem
2.
Some problem
3.
A significant problem
4.
A major problem
Over the last 2 weeks, how much of a problem have you had maintaining or getting to the weight 
you would like to be? 
0.
No problem
1.
A minor problem
2.
Some problem
3.
A significant problem
4.
A major problem
How often has the feeling of fatigue or of being tired and worn out been a problem for you 
during the last 2 weeks? 
0.
Never
1.
Rarely
2.
Sometimes
3.
Often
4.
All the time
The GI symptoms will be summarized and listed.
Suitable graphs (domain scores plot and waterfall plot) will be presented related to PROs. For 
this purpose, 95% CI may be reported if appropriate.
2.12
Biomarkers
Not applicable.
2.13
Other Exploratory analyses
Not applicable.
2.14
Interim analysis
One interim analysis is planned in this study.
The interim analysis will be performed at end of Core phase (Week 48) that is after all patients 
complete Week 48, to assess the patient preference after 6 months with deferasirox FCT 
treatment in comparison to deferasirox DT. The primary analysis to evaluate the patient 
preference of FCT over DT will be performed at this interim. Along with primary analysis, all 
baseline, key efficacy and safety analyses will also be performed till Core phase.


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3
Sample size calculation
Based on data from the ECLIPSE study (Taher et al 2018), the following assumptions have 
been made at Week 48, the patient preference for  deferasirox FCT (formulation) is 45% and 
preference for  deferasirox DT (formulation) is 25% and no preference to either of the 
formulations is 30%. This means the discordant pairs is 70 % (i.e. 70% preferred one 
formulation over another, 45 %) and concordant pairs= 30% (assuming same preference for 
each formulation, 15%).
At least 130 patients are needed at Week 48 to have 80% power to detect the difference of 
patient preference of 20% (i.e. 45% preference of FCT over DT and 25% preference of DT over 
FCT) at a two sided significance level of 0.05 using McNemar's test for matched pairs.
To allow for roughly 10% of subjects with missing measurement, a total of approximately 
145 evaluable patients aged ≥2 years male or female with TDT or NTDT requiring chelation 
therapy due to iron overload, need to be enrolled. Patients may have been previously treated 
with iron chelators (other than deferasirox DT) or be chelation-naïve.
EAST 6.0 is used to calculate the sample size.
4
Change to protocol specified analyses
Not applicable.
5
Appendix
5.1
Imputation rules
5.1.1
Study drug
Not applicable.
5.1.2
AE date imputation
AE date imputation is based only on a comparison of the partial AE start date to the treatment 
start date as mentioned in the Table 5.1-2 below.  
1. If the AE start date year value is missing, the date uncertainty is too high to impute a 
rational date. Therefore, if the AE year value is missing, the imputed AE start date is set to 
NULL.
2. If the AE start date year value is less than the treatment start date year value, the AE 
started before treatment.  Therefore:
a.
If the AE year is less than the treatment year and the AE month is missing, the 
imputed AE start date is set to the mid-year point (01JulYYYY).
b. Else if the AE year is less than the treatment year and the AE month is not missing, 
the imputed AE start date is set to the mid-month point (15MONYYYY).
3. If the AE start date year value is greater than the treatment start date year value, the AE 
started after treatment.  Therefore:


