Conditions: Transfusion-dependent Anemia
Keywords: New formulation deferasirox chelation iron overload compliance satisfaction palatability PRO PK safety PK/PD ICL670
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 224
Healthy volunteers: no

Brief summary:
This was a randomized, open-label, multicenter, two arm, phase II study to evaluate treatment compliance and change in serum ferritin of a deferasirox granule formulation and a deferasirox dispersible tablet (DT) formulation in children and adolescents aged ≥ 2 and \< 18 years at enrolment with any transfusion-dependent anemia requiring chelation therapy due to iron overload, to demonstrate the effect of improved compliance on iron burden.

Randomization was stratified by age groups (2 to \<10 years, 10 to \<18 years) and prior iron chelation therapy (Yes/ No). There were two study phases which include a 1 year core phase where participants were randomized to a 48 week treatment period to either Deferasirox DT or granules, and an optional extension phase where all participants received the granules up to 5 years. Participants who demonstrated benefit to granules or DT in the core phase, and/or expressed the wish to continue in the optional extension phase on granules, were offered this possibility until there was local access to the new formulation (granules or film-coated tablet (FCT)) or up to 5 years, whichever occurred first.

Detailed description:

Arms:
arm 1: Participants will be administered deferasirox dispersible tablets orally once daily based on body weight for 48 weeks. arm 2: Participants will be administered deferasirox granules orally once daily in the form of stick packs based on body weight for 48 weeks.

Interventions: intervention 1: Deferasirox granule formulation intervention 2: Deferasirox DT formulation
Intervention descriptions: intervention 1: Deferasirox granules will be provided as stick packs containing 90 mg, 180 mg and 360 mg granules for oral use and will be administered based on body weight. intervention 2: Deferasirox DT will be provided as 125 mg, 250 mg and 500 mg dispersible tablets for oral use and will be administered based on body weight.

Protocol document:
Prot_000.pdf: 
Novartis Research and Development
ICL670, deferasirox 
Protocol CICL670F2202 / NCT02435212
A randomized, open-label, multicenter, two arm, phase II 
study to evaluate treatment compliance, efficacy and safety 
of an improved deferasirox formulation (granules) in 
pediatric patients with iron overload
Document type:
Amended Protocol Version
EUDRACT number:
2013-004739-55
Version number:
06 (Clean) 
Development 
phase:
II
Document status:
Final
Release date:
24-Jun-2021
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis


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Table of contents
Table of contents .................................................................................................................2
List of figures ......................................................................................................................5
List of tables ........................................................................................................................5
List of abbreviations............................................................................................................7
Glossary of terms.................................................................................................................9
Protocol summary:.............................................................................................................10
Amendment 6 (24-Jun-2021) ............................................................................................17
Amendment 5 (06-Dec-2017)............................................................................................20
Amendment 4 (15-Jun-2017) ............................................................................................23
Amendment 3 (24-Aug-2016)...........................................................................................26
Amendment 2 (15-Jun-2016) ............................................................................................29
Amendment 1 (01-Dec-2015)............................................................................................30
1
Background........................................................................................................................37
1.1
Overview of disease pathogenesis, epidemiology and current treatment..............37
1.1.1
Overview of beta-thalassemia...............................................................37
1.1.2
Overview of sickle cell disease.............................................................38
1.2
Introduction to investigational treatment(s) and other study treatment(s).............38
1.2.1
Overview of deferasirox dispersible tablet ...........................................38
1.2.2
Overview of deferasirox granules .........................................................39
2
Rationale............................................................................................................................39
2.1
Study rationale and purpose...................................................................................39
2.2
Rationale for the study design ...............................................................................41
2.3
Rationale for dose and regimen selection..............................................................43
3
Objectives and endpoints...................................................................................................43
4
Study design ......................................................................................................................46
4.1
Description of study design ...................................................................................46
4.2
Timing of interim analyses and design adaptations...............................................48
4.3
Definition of end of the study................................................................................48
4.4
Early study termination..........................................................................................48
4.5
Rationale for Public Health Emergency mitigation procedures ............................48
5
Population..........................................................................................................................48
5.1
Patient population..................................................................................................48
5.2
Inclusion criteria ....................................................................................................49
5.3
Exclusion criteria...................................................................................................49
6
Treatment...........................................................................................................................50


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6.1
Study treatment......................................................................................................50
6.1.1
Dosing regimen.....................................................................................50
6.1.2
Treatment duration................................................................................53
6.2
Dose modifications................................................................................................53
6.2.1
Permitted study drug adjustments.........................................................53
6.2.2
Treatment interruption and treatment discontinuation..........................61
6.2.3
Follow-up for toxicities.........................................................................61
6.2.4
Follow up on potential drug-induced liver injury (DILI) cases ............61
6.2.5
Anticipated risks and safety concerns of the study drug.......................62
6.3
Prior and Concomitant medications.......................................................................63
6.3.1
Permitted concomitant therapy requiring caution and/or action...........63
6.3.2
Prohibited concomitant therapy ............................................................64
6.4
Patient numbering, treatment assignment or randomization .................................64
6.4.1
Patient numbering .................................................................................64
6.4.2
Treatment assignment or randomization...............................................64
6.4.3
Treatment blinding................................................................................65
6.5
Study drug preparation and dispensation...............................................................65
6.5.1
Study drug packaging and labeling.......................................................65
6.5.2
Drug supply and storage........................................................................66
6.5.3
Study drug compliance and accountability ...........................................66
6.5.4
Disposal and destruction .......................................................................66
7
Visit schedule and assessments .........................................................................................66
7.1
Study flow and visit schedule................................................................................66
7.1.1
Screening...............................................................................................78
7.1.2
Treatment period...................................................................................79
7.1.3
Discontinuation of study treatment .......................................................80
7.1.4
Withdrawal of consent ..........................................................................81
7.1.5
Follow up period ...................................................................................81
7.2
Assessment types...................................................................................................81
7.2.1
Compliance with prescribed treatment..................................................81
7.2.2
Serum Ferritin .......................................................................................81
7.2.3
Patient / Observer Reported Outcomes.................................................82
7.2.4
Safety and tolerability assessments.......................................................83
7.2.5
Pharmacokinetics ..................................................................................89
7.2.6
Resource utilization...............................................................................91
8
Safety monitoring and reporting........................................................................................91


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8.1
Adverse events.......................................................................................................91
8.1.1
Definitions and reporting ......................................................................91
8.1.2
Laboratory test abnormalities................................................................93
8.2
Serious adverse events...........................................................................................93
8.2.1
Definitions.............................................................................................93
8.2.2
Reporting...............................................................................................94
8.3
Emergency unblinding of treatment assignment ...................................................94
8.4
Pregnancies............................................................................................................95
8.5
Warnings and precautions......................................................................................95
8.6
Data Monitoring Committee..................................................................................95
8.7
Steering Committee ...............................................................................................95
9
Data collection and management.......................................................................................96
9.1
Data confidentiality ...............................................................................................96
9.2
Site monitoring ......................................................................................................96
9.3
Data collection.......................................................................................................97
9.4
Database management and quality control............................................................97
10 Statistical methods and data analysis ................................................................................98
10.1
Analysis sets ..........................................................................................................98
10.1.1
Full Analysis Set ...................................................................................98
10.1.2
Safety Set ..............................................................................................98
10.1.3
Per protocol Set.....................................................................................99
10.1.4
Pharmacokinetic Analysis Set...............................................................99
10.2
Patient demographics/other baseline characteristics .............................................99
10.3
Treatments (duration of exposure, concomitant therapies, percentage of 
planned dose taken) .............................................................................................100
10.4
Primary objective.................................................................................................100
10.4.1
Variables and analysis set ...................................................................100
10.4.2
Statistical method of analysis..............................................................101
10.4.3
Handling of missing values/discontinuations......................................102
10.4.4
Supportive analyses.............................................................................102
10.5
Secondary objectives ...........................................................................................102
10.5.1
To evaluate both formulations on change in serum ferritin and 
compliance measured by stick pack /tablet count after 48 weeks of 
treatment in ICT naïve patients...........................................................102
10.5.2
To evaluate both formulations on change in serum ferritin in ICT 
naïve and pre-treated patients..............................................................102


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10.5.3
To evaluate both formulations on patient satisfaction and 
palatability using PRO/ObsRO questionnaires ...................................103
10.5.4
To evaluate both formulations on overall safety, measured by 
frequency and severity of adverse events and changes in laboratory 
values...................................................................................................103
10.5.5
To evaluate compliance using a daily PRO/ObsRO questionnaire.....105
10.5.6
Pharmacokinetics ................................................................................105
10.6
Other analyses......................................................................................................106
10.6.1
Other safety data .................................................................................106
10.7
Interim analysis....................................................................................................108
10.8
Sample size calculation........................................................................................108
11 Ethical considerations and administrative procedures ....................................................110
11.1
Regulatory and ethical compliance......................................................................110
11.2
Responsibilities of the investigator and IRB/IEC/REB.......................................110
11.3
Informed consent procedures...............................................................................110
11.4
Discontinuation of the study................................................................................111
11.5
Publication of study protocol and results.............................................................111
11.6
Study documentation, record keeping and retention of documents.....................111
11.7
Confidentiality of study documents and patient records .....................................112
11.8
Audits and inspections.........................................................................................112
11.9
Financial disclosures............................................................................................112
12 Protocol adherence ..........................................................................................................112
12.1
Amendments to the protocol................................................................................112
13 References (available upon request)................................................................................113
14 Appendices ......................................................................................................................115
14.1
Equivalent dose guidance ....................................................................................115
14.2
Dosing tables (Deferasirox DT, Deferasirox granules).......................................118
List of figures
Figure 4-1
Study schema ........................................................................................47
List of tables
Table 3-1
Objectives and related endpoints ..........................................................44
Table 6-1
Dose and treatment schedule.................................................................52
Table 6-2
Criteria for interruption and re-initiation of Deferasirox treatment......54
Table 7-1
Visit evaluation schedule ......................................................................68


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Table 7-2
Visit evaluation schedule (for the optional extension phase)................74
Table 7-3
Central Imaging Assessments Collection Plan .....................................85
Table 7-4
Central Clinical laboratory parameters collection plan, [Egypt: 
Local Laboratory]..................................................................................86
Table 7-5
PK blood collection log (all patients)....................................................90
Table 7-6
PK sample labels...................................................................................91
Table 10-1
Definition of notable/extended ranges for laboratory tests.................105
Table 10-2
Definition of notable ranges for pulse rate and weight.......................107
Table 10-3
Precision in the estimate of the serum ferritin change ........................109
Table 14-1
Patients pre-treated with deferasirox...................................................115
Table 14-2
Patients pre-treated with deferoxamine...............................................115
Table 14-3
Examples of light meal........................................................................116
Table 14-4
Dosing table for deferasirox DT .........................................................119
Table 14-5
Dosing table for deferasirox granules .................................................121


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List of abbreviations
AE
Adverse Event
AESI
Adverse Events of Special Interest
ALP
Alkaline Phosphatase
ALT
Alanine aminotransferase/glutamic pyruvic transaminase/GPT
AST
Aspartate aminotransferase/glutamic oxaloacetic transaminase/GOT
AUC
Area Under Curve
AV
Atrioventricular 
CMV
Cytomegalovirus
CRF
Case Report/Record Form; the term CRF can be applied to either EDC or Paper
CRO
Contract Research Organization
COVID-19
Coronavirus disease 2019
CSR
Clinical study report
CV
Coefficient of Variation
DAR
Dose Administration Record
DFO
Deferoxamine
DS&E
Drug Safety and Epidemiology
DT
Dispersible Tablet
EBV
Epstein-Barr Virus
ECG
Electrocardiogram
eCRS
Electronic Case Retrieval Strategy
ELISA
Enzyme-Linked Immunosorbent Assay
EOT
End Of Treatment
FAS
Full Analysis Set
FCT
Film-coated tablet
GCP
Good Clinical Practice
GGT
Gamma-glutamyl transferase
GI 
Gastrointestinal
HCV
Hepatitis C Virus
HDL
High Density Lipoprotein
HIV
Human Immunodeficiency Virus
HSV
Herpes Simplex Virus
IA
Interim Analysis
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Council for Harmonization
ICT
Iron chelation therapy
IEC
Independent Ethics Committee
IMP
Investigational Medicinal Product
INR
International Normalized Ratio
IRB
Institutional Review Board
IRT
Interactive Response Technology that includes Interactive Voice Response System (IVRS) and 
Interactive Web Response System (IWRS)
LDH
Lactate Dehydrogenase
LDL
Low Density Lipoprotein
LFTs
Liver Function Tests
MCH
Mean cell Hemoglobin


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MCHC
Mean cell Hemoglobin Concentration
MCV
Mean cell Volume
NSAIDs
Nonsteroidal Anti-Inflammatory Drugs
ObsRO
Observer Reported Outcomes
p.o.
per os/by mouth/orally
PAS
Pharmacokinetics Analysis Set
PD
Pharmacodynamic
PHI
Protected Health Information
PK
Pharmacokinetics
PPS
Per Protocol Set
PRBC
Pack Red Blood Cells
PRO
Patient Reported Outcome
RBC
Red Blood Cell
REB
Research Ethics Board
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SCD
Sickle Cell Disease
SD
Standard Deviation
SICT
Satisfaction Iron Chelation Therapy
SJS
Stevens-Johnson syndrome
SOC
System Organ Class
TBIL
Total Bilirubin
ULN
Upper Limit of Normal range
UPCR
Urine Protein Creatinine Ratio
WBC
White Blood Cells
WHO ATC
Anatomical Therapeutic Chemical classification system


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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
New formulation
Granules or film-coated tablets (FCT) – both are of the same qualitative and 
quantitative composition, using the same active ingredients at the same doses, and 
the same excipients (with exception of the film-coating ingredients only used in the 
FCT). In the context of this study, the new formulation is provided by means of 
Granules.
Patient Number
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.
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.
Randomization number
A unique treatment identification code assigned to each randomized patient, 
corresponding to a specific treatment arm assignment
Stage related to study 
timeline
A major subdivision of the study timeline; begins and ends with major study 
milestones such as enrollment, randomization, completion of treatment, etc.
Stick pack 
Aluminum foil pouches, or sachets used to package the deferasirox granules.
Stop study participation
Point/time at which the patient came in for a final evaluation visit or when study 
treatment was discontinued whichever is later
Study treatment
Includes any drug or combination of drugs in any study arm administered to the 
patient as part of the required study procedures, including placebo and active drug 
run-ins.
Study treatment 
discontinuation
Point/time when patient permanently stops taking study treatment for any reason; 
may or may not also be the point/time of premature patient withdrawal
Treatment group
A treatment group defines the dose and regimen or the combination, and may 
consist of 1 or more cohorts. Cohorts are not expanded, new cohorts are enrolled.
Variable
Identifier used in the data analysis; derived directly or indirectly from data collected 
using specified assessments at specified time points


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Protocol summary:
Protocol number
CICL670F2202
Title
A randomized, open-label, multicenter, two arm, phase II study to evaluate 
treatment compliance, efficacy and safety of an improved deferasirox formulation 
(granules) in pediatric patients with iron overload
Brief title
Study to evaluate treatment compliance, efficacy and safety of an improved 
deferasirox formulation (granules) in pediatric patients (2-<18 years old) with iron 
overload
Sponsor and
Clinical Phase
Novartis
Phase II
Investigation type
Drug
Study type
Interventional
Purpose and rationale
The purpose of the present study is to:

assess the compliance of the granule and the dispersible tablet (DT) 
formulations in pediatric patients with iron overload over 24 weeks and 48 
weeks of treatment, using stick pack/tablet count and pre-dose 
pharmacokinetic (PK) concentrations and a PRO questionnaire.

assess the clinical benefit due to improved compliance of the new formulation 
by measurements of serum ferritin levels for both formulations, after 24 and 
48 weeks of treatment.

assess Patient / Observer Reported Outcomes (PRO/ObsRO) on palatability 
and treatment satisfaction

assess the safety of both formulations

examine the pre- and post-dose concentrations of both formulations using 
sparse PK sampling

explore exposure-response (PK/PD) relationships for measures of safety and 
effectiveness

assess long term safety of granules formulation via an optional extension 
phase consisting of up to 5 years for those who complete 48 weeks of core 
treatment phase and choose to continue in the extension phase
Primary Objective(s)
To evaluate patient compliance (using stick pack or tablet counts) and change in 
serum ferritin over time for both formulations of deferasirox, i.e., granules and 
dispersible tablet (DT) in iron chelation therapy (ICT) naïve patients in the first 24 
weeks of treatment during the core phase.
Secondary Objectives

To evaluate both formulations on patient compliance (using stick pack or 
tablet counts) and change in serum ferritin in ICT naïve patients, after 48 
weeks of treatment

To evaluate both formulations on change in serum ferritin in ICT naïve and 
pretreated patients, after 24 weeks and 48 weeks of treatment

To evaluate both formulations on patient satisfaction and palatability using 
PRO/ObsRO questionnaires

To evaluate both formulations on overall safety

To evaluate compliance using a daily PRO/ObsRO questionnaire

To evaluate pre-dose PK data to support the assessment of compliance

To obtain pre- and post-dose concentrations to explore exposure-response 
relationships

To assess long-term safety of the granules formulation during the optional 
extension phase for patients who choose to continue


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Study design
This is a randomized, open-label, multicenter, two arm, phase II study to 
evaluate treatment compliance and change in serum ferritin of a deferasirox 
granule formulation and a deferasirox DT formulation in children and adolescents 
aged ≥ 2 and < 18 years at enrollment with any transfusion-dependent anemia 
requiring chelation therapy due to iron overload, to demonstrate the effect of 
improved compliance on iron burden. Randomization will be stratified by age 
groups (2 to <10 years, 10 to <18 years) and prior iron chelation therapy (Yes/ 
No). There will be two study phases which include a 1 year core phase where 
patients will be randomized to a 48 week treatment period to either Deferasirox 
DT or granules, and an optional extension phase where all patients will receive 
the granules up to 5 years from entering extension phase. Patients who 
demonstrated benefit to granules or DT in the core phase, and/or express the 
wish to continue in the optional extension phase on granules, will be offered this 
possibility until there is local access to the new formulation (granules or FCT) or 
up to 5 years from entering extension phase, whichever occurs first. 
One interim analysis has been added to allow for early analysis of the core 
phase data if requested by the health authority.  All patients randomized in the 
study and who have completed a minimum of 12 weeks of treatment exposure or 
discontinued from treatment core phase at the time of the cutoff date will be 
included in the interim analysis.
Population
Up to 216 naïve and pre-treated (96 ICT naïve and up to 120 pre-treated ) male 
and female children and adolescents aged ≥ 2 and < 18 years at enrollment with 
any transfusion-dependent anemia requiring chelation therapy due to iron 
overload, and a treatment goal to reduce iron burden will be included in this 
study. At least 96 (48 per treatment arm) patients should be iron chelation naïve.
The optional extension phase will give the patients who have participated and 
completed the 48 weeks core treatment phase as per protocol, the possibility to 
extend treatment with granules for a maximum of 5 years after completing the 
core treatment phase or until there is local access to new formulation (granules 
or FCT), whichever occurs first. All patients who choose to continue in the 
extension phase will receive granules during the optional extension phase.
There will be two study phases which include a 1 year core phase where 
patients will be randomized to a 48 week treatment period to either Deferasirox 
DT or granules, and an optional extension phase where all patients will receive 
the granules up to 5 years from entering extension phase. Patients who 
demonstrated benefit to granules or DT in the core phase, and/or express the 
wish to continue in the optional extension phase on granules, will be offered this 
possibility until there is local access to the new formulation (granules or FCT) or 
up to 5 years from entering extension phase, whichever occurs first.
Inclusion criteria

Written informed consent/assent before any study-specific procedures. 
Consent will be obtained from patients, parent(s) or legal guardians. 
Investigators will also obtain consent/assent of patients according to local 
guidelines.