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a.
If the AE year is greater than the treatment year and the AE month is missing, the 
imputed AE start date is set to the year start point (01JanYYYY).
b. Else if the AE year is greater than the treatment year and the AE month is not 
missing, the imputed AE start date is set to the month start point (01MONYYYY).
4. If the AE start date year value is equal to the treatment start date year value:
a.
And the AE month is missing or the AE month is equal to the treatment start 
month, the imputed AE start date is set to one day after treatment start.
b. Else if the AE month is less than the treatment start month, the imputed AE start 
date is set to the mid-month point (15MONYYYY).
c.
Else if the AE month is greater than the treatment start month, the imputed AE 
start date is set to the start month point (01MONYYYY).
Table 5.1-2: AE date imputation
MON
MON < CFM
MON = CFM
MON > CFM
MISSING
YYYY 
MISSING NULL
NULL
NULL
NULL
Uncertain
Uncertain
Uncertain
Uncertain
YYYY < 
CFY
( D ) = 01JULYYYY
( C )= 15MONYYYY ( C )= 15MONYYYY ( C )= 15MONYYYY
Before Treatment Start Before Treatment Start Before Treatment Start Before Treatment Start
YYYY = 
CFY
(B)= TRTSTD+1
( C )= 15MONYYYY (A)= TRTSTD+1
(A)= 01MONYYYY
Uncertain
Before Treatment Start Uncertain
After Treatment Start
YYYY > 
CFY
(E)= 01JANYYYY
(A)= 01MONYYYY
(A)= 01MONYYYY
(A)= 01MONYYYY
After Treatment Start After Treatment Start After Treatment Start After Treatment Start 
Before Treatment Start 
Partial indicates date prior to Treatment Start Date
After Treatment Start 
Partial indicates date after Treatment Start Date
Uncertain
Partial insufficient to determine relationship to Treatment Start Date
LEGEND:
(A)
         MAX(01MONYYYY,TRTSTD+1)
(B)
         TRTSTD+1
(C)
15MONYYYY
(D)
01JULYYYY
(E)
01JANYYYY
5.1.3
Concomitant medication date imputation
Concomitant medication (CMD) date imputation uses both a comparison of the partial CMD 
start date to the treatment start date, and the value of the CMDTYP1C flag (1, 2, or 3).  Event 
date comparisons to treatment start date are made based on the year and month values only (any 
day values are ignored) in Table 5.1-3 below.


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1. If the CMD start date year value is missing, the date will be imputed based on the 
CMDTYP1C flag value.  If the flag value is 1 or 3, the imputed CMD start date is set to 
one day before the treatment start date.  Else, if the flag value is missing or 2, the imputed 
CMD start date is set to one day after the treatment start date.  (Note that for some legacy 
data, the CMDTYP1C variable may not exist in the data.  When this happens and the 
CMD start date year value is missing, the imputed date value will be NULL.)
2. If the CMD start date year value is less than the treatment start date year value, the CMD 
started before treatment.  Therefore:
a.
if the CMD year is less than the treatment year and the CMD month is missing, the 
imputed CMD start date is set to the mid-year point (01JulYYYY).
b. Else if the CMD year is less than the treatment year and the CMD month is not 
missing, the imputed CMD start date is set to the mid-month point 
(15MONYYYY).
If the CMD start date year value is greater than the treatment start date year value, the CMD 
started after treatment. Therefore:
a.
If the CMD year is greater than the treatment year and the CMD month is missing, 
the imputed CMD start date is set to the year start point (01JanYYYY).
b. Else if the CMD year is greater than the treatment year and the CMD month is not 
missing, the imputed CMD start date is set to the month start point 
(01MONYYYY).
3. If the CMD start date year value is equal to the treatment start date year value:
a.
and the CMD month is missing or the CMD month is equal to the treatment start 
month,
i.
If the flag value is 1 or 3, the imputed CMD start date is set to one day 
before the treatment start date.
ii.
Else, if the flag value is missing or 2, the imputed CMD start date is set to 
one day after the treatment start date.
a.
Else if the CMD month is less than the treatment start month, the imputed CMD 
start date is set to the mid-month point (15MONYYYY).
b. Else if the CMD month is greater than the treatment start month, the imputed 
CMD start date is set to the start month point (01MONYYYY).
Table 5.1-3:  CMD date imputation
MON MISSING
MON < CFM
MON = CFM
MON > CFM
YYYY 
MISSING (F)
(F)
(F)
(F)
Uncertain
Uncertain
Uncertain
Uncertain
YYYY < 
CFY
(D)=01JULYYYY
(C)=15MONYY
(C)=15MONYY
(C)=15MONYY
Before Treatment Start
Before Treatment Start Before Treatment Start
Before Treatment Start