Male and female children and adolescents aged ≥ 2 and < 18 years.* 
[France: Male and female children and adolescents aged ≥ 2 and < 18 
years, however children aged ≥ 2 and ≤ 6 years can be enrolled only when 
deferoxamine treatment is contraindicated or inadequate in these patients 
as per investigator decision] *Applicable to core phase only. Once in the 
core phase patients can turn 18 years and still be considered eligible, also 
for participation in the optional extension phase.

Any transfusion-dependent anemia associated with iron overload requiring 
iron chelation therapy and with a history of transfusion of approximately 20 
PRBC units, and a treatment goal of reduction, not maintenance of iron 
burden as measured by serum ferritin.

Serum ferritin > 1000 ng/mL, measured at screening Visit 1 and screening 
Visit 2 (the mean value will be used for eligibility criteria).


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
Completion of core phase per protocol (For the optional extension phase 
criteria only).
Exclusion criteria

Creatinine clearance below the contraindication limit in the locally approved 
prescribing information.  Creatinine clearance will be estimated from serum 
creatinine (using the Schwartz formula) at screening Visit 1 or screening 
Visit 2.

Serum creatinine > 1.5 xULN at screening Visit 1 or screening Visit 2. 

ALT or AST >3.0 x ULN at screening visit 1 or screening visit 2.

Direct (conjugated) bilirubin >2 x ULN at screening visit 1 or screening visit 2.

(Criterion no longer applicable, removed as part of Amendment 1): Prior iron 
chelation therapy

Liver disease with severity of Child-Pugh class B or C.

Significant proteinuria as indicated by a urinary protein/creatinine ratio >0.5 
mg/mg in a second morning urine sample at screening Visit 1 or screening 
Visit 2.

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 or Hepatitis C (HBsAg in 
the absence of HBsAb OR HCV Ab positive with HCV RNA positive).

Patients with psychiatric or addictive disorders which prevent them from 
giving their informed consent/assent or undergoing any of the treatment 
options or patients unwilling or unable to comply with the protocol (including 
use of electronic devices for ePRO).

Local access to new formulation (granules or FCT) is available for the patient 
(For the optional extension phase criteria only).
Investigational and 
reference therapy

Patients will be randomized to either Deferasirox granules or Deferasirox DT 
(Exjade) in the core phase.

All patients who choose to continue in the extension phase will receive 
deferasirox granules in the extension phase.
Efficacy assessments
The co-primary efficacy endpoints assessed during the core phase will be:

Compliance measured by stick pack/tablet count over 24 weeks of treatment 
(i.e. assessed at week 25 visit).

Change from baseline in serum ferritin after 24 weeks of treatment (i.e. 
Serum Ferritin at week 25 visit).
Primary endpoint 
assessments

Compliance will be measured by stick pack/tablet count over 24 weeks of 
treatment (i.e. assessed at week 25 visit): it will be performed by study 
personnel every 4 weeks (weeks 5, 9, 13, 17, 21, 25 and End of Treatment 
(EOT) (core)/777 visits) during the core phase based on the amount of 
medication dispensed, returned and reported as lost/wasted by the patient / 
caregiver

Serum ferritin test will be performed at Screening Visits 1 and 2 and every 4 
weeks from week 5 till after 24 weeks of treatment (i.e. assessed at week 25 
visit)..
Secondary endpoint 
assessments
Core phase:

Compliance will be measured by stick pack/tablet count over 48 weeks of 
treatment: it will be performed by study personnel every 4 weeks (weeks 5, 
9, 13, 17, 21, 25 29, 33, 37, 41, 45, and EOT(core)/777 visits) during the 
core phase based on the amount of medication dispensed, returned and 
reported as lost/wasted by the patient / caregiver

Serum ferritin test will be performed at Screening Visits 1 and 2 and every 4 
weeks from week 5 till end of treatment visit.


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
The study will include the use of a Satisfaction with Iron Chelation Therapy 
questionnaire, a Palatability questionnaire and a compliance diary to 
evaluate both formulations on these patient / observer reported outcomes.

Safety will be monitored by assessing the following parameters:

Hematology, chemistry (including renal and hepatic parameters), urinalysis

Adverse events; including renal toxicity (including renal failure), hepatic 
toxicity (including hepatic failure) and gastrointestinal hemorrhage, which 
will be actively monitored until symptom resolution or until the condition 
stabilizes

Vital signs

Physical examinations

Ocular examinations

Auditory examinations

Cardiac examinations (ECG and echocardiogram)

Growth parameters and development parameters

Deferasirox concentrations will be measured in plasma at predefined time 
points on all patients. [Egypt: PK samples will not be collected due to 
restriction on sample exportation]

Pharmacokinetic samples collected by sparse PK sampling in all patients 
[Egypt: PK samples will not be collected] will be analyzed using modeling 
approaches to explore PK/PD (safety and efficacy) relationships.
Optional Extension phase:

Long term safety of granules in the optional extension phase:

Overall safety, as measured by frequency and severity of adverse events
(including active monitoring for renal toxicity; including renal failure, hepatic 
toxicity; including hepatic failure, and gastrointestinal hemorrhage), and 
changes in laboratory values from baseline (serum creatinine, creatinine 
clearance, ALT, AST, RBC and WBC). In addition, vital signs, physical,
ophthalmological, audiometric, and growth and development evaluations will 
be assessed.
Other assessments
Daily questionnaire on study treatment compliance completed through core 
phase only.
Data analysis
Analysis sets:
The Full Analysis Set 1 (FAS-1) comprises all ICT naïve patients to whom study 
treatment has been assigned by randomization. The Full Analysis Set 2 (FAS-2) 
comprises all ICT pre-treated patients to whom study treatment has been 
assigned by randomization. The Full Analysis Set 3 (FAS-3) comprises all ICT 
pre-treated and naïve patients to whom study treatment has been assigned by 
randomization. According to the intent to treat principle, patients will be analyzed 
according to the treatment and stratification factors they have been assigned to 
during the randomization procedure.
The Safety Set 1 includes all ICT naïve patients who received at least one dose 
of study medication. The Safety Set 2 includes all ICT pre-treated patients who 
received at least one dose of study medication. The Safety Set 3 includes all ICT 
pre-treated and naïve patients who received at least one dose of study 
medication. The Safety Set 4 will consist of all patients who received at least one 
dose of granules formulation during the core or extension phase. Patients will be 
analyzed according to the study treatment they actually received.
The Per Protocol Set consists of all ICT naïve patients from the FAS-1 without 
any major protocol deviation.
The major protocol deviations that will lead to exclusion of patients from the PPS 
will be detailed in the Statistical Analysis Plan (SAP).
The Pharmacokinetic Analysis Set (PAS) consists of all patients who have at 


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least one evaluable pre or post-dose PK concentration (deferasirox). More 
details are provided in Section 10.1.4.
Statistical Analyses:
Primary efficacy endpoints: All analyses for the primary objective will be 
performed based on core period and on the FAS-1 and presented by treatment 
group: deferasirox DT and deferasirox granule formulation. The co-primary 
efficacy variables are:

Compliance measured by stick pack /tablet count based on amount of 
medication dispensed, returned and reported as lost/wasted by the patient 
or caregiver over 24 weeks of treatment (i.e. assessed at week 25 visit). 
Compliance will be calculated 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 over 24 weeks of treatment (i.e. assessed at week 25 
visit);

total count prescribed is cumulative prescribed count over 24 weeks of 
treatment (i.e. assessed at week 25 visit).

Change from baseline in serum ferritin after 24 weeks of treatment (i.e. 
serum ferritin assessment at week 25 visit).
The primary efficacy analysis will be the comparison of means between the two 
treatment arms of change from baseline after 24 weeks of treatment in SF and 
mean relative consumed stick pack /tablet count over 24 weeks of treatment.
Analysis of covariance (ANCOVA) will be performed for comparison between 
treatment groups at a one-sided 5% level of significance. The ANCOVA model 
for compliance endpoint will include treatment group and age group (2 to<10 
years, 10 to <18 years), as factors. The model for serum ferritin endpoint will 
also include the serum ferritin value at baseline as covariate.
The trial will be claimed successful if the superiority of granule formulation 
relative to DT formulation could be demonstrated with regard to both endpoints. 
Therefore, no adjustment of the type I error (alpha) is required.
Sample size calculation: The primary objective is to evaluate patient 
compliance (using stick packs or tablets counts) and change in serum ferritin 
(SF) over time for both formulations of deferasirox in pediatric ICT naïve patients 
with iron overload after 24 weeks of treatment.
The sample size was calculated to show superiority of the granule formulation 
relative to DT formulation with regard to both co-primary endpoints.
The assumptions made for this study were as follows:

For serum ferritin:
An expected improvement between both formulations in SF change from 
baseline after 24 weeks of treatment of −450 ng/mL with a standard deviation 
(SD) of 900 ng/mL based on results from study CICL670A0107 in pediatric 
patients treated with Exjade on ≥25 mg/kg/day after 24 weeks of treatment.

For compliance over 24 weeks of treatment using stick packs or tablets 
counts:
An expected improvement between both formulations in mean relative 
consumed tablet count of 10% with a SD equal to 17.625% based on the pooled 
analysis on pediatric patients (77) from Exjade studies [ICL670A2206] (39), 
[ICL670A2204] (24) and [ICL670A2214] (14).
The sample size driven by the calculation for serum ferritin, has been determined 
to obtain 76% power at one-sided 5% level of significance for showing 
superiority of granule formulation over DT formulation with respect to change 
from baseline after 24 weeks of treatment in serum ferritin, assuming a dropout 
rate of 5%.
A sample size of 48 in each group will have 76% power to detect a difference in 
means of 400.0 ng/mL assuming that the common SD is 800.0 ng/mL using a 


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two group t-test with a 0.050 one-sided significance level. With 48 patients per 
arm, the power to detect a 10% difference in mean compliance is about 84%.
In addition, the clinical trial will enroll patients previously treated with iron 
chelation. Considering that a direct comparison of granule and DT formulations 
in terms of efficacy is not foreseen in previously chelated patients, the required 
sample size is not based on power calculations as usual. The selection of 
number of patients is based on the precision in the estimate of SF change at 48 
weeks of treatment and on practical considerations.
A maximum of 120 patients (60 patients will be in each formulation group) 
previously chelated patients will be enrolled. Sixty patients will provide an 
estimate of SF change with precision (half-width of 95% confidence interval) 
equal to 303.6.
The table below lists the precisions in the estimates of SF change for different 
numbers of patients using the estimated SD obtained from the CICL670A0107 
study results in pediatric patients treated with Exjade on ≥25 mg/kg/day at week 
48 of treatment.
Precision in the estimate of the serum ferritin change
Number of 
patients
Half-width of 95% confidence interval in the estimate 
of the SF change
40
371.8
45
350.6
50
332.6
55
317.1
60
303.6
The total required sample size for this clinical trial is up to 108 patients for each 
treatment group (up to 216 patients in total), including 48 iron chelation naive 
patients per group (96 patients in total).
Safety: The assessment of safety will be based mainly on the frequency and 
severity of AEs and changes in laboratory values. Other safety data (e.g., ECGs, 
vital signs, echocardiogram, ocular, auditory examinations) will also be 
summarized. For all safety analyses, the safety set will be used.
Pharmacokinetics:
Pre- and post-dose concentrations will be summarized descriptively and 
graphically presented.
The analyses will be based on the PAS.
To explore PKPD relationship:
Serum ferritin change from baseline will be fitted by a linear mixed effect model 
with log- transformed matching pre-dose concentrations as covariates and 
subject as random effect.
Serum creatinine change from baseline, serum creatinine clearance change from 
baseline and urine protein creatinine ratio change from baseline will be fitted by 
a linear mixed effect model with log-transformed matching pre-dose 
concentrations and post-dose concentrations respectively as covariates and 
subject as random effect.  Incidence of notable serum creatinine events will be 
analyzed by a logistic regression fitted by GEE methods as appropriate including 
matching log-transformed pre-dose concentrations and post-dose concentrations 
respectively.
Incidence of notable serum creatinine clearance events will be analyzed by a 
logistic regression fitted by GEE methods as appropriate including matching log-
transformed pre-dose concentrations post-dose concentrations respectively.
For all statistical models other covariates such as demographic characteristics 
may be included if appropriate.
All analyses will be based on the Safety Set or FAS of the core phase. 


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Interim analysis:
All the analyses included in the interim analysis will be descriptive. Testing of 
hypotheses will not be performed and no decisions regarding the future course 
of the trial is anticipated at the time of the IA and the trial will continue. Therefore 
adjustment for multiplicity is not performed. Descriptive statistics will be provided 
by treatment arm on the primary endpoints (i.e. change from baseline in serum 
ferritin and compliance measured by stick pack /tablet count) and key safety 
data.
Key words
New formulation, deferasirox, chelation, iron overload, compliance, satisfaction, 
palatability, PRO, PK, safety, PK/PD


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Amendment 6 (24-Jun-2021) 
Amendment rationale 
As of 24-Jun-2021, 67 patients are ongoing in the extension phase of the study. All patients had
completed the Core phase of the study by 18-Dec-2018. The primary analysis for this study was 
completed on 07-Dec-2018 (data cut-off date 31-May-2018). 
The main purpose of this amendment is to introduce the requirement for central collection and 
assessment of photographs from ocular examinations (lens photographs and wide angle fundus 
photographs) collected during the study by a Novartis designated imaging Contract Research 
Organization (CRO). This change is in response to a Health Authority request to submit 
CALYPSO ophthalmic data (for up to 2 years of follow up) to support the ocular safety 
evaluation of deferasirox. 
Clarification was also added to state that for patients who need correction, the best corrected 
visual acuity should be tested when performing the distance visual acuity test and that the 
corrected visual acuity should be documented in the source records.
In addition, mitigation procedures have been implemented throughout the protocol to ensure 
participant safety and trial integrity during a Public Health emergency, as declared by Local or 
Regional authorities i.e. pandemic, epidemic or natural disaster. 
Finally, assessment of the study Risk/Benefit in light of the ongoing coronavirus disease 2019 
(COVID-19) pandemic at the time of this protocol amendment concluded that there are no 
additional risks related to COVID-19 for this study. Patient with cytopenias are more 
susceptible to infections in general, compared to patients without cytopenias. There have been 
postmarketing reports of cytopenias in patients treated with deferasirox and patients with 
cytopenias may be at higher risk of COVID-19 with a poorer prognosis. The periodic 
monitoring of blood counts and interruption of study treatment in patients who develop 
unexplained cytopenia, as defined in the protocol, are expected to mitigate this risk.
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions.

List of Abbreviations (LOA) and Protocol summary (data analysis): Aligned with 
updates in the protocol.

Section 4.5: New section added, describing the rationale for public health emergency 
mitigation procedures.

Section 6.5: Included public health emergency mitigation guidelines, regarding the 
delivery of IMP directly to the participant’s home at the discretion of the Investigator.

Section 7.1: Updated to add a ± 30-day window for yearly assessments, i.e. audiometry,
ocular, and growth and development examinations, in the extension phase, to allow 
more flexibility for the sites. 


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
Section 7.1: Included public health emergency mitigation guidelines, regarding 
alternative methods of providing continued care, such as phone calls and virtual contacts, 
to replace on-site study visits for the duration of the disruption.

Table 7-1 and Table 7-2: Separated Audiometry and Ocular sections and updated 
protocol section numbers.

Section 7.2.4: Included public health emergency mitigation guidelines, regarding the 
inclusion of phone or virtual calls for safety monitoring and discussion of the 
participant’s health status for the duration of the disruption. 

Section 7.2.4.4: Removed the reference to ocular examinations from this section as a 
new section (7.2.4.5) was added to clarify more detail about central imaging assessments.

Section 7.2.4.5, Table 7-3: New section and table added for ocular examinations and 
central imaging assessments. This section was included to introduce the requirement for 
central collection and assessment by an imaging CRO.

Section 7.2.4.6:  Included public health emergency mitigation guidelines, regarding the 
use of a local laboratory if the subject is unable to conduct safety laboratory assessments 
at the site. 

Section 8.4: Updated the duration for pregnancy reporting after the estimated date of 
delivery.

Section 9.3: Included ocular examination photographs as an additional component of 
data collection.

Section 9.4: Included ocular examination photographs as an additional component of 
data being collected and processed centrally.

Section 10: Added public health emergency mitigation guidelines regarding statistical 
methods and data analysis.

Section 10, Section 10.1.2, Section 10.1.3, Section 10.4.4, Section 10.5.3, Section 
10.5.4.2, Section 10.5.5: Changed RAP to SAP

Section 10.2: Removed Safety Set 4 demographic and other background data summary, 
as these are already presented in FAS-3 summary.  

Section 10.3: Corrected the definition of average daily dose calculation and updated the 
concomitant medication definition to align text with the SAP. 

Section 10.4.4, Section 10.5.1: Changed the term ‘sensitivity analysis’ to 
‘supplementary analysis’.

Section 10.5.4.1: Updated AESI maintenance and retrieval to align with the current 
Novartis internal process.