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YYYY = 
CFY
(B)
(C)=15MONYY
(B)
(A)=01MONYYYY
Uncertain
Before Treatment Start Uncertain
After Treatment Start
YYYY > 
CFY
(E)= 01JANYYYY
(A)=01MONYYYY
(A)=01MONYYYY
(A)=01MONYYYY
After Treatment Start
After Treatment Start
After Treatment Start
After Treatment Start
Before Treatment Start 
Partial indicates date prior to Treatment Start Date
After Treatment Start 
Partial indicates date after Treatment Start Date
Uncertain
Partial insufficient to determine relationship to Treatment Start Date
         LEGEND:
(A)
MAX(01MONYYYY,TRTSTD+1)
(B)
IF CMDTYP1C IN (1,3) THEN TRTSTD-1
     ELSE IF CMDTYP1C in(. , 2) THEN TRTSTD+1
(C)
15MONYYYY
(D)
01JULYYYY
(E)
01JANYYYY
(F)
IF CMDTYP1C IN (1,3) THEN TRTSTD-1
    ELSE IF CMDTYP1C in  (. , 2) THEN TRTSTD+1
5.1.3.1
Prior therapies date imputation
Not applicable.
5.1.3.2
Post therapies date imputation
Not applicable.
5.1.3.3
Other imputations
Not applicable.
5.2
AEs coding/grading
The verbatim term recorded on CRF will be identified as adverse event and will be coded by 
primary system organ class and preferred term using Medical Dictionary for Regulatory 
Activities (MedDRA) version 18.1 and above.


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5.3
Laboratory parameters derivations
Table 5.3.1
Definition of notable/extended ranges for laboratory test
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
ALT and AST
>5 x ULN and >2 x baseline value (extended 
range >10×ULN and >2×baseline value)
* Creatinine clearance will be estimated using the Schwartz formula
Table 5.3.2
Definition of notable ranges for vital signs and weight
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
5.4
Statistical models
5.4.1
Primary analysis
SAS code for Mc Nemar’s test
proc freq data=; 
table p12*p21; 
exact mcnem; 
weight patients;
run;
p12 and p21 respectively denote the proportion of patients with preference of FCT over DT and 
vice versa.


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5.4.2
Secondary analysis
SAS code for Homogeneity test:
proc freq data=; 
tables Drug_A Drug_B Drug_C / nocum; 
tables Drug_A*Drug_B*Drug_C / agree noprint; 
format Drug_A Drug_B Drug_C $ResponseFmt.; 
weight Count; 
title ‘xxxxxxxx'; 
run; Drug_A=FCT, Drug_B= DT and Drug_C= iron chelation 
SAS code for ANCOVA
proc glm data = ; 
class treatmentgroups; 
model compliance = treatmentgroups  agegroup thalassemiatransdep;
run;
quit;
Example SAS Code for Forest plot
%let gpath='C:\';
%let dpi=200;
data ae;
  input Pref $1-30 NA NB SNA SNB;
datalines;
ABDOMINAL PAIN                20    61    216    431
ANOREXIA                       2    15    216    431
ARTHRALGIA                     1    15    216    431
BACK PAIN                     10    23    216    431
BRONCHITIS                     8    11    216    431
CHEST PAIN                     9    12    216    431
CHRONIC OBSTRUCTIVE AIRWAY    76    95    216    431
COUGHING                      13    26    216    431
DIARRHEA                      23    90    216    431
DIZZINESS                      9    29    216    431
DYSPEPSIA                      8    42    216    431
DYSPNEA                       15     9    216    431
FATIGUE                        4    16    216    431
FLATULENCE                     6    20    216    431
GASTROESOPHAGEAL REFLUX        5    12    216    431
HEADACHE                      14    36    216    431
HEMATURIA                      2    14    216    431
HYPERKALEMIA                   4     9    216    431
INFECTION VIRAL               12    26    216    431
INJURY                        12    30    216    431