Section 10.6.1.2, Table 10-2: The normal ranges for pulse rate and weight were updated 
for pediatric patients. Notable ranges for systolic and diastolic blood pressure were 
removed.


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
Section 11.3: Included public health emergency mitigation guidelines, regarding the 
inclusion of remote informed consent discussion due to limits that prevent an on-site 
visit.

Section 13: Added a new reference.
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 
protocol amendment.


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Amendment 5 (06-Dec-2017)
Amendment rationale 
As of 06-Dec-2017, 210 patients have been randomized (94 chelation naïve and 116 pre-treated 
patients).  The pre-treatment arm is fully accrued.
The purpose of this amendment is to modify the assessment timepoint for the primary analysis 
(currently change from baseline for serum ferritin and compliance after 48 weeks of treatment), 
and to reduce the sample size for the chelation naive patients , following recent interaction with 
Health Authorities. The eligibility criteria for the extension phase have been modified.
Amendment rationales are as follows:
1. The assessment timepoint for the primary analysis will be modified for serum ferritin and 
compliance to 24 weeks of treatment (as assessed at week 25 visit), in lieu of 48 weeks. A 
linear relationship between changes from baseline at 24 and 48 weeks of treatment has 
been established based on a pool of representative randomized studies (CICL670A0105, 
CICL670A0107, CICL670A0109 and CICL670A2206) with serum ferritin available at 6 
and 12 months for deferoxamine and deferasirox arms. The model fits well in the set of 
observations and showed that the treatment effect at 6 and 12 months are correlated, with 
a slightly more pronounced effect at 12 months. This finding supports the use of the 6 
months time-point as reliable surrogate for the 12 months time-point (Novartis data on 
file).  Primary endpoints based on changes from baseline after 24 weeks of treatment will 
allow an earlier disclosure of primary analysis. The compliance (using drug count) has 
been evaluated in pediatric patients over 6 months and 12 months for deferoxamine and 
deferasirox arms in the ICL670A2206 study. The observed treatment effect over 6 months 
vs. 12 months is similar. This suggests compliance over 6 months is accurate at predicting 
compliance over 12 months. Furthermore data comparing deferoxamine and deferasirox 
suggest a self-reported adherence to deferasirox DT of 97% after one year. Therefore it 
can be assumed that the 6 month reported adherence will be very similar and can serve as 
a surrogate (Trachtenberg  2011)The rationale is also based on the demonstrated 
relationship of efficacy as assessed by serum ferritin with deferasirox dose, iron burden 
and continuous iron intake (Cappellini et al 2006).
2. The recruitment of chelation of naïve patients has been much slower than anticipated due 
to the global availability of chelation therapies in these indications. Through recent 
interactions with Health Authorities, it has been discussed and agreed that the sample size 
for chelation naïve patients has been reduced to reflect the modification of primary 
endpoints. At least of 96 chelation naive patients are planned to be enrolled instead of 120 
patients. This lower sample size will allow to obtain 76% power at a one-sided 5% level of 
significance for showing superiority of granule formulation over DT formulation with 
respect to change from baseline after 24 weeks of treatment in serum ferritin, assuming a 
dropout rate of 5%. This power is considered adequate to demonstrate targeted treatment 
effect, and will allow an earlier full recruitment of chelation naïve patients in the study, 
and therefore an earlier disclosure of primary analysis. 
3. Eligibility criteria for the extension phase are being updated in order to allow patients who 
have participated and completed 48 weeks of treatment in the core phase and for whom 


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new formulation is not yet available, to continue in the extension phase if they derive 
clinical benefit from the study drug, as confirmed by Investigator.  The current criteria are 
too stringent and would unnecessarily exclude patients who are benefiting from the study 
drug. During the extension phase patients will continue to follow the protocol including 
any dose modification guidelines and early withdrawal/discontinuation guidelines as they 
did in the core phase of the study.  
Changes to the protocol

Protocol Summary section - Purpose and rationale has been updated to assess compliance 
at 24 weeks and 48 weeks of treatment.  Population requirements reduced from 240 to 216 
naive and pre-treated patients, and 120 naive patients has been reduced to 96.  Number of 
patients per treatment arm has been reduced from 60 to 48 patients.  Inclusion/exclusion 
criteria have been updated for the extension phase.  Primary endpoint assessments have 
been modified from 48 to after 24 weeks of treatment, i.e. at Week 25 visit.  Secondary 
endpoint assessments have been confirmed in light of the new primary endpoint 
assessments.  Data analysis section has been updated to reflect new primary endpoints and 
sample size.  

Duration of extension phase has been clarified throughout protocol.  

EOT/777 refer to the end of treatment core visit.  This has been updated to reference the 
EOT core visit throughout protocol.

For clarification any reference to Week 25 is designated as ‘Week 25 visit’ and any 
reference to 24 weeks of treatment is designated as ‘24 weeks of treatment’ throughout 
protocol. 

Rationale for modifying primary endpoints to 24 weeks of treatment has been added to 
Sections 2.1. 

Primary endpoints have been updated throughout protocol (Sections 2.1, 2.2, Table 3-1, 
Sections 4.2, 10.4.1, 10.4.2, 10.4.4 and 10.8)

Definition of end of study has been updated to indicate when primary and final analyses 
will occur (Section 4.3).

Section “Handling of missing values/discontinuations” for the primary endpoint has been 
added (Section 10.4.3)

Sample size has been updated throughout protocol (Sections 2.2, 5.1 and 10.8)

Secondary objectives/endpoints have been updated throughout protocol (Table 3-1, 
Sections 10.5, 10.5.1 and 10.5.2) 

Re-aligned the criteria for re-starting dose after omission due to increase in direct 
(conjugated) bilirubin.  Currently re-starting criteria (1.5 x ULN) are not aligned with dose 
modification criteria (2.0 x ULN).  

Eligibility criteria for extension phase has been updated throughout protocol (Sections 5.2, 
5.3, Table 7-2, Sections 7.1.1, 7.2.2 and 7.2.4.5) 

Section 7.2.5.2:  Updated PK analytical method and provider to allow for a new PK lab to 
be used, as 
. is no longer the only lab participating in PK 
analysis for the study.

Sections 10.2 and 10.6.1.5:  Changed FAS-4 to Safety Set as FAS-4 has been removed.


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
Sections 10.4.3 to 10.4.4 and 10.5.1 to 10.5.5 re-numbered to align with rest of protocol.

Section 13:  Addition of references to support change in primary endpoints.  

Minor editorial changes have been made throughout protocol.
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions.
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 
protocol amendment.


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Amendment 4 (15-Jun-2017)
Amendment rationale 
As of 15-Jun-2017, 178 patients have been randomized (60 chelation naïve and 118 pre-treated 
patients).  The pre-treatment arm is fully accrued.
The purpose of this amendment is to include an interim analysis, allow for paper PRO 
completion, and clarify various points to improve site understanding and consistency in 
implementation of the protocol.
Amendment rationales are as follows:
1. With this amendment, one interim analysis has been added to allow for early analysis of 
the data if requested by the health authority.
2. To allow for paper PRO questionnaires use in case of technical issue or malfunctioning of 
the electronic device.
3. To clarify the completion of the ObsPRO questionnaires for patients who turn 10 years 
will continue to be completed by the caregiver.
4. To clarify the inclusion/exclusion criteria for the optional extension phase.
5. To clarify that when either TBIL or direct bilirubin are increased and > 2 x ULN, it always 
needs to be checked whether there is also an increase of ALT/AST that meets the 
definition of DILI. 
6. To modify the dose modification and exclusion criteria for direct bilirubin to enhance 
enrolment and reduce the amount of study drug interruptions without compromising 
safety. Many transfusion-dependent anemia patients have higher baseline level of direct 
bilirubin due to hemolysis.  Implementation of these less strict exclusion and dose 
modification criteria will not have any impact on capturing patients with Drug induced 
liver injury as this only occurs in case of increase of direct bilirubin > 2x ULN. 
7. To include dose modifications in case of Toxic epidermal necrosis (TEN) on Table 6-2 as 
per latest IB update. 
8. To correct height and weight to monthly in the optional extension phase to align with the 
CRF and collection requirements. 
9. To re-define Safety Set 4. At the end of the study, safety data for the optional extension 
phase data will be analyzed considering core and extension phases for patients who 
received granule formulation.  The Safety Set 4 will be used and the FAS-4 has been 
removed.
10. Baseline categories for serum creatinine, creatinine clearance, ALT, AST and urine 
protein/creatinine ratio have been re-defined to align with the protocol exclusion and dose 
modification criteria.
11. To clarify the endpoint for PK/PD analyses: notable serum creatinine/creatinine clearance 
‘values’ replaced with ‘events’ as two consecutives lab values need to be above/below the 
range to be considered as notable. 
12. To clarify the level of blinding of Sponsor and the procedure to minimize the potential 
impact of treatment knowledge.


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13. Clarified and corrected VES for optional extension phase (Table 7-2).
14. For the ObsRo/PRO data analyses, the term “Baseline” has been removed as the first 
assessment done at Week 2 after the randomization will not be considered as a baseline 
assessment.
15. PK analyses have been clarified to be aligned and consistent with the study objectives
Changes to the protocol

Cover page:  Author update from 
 to 
 and from 
 to 
 
due to change in Study Lead and Medical Lead, respectively.

List of Abbreviations – Added abbreviations used in protocol but previously not included 
in list. 

Added details of interim analysis to Protocol Summary section and Sections 4.1, 4.2 and 
10.7. 

Added consent of patients throughout protocol as patients may be expected to become age 
of consent during course of study.

Added clarification of the inclusion/exclusion criteria for the optional extension phase 
throughout protocol.

Modified the dose modification and exclusion criteria for direct bilirubin in Protocol 
Summary section, Section 5.3 and Table 6-2.

Clarified that when either TBIL or direct bilirubin are increased and > 2 x ULN, it always 
needs to be checked whether there is also an increase of ALT/AST that meets the 
definition of DILI (Table 6-2). 

Included dose modifications in case of Toxic epidermal necrosis (TEN). (Table 6-2). 

Added procedure to minimize the potential impact of treatment knowledge (Section 6.4.3).

Updated Visit Evaluation Schedule for Extension phase to include monthly height and 
weight (Table 7-2 and Section 7.2.4.3).

Removed Full Analysis Set 4 (FAS-4) from Protocol Summary section and Section 10.1.1. 

Redefined Safety Set 4 in Protocol Summary section and Section 10.1.2. 

Added urine protein creatinine ratio change from baseline to explore exposure-response 
relationships in Protocol Summary section, Table 3-1 and Section 10.5.5.3.

Notable serum creatinine ‘values’ has been replaced with ‘events’ in Protocol Summary 
section, Table 3-1 and Section 10.5.5.3.

Clarified starting dose as compared to pre-washout dose (Sections 2.3, 4.1 and 6.1.1).

Section 6.1.1:  Clarified need to return empty stick packs and bottles.

Section 6.4.3:  Updated language for treatment blinding.  

Table 7-2:  Clarified VES for ECG and echocardiogram assessments.  Added Urine 
pregnancy test at EOT visit. 

Section 7.2.2:  Clarified timing of serum ferritin testing for optional extension phase 
eligibility.  


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
Section 7.2.3:  Updated section to allow for paper ObsRO/PRO questionnaires use.  
Clarified the completion of the ObsPRO questionnaires for patient after turn 10.  Clarified 
compliance diary will no longer be collected during the optional extension phase. 

Section 7.2.4.3:  Updated height and weight to align with Exjade prescribing information.

Section 7.2.4.6.2:  Clarified schedule for echocardiogram assessments.

Section 8.2.2:  Updated SAE reporting contact details.  

Section 8.4:  Updated pregnancy reporting contact details.

Section 9.4:  Updated section to allow for paper PRO questionnaires use.  

Section 10.2: Redefined baseline categories for serum creatinine, creatinine clearance, 
ALT, AST and urine protein/creatinine ratio

Sections 10.5.2: Removal of the term “Baseline for ObsRO/PRO data analyses. 

Sections 10.5.5, 10.5.5.1 and 10.5.5.2 and Protocol Summary section: Clarified PK/PD 
and PK parameters analyses.

Section 14.3:  Clarified dosing based on patient’s body weight. 

In addition, clarifications were added to correct typographical errors and inconsistencies in 
different sections throughout protocol.
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions.
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 
protocol amendment.


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Amendment 3 (24-Aug-2016)
Amendment rationale
At the time of this amendment thirty nine patients have been randomized.
The purpose of this amendment is as follows:
1. To add an optional extension phase to the existing study. This optional extension phase 
will give the patients who have participated and completed the 48 weeks core treatment 
phase as per protocol and do not have access to the new formulation (granules or FCT) the 
possibility to extend treatment with deferasirox granules for a maximum of 5 years after 
completing the core treatment phase or until there is local access to new formulation 
(granules or FCT) whichever occurs first. Patients must have demonstrated benefit to 
granules or DT in the core phase, and/or express the wish to continue in the optional 
extension phase on granules in order to start the optional extension phase.
2. To sharpen the clarification of the eligibility criteria related to renal criteria in order to 
promote better Investigator understanding, leading to better adherence and improved renal 
safety.
3. To provide the investigators with further clarified dose modification guidance for renal 
monitoring with regards to creatinine clearance, increased serum creatinine and 
proteinuria. Clear guidance on how to reinitiate treatment after required dose interruption 
has also been included in order to improve patient safety.
In addition, clarifications were added to correct typographical errors and inconsistencies in 
different sections.
Changes to the protocol

List of Abbreviations: Added FCT (Film-coated tablet)

Glossary of Terms: Defined new formulation and stickpack.

Protocol Summary: Made distinctions between core phase and the optional extension 
phases in Primary Objectives, Study design, Inclusion criteria, Efficacy assessments, 
Primary endpoint assessments, Secondary endpoint assessments, and Other assessments 
Sections.

Protocol Summary: Added details of the optional extension phase to Purpose and 
rationale, Secondary Objectives, Population, Inclusion criteria, Exclusion criteria, 
Investigational and reference therapy, and Secondary endpoint assessments Sections.

Protocol Summary: Further clarified laboratory exclusion criteria

Protocol Summary: Clarified extended FAS, made distinction between core phase and the 
optional extension phase, and added extension phase details in Data analysis Section.

Section 1.2.2: Added description of stick pack and film-coated tablets. Added warm 
porridge as a vehicle for granule administration.

Section 2.1: Provided rationale for giving all patients granule formulation in the optional 
extension phase. Added extension phase purpose.


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
Section 2.2: Distinguished between the two phases of study treatment (core and optional 
extension). Provided rationale for including the optional extension phase.

Section 2.3: Distinguished between core and optional extension phases.

Table 3-1: Added Objective of the optional extension phase.

Section 4.1: Added the optional extension phase design. Updated end of treatment visit 
timelines.

Figure 4-1: Updated Study schema.

Section 4.3: Updated definition of end of study.

Section 5.2: Updated inclusion criteria for the optional extension phase.

Section 5.3: Further clarified laboratory exclusion criteria. Added the optional extension 
phase exclusion criteria.

Section 6.1: Distinguished study treatment between core and the optional extension 
phases.

Section 6.1.1: Further clarified dosing regimen based on lab values and prior dosing in 
core phase. Added dose adjustment guidelines for optional extension phase. Added warm 
porridge as vehicle for granule administration.

Table 6-1: Further clarified starting dose.

Section 6.1.2: Updated treatment duration to include the optional extension phase.

Section 6.2.1: Dose adjustment outside or protocol sections now require a written request 
from Investigator.

Table 6-2: Further clarified dose modifications based on changes in body weight, serum 
creatinine and/or creatinine clearance, isolated direct (conjugated) bilirubin elevation, 
serum ferritin, urine protein/creatinine ratio, as well as auditory and ocular disturbances, 
and hypersensitivity reactions.

Section 6.2.2: Added end of treatment guidance for the optional extension phase. Added 
SEC eCRF completion requirement.

Section 6.2.3: Updated follow-up for patients permanently discontinuing due to adverse 
event or abnormal laboratory value.

Section 6.3: Updated conmed reporting by patient.

Section 6.3.1: Clarified timing of PK vs transfusions.

Section 6.3.2: Clarified language for use of other iron chelators.

Section 6.4.2: Made distinction between core and optional extension phases. Added the 
optional extension phase details.

Section 7.1: Made distinction between core and optional extension phases. Added the 
optional extension phase details and updates to assessments during the optional extension 
phase throughout Section 7.1.

Table 7-1: Renamed Visits 777 and 778 and specified table for core phase of study.

Table 7-2: Created Table 7-2 to include the optional extension phase visits and 
assessments. Tables 7-3 through 7-5 numbering updated.

Section 7.1.5: Added collection of death details during follow-up period.


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
Section 7.2: Assessment updates for the optional extension phase have been added, 
including removal of stick pack count, removal of ePRO assessments and updated 
schedules for the assessments per Table 7-2. Patients transitioning from being on DT in 
the core will require additional renal safety labs per Section 7.2.4.5.2.

Section 7.2.4.5: Clarified pregnancy testing schedule

Table 7-4: PK collections no longer required were removed for clarity.

Table 7-5: Added ‘taken pre-dose’ and ‘taken post-dose’ for clarity.

Section 8: Added collection of death details during follow-up period.

Section 8.4: Updated pregnancy section for the optional extension phase.

Section 10: Clarified study purpose. Clarified extended FAS and added FAS-4 for the 
optional extension phase throughout section. Clarified extended Safety Set and added 
Safety Set-4 for the optional extension phase throughout section.

Section 10.3: Added duration of exposure in weeks for core phase. The optional extension 
phase will be in months. Clarified prior and concomitant meds.

Section 10.4: Clarified primary objective for core phase.

Section 10.5: Added the optional extension Visit 17. Made distinction between core and 
optional extension phases where needed. Added ‘Summary tables for AEs will be repeated 
for the optional extension phase on the Safety Set 4. Lab abnormalities will be described 
for the optional extension phase on the Safety Set 4. Added ‘matching’ to log-transformed 
pre- and post-dose concentrations in Section 10.5.5.3.

Table 10-2: Updated definition of notable weight ranges.

Section 10.6: Updated ‘Other safety data’ section. Distinguished between assessments for 
core and optional extension phases.

Section 10.6.1.5: Serum ferritin during the optional extension phase added.

Table 14-3: Corrected body weight ranges.

Table 14-4: Corrected body weight ranges.

In addition, clarifications were added to correct typographical errors and inconsistencies in 
different sections.
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions.
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 
protocol amendment.


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Amendment 2 (15-Jun-2016)
Amendment rationale
At the time of this amendment 13 patients have been randomized.
The purpose of this amendment is:
1. To allow the sites in Egypt to use a local laboratory instead of central laboratory for the 
analysis of safety required in this trial and to exempt patients’ enrolled in Egypt from the 
collection of PK samples. This exemption is granted to Egypt due to national restriction on 
export of any biological samples out of Egypt.
2. To clarify the inclusion criteria #2 for France concerning children aged from 2 to 6 years 
old as per Exjade prescribing information.
In addition, clarifications were added to correct typographical errors and inconsistencies in 
different sections.
Changes to the protocol

Protocol Summary: inclusion criteria and secondary endpoint assessments.

Section 2.2: added exemption to collect PK samples in Egypt.

Section 5.2: Clarify inclusion criteria # 2 for France.

Table 6-2: Added laboratory testing will be done in a local laboratory for Egypt.

Section 7.1.1.3: Added laboratory testing will be done in a local laboratory for Egypt.

Section 7.2.2: Added laboratory testing will be done in a local laboratory for Egypt.

Section 7.2.4.5: Added local laboratory will be used in Egypt for hematology, clinical 
chemistry and urinalysis.

Section 7.2.5.1: added exemption to collect PK samples in Egypt.

Section 9.3: added only safety samples will be collected in Egypt.

Section 9.4: added data for laboratories sampling will be processed locally sites in Egypt.
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.
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 are non-substantial and do not require IRB/IEC 
approval prior to implementation.


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Amendment 1 (01-Dec-2015)
Amendment rationale
At the time of this amendment one patient has been randomized.
The purpose of this amendment is as follows:
1. Expand the study population by revising the inclusion criteria to allow for the enrollment 
of up to 120 patients who have prior history of iron chelation treatment in addition to the 
120 chelation naïve patients originally planned, which would allow the continuation of the 
study if the recruitment of chelation naïve patients becomes challenging to complete in a 
reasonable timeframe.
2. Modify the secondary objectives:
a. Revised sparse PK sampling schedule to reduce required blood draws and 
extensive/overnight hospital stays in this pediatric population to improve feasibility of 
study.
b. Addition of new objective to evaluate the change in serum ferritin in both populations 
(chelation naïve and pre-treated chelation patients)
3. In order to optimize the patient safety and the toxicity monitoring, eligibility criteria and 
the management guidelines for cardiac and hepatic toxicity have been revised. In addition 
pregnant and nursing (lactating) women have been included as exclusion criteria in 
alignment with the prescribing Exjade information.
4. The amendment also provides the investigators with modified dose modification rules for 
hepatic toxicity management guidelines. Specific work-up guidelines for potential Drug 
Induced Liver Injury (DILI) cases has been added to the protocol, the dose modification 
rules as well as the follow-up evaluations for hepatic toxicities have also been updated 
accordingly.
5. ePRO assessment schedule has been updated.
6. Clarification to the concomitant medications and contraception as detailed below:
a. Guidance was updated on the use of contraception, the sentence included in the 
exclusion criteria section regarding the definition of “not of child-bearing potential” 
has been removed as it was not appropriate to pediatric population but to menopause 
or post-sterilization women.
b. Guidance was updated regarding the concomitant administration of deferasirox with 
CYP3A4, CYP1A2 and CYP1A2 substrates that have a narrow therapeutic index in 
alignment with the prescribing Exjade information
7. Statistical methods and data analysis section has been updated in alignment with the 
updated PK sampling and the inclusion of ICT pre-treated patients.
8. Additional guidance for iron chelation pre-treated patients starting dose has been added as 
Appendix 14.1.
9. Definition of a light meal added as Appendix 14.2.
In addition, clarifications were added to correct typographical errors and inconsistencies in 
different sections.


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Changes to the protocol
Changes to List of Tables

Renumbered Table 10-4 to Table 10-2 to be aligned with protocol updates
Changes to List of Abbreviations

Updated to follow abbreviations used in protocol
Changes to Protocol summary

Purpose and rationale, primary and secondary objectives, study design, population, 
inclusion and exclusion criteria, secondary endpoint assessments, other assessments and 
data analysis updated
Changes to Section 1.2.2 Overview of deferasirox granules

Reference to Appendix 14.2 added
Changes to Section 2.1 Study rational and purpose

Purpose of the study updated
Changes to Section 2.2 Rationale for the study design

Iron chelation pre-treated patient population included

Stratification updated
Changes to Section 2.3 Rationale for dose and regime selection

Guidance for the study starting dose for the different population (naïve versus iron 
chelation pre-treated patients) included and allowed dose adjustments included
Changes to Section 3 Objectives and Endpoint

Primary and Secondary objectives and endpoints updated
Changes to Section 4 Study Design.1 Description of study design

Inclusion of a washout period during screening period for those iron chelation pre-treated 
patients.

Stratification updated

Guidance for the study starting dose for the different population (naïve versus iron 
chelation pre-treated patient) included
Changes to Section 5.1 Patient population

Removing the sentence: Patient must be iron-chelation naïve.

Iron chelation pre-treated patient population included
Changes to Section 5.2 Inclusion criteria

Criterion #2 has been updated to include Iron chelation pre-treated patient population

Criterion #3 has been updated to include PRBC clarification for pediatric population
Changes to Section 5.3 Exclusion criteria

Criterion # 3 has been updated to exclude alanine/aspartate transaminase (ALT/AST) > 
3.0 x ULN,

Criterion #4 is no longer applicable to be aligned with the updated patient population


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
Criterion #15 has been updated to clarify the definition of females of child bearing, and 
effective contraception language has been moved to Section 7.2.4.5.4.

Added criterion #17 to exclude pregnant and nursing (lactating) women.

Added criterion #18 to exclude patients with direct (conjugated) bilirubin >1.5 x ULN

Added criterion #19 to exclude any patient with history or current diagnosis of cardiac 
disease
Changes to Section 6.1 Dosing regimen

Inclusion of a washout period during screening period for those iron chelation pre-treated 
patients.

Guidance for the study starting dose for the different population (naïve versus iron 
chelation pre-treated patient) and dose adjustment allowances added
Changes to Section 6.2 Dose modifications

Inclusion of a dose adjustment guideline Table 6-2 instead of text. In addition, inclusion of 
hepatic dose modification wording in the table.
Added new Section 6.2.4 Follow up on potential drug-induced liver injury (DILI) cases
Added new Section 6.2.5 Anticipate risk and safety concerns of the study drug
Changes to Section 6.3 Prior and Concomitant medications

Removed guidance to report blood transfusions on concomitant medication CRF (separate 
blood transfusion CRF page available).
Changes to Section 6.3.1 Permitted concomitant therapy requiring caution and/or action

Guidance added related to the use of concomitant administration of deferasirox with 
CYP3A4, CYP1A2 and CYP1A2.
Changes to Section 6.3.2 Prohibited concomitant therapy

Updated as per Exjade prescribing info.
Changes to Section 6.4.2 Treatment assignment or randomization

Stratification updated
Changes to Section 6.4.3 Treatment blinding

Removed blinding details
Changes to Table 7-1

Include prior chelation assessment

Assessment schedule updated for the SICT and palatability questionnaires.
Assessment schedule updated for the PK post-sampling. Changes to Section 7.1.1 Screening

Ocular and Audiometry assessments guidance updated.
Changes to Section 7.1.2 Treatment period

Guidance for the study starting dose for the different population (naïve versus iron 
chelation pre-treated patient) included.


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Changes to Section 7.1.3 End of treatment visit including study completion and premature 
withdrawal

Section removed and new Section 7.1.4 Withdrawal of consent added to provide 
additional guidance to patients withdrawal
Changes to Section 7.1.3.1 Criteria of premature patient withdrawal

Section removed and new Section 7.1.3 Discontinuation of study treatment added to 
provide additional guidance to patients who discontinued study treatment
Section 7.1.3.2 PK Replacement Policy

Section removed
Changes to Section 7.2.3 Patient/Observer Reported Outcomes

Visits schedule updated for the SICT and palatability questionnaires.
Changes to Section 7.2.4.4 auditory and ocular examination

Ocular and Audiometry assessments guidance updated.
Changes to Section 7.2.4.5.2 Clinical chemistry

Creatinine clearance calculation clarified for patients who turn 18 years old during the 
study.
Changes to Section 7.2.4.5.4 Pregnancy and assessments of fertility

Guidelines for pregnancy prevention updated

Breastfeeding included as criteria for exclusion.
Changes to Section 7.2.4.6.1 Electrocardiogram (ECG)

Documentation, labeling and storage of ECGs during the study have been updated.
Changes to Section 7.2.4.6.2 Echocardiography

Documentation, labeling and storage of echocardiography during the study have been 
updated.
Changes to Section 7.2.5.1 PK blood sample collection and handling

PK sampling time points updated
Remove of Section 7.2.5.3 PK parameters in alignment to the updated PK objective
Changes to Section 7.2.7 Resource utilization

Sentence removed in alignment with the new PK sampling.

Added Not Applicable to this section.
Changes to Section 8.1.1 Definitions and reporting

Severity of adverse events used in this trial has been clarified.
Changes to Section 8.1.2.1 Definitions and reporting

Clarification of severe event.
Changes to Section 8.4 Pregnancies

Pregnancy reporting and management updated


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Changes to Section 10.1.1 Full Analysis set

Full Analysis set updated to include only ICT naïve patient

Extended Full Analysis set added to include ICT pre-treated and naïve patients

Updated stratification
Changes to Section 10.1.2 Safety set

Safety set updated to include only ICT naïve patient

Extended Safety set added to include ICT pre-treated and naïve patients
Changes to Section 10.1.3 Per Protocol set

Per protocol set updated to include only ICT naïve patient
Changes to Section 10.1.4 Pharmacokinetics Analysis set

Pharmacokinetics Analysis set updated in alignment with the updated PK sampling
Changes to Section 10.2 Patient demographics/other baseline characteristics

Other background data updated to include prior chelation therapy and prior deferasirox 
chelation therapy
Changes to Section 10.3 Treatment (duration of exposure, concomitant therapies, percentage of 
planned dose taken)

Section updated to include extended Safety set
Changes to Section 10.4 Primary objective

Primary objective modified to include only ICT naïve patient
Changes to Section 10.4.1 Variables and analysis set

Updated FAS to FAS-1
Changes to Section 10.4.2 Statistical methods of analysis

Updated FAS to FAS-1

Stratification factor updated
Changes to Section 10.4.3 Supportive analysis

Primary analysis updated to include extended full analysis set
Changes to Section 10.5.1 To evaluate both formulations on patients’ satisfaction and 
palatability using PRO/ObsPRO questionnaires

Extended Full Analysis set included

Scheduled of assessment for the SICT and Palatability questionnaires updated
Changes to Section 10.5.2 To evaluate both formulations on overall safety, measured by 
frequency and severity of adverse events and changes in laboratory values

Extended Safety set included

Clarified scoring of palatability questionnaire
Changes to Section 10.5.3 To evaluate compliance using a daily PRO/ObsPRO questionnaire

Extended Full Analysis set included


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
Removed handling of on-treatment AE section

Updated standard descriptive analysis section
Changes to Section 10.5.3.1 Adverse Events (AEs)

Added summary of type of AEs to be presented

Added how incidence of AESI will be summarized
Changes to Section 10.5.4 Pharmacokinetics

Section updated to include description of and compliance assessment Cmin and Cmax
Changes to Section 10.5.5.1 To evaluate pre-dose PK data to support the assessment of 
compliance

Section updated
Remove of Section 10.4.7.2 Derivation PK parameters in alignment to the updated PK objective.
Changes to Section 10.5.5.2 Description of individual PK concentrations and parameters

Section updated
Changes to Section 10.5.5.3 to explore PK/PD relationship

Section updated
Remove of Section 10.4.7.5 Derivation of optimal PK sampling and trial simulation in 
alignment to the updated PK objective.
Changes to Section 10.6.1 Other safety data

Extended Safety set included
Changes to Section 10.6.1.2 Vital signs and body weight

Added vital signs and weight

Renumbered Table 10-4 to Table 10-2 to align with protocol updates
Changes to Section 10.6.1.3 Auditory and Ocular assessment evaluations

Added ‘Week’.
Changes to Section 10.7 sample size calculation

Section updated to include the ICT pre-treated patients

Renumbered Table 10-2 to Table 10-3 to be aligned with protocol updates.
Changes to Section 13 References (Available upon request)

Updated references to align with protocol updates
Changes to Section 14.1 equivalent dose guidance

Guidance added for starting dose for iron pre-treated patient

Examples of light meal added
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.


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


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1
Background
1.1
Overview of disease pathogenesis, epidemiology and current 
treatment
Transfusion-dependent hemoglobinopathies, such as thalassemia and sickle cell disease (SCD) 
represent a major global health burden, with > 300 000 infants born with SCD or thalassemia 
annually and iron overload is an inevitable clinical consequence for patients with transfusion-
dependent anemias. Iron chelation therapy (ICT) is, therefore, an important and integral part of 
their supportive care.
Deferoxamine (DFO) was the only iron chelator available in the United States between 1962 
and 2005. DFO is used as a subcutaneous infusion over 8 to 10 hours, 5 to 7 days a week, 
usually overnight. Many patients find DFO inconvenient and therefore adherence to this 
treatment is suboptimal. Deferasirox (Exjade®) became commercially available in the US in 
November 2005. As the first oral iron chelator, Exjade represented a substantial advancement 
in chelation treatment with many benefits over parenteral therapy, especially for pediatric 
patients and their families. Adherence to prescribed iron chelation is crucial to reduce or prevent 
iron overload and has been correlated with improved patient survival (Kushner et al 2001; 
Borgna-Pignatti et al 2004, Gabutti and Piga 1996). The goal of chelation is to maintain a serum 
ferritin of less than 1000 ng/ml, however most patients live with significantly higher serum 
ferritins due to compliance issues with their chelation therapy (Standard of Care Guidelines for 
Thalassemia 2012). Pediatric patients who are not adequately chelated risk delayed sexual 
maturation, retarded growth, progressive liver and heart disease, and a reduced life expectancy 
(Vichinsky 2008).
1.1.1
Overview of beta-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.


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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 2008a).
1.1.2
Overview of sickle cell disease
Sickle cell disease is a multisystem disease, associated with episodes of acute illness and 
progressive organ damage, and is one of the most common severe monogenic disorders 
worldwide (Weatherall 2010). It is caused by the sickle mutation affecting the β-globin chain 
of hemoglobin. Erythrocytes containing hemoglobin S have irregular morphology and under 
low oxygen conditions, hemoglobin S polymerizes leading to ‘sickled’ cells. The pathogenesis 
of SCD relates to the shortened lifespan of the sickled erythrocytes (16 to 20 days in contrast to 
a lifespan of 120 days for normal erythrocytes) and adhesion of the sickled erythrocytes to the 
microvascular endothelium.
Transfusion of red blood cells on a chronic or intermittent basis is therefore important in the 
management of SCD. There is increasing evidence of the value of transfusions particularly in 
reducing the risk of stroke, vaso-occlusive events, acute chest syndrome, and growth failure in 
pediatric patients with SCD.
However, progressive iron loading and tissue injury is an inevitable result of frequent blood 
transfusions, although the pattern of hemosiderosis seems different to that described in 
thalassemia. In particular, most iron loading occurs in the liver, with little cardiac iron 
deposition.
Assessment of SCD-specific populations has demonstrated that elevated iron levels are 
associated with an increased frequency of acute events, hospitalizations, and death (Inati et al 
2011).
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, and then rounded up or down to the 
nearest whole tablet according to the available strengths. The currently approved dose range is 
up to 40 mg/kg/day; the approved starting dose in US is 20 mg/kg/day. Outside the US 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 


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before the next meal. Administration requires dispersion of the tablets in an appropriate amount 
of water, orange juice or apple juice, which takes approximately 3 minutes.
Detailed information on preclinical and clinical evaluation of deferasirox DT is provided in the 
current [Investigators’ Brochure].
1.2.2
Overview of deferasirox granules
Because of the chronic nature of chelation therapy and the importance of patient compliance, 
an improved deferasirox formulation for oral administration is being developed. The granule 
formulation to be used in this study contains the same active substance but has been strength-
adjusted to achieve comparable exposure to the currently approved DT formulation. In addition 
several excipients have been modified. The granule formulation is packaged in aluminum foil 
pouches (alternatively referred to as stick packs or sachets). The stick packs will be available 
in three dosing strengths (90, 180 and 360 mg) and is dosed based on body weight, and then 
rounded up or down to the nearest whole stick pack according to the available strengths.
The granules are of the qualitative and quantitative composition as the film-coated tablets (FCT) 
that are currently being registered worldwide; both granules and FCT are using the same active 
ingredients at the same doses, and the same excipients (with exception of the film-coating 
ingredients only used in the FCT).
The granules should be administered by sprinkling the full dose on a soft food (e.g., yogurt, 
applesauce or warm porridge). The dose should be immediately and completely consumed, and 
not stored for future use. The granules should be taken once a day, preferably at the same time 
each day, and may be taken on an empty stomach or with a light meal, (please refer to Appendix 
14.2).
2
Rationale
2.1
Study rationale and purpose
The availability of deferasirox DT 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 2006; Osborne et al 2007).
Since its approval, oral chelation with deferasirox DT has become well established, with many 
children never experiencing parenteral therapy. However prescribers, patients and their care-
givers report limitations related to the convenience, palatability and GI tolerability of the current 
DT formulation, all factors that can play a significant role in the appropriate administration and
compliance with chelation treatment, especially in children. (Haghpanah et al 2014) reported 
that 30% of adult patients treated with deferasirox DT complain about its undesirable taste. In 
the pediatric population, undesirable taste is expected to have even more impact on compliance 
then in the adult population. In a survey of more than 800 pediatricians on the perceived barriers 
to treatment completion in the pediatric population with chronic illnesses, the most frequent 
issues were 1. Frequency of dosing (91%), 2. Side effects of medication (88%) and 3. 
Unpleasant taste (84%) (Tuleu C 2011). Depending on the degree of palatability, compliance 
rates in the pediatric population can range from 11% to 93% (Tuleu C 2011).