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INSOMNIA                       4    26    216    431
MELENA                         7    12    216    431
MYALGIA                        6    12    216    431
NAUSEA                        10   82    216    431
PAIN                           4    17    216    431
RASH                           4     9    216    431
RESPIRATORY DISORDER           4    11    216    431
RHINITIS                      11    17    216    431
SINUSITIS                     13    28    216    431
UPPER RESP TRACT INFECTION    33    68    216    431
URINARY TRACT INFECTION        6    12    216    431
VOMITING                       6    37    216    431
WEIGHT DECREASE                2     9    216
run;
/*--Compute Proportions for treatment A & B, Mean and Risk--*/
data ae_risk;
  set ae;
  keep pref a b mean lcl ucl;
  a=na/sna;
  b=nb/snb;
  factor=1.96*sqrt(a*(1-a)/sna + b*(1-b)/snb);
  lcl=a-b+factor;
  ucl=a-b-factor;
  mean=0.5*(lcl+ucl);
run;
/*--Sort by mean value--*/
proc sort data=ae_risk out=ae_sort;
  by mean;
run;
/*--Add alternate reference lines--*/
data ae_ref;
  set ae_sort;
  if mod(_n_, 2) eq 0 then ref=pref;
run;
proc print;run;
/*--Create template for AE graph--*/
proc template;
  define statgraph AEbyRelativeRisk;
    dynamic _thk _grid;
    begingraph;
      entrytitle 'Most Frequent On-Therapy Adverse Events Sorted by Risk 
Difference';
      layout lattice / columns=2 rowdatarange=union columngutter=5;
  
        /*--Row block to get common external row axes--*/
rowaxes;
  rowaxis / griddisplay=_grid display=(tickvalues) 
tickvalueattrs=(size=5);
endrowaxes;
/*--Column headers with filled background--*/
column2headers;


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  layout overlay / border=true backgroundcolor=cxdfdfdf opaque=true; 
            entry "Proportion"; 
          endlayout;
  layout overlay / border=true backgroundcolor=cxdfdfdf opaque=true; 
            entry "Risk Difference with 0.95 CI"; 
          endlayout;
        endcolumn2headers;
/*--Left side cell with proportional values--*/
        layout overlay / xaxisopts=(display=(ticks tickvalues)  
tickvalueattrs=(size=7));
      referenceline y=ref / lineattrs=(thickness=_thk) 
datatransparency=0.9;
          scatterplot y=pref x=a / 
markerattrs=graphdata2(symbol=circlefilled)
                        name='a' legendlabel="Treatment (N=&NA)";
  scatterplot y=pref x=b / 
markerattrs=graphdata1(symbol=trianglefilled)
                        name='b' legendlabel="Control (N=&NB)";
endlayout;
/*--Right side cell with Relative Risk values--*/
layout overlay / xaxisopts=(label='Less Risk                    More 
Risk'
                         labelattrs=(size=8)  tickvalueattrs=(size=7));
  referenceline y=ref / lineattrs=(thickness=_thk) 
datatransparency=0.9;
          scatterplot y=pref x=mean / xerrorlower=lcl xerrorupper=ucl 
                      markerattrs=(symbol=circlefilled size=5);
  referenceline x=0 / lineattrs=graphdatadefault(pattern=shortdash);
endlayout;
/*--Centered side bar for legend--*/
        sidebar / spacefill=false;
          discretelegend 'a' 'b' / border=false;
endsidebar;
      endlayout;
    endgraph;
  end;
run;
ods html close;
ods listing gpath=&gpath image_dpi=&dpi style=listing;
/*--Render the graph with grid lines without horizontal bands--*/
ods graphics / reset width=6in height=4in imagename='AEbyRelativeRisk';
proc sgrender data=ae_ref template=AEbyRelativeRisk;
  dynamic _thk='0' _grid='on';
run;
/*--Render the graph without grid lines and with horizontal bands--*/
ods graphics / reset width=6in height=4in imagename='AEbyRelativeRiskRef';
proc sgrender data=ae_ref template=AEbyRelativeRisk;
  dynamic _thk='9' _grid='off';
run;