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As it is well established that long-term compliance to chelation therapy impacts outcome in 
thalassemia and other congenital anemias (Mednick et al 2010); improvements in 
convenience, palatability and tolerability of the formulation can bring substantial therapeutic 
benefit to patients.
Novartis has developed a new deferasirox formulation of granules and FCT with the same active 
substance as the deferasirox DT but with modified excipients.
After strength-adjustment, the granule formulation was shown to achieve the same overall 
exposure (AUClast and AUCinf) as the currently approved DT formulation in single-dose 
healthy volunteer studies; the peak serum concentrations (Cmax) were approximately 18% 
higher ([CICL670F2104]). In addition, a food effect study ([CICL670F2106]) indicated that the 
granule formulation can be taken either with or without a light meal.
The granule formulation of deferasirox, with its improved pharmaceutical properties and 
changes in composition, offers an opportunity to provide pediatric patients significant 
improvements such as:

the freedom to take deferasirox with food (due to the absence of a substantial food effect as 
shown in ([CICL670F2106]) which obviates the requirement to take the drug on an empty 
stomach at least 30 minutes before food and therefore allows patients more convenience 
and flexibility in the scheduling and administration of their daily dose;

a better tolerability profile as the exclusion of lactose and sodium lauryl sulfate in the new 
formulations alleviates concerns with use in patients with rare hereditary problems of 
galactose intolerance, the Lapp lactase deficiency, glucose-galactose malabsorption or 
severe lactase deficiency and may improve the gastrointestinal tolerability of deferasirox;

and overall, better convenience/palatability as a granule formulation.
It is for these reasons that Novartis will be providing all patients in the optional extension phase 
of the study with the granule formulation of deferasirox. Those on DT formulation in the core 
phase will switch to the granules in the optional extension phase. The purpose of the study is 
to:

assess the compliance of the granule and the DT formulations in pediatric patients with iron 
overload treated over 24 and 48 weeks using stick pack/tablet count, pre-dose 
pharmacokinetic (PK) concentrations and a PRO/ObsRO questionnaire

assess the clinical benefit due to improved compliance of the new formulation by 
measurements of serum ferritin levels for both formulations after 24 and 48 weeks of 
treatment.

assess Patient / Observer Reported Outcomes (PRO/ObsRO) on palatability and treatment 
satisfaction, both factors influencing patient compliance and adherence.

assess the safety of both formulations; renal toxicity (including renal failure), hepatic 
toxicity (including hepatic failure) and gastrointestinal hemorrhage will be actively 
monitored

examine the pre-and post-dose concentrations of both formulations using sparse PK 
sampling.

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
assess long term safety of granules formulation during the optional extension phase 
consisting of up to 5 years for those who complete 48 weeks of core treatment phase
2.2
Rationale for the study design
This is an open-label, randomized, multicenter, two arm, phase II study. Female and male 
children and adolescents aged ≥ 2 and < 18 years at enrollment with any transfusion-dependent 
anemia requiring chelation therapy due to iron overload, and a treatment goal to reduce iron 
burden will be enrolled in this study.
Children and adolescents who are chelation naïve ( sample size of at least96 patients) and those 
previously treated with iron chelators (maximum sample size of 120 patients) can participate in 
this study. The addition of the previously chelated patients will allow for an assessment of safety 
and efficacy between the two populations.
A washout period of 5 days prior to randomization is required for previously treated patients.
The randomization will be stratified by age groups and by prior ICT to ensure a balanced 
distribution of patients to the two treatment arms on stratifying factors: age groups (2 to <10 
years (using ObsRO questionnaires) and 10 to <18 years (using PRO questionnaires) and prior 
ICT (Yes/No), as described in Section 4.1.
The core treatment duration of 48 weeks is considered sufficient to assess the compliance, 
serum ferritin, safety and patient / observer reported outcome (PRO/ObsRO) profiles of the two 
formulations.
The primary objective is to evaluate the impact in ICT naïve patients of these new 
pharmaceutical properties and changes in composition of the granule formulation on patient 
compliance and change in serum ferritin with study treatment during the core phase, after 24 
weeks of treatment. It is well documented that compliance to chelation therapy is associated 
with clinical outcome (Standards of Care Guidelines for Thalassemia 2012). There are both 
direct and indirect methods to assess patient compliance, each method has advantages and 
disadvantages. Directly observed therapy, measurement of concentrations of drug or its 
metabolites in blood or urine, and detection or measurement in blood of a biologic marker are 
examples of direct methods of measures. Indirect methods include asking the patients about 
how easy it is for them to take prescribed medication, performing pill counts, collecting patient 
questionnaires, and assessing children’s adherence by asking help of a caregiver (Osterberg and 
Blaschke 2005). In the absence of a preferred standard of measurement, multiple measures are 
often used to best assess this behavior (Partridge et al 2002).
In the core phase, treatment compliance of a pediatric population will be assessed using both 
direct and indirect methods:

Adherence to the quantity of prescribed medication will be estimated via stick pack/tablet 
counts (known more generally throughout literature as “pill counts”) in the core phase. Pill 
counts are known to overestimate adherence and obscure short-term variability in behavior 
within and between subjects, even in a population selected for high levels of compliance. 
The Hawthorne Effect has been observed in studies where patients are aware that a specific 
behavior is being monitored (Partridge, et al 2002). This phenomenon, in which subjects 
alter a behavior because they are aware that they are under observation, may be heightened 


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during pill counts performed during clinic visits. Such an effect may lead to pill dumping 
or similar activities by subjects to obscure lapses in their medication adherence (Rudd, et al 
1989).

Pre-dose PK levels will be measured in all patients at start of treatment and at regular 
intervals during the study period in the core phase to support the assessment of compliance. 
[Egypt: no PK samples will be collected due to restriction on export of samples]

Adherence with medication regimen instructions will also be recorded via a patient daily 
questionnaire in the core phase. Requiring daily entries documenting medication behavior 
decreases recall bias from less frequent recording, but may also overestimate adherence 
behavior as patients tend to answer in a way they judge to be desirable to clinic staff. 
Asking medication consumption questions in a way that normalizes non-adherence can 
help mitigate some of this bias (Osterberg and Blaschke 2005). This method may also be 
subject to less of a Hawthorne Effect, particularly as patients become normalized to 
completing daily diary entries, which include questions about medication consumption.
The clinical benefit related to improved compliance will be assessed by changes in serum 
ferritin over time. The starting dose and the dose adjustment considerations in this study will 
take into account that the therapeutic goal is reduction of iron burden (as opposed to 
maintenance of iron burden). In clinical practice it is recommended to dose adjust for efficacy 
after 3 months of treatment based on trends in serum ferritin. A treatment duration of 48 weeks; 
with dose regimens aimed to reduce iron burden provides sufficient time to determine if 
improved compliance to treatment is leading to greater reduction in serum ferritin from baseline. 
A linear relationship between changes from baseline at 24 and 48 weeks of treatment has been 
established based on a pool of representative randomized studies (CICL670A0105, 
CICL670A0107, CICL670A0109 and CICL670A2206) with Serum ferritin available at 6 and 
12 months for deferoxamine and deferasirox arms and is supportive of the primary analysis at 
24 weeks of treatment.  Furthermore data comparing deferoxamine and deferasirox suggest a 
self-reported adherence to deferasirox DT of 97% after one year. Therefore it can be assumed 
that the 6 month reported adherence will be very similar and can serve as a surrogate 
(Trachtenberg 2011).  The rationale is also based on the demonstrated relationship of efficacy 
as assessed by serum ferritin with deferasirox dose, iron burden and continuous iron intake 
(Cappellini et al 2006).
In addition treatment satisfaction and palatability will be measured via age adapted validated 
questionnaires in the core phase.
Overall safety will be addressed by measuring the frequency and severity of adverse events, 
including renal toxicity, hepatic toxicity, and gastrointestinal hemorrhage; which will be 
actively monitored and changes in laboratory values. Additional safety assessments will include 
vital signs, physical exam, ophthalmological, audiometric, cardiac, and growth and 
development evaluations. Time points for assessing laboratory values have been chosen based 
on the current labeling information of deferasirox DT (Exjade®) in order to be as close as 
possible to the daily practice in administering the study treatment. The rationale to include the 
optional extension phase is to collect additional safety data about the new formulation and to 
provide access to the new deferasirox formulation (granules) to patients for continuity of 
treatment. This optional extension phase will give the patients who have participated and 
completed the 48 weeks core treatment phase as per protocol and do not have access to the new 


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formulation (granules or FCT) the possibility to extend treatment with deferasirox granules until 
there is local access to the new formulation (granules or FCT) or up to 5 years from entering 
extension phase, whichever occurs first. Patients must have demonstrated benefit to granules or 
DT in the core phase, and/or express the wish to continue in the optional extension phase on 
granules in order to start the optional extension phase.
2.3
Rationale for dose and regimen selection
Deferasirox is available in three dosing strengths (125, 250 and 500 mg for DT and 90, 180 and 
360 mg for the granule formulation). 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/stick pack 
configuration. This dosing paradigm is consistent with how deferasirox DT (Exjade®) has been 
developed with regard to safety and efficacy.
Children and adolescents aged ≥ 2 and < 18 years at enrollment in the core phase with any 
transfusion-dependent anemia requiring chelation therapy due to iron overload will be 
randomized to either the DT or the granules treatment arm in a 1:1 ratio.
All ICT naïve patients randomized to the study will use either the DT starting dose of 20 
mg/kg/day; which is the only approved starting dose in the US, and the commonly 
recommended starting dose in other countries, or the equivalent strength-adjusted granules 
starting dose of 14 mg/kg/day.
The deferasirox granules dose is strength-adjusted due to a higher bioavailability of this 
formulation compared to the dispersible tablets.
All ICT pre-treated patients will use a deferasirox DT or an equivalent strength-adjusted 
granules starting dose corresponding to their closest pre-washout dose, please refer to Appendix 
14.1. Further dose adjustment, based on serum ferritin levels, safety parameters and 
investigator’s judgment, will be allowed. 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.
In the optional extension phase, all patients will be provided the deferasirox formulation 
(granules). Patients on DT formulation during the core phase will receive the equivalent 
strength-adjusted granules dose corresponding to the last DT dose in the core phase taking dose 
adjustment guidelines into account (please refer to Table 6-2 and Appendix 14.1). Patients in 
granules during the core phase will continue on the same dose as was given at the end of the 
core phase taking dose adjustment guidelines into account. Please refer to Table 6-2 as 
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
●
To evaluate both formulations on patient 
compliance, using stick pack/tablet count over 24 
weeks of treatment in ICT naïve patients during core 
phase
●
To evaluate the change from baseline in serum 
ferritin  after 24 weeks of treatment for both 
formulations in ICT naïve patients during the core 
phase
●
Compliance measured by stick pack/tablet count  
over 24 weeks of treatment (i.e. assessed at week 25 
visit)
●
Change from baseline in serum ferritin after 24 
weeks of treatment (i.e. serum ferritin at week 25 
visit)
Refer to Section 10.4
Refer to Section 10.4
Secondary (Core phase)
To evaluate both formulations on change in serum 
ferritin and compliance in ICT naive patients, after 48 
weeks of treatment
●
Compliance measured by stick pack/tablet count 
after 48 weeks of treatment
●
Change from baseline in serum ferritin  after 48 
weeks of treatment   
Refer to Section 10.5.1
To evaluate both formulations on change in serum 
ferritin after 24 weeks and 48 weeks of treatment in 
ICT naïve and pre-treated patients
Change from baseline in serum ferritin after 24 weeks 
(i.e. assessed at week 25 visit) and 48 weeks of 
treatment
Refer to Section 10.5.2
To evaluate both formulations on patient satisfaction 
and palatability using Patient / Observer Reported 
Outcomes (PRO/ObsRO) questionnaires
Domain scores of treatment satisfaction and 
palatability over time
Refer to Section 10.5.3
To evaluate both formulations on overall safety
Overall safety, as measured by frequency and 
severity of adverse events (including active 
monitoring for renal toxicity; including renal failure, 
hepatic toxicity; including hepatic failure, and 
gastrointestinal hemorrhage), and changes in 
laboratory values from baseline (serum creatinine, 
creatinine clearance, ALT, AST, RBC and WBC). In 
addition, vital signs, physical, ophthalmological, 
audiometric, cardiac, and growth and development 
evaluations will be assessed.
Refer to Section 10.5.4
To evaluate compliance using a daily PRO/ObsRO 
questionnaire
Rate of dosing instructions deviations (doses missed / 
not taken at the same time every day)
Refer to Section 10.5.5


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Objective
Endpoint
Analysis
To evaluate pre-dose PK data to support the 
assessment of compliance
Pre-dose deferasirox concentrations in all patients 
[except Egypt] at Weeks 1, 3, 5, 9, 13, 17, 21, 25, 29, 
33, 37, 41 and 45 visits(13 samples) 
Refer to Section 10.5.6.1
Post-dose data to be analyzed along with pre-dose 
PK data
Post-dose deferasirox concentrations between 2 and 
4 hours post-dose at Weeks 5 and 9 (2 samples)
Refer to Section 10.5.6.2
To explore exposure-response relationships for 
measures of safety and effectiveness 
Serum creatinine change from baseline, notable 
serum creatinine event, serum creatinine clearance 
change from baseline and notable serum creatinine 
clearance events, urine protein creatinine ratio 
change from baseline and serum ferritin change from 
baseline, in relationship to pre- and post-dose 
deferasirox concentrations.
Refer to Section 10.5.6.3
Secondary (Optional Extension phase)
To assess additional safety data about new 
formulation (granules) in pediatric population
Overall safety, as measured by frequency and 
severity of adverse events (including active 
monitoring for renal toxicity; including renal failure, 
hepatic toxicity; including hepatic failure, and 
gastrointestinal hemorrhage), and changes in 
laboratory values from baseline (serum creatinine, 
creatinine clearance, ALT, AST, RBC and WBC). In 
addition, vital signs, physical, ophthalmological, 
audiometric, and growth and development 
evaluations will be assessed.
Refer to Section 10.5.4 and Section 10.6.1


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4
Study design
4.1
Description of study design
This is a randomized, open-label, multicenter, two arm, phase II study to evaluate treatment 
compliance and change in serum ferritin over time of a deferasirox granule formulation and a 
deferasirox DT formulation in children and adolescents aged ≥ 2 and < 18 years at enrollment
with any transfusion-dependent anemia requiring chelation therapy due to iron overload, and 
having a treatment goal to reduce iron burden as measured by serum ferritin.
It is a pre-requisite for the patient to provide written consent/assent to participate in this study. 
Consent will be obtained from patients, parent(s) or legal guardians. Investigators will also 
obtain patient’s consent/assent according to local guidelines. This must be in place prior to 
performing any study-related procedures or assessments, including those described at the 
screening visits (Table 7-1).
As described in Figure 4-1, a screening period (from Day -21) will be used to assess eligibility 
of patients and will consist of two visits at least 7 days apart. All inclusion and exclusion criteria 
must be evaluated and documented in the source documents as being met and the results of all 
screening assessments must be available and reviewed by the investigator. Patients whose 
eligibility is confirmed will be enrolled and any current chelation therapy will be discontinued 
to undergo a 5-day chelation washout period (only applicable to patients previously treated with 
iron chelation therapy) prior to commencing a 48-week randomized treatment period with either 
deferasirox DT (taken as per local label) or deferasirox granule formulation (taken with or 
without a light meal) beginning on Day 1.    
All participants who have completed the core study as per protocol and who do not have local 
access to the new formulation (granules or FCT) have the option to continue to the optional 
extension phase of the study where they will be provided with granules until there is local access 
to the new formulation (granules or FCT) or up to 5 years from beginning extension phase, 
whichever occurs first. Patients on DT in the core phase will switch to granules in the optional 
extension, whereas those on granules in the core phase will remain on granules in the optional 
extension phase. Patients must have demonstrated benefit to granules or DT in the core phase, 
and/or express the wish to continue in the optional extension phase on granules in order to start 
the optional extension phase.
An end of treatment visit (EOT) will occur within 7 days of last dose of study drug and a Safety 
Follow-up 30 days following the last dose of study drug.

For patients participating in the optional extension phase, end of study and safety follow-
up will be performed within 30 days last dose was given in the optional extension phase.

For patients not participating in the optional extension phase, end of study and safety
follow up will occur within 30 days last dose was given in the core phase.
Randomization will be stratified using an interactive voice/web response system (IVRS/IWRS). 
The stratification will be defined by age groups (2 to <10 years, 10 to <18 years) and by prior 
ICT (Yes/No). Details on stratification will be outlined in the study manual provided by the 
IVRS vendor.


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At the start of treatment, ICT naïve patients will receive either deferasirox DT 20 mg/kg once 
daily or deferasirox granules 14 mg/kg once daily.
All ICT pre-treated patients will use a deferasirox DT or an equivalent strength-adjusted 
granules starting dose corresponding to their closest pre-washout dose, please refer to Appendix 
14.1.  
Study treatment should be administered by the patient once per day and the PRO questionnaires 
be completed by all patients aged between 10 and <18 years as per instructions provided by the 
investigator. During the 48 weeks treatment period, patients will return to the site for study 
assessments weekly for the first 3 weeks and then every 4 weeks starting from week 5 until the 
end of treatment visit, as specified in Table 7-1.
In the optional extension phase, all patients will be provided with the granules. Patients on DT 
formulation during the core phase will receive the equivalent strength-adjusted granules dose 
corresponding to the last DT dose in the core phase taking dose adjustment guidelines into 
account (please refer to Table 6-2 and Appendix 14.1). Patients in granules during the core 
phase will continue on the same dose as was given at the end of the core phase taking dose 
adjustment guidelines into account. Please refer to Table 6-2 as applicable.
Patients who discontinue study treatment before completing the core or optional extension 
phase should be scheduled for an end of treatment visit within 7 days of the last dose of study 
treatment, at which time all of the assessments listed for the end of treatment (Visit 777 (for the 
core) or Visit 779 (for the optional extension)) will be performed.
All patients, regardless if they discontinue the study treatment early or per protocol, will be 
contacted for safety evaluations for 30 days after the last dose of study treatment.
One interim analysis has been added to allow for early analysis of the core phase data if 
requested by the health authority. 
Figure 4-1
Study schema


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4.2
Timing of interim analyses and design adaptations
One interim analysis has been added to allow for early analysis of the data if requested by the 
health authority. All the analyses included in the interim analysis will be descriptive. The IA 
will be performed by the Novartis study team. No decisions regarding the future course of the 
trial is anticipated at the time of the IA and the trial will continue. 
All patients randomized in the study and who have completed a minimum of 12 weeks of 
treatment exposure or discontinued from treatment core phase at the time of the cut-off date 
will be included in the interim analysis (Section 10.7).
The cut-off for the primary analysis will be 24 weeks after approximately 96 ICT naive patients 
have been randomized. 
The core data analysis is planned when all patients have completed their 48 week study 
treatment in the core phase including safety follow-up (if applicable).
4.3
Definition of end of the study
Completion of this study as a whole will occur upon the availability and accuracy verification 
of the last data point required for statistical analysis of the optional extension phase. Data 
collection will terminate and End of Study will be declared after all patients have completed the 
treatment phase of the optional extension phase (up to 305 weeks) including the safety follow-
up period (30 days after treatment discontinuation).
4.4
Early study termination
The study can be terminated at any time for any reason by Novartis. Should this be necessary, 
the patient should be seen as soon as possible 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.
4.5
Rationale for Public Health Emergency mitigation procedures
During a Public Health emergency as declared by Local or Regional authorities i.e. pandemic, 
epidemic or natural disaster, mitigation procedures to ensure participant safety and trial integrity 
are listed in relevant sections. Notification of the Public health emergency should be discussed 
with Novartis prior to implementation of mitigation procedures, and permitted/approved by 
Local or Regional Health Authorities and Ethics Committees as appropriate.
5
Population
5.1
Patient population
Up to 216 ICT naïve and pre-treated (at least 96 ICT naïve and up to 120 pre-treated) male and 
female children and adolescents aged ≥ 2 and < 18 years at enrollment with any transfusion-
dependent anemia requiring chelation therapy due to iron overload, and a treatment goal to 


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reduce iron burden will be included in this study. At least 96 (48 per treatment arm) patients 
should be iron 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 enrollment in the study.
5.2
Inclusion criteria
Patients eligible for inclusion in this study have to meet all of the following criteria at screening 
Visit 1 and 2 unless otherwise specified:
1. Written informed consent/assent before any study-specific procedures. Consent will be 
obtained from parent(s) or legal guardians. Investigators will also obtain consent/assent of 
patients according to local guidelines.
2. Male and female children and adolescents aged ≥ 2 and < 18 years. [France: Male and 
female children and adolescent aged ≥ 2 and < 18 years old, however children aged ≥ 
2 and ≤ 6years can be enrolled only when deferoxamine treatment is contraindicated 
or inadequate in these patients as per investigator decision. Applicable to core phase 
only. Once in the core phase patients can turn 18 years and still be considered eligible, 
also for participation in the optional extension phase.
3. Any transfusion-dependent anemia associated with iron overload requiring iron chelation 
therapy and with a history of transfusion of approximately 20 PRBC units and a treatment 
goal to reduce iron burden (300mL PRBC = 1 unit in adults whereas 4 ml/kg PRBC is 
considered 1 unit for children).
4. Serum ferritin > 1000 ng/mL, measured at screening Visit 1 and screening Visit 2 (the mean 
will be used for eligibility criteria).
5. Patient has to have participated and completed the 48 weeks core phase treatment as per 
protocol (For optional extension phase eligibility only).
5.3
Exclusion criteria
1.
Creatinine clearance below the contraindication limit in the locally approved prescribing 
information (using Schwartz formula) at screening visit 1 or screening visit 2.
2. Serum creatinine > 1.5 xULN at screening Visit 1 or screening Visit 2.
3. ALT and/or AST > 3.0 x ULN at screening visit 1 or screening visit 2.
4. (Criterion no longer applicable, removed as part of Amendment 1): Prior iron chelation 
therapy
5. Liver disease with severity of Child-Pugh class B or C.
6. Significant proteinuria as indicated by a urinary protein/creatinine ratio > 0.5 mg/mg in a 
second morning urine sample at screening Visit 1 or screening Visit 2.
7. 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).
8. 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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9. 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.
10. Patients with a known history of HIV seropositivity (Elisa or Western blot).
11. 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 or squamous cell carcinoma of the skin.
12. Patients participating in another clinical trial or receiving an investigational drug.
13. History of hypersensitivity to any of the study drug or excipients.
14. 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.).
15. Female patients of childbearing potential (e.g. are menstruating) who do not agree to 
abstinence or, if sexually active, do not agree to the use of contraception as defined in 
Section 7.2.4.6.4.
16. For prohibited medication please refer to Section 6.3.2
17. Pregnant or nursing (lactating) women
18. Direct (conjugated) bilirubin >2 x ULN at screening visit 1 or screening visit 2.
19. History or current diagnosis of cardiac disease indicating significant risk of safety for 
patients participating in the study such as uncontrolled or significant cardiac disease, 
including any of the following:
●
Clinically significant (symptomatic) cardiac arrhythmias (e.g., sustained ventricular 
tachycardia, and clinically significant second or third degree AV block without a 
pacemaker).
20. Local access to new formulation (granules or FCT) is available (For optional extension 
phase eligibility only).
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 (during core phase).

Deferasirox granules will be provided as stick packs containing 90 mg, 180 mg and 360 
mg granules for oral use (during core and optional extension phase).
6.1.1
Dosing regimen
Having completed the Screening period (including the 5-day chelation washout period for 
patients previously treated with iron chelators), eligible patients for the core phase will be 
randomized to one of the following Treatment Arms in a ratio of 1:1:

Treatment Arm 1 with deferasirox DT

Treatment Arm 2 with deferasirox granules


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At the start of treatment, ICT naïve patients will receive either deferasirox DT 20 mg/kg once 
daily or deferasirox granules 14 mg/kg once daily. All ICT pre-treated patients will use a 
deferasirox DT or an equivalent strength-adjusted granules starting dose corresponding to their 
closest pre-washout dose, please refer to Appendix 14.1.
When creatinine clearance at study start is ≥40ml/min and <60 ml/min (where locally 
applicable), starting dose needs to be reduced by 50%. This means for treatment naive patients 
that they will need to start at 10 mg/kg for DT and 7 mg/kg for granules. For pretreated patients, 
they will need to start at 50% of the pre-washout dose when creatinine clearance ≥40ml/min 
and <60 ml/min during at least one screening visit. For patients with an already existing reduced 
creatinine clearance (≥40ml/min and <60 ml/min before study start), a dose reduction of 50% 
is only necessary when this was not already performed.
In the optional extension phase, all patients will be provided with the granules at visit 17. 
Patients on DT formulation during the core phase will receive the equivalent strength-adjusted 
granules dose corresponding to the last DT dose in the core phase taking dose adjustment 
guidelines into account (please refer to Table 6-2 and Appendix 14.1). Patients in granules 
during the core phase will continue on the same dose as was given at the end of the core phase 
taking dose adjustment guidelines into account. Please refer to Table 6-2 as applicable.
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/stick pack according to the 
available strengths of deferasirox formulations (125 mg, 250 mg and 500 mg for the DT and 90 
mg, 180 mg and 360 mg for the granules, see Appendix 14.1).
Recommended 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 - 7.0 mg/kg/day for deferasirox 
granules.
During the optional extension phase, dose adjustments in steps of 3.5 to 7.0 mg/kg for 
deferasirox granules are also only allowed every 3 months.
Dose adjustments based on safety are allowed at any time point in the study. The maximum 
dose of deferasirox DT will be 40 mg/kg/day and the maximum dose of deferasirox granules 
will be 28 mg/kg/day.
The starting dose and the dose adjustment considerations must take into account that the 
therapeutic goal is reduction of iron burden (as opposed to maintenance of iron burden).
The investigator should instruct the patient and/or the legal patient’s representative to take the 
study treatment as prescribed. All doses planned and prescribed to the patient and all dose 
changes, including the reasons for change, during the study must be recorded in the electronic 
Case Report Form (eCRF).
During the regular study visits, the investigator or pharmacist will dispense to the patient and/or 
legal patient’s representative, an appropriate number of deferasirox tablets / stick packs 
depending on the patients calculated dose and Treatment Arm assignment. The number of 
tablets / stick packs of each strength dispensed will be recorded in the Study Drug Dosing Log. 
Each time the deferasirox study treatment is dispensed to the patient and/or legal patient’s 


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representative, the investigator will provide detailed instructions on how to prepare and 
administer the dose. Patients / caregivers will be instructed to take / to administer the assigned 
amount of study drug and to return all unused study medication including empty stick packs 
and bottles at their next visit. Study medication returned at each visit will be counted and unused 
study medication will be recorded by the investigator/ pharmacist involved in the study. Drug 
accountability will be noted by the field monitor during site visits and at the completion of the 
trial.
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 randomized to Treatment arm 1 will take the deferasirox DT every day on an empty 
stomach, at least 30 minutes before the next meal. The patient will disperse the required number 
of deferasirox tablets in an appropriate amount 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.
Patients randomized to Treatment arm 2 should administer the granules by sprinkling the full 
dose on a soft food (e.g., yogurt, applesauce or warm porridge). The dose should be immediately 
and completely consumed, and not stored for future use. The granules should be taken once a 
day, preferably at the same time each day, and may be taken on an empty stomach or with a 
light meal.
It is recommended that the doses be timed such that they occur at almost the same time each 
day. For example, if the patient took the study medication at 8:00AM on first day of treatment, 
the subsequent dose would also be taken at approximately 8:00AM on the next day, and so on.  
Table 6-1
Dose and treatment schedule
Study 
treatments
Pharmaceutical form 
and route of 
administration
Starting Dose*
Dose 
adjustment 
steps
Maximum 
dose
Frequency
Deferasirox DT
Dispersible tablets, 
p.o.
20 mg/kg/day 
(10 mg/kg/day 
when creatinine 
clearance ≥ 40 
and <60 ml/min)
+/- 5-10
mg/kg/day
40 mg/kg/day
Once daily
Deferasirox 
granules
Granules, p.o.
14 mg/kg/day (7 
mg/kg/day 
when creatinine 
clearance ≥ 40 
and <60 ml/min)
+/- 3.5-7.0
mg/kg/day
28 mg/kg/day
Once daily
*Iron chelation naïve patients. For all iron chelation pre-treated patients see Section 6.1.1 and Appendix 14.2
for guidance.


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6.1.2
Treatment duration
The total duration of study treatment during the core phase is 48 weeks. The total duration of 
the core phase is approximately 55 weeks (including the Screening, Treatment and Safety 
Follow-up visits).
The maximum duration of the optional extension phase will be 5 years. This optional extension 
phase will give the patients who have participated and completed the 48 weeks core treatment 
phase as per protocol and do not have access to the new formulation (granules or FCT) the 
possibility to extend treatment with deferasirox granules until there is local access to the new 
formulation (granules or FCT) or up to 5 years from entering extension phase, whichever occurs 
first. Patients must have demonstrated benefit to granules or DT in the core phase, and/or 
express the wish to continue in the optional extension phase on granules in order to start the 
optional extension phase.
6.2
Dose modifications
6.2.1
Permitted study drug adjustments
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.
For all cases where a dose adjustment is considered necessary but is not covered in the following 
sections, the investigator must 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.
Any dose-adjustments for any reason, specified by the protocol (such as safety, efficacy, other) 
or not, must be recorded on the dosage administration record eCRF together with the reason for 
each dose-adjustment. It is important to keep accurate dose-adjustment records to enable an 
adequate evaluation of the co-primary endpoint of compliance.
A summary of dose adjustment guidelines is presented in Table 6-2.


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Table 6-2
Criteria for interruption and re-initiation of Deferasirox treatment
Dose modifications for deferasirox
Body weight
Increase/decrease of weight by >10% compared to Visit 
3 (baseline weight) or body weight at last dose 
adjustment due to change in patient’s body weight
Dose of study medication needs to be adapted using Dosing Table (provided in Appendix 14.2). Only when 
weight changes with >10% compared to baseline weight or body weight at last dose adjustment due to 
change in patient’s body weight, dose needs to be adapted. Smaller variations in body weight (<10%) 
during study, does not require adjustments in dose. In this case, baseline body weight can be used to 
calculate correct dose.
Investigations (Renal)
Serum creatinine and/or creatinine clearance
Single increase in serum creatinine ≥33%
Maintain dose level and repeat the assessment at next visit as clinically indicated
For pediatric patients:
   - Single increase ≥33% above baseline value (visit 
3/week1) and >ULN
For adult patients:
   - Increases by 33% or more above the baseline (visit 
3/week1) measurement, repeat the serum creatinine 
within 1 week, and if still elevated by 33% or more
Deferasirox dose reduction by 10 mg/kg/day for the DT and by 7 mg/kg/day for the granules is necessary.
If after a dose reduction, a progressive increase in serum creatinine beyond the ULN is observed, a 
treatment interruption is mandated.
If after dose reduction/interruption, resolution of serum creatinine occurs (<33%) at the next study visit and 
within normal limits, dose can be resumed again at 100%. If increase in serum creatinine reoccurs again 
within 2 months according to guidelines above, therapy needs to be reduced to 50% of the last dose.
After 2 months, if the serum creatinine increase does not recur, study medication can be returned to 100% 
of the last dose.
Creatinine clearance between 40 and less 60 mL/min
Reduce dose with 50%.
If after dose reduction, resolution of creatinine clearance occurs (>60 ml/min), dose can be resumed again 
at 100%.
Creatinine clearance < 40 mL/min or serum creatinine 
increases > 2 times the age-appropriate ULN
Deferasirox therapy must be discontinued


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Investigations (Hepatic)
Isolated direct (conjugated) Bilirubin elevation
> ULN – 2 x ULN
Maintain dose level
> 2 - 3.0 x ULN 
Omit dose with weekly monitoring of LFTsa, or more frequently if clinically indicated, until resolved to ≤ 2.0 
x ULN:
If resolved in ≤ 14 days, then maintain dose level
If resolved in > 14 days, then dose reduction of 5 or 10 mg/kg/day for deferasirox DT and of 3.5 or 7 
mg/kg/day for deferasirox granules.
> 3.0 - 10.0 x ULN* 
Omit dose with weekly monitoring of LFTsa, or more frequently if clinically indicated, until resolved to ≤ 2.0 
x ULN:
If resolved in ≤ 14 days, then dose reduction of 5 or 10 mg/kg/day for deferasirox DT and of 3.5 or 7 
mg/kg/day for deferasirox granules.
If resolved in > 14 days, then discontinue patient from study drug treatment. The patient needs to be 
monitored weekly (including LFTsa), or more frequently if clinically indicated, until direct (conjugated) 
bilirubin have resolved to baseline or stabilization over 4 weeks.
> 10.0 x ULN*
Discontinue patient from study drug treatment
The patient needs to be monitored weekly (including LFTsa), or more frequently if clinically indicated, until 
direct (conjugated) bilirubin have resolved to baseline or stabilization over 4 weeks.
Isolated AST or ALT elevation
> ULN - 3.0 x ULN
Maintain dose level
> 3.0 - 5.0 x ULN
For patients with baseline value ≤ 3.0 x ULN
For patients with baseline value > 3.0 -5.0 x ULN
Maintain dose level. Repeat LFTsa as soon as possible, preferably within 48-72 hours from awareness of 
the abnormal results; if abnormal lab values are confirmed upon the repeat test, then monitor LFTsa
weekly, or more frequently if clinically indicated, until resolved to ≤ 3.0 x ULN
Maintain dose level


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> 5.0 - 10.0 x ULN
For patients with baseline value ≤ 3.0 x ULN
For patients with baseline value > 3.0 -5.0 x ULN
Omit dose. Repeat LFTsa as soon as possible, preferably within 48-72 hours from awareness of the 
abnormal results; monitor LFTsa weekly, or more frequently if clinically indicated, until resolved to ≤ 3.0 x 
ULN
If resolved in ≤ 14 days, maintain dose level
If resolved in > 14 days, then dose reduction of 5 or 10 mg/kg/day for deferasirox DT and of 3.5 or 7 
mg/kg/day for deferasirox granules.
Maintain dose level. Repeat LFTsa as soon as possible, preferably within 48-72 hours from awareness of 
the abnormal results; if abnormal lab values are confirmed upon the repeat test, then monitor LFTsa, 
weekly, or more frequently if clinically indicated, until resolved to ≤ 5.0 x ULN
> 10.0 - 20.0 x ULN 
Omit dose. Repeat LFTsa as soon as possible, preferably within 48-72 hours from awareness of the 
abnormal results; monitor LFTsa weekly, or more frequently if clinically indicated, until resolved to ≤ 
baseline. Then dose reduction of 5 or 10 mg/kg/day for deferasirox DT and of 3.5 or 7 mg/kg/day for 
deferasirox granules.
> 20.0 x ULN
Discontinue patient from study drug treatment
Repeat LFTsa as soon as possible, preferably within 48-72 hours from awareness of the abnormal results; 
monitor LFTsa weekly, or more frequently if clinically indicated, until resolved to baseline or stabilization 
over 4 weeks.
Combined b elevations of AST or ALT and bilirubin (direct (conjugated) and/or total)
For patients with normal baseline ALT or AST or direct 
(conjugated) bilirubin value:
AST or ALT >3.0xULN combined with direct (conjugated) 
bilirubin >2.0 x ULN without evidence of cholestasisc
OR
(Note to study team: If supported by available data) For 
patients with elevated baseline AST or ALT or direct 
(conjugated)bilirubin value 
[AST or ALT>2x baseline AND > 3.0 xULN] OR [AST or 
ALT > 8.0 xULN], whichever is lower, combined with 
[direct (conjugated) bilirubin >2x baseline AND >2.0 
xULN
Permanently discontinue patient from study drug treatment.
Repeat as soon as possible, preferably within 48 hours from awareness of the abnormal results, then with 
weekly monitoring of LFTsa), or more frequently if clinically indicated, until AST, ALT, or bilirubin have 
resolved to baseline or stabilization over 4 weeks. Refer to Section 6.3.2 for additional follow-up 
evaluations as applicable.