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# Here you have to creat a dataset for SOC with counts for DT and FCT and 
then proceed.
Example code for Kaplan-Meier and Logrank test
proc lifetest data=BMT 
plots=survival(atrisk(outside(0.15))); 
time T * Status(0); 
strata Group / order=internal; 
format group bmtfmt.;
run;
ods graphics on;
proc lifetest data=Exposed plots=(survival(atrisk) logsurv);
time Days*Status(0);
strata Treatment;
run;
ods graphics off;
5.5
Rule of exclusion criteria of analysis sets 
Table 1
Protocol deviations that cause subjects to be excluded
Deviation 
ID
Description of Deviation
Exclusion in Analyses
Severity 
code
D02
Patient enrolled correctly but did not 
receive any study treatment and not 
withdrawn.
EXCLUDE FROM FAS 
AND SAF
3
D03
Pregnancy occurred while pt actively 
participating in study. Study drug was 
administered after notice of pregnancy 
and the pt was NOT discontinued from 
the study.
EXCLUDE FROM PPS
4
D04
Patients not discontinued from study 
despite is fulfilling the discontinuation 
criteria as per protocol section 7.1.3.1 
and 7.1.3.2.
EXCLUDE FROM PPS
4
E01
Creatinine clearance below the 
contraindication limit in the locally 
approved prescribing information. 
Creatinine clearance will be estimated 
from serum creatinine at screening visit.
EXCLUDED FROM PPS
4
E02
Serum creatinine > 1.5 x ULN at 
screening measured at screening visit.
EXCLUDED FROM PPS
4
E03a
ALT (SGPT) > 5 x ULN unless 
LIC >10mg Fe/dw within 6
months prior to screening visit
EXCLUDED FROM PPS
4


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Deviation 
ID
Description of Deviation
Exclusion in Analyses
Severity 
code
E03b
AST (SGOT) > 5 x ULN unless 
LIC >10mg Fe/dw within 6
months prior to screening visit
EXCLUDED FROM PPS
4
E04
Urinary protein / creatinine ratio >0.5 
mg/mg in a non-first void urine sample 
at screening visit.
EXCLUDED FROM PPS
4
E05
Patients with significant impaired 
gastrointestinal function that may 
significantly alter the absorption of oral 
deferasirox at screening visit.
EXCLUDE FROM PPS
4
E06
Serum pregnancy test not done at visit 
1 in females of child bearing potential.
INCLUDE IN 
EVERYTHING
0
E06a
Hepatitis B or Hepatitis C tests were not 
performed at visit 1.
INCLUDE IN 
EVERYTHING
0
E07
Clinical or laboratory evidence of active 
Hepatitis B or C at visit 1.
EXCLUDED FROM PPS
4
E08
Known history of HIV seropositivity 
(Elisa or Western blot).
EXCLUDED FROM PPS
4
E9
History of malignancy of any organ 
system, treated or untreated, within the 
past 5 years (protocol section 5.3)
EXCLUDED FROM PPS
4
E10
Patients participating in another clinical 
trial or receiving an investigational drug.
EXCLUDE FROM FAS
1
E11
History of hypersensitivity to any of the 
study drugs or their excipients
EXCLUDED FROM PPS
4
E12
Significant medical condition interfering 
with the ability to take part in this study
EXCLUDE FROM PPS
4
E13
Female of child bearing potential 
unwilling to use contraception as 
requested by the protocol
INCLUDE IN 
EVERYTHING
0
E14
Female not meeting post-menopausal 
criteria stated in the protocol and not 
using the contraception methods 
requested in the protocol
INCLUDE IN 
EVERYTHING
0
E15
Female of child bearing potential with a 
positive serum pregnancy in the 
screening visit however subject is 
enrolled into the study
EXCLUDE FROM PPS
4
E16
Sexually active males not using 
condom during intercourse while taking 
drug and for 28 days after stopping 
study medication
INCLUDE IN 
EVERYTHING
0
E17
Patients with psychiatric or addictive 
disorders preventing from giving 
informed consent or undergoing any of 
the treatment options or unable or 
unwilling to comply with the protocol
EXCLUDE FROM FAS
AND SAF
3