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Dose modifications for deferasirox
For patients with normal baseline ALT or AST or total 
bilirubin value:
AST or ALT >3.0xULN combined with total 
bilirubin >2.0xULN without evidence of cholestasisc
OR
(Note to study team:  If supported by available data) For 
patients with elevated baseline AST or ALT or total 
bilirubin value
[AST or ALT>2x baseline AND >3.0xULN]  OR [AST or 
ALT>8.0 ULN], whichever is lower, combined with total 
bilirubin >2x baseline AND >2.0xULN
Permanently discontinue patient from study drug treatment.
Repeat as soon as possible, preferably within 48 hours from awareness of the abnormal results, then with 
weekly monitoring of LFTsa), or more frequently if clinically indicated until AST, ALT, or bilirubin have 
resolved to baseline or stabilization over 4 weeks.  Refer to Section 6.3.2 for additional follow-up 
evaluations as applicable.  
Hepatic impairment
Moderate hepatic impairment (Child-Pugh Class B)
The study medication will be interrupted and patient monitored. If liver disease prognosis improves, 
deferasirox can be reintroduced at 10 mg/kg/day for DT and at 7 mg/kg/day for granules or 50% of 
previous dose, whichever is less. While monitoring continues, dose may be increased by 5 mg/kg/day for 
DT and by 3.5 mg/kg/day for granules every 2 weeks, to a maximum of 50% of patient’s previous dose if 
the investigator determines that dose increase is in the best interest of the patient. Study medication must 
be used with caution in such patients.
In patients who develop severe hepatic impairment 
(Child-Pugh Class C) during the study
Study medication must be discontinued.
Other dose modifications
Changes in Serum Ferritin
The dose of deferasirox DT or granules should be adjusted if necessary every 3 months based on the 
trends in serum ferritin and investigator’s judgement. ICT naïve patients can adapt dose after 4 weeks.
Dose adjustments need to be made in steps of 5 or 10 mg/kg/day for deferasirox DT and of 3.5 or 7 
mg/kg/day for deferasirox granules and are to be tailored to the individual patient’s response and the 
therapeutic goal of (reduction of iron burden). In patients not adequately controlled with deferasirox DT 
doses of 30 mg/kg/day, doses of up to 40 mg/kg/day may be considered. In patients not adequately 
controlled with deferasirox granules doses of 21 mg/kg/day, doses of up to 28 mg/kg/day may be 
considered. The starting dose and the dose adjustment considerations must take into account that the 
therapeutic goal is reduction of iron burden (as opposed to maintenance of iron burden). Doses above 40 
mg/kg/day for deferasirox DT and above 28 mg for deferasirox granules are not allowed.


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Dose modifications for deferasirox
500 – 1000 ng/mL
Dose reductions in steps of 5 to 10 mg/kg/day for deferasirox DT and of 3.5 or 7 mg/kg/day for deferasirox 
granules is required to maintain serum ferritin levels within the target range.
< 500 ng/ml
Interruption of study treatment is required until serum ferritin rises above 500 ng/mL
Changes in urine protein/creatinine ratio
For patients who develop proteinuria or a worsening of pre-existing proteinuria (assessed by a dipstick) at any visit, urine samples should be collected and assessed by 
the central laboratory. [Egypt: Local laboratory]
In case of a single increase of the urinary protein/creatinine ratio the assessment should be repeated at the next visit.
> 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 dose reduction by 50%
When resolution of UPCR (<0.5mg/mg) at the next study visit, dose can be resumed again at 100%
If increase in UPCR >0.5mg/mg recurs again within 2 months after initial increase, therapy needs to be 
reduced to 50% of the last dose. If increase in UPCR does not recur after 2 months at reduced dose 
(50%) , study medication can be returned to 100% of the last dose
> 1.0 (mg/mg) in one single second-void urine samples.
Interrupt study treatment.
When resolution of increase in UPCR (<0.5mg/mg) at the next study visit, dose can be resumed again at 
50% of the last dose. If increase in UPCR does not recur after 1 month at reduced dose (50%), study 
medication can be returned to 100% of the last dose.
In case of persistent proteinuria 
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 
laboratory results. [Egypt: Local laboratory]
Severe skin reactions
Severe skin reactions, including Stevens-Johnson 
syndrome (SJS) and Toxic epidermal necrosis (TEN)
Have to be reported during Exjade therapy.
If SJS or TEN are suspected, study treatment must be immediately discontinued and not be reintroduced
Skin Rash (other than SJS)
For skin rash of mild/moderate severity (defined as those 
causing minimal symptoms which require no or minimal 
supportive treatment)
Study drug should be continued without dose adjustment. The skin rash may resolve spontaneously 
without further intervention. If the rash persists for >1 week or becomes more severe, 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 dose back to 100% of patients dose after 2 weeks.


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Severe rash (distressing symptoms requiring 
discontinuation and/or systemic steroids)
Discontinue treatment until resolution of rash.
Once the rash has resolved, resume at 50% of patient’s dose. If necessary, a brief course of oral steroids 
may be given concurrently with resumption of study drug. If the rash does not recur, increase by steps of 5 
mg/kg/day for deferasirox DT and of 3.5 mg/kg/day for deferasirox granules every 2 weeks until 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
Dose modification criteria for auditory and ocular disturbances
Auditory (decreased hearing) and ocular (lens opacities) 
disturbances have been reported with deferasirox 
treatment.
Auditory and ophthalmic testing (including fundoscopy) is required before the start of deferasirox treatment.
If disturbances are noted dose reduction or interruption may be considered and a repeated testing 
performed as per investigator’s judgement.
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.
Deferasirox should not be reintroduced in patients who have experienced previous hypersensitivity 
reactions on Exjade due to the risk of anaphylactic shock
Dose modification criteria for cytopenias
Unexpected 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.


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Gastrointestinal disturbances
Gastrointestinal issues (including diarrhea, constipation, 
nausea, vomiting and abdominal pain)
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 the patient to 
discontinue any laxative preparations or stool softeners they may be taking and to 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; however the deferasirox granules do 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.
Should the gastrointestinal issues (including diarrhea, constipation, nausea, vomiting and abdominal pain) 
persist, study drug may be discontinued if the investigator believes it is in the best interest of the patient.
Novartis may be contacted by the investigator to discuss dosing options if the investigator so desires.
All dose modifications should be based on the worst preceding toxicity.
a Core LFTs consist of ALT, AST, GGT, total bilirubin (fractionated [direct and indirect], if direct (conjugated) bilirubin > 2.0 x ULN), and alkaline phosphatase 
(fractionated [quantification of isoforms], if alkaline phosphatase > 2.0 x ULN.)
b “Combined” defined as direct (conjugated) bilirubin  increase to the defined threshold concurrently with ALT/AST increase to the defined threshold
If combined elevations of AST or ALT and direct (conjugated) bilirubin do not meet the defined thresholds, please follow the instructions for isolated elevation of direct 
(conjugated) bilirubin and isolated elevation of AST/ALT, and take a conservative action based on the degree of the elevations (e.g. discontinue treatment at the 
situation when omit dose is needed for one parameter and discontinue treatment is required for another parameter). After all elevations resolve to the defined 
thresholds that allow treatment re-initiation, re-start the treatment either at the same dose or at one dose lower if meeting a criterion for dose reduction
c “Cholestasis” defined as ALP elevation (>2.0 xULN and R value <2 ) in patients without bone metastasis, or elevation of ALP liver fraction in patients with bone 
metastasis
Note: The R value is calculated by dividing the ALT by the ALP, using multiples of the ULN for both values. It denotes the relative pattern of ALT and/or ALP elevation 
is due to cholestatic or hepatocellular liver injury
* Note: If total bilirubin > 3.0 x ULN is due to the indirect (non-conjugated) component only, and hemolysis as the etiology has been ruled out as per institutional 
guidelines (e.g., review of peripheral blood smear and haptoglobin determination), then dose reduction of 5 or 10 mg/kg/day for deferasirox DT and of 3.5 or 7 
mg/kg/day for deferasirox granules and continue treatment at the discretion of the investigator.


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6.2.2
Treatment interruption and treatment discontinuation
Patients who permanently discontinue study drug before completing the core phase should be 
scheduled for an End of Treatment visit within 7 days from last dose, at which time all of the 
assessments listed for the End of treatment visit will be performed. Patients discontinuing the 
optional extension phase at any time need to be scheduled for an End of Treatment visit within 
7 days of the last dose. The End of Treatment eCRF should be completed for all patients at the 
end of both the core and the optional extension treatment phases, documenting the date and 
reason for stopping randomized study treatment. For the core phase the patient will be asked if 
they are continuing on to the optional extension phase. 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, will be contacted by the investigational site for safety evaluations during the 30 
days following the last dose of study drug and the Study Evaluation Completion eCRF should 
be completed.
Patients who discontinue study drug should be considered withdrawn from the study after the 
final visit assessments are performed or when it is clear that the patient will not return for these 
assessments.
All patients must be followed for AEs and SAEs for 30 days after the last dose of study 
treatment. Patients lost to follow up should be recorded as such on the eCRF. For patients who 
are lost to follow-up, the investigator should show “due diligence” by documenting in the source 
documents steps taken to contact the patient, e.g., dates of telephone calls, registered letters, etc.
6.2.3
Follow-up for toxicities
All patients will be followed for at least 30 days following their last dose of treatment. Patients 
whose treatment is interrupted due to an adverse event or abnormal laboratory value must be 
followed at least once a week for 4 weeks, and subsequently at 4 week intervals, until resolution 
or stabilization of the event, whichever comes first. Patients whose treatment is permanently 
discontinued due to an adverse event or abnormal laboratory value must be followed (for 
adverse events and serious adverse events) for at least 30 days following the last dose of 
treatment.
6.2.4
Follow up on potential drug-induced liver injury (DILI) cases
Patients with transaminase increase combined with TBIL increase may be indicative of 
potential DILI, and should be considered as clinically important events.
The threshold for potential DILI may depend on the patient’s baseline AST/ALT and TBIL 
value; patients meeting any of the following criteria will require further follow-up as outlined 
below:


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
For patients with normal ALT or AST or TBIL value at baseline: AST or ALT > 3.0 x 
ULN combined with TBIL > 2.0 x ULN

For patients with elevated AST or ALT or TBIL value at baseline: [AST or ALT > 2 x 
baseline AND > 3.0 x ULN] OR [AST or ALT > 8.0 x ULN], whichever is lower, 
combined with [TBIL > 2 x baseline AND > 2.0 x ULN]
Medical review needs to ensure that liver test elevations are not caused by cholestasis, defined 
as ALP elevation > 2.0 x ULN with R value < 2 in patients without bone metastasis, or elevation 
of ALP liver fraction in patients with bone metastasis.
Note: (The R value is calculated by dividing the ALT by the ALP, using multiples of the ULN 
for both values. It denotes the relative pattern of ALT and/or ALP elevation is due to cholestatic 
or hepatocellular liver injury).
In the absence of cholestasis, these patients should be immediately discontinued from study 
drug treatment, and repeat LFT testing as soon as possible, preferably within 48 hours from the 
awareness of the abnormal results. The evaluation should include laboratory tests, detailed 
history, physical assessment and the possibility of liver metastasis or new liver lesions, 
obstructions/compressions, etc.

Laboratory tests should include ALT, AST, albumin, creatine kinase, total bilirubin, direct 
and indirect bilirubin, GGT, prothrombin time (PT)/INR and alkaline phosphatase.

A detailed history, including relevant information, such as review of ethanol, concomitant 
medications, herbal remedies, supplement consumption, history of any pre-existing liver 
conditions or risk factors, should be collected.

Further testing for acute hepatitis A, B, C or E infection and liver imaging (e.g. biliary 
tract) may be warranted.

Obtain PK sample, as close as possible to last dose of study drug, if PK analysis is 
performed in the study.

Additional testing for other hepatotropic viral infection (CMV, EBV or HSV), 
autoimmune hepatitis or liver biopsy may be considered as clinically indicated or after 
consultation with specialist/hepatologist.
All cases confirmed on repeat testing meeting the laboratory criteria defined above, with no 
other alternative cause for LFT abnormalities identified should be considered as “medically 
significant”, thus, met the definition of SAE (Section 8.2.1) and reported as SAE using the term 
“potential drug-induced liver injury”. All events should be followed up with the outcome clearly 
documented.
6.2.5
Anticipated risks and safety concerns of the study drug
Appropriate eligibility criteria as well as specific dose modification rules are included in this 
protocol. Guidelines for prophylactic or supportive treatment for expected toxicities, including 
management of study-drug induced adverse events, i.e., please refer to Section 6.2.1 (Table 6-
2).
Refer to preclinical toxicity and or clinical data found in the [Investigator’s Brochure].


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6.3
Prior and Concomitant medications
The patient must be told to notify the investigational site about any prior and new medications 
he/she takes after the start of the study drug. All medications (other than study drug) and 
significant non-drug therapies (including physical therapy and herbal/natural medications) 
administered during the study must be listed on the Concomitant Medications eCRF.
6.3.1
Permitted concomitant therapy requiring caution and/or action
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 were also 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 of ≥9 g/dL. If transfusion needs to be performed on a PK sampling day, PK 
sampling must occur prior to the transfusion.
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.

Deferasirox, as a weak CYP3A4 inducer, may potentially decrease serum levels of 
substances metabolized through CYP3A4 (e.g. alfentanil, aprepitant, budesonide, buspirone, 
conivaptan, 
cyclosporine, 
darifenacin, 
darunavir, 
dasatinib, 
dihydroergotamine, 
dronedarone, eletriptan, eplerenone, everolimus, felodipine, fentanyl, hormonal 
contraceptive agents, indinavir, fluticasone, lopinavir, lovastatin, lurasidone, maraviroc, 
midazolam, nisoldipine, pimozide, quetiapine, quinidine, saquinavir, sildenafil, simvastatin, 
sirolimus, tacrolimus, tolvaptan, tipranavir, triazolam, ticagrelor, and vardenafil).

Deferasirox is a moderate inhibitor of CYP2C8 and therefore it may increase serum 
concentrations of substances metabolized through CYP2C8 (e.g. repaglinide, paclitaxel).

Deferasirox can potentially increase the exposure of the concomitantly administered 
CYP1A2 substrates (e.g. theophylline, clozapine, tizanidine). When deferasirox and 
theophylline are used concomitantly, monitoring of theophylline concentration and 
theophylline dose reduction should be considered.

The concomitant use of deferasirox with potent UGT inducers (e.g. rifampicin, phenytoin, 
phenobarbital, ritonavir) may result in a decrease in deferasirox efficacy due to a possible 
decrease in deferasirox concentration.


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6.3.2
Prohibited concomitant therapy

Aluminium containing antacid therapies should be avoided because they may bind to 
deferasirox.

Concomitant use of bile acid sequestrants decreases deferasirox systemic exposure. Avoid 
the concomitant use of bile acid sequestrants (e.g., cholestyramine, colesevelam, colestipol) 
with deferasirox.

Concomitant use of any other iron chelation therapy (deferoxamine, deferiprone, 
deferasirox) during study treatment phases are not allowed.

Any investigational drug other than study medication.
6.4
Patient numbering, treatment assignment or randomization
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.
The investigator or designated staff will contact the IRT and provide the requested identifying 
information for the patient to register them into the IRT. Once assigned, the Patient No. must 
not be reused for any other patient and the Patient No. for that individual must not be changed, 
even if the patient is re-screened. If the patient fails to be randomized or start treatment for any 
reason, the reason will be entered into the Screening Log.
IRT must be notified within 2 days that the patient was not randomized.
6.4.2
Treatment assignment or randomization
Patients will be assigned to one of the 2 treatment arms, deferasirox DT or granules (Section 
4.1 and Section 6.1) in a ratio of 1:1 during the core phase.
Randomization will be stratified by age groups (2 to <10 years, 10 to <18 years) and by prior 
ICT (Yes/No). The randomization numbers will be generated using the following procedure to 
ensure that treatment assignment is unbiased and concealed from patients and investigator staff. 
A patient randomization list will be produced by the Interactive Response Technology (IRT) 
provider using a validated system that automates the random assignment of patient numbers to 
randomization numbers. These randomization numbers are linked to the different treatment 
arms, which in turn are linked to medication numbers. A separate medication randomization list 
will be produced by or under the responsibility of Novartis Drug Supply Management using a 
validated system that automates the random assignment of medication numbers to medication 
packs containing each of the study treatments.
Prior to dosing, all patients who fulfill all inclusion/exclusion criteria will be randomized via 
IRT to one of the treatment arms. The investigator or his/her delegate will call or log on to the 
IRT and confirm that the patient fulfills all the inclusion/exclusion criteria. The IRT will assign 


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a randomization number to the patient, which will be used to link the patient to a treatment arm 
and will specify a unique medication number for the first package of study treatment to be 
dispensed to the patient. The randomization number will not be communicated to the caller.
During optional extension phase, all patients will be provided with new deferasirox formulation 
(granules). No randomization will be done.
6.4.3
Treatment blinding
This is an open-label study and patients, investigators, study site staff and sponsor will have full 
knowledge of treatment allocation.
In order to minimize the potential impact of treatment knowledge, until the primary analysis is 
conducted, no aggregated statistical analysis (efficacy or safety) will be performed by treatment, 
other than the analyses specified in the protocol (Section 4.2).
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. All dosages prescribed to the patient and all dose changes during the study must 
be recorded on the Dosage Administration Record eCRF.
As per Section 4.5, during a Public Health emergency as declared by Local or Regional 
authorities i.e. pandemic, epidemic or natural disaster, that limits or prevents on-site study visits, 
delivery of Investigational Medicinal Product (IMP) directly to a participant’s home may be 
permitted (if allowed by Local or Regional Health Authorities and Ethics Committees as 
appropriate) in the event the Investigator has decided that an on-site visit by the participant is 
no longer appropriate or possible, and that it is in the interest of the participant’s health to 
administer the study treatment even without performing an on-site visit. The dispatch of IMP 
from the site to the participant’s home remains under the accountability of the Investigator. 
Each shipment/provisioning will be for a maximum of 1 month’s supply. In this case, regular 
phone calls or virtual contacts (every 4 weeks or more frequently if needed) will occur between 
the site and the participant for instructional purposes, safety monitoring, drug accountability, 
investigation of any adverse events, ensuring participants continue to benefit from treatment 
and discussion of the participant´s health status until the participants can resume visits at the 
study site.
6.5.1
Study drug packaging and labeling
The study medication packaging has a 2-part label. A unique medication number is printed on 
each part of this label which corresponds to one of the treatment arms. Responsible site 
personnel will identify the study treatment package(s) to dispense to the patient by using the 
IRT and obtaining the medication number(s). Site personnel will add the patient number on the 
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 source document (Drug Label Form) 
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.