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Deviation 
ID
Description of Deviation
Exclusion in Analyses
Severity 
code
G01
Patients not completed the safety follow 
up evaluation
INCLUDE IN 
EVERYTHING
0
G02a
Patient did not complete the preference 
questionnaire in each period (W28 and 
W48)
INCLUDE IN 
EVERYTHING
0
G02b
Patient did not complete/partially 
complete the preference questionnaire 
at the required visits as per protocol (for 
W4, W24, W28 and W48)
INCLUDE IN 
EVERYTHING
0
G02c
Patient did not complete/partially 
complete the preference questionnaire 
at immediate next visit after unplanned 
treatment switch protocol.
INCLUDE IN 
EVERYTHING
0
G03
Do not have the pill counting 
information for deferasirox FCT
INCLUDE IN 
EVERYTHING
0
G04
Do not have the pill counting 
information for deferasirox DT
INCLUDE IN 
EVERYTHING
0
G05
Non-Compliance with safety/serious 
adverse event (SAE) reporting as per 
protocol.
INCLUDE IN 
EVERYTHING
0
G06
Patient did not completed/partially 
completed the SICT, Palatability, GI 
symptoms questionnaire (for W1, W4, 
W24, W28 and W48)
INCLUDE IN 
EVERYTHING
0
G07
Any protocol deviation identified non 
GCP compliant as per protocol.
INCLUDE IN 
EVERYTHING
0
G08
Missing Lab Parameters for Lab 
Biochemistry at 2 consecutive Visits
INCLUDE IN 
EVERYTHING
0
G09
Missing Lab Parameters for Lab Bio 
chemistry at  Visit 9 or Visit 15
INCLUDE IN 
EVERYTHING
0
G10
Missing Lab Parameters for Lab 
Hematology at 2 consecutive Visits
INCLUDE IN 
EVERYTHING
0
G11
Missing Lab Parameters for Lab 
Hematology at Visit 9 or Visit 15
INCLUDE IN 
EVERYTHING
0
G12
Missing Lab Parameters for Lab 
Urinalysis at 2 consecutive Visits.
INCLUDE IN 
EVERYTHING
0
G13
Missing Lab Parameters for Lab 
urinalysis at Visit 9 or Visit 15
INCLUDE IN 
EVERYTHING
0
G14
Serum pregnancy test not done at Visit 
15 in females of child bearing potential
INCLUDE IN 
EVERYTHING
0
G15
Urine pregnancy test not done at Visit 2 
in females of child bearing potential
INCLUDE IN 
EVERYTHING
0
G16
Full visit is missing.
EXCLUDE FROM PPS
4
G17
The visit has been performed out of 
protocol window.
INCLUDE IN 
EVERYTHING
0


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Deviation 
ID
Description of Deviation
Exclusion in Analyses
Severity 
code
G18
Patient did not complete/partially 
complete the preference questionnaire
at the immediate next visit after 
treatment switch.
INCLUDE IN 
EVERYTHING
0
G19
Hepatitis B or Hepatitis C tests were not 
performed at visit 15
INCLUDE IN 
EVERYTHING
0
G20
Treatment start date is outside the 
window period without an official 
medical interruption.
EXCLUDE FROM PPS
4
G21
Ocular Examination was not performed
INCLUDE IN 
EVERYTHING
0
G22
Audiometric Examination was not 
performed
INCLUDE IN 
EVERYTHING
0
I01a
ICF is not obtained from Subject.
EXCLUDE FROM FAS 
AND SAF
3
I01b
ICF is not obtained from Parent(s) or 
Legal patient(s) representative.
EXCLUDE FROM FAS 
AND SAF
3
I01c
Missing informed consent date for 
Subject.
INCLUDE IN 
EVERYTHING
0
I01d
Missing informed consent date from 
parent(s) or legal patient’s 
representative.
INCLUDE IN
EVERYTHING
0
I02
Subject is < 2 years or age missing
EXCLUDE FROM PPS
4
I03a
Subjects being treated with Deferasirox 
during the 6 months within study 
participation.
EXCLUDE FROM PPS
4
I03b
Subjects being treated with other 
chelators during the 6 months within 
study participation.
EXCLUDE FROM PPS
4
I03c
Subjects being treated with DFP or 
DFO or combination (DFP+DFO) at
least 6 months continuously.
EXCLUDE FROM PPS
4
I04
Subject is not willing to discontinue 
current iron chelation therapy at least 5
days prior to the first day and for the 
duration of the study
EXCLUDE FROM PPS
4
I05
Patients with transfusion-dependent 
thalassemia (independent of underlying 
condition) with transfusional iron 
overload as shown by: a serum ferritin 
level of <=1000 ng/ml at screening and 
if available, LIC <= 3 mg Fe/g dw until 6 
months prior to screening
INCLUDE IN 
EVERYTHING
0


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SAP
CICL670FIC05
Deviation 
ID
Description of Deviation
Exclusion in Analyses
Severity 
code
I06
Patients with non-transfusion-
dependent thalassemia with iron 
overload as shown by: a serum ferritin 
level of < 800 ng/ml at screening and if 
available, LIC < 5 mg Fe/g dw until 6 
months prior to screening
INCLUDE IN 
EVERYTHING
0
I07a
Date informed consent obtained from 
subject after screening procedures
INCLUDE IN 
EVERYTHING
0
I07b
Date informed consent obtained from 
parent(s) or legal patient’s 
representative obtained after screening 
procedures
INCLUDE IN 
EVERYTHING
0
M01
Use of Prohibited medication as per 
protocol section 6.3.2.
EXCLUDE FROM PPS
4
M02
Any investigational drug other than the 
study drug
EXCLUDE FROM PPS
4
S01
Starting dose of deferasirox DT is not 
compliant with Protocol table 6-2.
EXCLUDE FROM PPS
4
S02
Starting dose of deferasirox FCT is not 
compliant with Protocol table 7-3.
EXCLUDE FROM PPS
4
S03
Deferasirox DT and/or FCT is not 
compliant with Protocol table 6-3 based 
on serum ferritin levels.
EXCLUDE FROM PPS
4
S04
Study dose should be adjusted if there 
is a change in body weight (increase or 
decrease) of minimum 10% compare to 
visit 2 or last dose adjustment due to 
change in patient's body weight.
EXCLUDE FROM PPS
4
S05
Patient in period 1 of Core phase 
received Deferasirox FCT by error 
(except patients who switched from 
Deferasirox DT to Deferasirox FCT)
EXCLUDE FROM FAS 
1
S06
Patient in period 2 of Core phase or 
extension phase took Deferasirox DT
by error (except patients who switched 
from Deferasirox FCT to Deferasirox 
DT).
EXCLUDE FROM FAS 
1
S07a
Patient re-switched treatment within the 
same period of the study (that is, 
patient switched from Deferasirox DT to 
Deferasirox FCT and the switch back to 
Deferasirox DT)
EXCLUDE FROM FAS
1
S07b
Patient re-switched treatment within the 
same period of the study (that is, 
patient switched from Deferasirox FCT 
to Deferasirox DT, and then back to 
Deferasirox FCT)  
EXCLUDE FROM FAS
1


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SAP
CICL670FIC05
Deviation 
ID
Description of Deviation
Exclusion in Analyses
Severity 
code
S08
Iron chelation pre-treated patient who is 
well-managed on treatment with 
deferoxamine DFO/deferiprone DFP or 
combination of DFO+DFP did not 
receive the equivalent deferasirox 
DT/FCT dose per app. 14.1
EXCLUDE FROM PPS 
4
S09
Dose adjustment (based on Serum 
ferritin levels and investigator's 
judgement) in ICT naïve patients done 
before 4 weeks of study treatment and 
it was not performed for safety reasons
EXCLUDE FROM PPS
4
S10
Dose adjustment (based on Serum 
ferritin levels and investigator's 
judgement ) ICT pre-treated patients 
done before 3 months of study 
treatment and it was not performed for 
safety reasons
EXCLUDE FROM PPS
4
S11
The dose adjustment in deferasirox DT 
not performed in increments of 5-10 
mg/kg/day
INCLUDE IN 
EVERYTHING
0
S12
The dose adjustment in deferasirox 
FCT not performed in increments of 
3.5-7 mg/kg/day
INCLUDE IN 
EVERYTHING
0
S13
Deferasirox dose was not temporarily 
interrupted despite urinary 
protein/creatinine ratio increases to > 
1.0 (mg/mg) in two consecutive second-
void urine samples (a minimum of 48h 
apart)
INCLUDE IN 
EVERYTHING
0
S14
Deferasirox dose was not temporarily 
interrupted even though the skin rash 
persists for > 1 week or becomes more 
severe
INCLUDE IN 
EVERYTHING
0
S15
Maximum dose of deferasirox DT is not 
compliant with Protocol table 6-2.
EXCLUDE FROM PPS
4
S16
Maximum dose of deferasirox FCT is 
not compliant with Protocol table 6-2.
EXCLUDE FROM PPS
4
S17
Dose adjustment of deferasirox DT is 
not compliant with Protocol table 6-2.
EXCLUDE FROM PPS
4
S18
Dose adjustment of deferasirox FCT is 
not compliant with Protocol table 6-2.
EXCLUDE FROM PPS
4
S19
Patient received incorrect dose due to 
dispensing error.
Include in Everything
0
S20
Cautious re-initiation of Deferasirox 
treatment at a lower dose was not done 
following Study medication interruption 
due to Increased liver enzyme levels 
(ALT/AST).
Include in Everything
0


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Page 43
SAP
CICL670FIC05
Deviation 
ID
Description of Deviation
Exclusion in Analyses
Severity 
code
S21
Deferasirox dose reduction by 10 
mg/kg/day for the DT formulation and 
by 7 mg/kg/day for the FCT formulation 
was not performed following a rise in 
serum creatinine by 33% above 
baseline value resulting in a serum 
creatinine above the ULN on two 
consecutive visits (a minimum of 7 days 
apart)
Include in Everything
0
S22
Resuming study medication dose is not 
done according to protocol following 
treatment interruption for abnormal 
Serum Creatinine.
Include in Everything
0
Table 2
Analysis set exclusions based on population codes
Analysis set 
Population codes that cause a subject to be 
excluded
RAN 
NA
SAF 
2, 3, 6
FAS 
1, 3
PPS
4, 6
Table 3
Population code text
Population Code
Population code text
0
INCLUDE IN EVERYTHING
1
EXCLUDE FROM FULL ANALYSIS SET (FAS)
2
EXCLUDE FROM SAFETY SET (SAF)
3
EXCLUDE FROM FAS AND SAF
4
EXCLUDE FROM PER-PROTOCOL SET (PPS)
6
EXCLUDE FROM SAF AND PPS
Unless otherwise stated, summary tables, figures and listings will be on all subjects included in 
the analysis set under consideration.
6
Reference
1. Study protocol: Oncology study protocol CICL670FIC05.
2. Taher AT, Origa R, Perrotta S et al (2018) Patient-reported outcomes from a randomized 
phase II study of the deferasirox film-coated tablet in patients with transfusion-
dependent anemias. Health Qual Life Out; 16:216.