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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
Patient compliance with study treatment, the co-primary variable in this study, will be evaluated 
using the stick pack/tablet count (for detailed information please refer to Section 7.2.1)
Compliance will be assessed by the investigator and/or study personnel every 4 weeks and 
information provided by the patient and/or caregiver will be captured in the Drug 
Accountability Log. This information must be captured in the source document at each patient 
visit.
6.5.3.2
Study drug accountability
Information on study drug prescribing will be collected on the Dose Administration Record 
(DAR) eCRF and will include the planned daily dose, actual daily dose taken, reason for the 
dose change, start date and end date.
The investigator or designee must maintain an accurate record of the shipment and dispensing 
of study treatment in a drug accountability log. Drug accountability will be noted by the field 
monitor during site visits and at the completion of the study. Patients / caregivers 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 or to the Novartis address provided in the investigator 
folder at each site.
6.5.4
Disposal and destruction
The study drug supply can be destroyed at the local Novartis facility, Drug Supply group or 
third party, as appropriate.
7
Visit schedule and assessments
7.1
Study flow and visit schedule
Table 7-1 lists all of the assessments for the core phase and Table 7-2 lists all of the assessments 
for the optional extension phase and both indicate with an “X”, the visits when they are 
performed. Patients in the core phase who complete Visit 16 and decide to proceed to the 
optional extension phase will begin following all the assessments included in the visit 777 in 
Table 7-1 and then follow the optional extension assessment visit 17 listed in Table 7-2 on the 


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same day so as to avoid a gap in treatment. Patients who were on the DT arm during core phase 
of study who have switched to granules at Visit 17 as part of the optional extension phase will 
need to return weekly (Visits 18, 19 and 20) for the first month after beginning the optional 
extension phase (granules) for serum creatinine and creatinine clearance. Thereafter they will 
follow the same schedule as patients who were on granules arm during the core phase. Visit 
778 should not be completed by patients who continue into the optional extension phase. Should 
a patient discontinue the core phase at or prior to Visit 16, they should perform Visits 777 and 
778 including safety follow up as per Table 7-1.
Patients in the optional extension phase will complete Visit 779 and 780 at the end of the study 
or in case of earlier discontinuation.
Patients should be seen for all visits to perform the scheduled assessments on the designated 
day, or as close to is as possible, i.e., for the core phase not exceeding ± 2 days for assessments 
scheduled in Visits 1 to 6 and ± 7 days for all other visits until End of Treatment Visit 777. For 
the optional extension phase, not exceeding ± 7 days for all visits until End of Treatment Visit 
779. In this clinical trial, a week is 7 calendar days. For yearly assessments in extension phase, 
i.e. audiometry, ocular and growth and development examinations, ± 30day window is allowed.
All visits should be scheduled respective to the randomization date (Visit 3) for the core phase, 
rather than in relation to the previous visits. For the optional extension phase, all visits should 
be scheduled respective to Visit 17.
All data obtained from these assessments must be supported in the patient’s source 
documentation. No eCRF pages will be used as a source document.
As per Section 4.5, during a Public Health emergency as declared by Local or Regional 
authorities i.e. pandemic, epidemic or natural disaster that limits or prevents on-site study visits, 
alternative methods of providing continuing care may be implemented by the investigator as 
the situation dictates. If allowed by local Health Authority and depending on operational 
capabilities, phone calls, virtual contacts (e.g. tele consult) can replace on-site study visits, for 
the duration of the disruption until it is safe for the participant to visit the site again.
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
Study Procedure
Category
Protocol Section 
Screening
(2 visits 
at least 
7days 
apart)
Core Treatment Phase
End of 
CoreTreatment 
(continue to 
Visit 17 in 
Table 7-2 if 
going into 
extension 
phase) 
Study Evaluation 
Completion (Core 
phase) including 
Safety Follow up 
if not continuing 
to optional 
extension phase
Visit:
1
2
3
4
5
6
7
8
9
10
11
12, 13, 
14, 15 
&16
777
778
Week:
-3 Weeks
1
2
3
5
9
13
17 
21
25
29, 33, 
37, 41 & 
45 
(monthly)
Within 7 days 
of last dose 
for patients 
not 
participating 
in extension 
phase. (Week 
49 if going into 
extension 
phase.)
30 days after last 
dose
Obtain Informed Consent 
(and assent per local 
guidelines)
(D)
7.1.1
X
Randomization
(D)
6.4
X
Inclusion/exclusion criteria
(D)
7.1.1.3
X
X
Demography
(D)
7.1.1.3
X
Relevant medical 
history/current medical 
conditions
(D)
7.1.1.3
X
Prior chelation therapy
(D)
7.1.1.3
X
Disease history
(D)
7.1.1.3
X


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Study Procedure
Category
Protocol Section 
Screening
(2 visits 
at least 
7days 
apart)
Core Treatment Phase
End of 
CoreTreatment 
(continue to 
Visit 17 in 
Table 7-2 if 
going into 
extension 
phase) 
Study Evaluation 
Completion (Core 
phase) including 
Safety Follow up 
if not continuing 
to optional 
extension phase
Visit:
1
2
3
4
5
6
7
8
9
10
11
12, 13, 
14, 15 
&16
777
778
Week:
-3 Weeks
1
2
3
5
9
13
17 
21
25
29, 33, 
37, 41 & 
45 
(monthly)
Within 7 days 
of last dose 
for patients 
not 
participating 
in extension 
phase. (Week 
49 if going into 
extension 
phase.)
30 days after last 
dose
Prior medications and non-
drug therapies
(D)
6.3
X
X
Physical examination
(S)
7.2.4.1
X
X
X
X
X
X
X
X
X
X
X
X
Vital signs
(D)
7.2.4.2
X
X
X
X
X
X
X
X
X
X
X
X
X
Height 
(D)
7.2.4.3
X
X
X
X
X
X
X
X
X
X
X
X
X
Weight
(D)
7.2.4.3
X
X
X
X
X
X
X
X
X
X
X
X
X
Audiometry
(D)
7.2.4.4
X
Ocular Exam
(D)
7.2.4.5
X
X
X
ECG
(D)
7.2.4.7.1
X
X
Echocardiogram
(D)
7.2.4.7.2
X
X
Growth and development
(D)
7.2.4.8
X
X
Transfusion/RBC History
(D)
7.1.1.3
X
Transfusions
(D)
7.1.1.3
X
X
X
X
X
X
X
X
X
X
X


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Study Procedure
Category
Protocol Section 
Screening
(2 visits 
at least 
7days 
apart)
Core Treatment Phase
End of 
CoreTreatment 
(continue to 
Visit 17 in 
Table 7-2 if 
going into 
extension 
phase) 
Study Evaluation 
Completion (Core 
phase) including 
Safety Follow up 
if not continuing 
to optional 
extension phase
Visit:
1
2
3
4
5
6
7
8
9
10
11
12, 13, 
14, 15 
&16
777
778
Week:
-3 Weeks
1
2
3
5
9
13
17 
21
25
29, 33, 
37, 41 & 
45 
(monthly)
Within 7 days 
of last dose 
for patients 
not 
participating 
in extension 
phase. (Week 
49 if going into 
extension 
phase.)
30 days after last 
dose
PK sampling (Pre-dose)
(D)
7.2.5
X
X
X
X
X
X
X
X
X
PK sampling (Post-dose)
(D)
7.2.5
X
X


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Study Procedure
Category
Protocol Section 
Screening
(2 visits 
at least 
7days 
apart)
Core Treatment Phase
End of 
CoreTreatment 
(continue to 
Visit 17 in 
Table 7-2 if 
going into 
extension 
phase) 
Study Evaluation 
Completion (Core 
phase) including 
Safety Follow up 
if not continuing 
to optional 
extension phase
Visit:
1
2
3
4
5
6
7
8
9
10
11
12, 13, 
14, 15 
&16
777
778
Week:
-3 Weeks
1
2
3
5
9
13
17 
21
25
29, 33, 
37, 41 & 
45 
(monthly)
Within 7 days 
of last dose 
for patients 
not 
participating 
in extension 
phase. (Week 
49 if going into 
extension 
phase.)
30 days after last 
dose
Laboratory assessments -
Blood
7.2.4.6
Hematology
(D)
7.2.4.6.1
X
X
X
X
X
X
X
X
X
X
X
X
Biochemistry
(D)
7.2.4.6.2
X
X
X
X
X
X
X
X
X
X
X
X
Serum Ferritin
(D)
7.2.2
X
X
X
X
X
X
X
X
X
X
Serum Creatinine
(D)
7.2.4.6.2
X
X
X
X
X
X
X
X
X
X
X
X
X
Creatinine clearance
(D)
7.2.4.6.2
X
X
X
X
X
X
X
X
X
X
X
X
X
Hepatitis testing
(D)
7.2.4.6.5
X
Serum Pregnancy test
(D)
7.2.4.6.4
X
Laboratory assessments -
Urine
7.2.4.6
Urine dipstick
(D)
7.2.4.6.3
X
X
X
X
X
X
X
X
X
X
X
X
X


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Study Procedure
Category
Protocol Section 
Screening
(2 visits 
at least 
7days 
apart)
Core Treatment Phase
End of 
CoreTreatment 
(continue to 
Visit 17 in 
Table 7-2 if 
going into 
extension 
phase) 
Study Evaluation 
Completion (Core 
phase) including 
Safety Follow up 
if not continuing 
to optional 
extension phase
Visit:
1
2
3
4
5
6
7
8
9
10
11
12, 13, 
14, 15 
&16
777
778
Week:
-3 Weeks
1
2
3
5
9
13
17 
21
25
29, 33, 
37, 41 & 
45 
(monthly)
Within 7 days 
of last dose 
for patients 
not 
participating 
in extension 
phase. (Week 
49 if going into 
extension 
phase.)
30 days after last 
dose
Microscopic urine 
(in case of positive urine 
dipstick)
(D)
7.2.4.6.3
X
X
X
X
X
X
X
X
X
X
X
X
X
Proteinuria
(Urine protein/creatinine ratio) 
(D)
7.2.4.6.3
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine Pregnancy test
(D)
7.2.4.6.4
X
X
Dispensed stick pack / tablet 
count 
(D)
7.2.1
X
X
X
X
X
X
X
X
Study Drug administration 
(D)
6.1
Daily intake of study drug for 48 weeks
Returned stick pack / tablet 
count 
(D)
7.2.1
X
X
X
X
X
X
X
X
PRO / ObsRO
7.2.3
Compliance Questionnaire
(D)
7.2.3
Daily completion of questionnaire until last day of treatment in core 
phase


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Study Procedure
Category
Protocol Section 
Screening
(2 visits 
at least 
7days 
apart)
Core Treatment Phase
End of 
CoreTreatment 
(continue to 
Visit 17 in 
Table 7-2 if 
going into 
extension 
phase) 
Study Evaluation 
Completion (Core 
phase) including 
Safety Follow up 
if not continuing 
to optional 
extension phase
Visit:
1
2
3
4
5
6
7
8
9
10
11
12, 13, 
14, 15 
&16
777
778
Week:
-3 Weeks
1
2
3
5
9
13
17 
21
25
29, 33, 
37, 41 & 
45 
(monthly)
Within 7 days 
of last dose 
for patients 
not 
participating 
in extension 
phase. (Week 
49 if going into 
extension 
phase.)
30 days after last 
dose
Modified SICT questionnaire
(D)
7.2.3
X
X
X
X
Palatability questionnaire
(D)
7.2.3
X
X
X
X (day of last 
dose)
Concomitant medications
(D)
6.3
Recorded on an ongoing basis
Adverse events
(D)
8.1
Recorded on an ongoing basis


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Table 7-2
Visit evaluation schedule (for the optional extension phase)
Study 
Procedure
Category
Protocol
section
Optional Extension Treatment Phase
Optional 
Extension 
Treatment 
Phase
End of 
Treatment 
of 
Optional 
Extension 
Phase
Optional 
Extension 
phase - Study 
Evaluation 
Completion 
(Optional 
extension 
phase) 
including 
Safety Follow 
up
Visit
17
*18
*19
*20
21
22
23
24
25
26
27
28
29
30
31
32
33
From visit 
34 till visit 
84
779
780
*Prior DT arm only
Week
49
50
51
52
53
57
61
65
69
73
77
81
85
89
93
97
101
From week 
105 till week 
305
Within 7 
days of 
last dose
30 days after 
last dose
Physical 
examination
(S)
7.2.4.1
X
X
X
X
X
X
X
X
X
X
X
X
X
Monthly
X
Vital signs
(D)
7.2.4.2
X
X
X
X
X
X
X
X
X
X
X
X
X
Monthly
X
Height
(D)
7.2.4.3
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Monthly
X
Weight
(D)
7.2.4.3
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Monthly
X
Audiometry
(D)
7.2.4.4
X
X
Annually
X
Ocular Exam
(D)
7.2.4.5  
X
Annually
X
ECG
(D)
7.2.4.7.1
When 
clinically 
indicated 


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Study 
Procedure
Category
Protocol
section
Optional Extension Treatment Phase
Optional 
Extension 
Treatment 
Phase
End of 
Treatment 
of 
Optional 
Extension 
Phase
Optional 
Extension 
phase - Study 
Evaluation 
Completion 
(Optional 
extension 
phase) 
including 
Safety Follow 
up
Visit
17
*18
*19
*20
21
22
23
24
25
26
27
28
29
30
31
32
33
From visit 
34 till visit 
84
779
780
*Prior DT arm only
Week
49
50
51
52
53
57
61
65
69
73
77
81
85
89
93
97
101
From week 
105 till week 
305
Within 7 
days of 
last dose
30 days after 
last dose
Echocardiogram
(D)
7.2.4.7.2
When 
clinically 
indicated 
Growth and 
development
(D)
7.2.4.8
X
Annually
X
Transfusions
(D)
7.1.1.3
When 
clinically 
indicated
X
Laboratory 
assessments -
Blood
7.2.4.6
Hematology
(D)
7.2.4.6.1
X
X
X
X
Every 3 
months
X
Serum Ferritin
(D)
7.2.2
X
X
X
X
X
X
X
X
X
X
X
X
X
Monthly
X
Serum 
Creatinine
(D)
7.2.4.6.2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Monthly
X


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Study 
Procedure
Category
Protocol
section
Optional Extension Treatment Phase
Optional 
Extension 
Treatment 
Phase
End of 
Treatment 
of 
Optional 
Extension 
Phase
Optional 
Extension 
phase - Study 
Evaluation 
Completion 
(Optional 
extension 
phase) 
including 
Safety Follow 
up
Visit
17
*18
*19
*20
21
22
23
24
25
26
27
28
29
30
31
32
33
From visit 
34 till visit 
84
779
780
*Prior DT arm only
Week
49
50
51
52
53
57
61
65
69
73
77
81
85
89
93
97
101
From week 
105 till week 
305
Within 7 
days of 
last dose
30 days after 
last dose
Creatinine 
clearance
(D)
7.2.4.6.2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Monthly
X
Liver function 
testing
(ALT, AST, 
TBIL, alk 
phosphatase)
(D)
7.2.4.6.2
X
X
X
X
X
X
X
X
X
X
X
X
X
Monthly
X
Laboratory 
assessments -
Urine
7.2.4.6
Urine dipstick
(D)
7.2.4.6.3
X
X
X
X
X
X
X
X
X
X
X
X
X
Monthly
X
Microscopic 
urine (in case of 
positive urine 
dipstick)
(D)
7.2.4.6.3
X
X
X
X
X
X
X
X
X
X
X
X
X
As needed
X
Proteinuria 
(Urine 
(D)
7.2.4.6.3
X
X
X
X
X
X
X
X
X
X
X
X
X
Monthly
X


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Study 
Procedure
Category
Protocol
section
Optional Extension Treatment Phase
Optional 
Extension 
Treatment 
Phase
End of 
Treatment 
of 
Optional 
Extension 
Phase
Optional 
Extension 
phase - Study 
Evaluation 
Completion 
(Optional 
extension 
phase) 
including 
Safety Follow 
up
Visit
17
*18
*19
*20
21
22
23
24
25
26
27
28
29
30
31
32
33
From visit 
34 till visit 
84
779
780
*Prior DT arm only
Week
49
50
51
52
53
57
61
65
69
73
77
81
85
89
93
97
101
From week 
105 till week 
305
Within 7 
days of 
last dose
30 days after 
last dose
protein/creatinin
e ratio)
Urine 
Pregnancy test
(D)
7.2.4.6.4
At discretion of Investigator
X
Dispensed stick 
pack
(D)
7.2.1
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Monthly
Study Drug 
administration 
(D)
6.1
Daily intake of study drug
Returned stick 
pack / tablet 
bottle 
(D)
7.2.1
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Monthly
X
Concomitant 
medications
(D)
6.3
Record on an ongoing basis
Adverse events
(D)
8.1
Record on an ongoing basis 


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7.1.1
Screening
Prior to commencement of the screening examination, the patient / caregiver must have given
full informed consent on the appropriate form. Investigators will also obtain consent/assent of 
patients according to local guidelines. Once this has been signed and dated by the patient and/or 
by the caregiver, the investigator can take the patient through the study inclusion and exclusion 
criteria to make sure that the patient is fully eligible to participate.
Two Screening Visits are needed to perform key safety parameters prior to first dose 
administration as specified in the deferasirox drug label.
Specific safety examinations like ocular and audiometry examinations, ECG and 
echocardiography (currently indicated to be performed at screening visit 1) can be performed 
at either screening visit 1 or screening visit 2 to make it possible for the site to plan the 
examinations properly. These assessments must be performed at least once prior to patient 
starting study drug.
Ocular and Audiometry examinations must be performed at screening (also when entering in 
the optional extension phase at visit 17). 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 at Screening (Visits 1 and 2) and the value will be used for eligibility criteria. The 
serum ferritin samples should be obtained in the absence of known infection.
Pregnancy test will be required for females of child bearing potential only.
The full list of assessments to be performed during the screening period is detailed in Table 7-
1.
Re-screening is permissible on a case by case basis. All screening assessments at V1 and V2 
have to be repeated in case of re-screening of a patient with the exception of the Ocular, 
Audiometry and Echocardiography assessments. Please contact Novartis for guidance and see 
Section 7.1.1.2 to get information on how to process screen failures.
To enter the optional extension phase, patient must have completed core phase per protocol. 
Patients may proceed with entering the optional extension treatment phase once all Visit 777 
and 17 assessments are performed. Lab results from Visit 777 will be checked as soon as they 
become available and if any dose modifications are required will occur per Table 6-2.  
7.1.1.1
Eligibility screening
Following registering in the IRT for screening, patient eligibility will be checked once all 
screening procedures are completed. The eligibility check will be embedded in the IRT system. 
Please refer and comply with detailed guidelines in the IRT manual.
7.1.1.2
Information to be collected on screening failures
Patients who sign an informed consent but fail to be randomized and 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.


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The demographic information 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 during the Screening 
Phase (see Section 8 for SAE reporting details).
If the patient fails to be started on treatment, the IRT must be notified within 2 days of the 
screen fail that the patient was not randomized.
7.1.1.3
Patient demographics and other baseline characteristics
In the core phase, data will be collected on patient characteristics including demographic 
information (age, sex, ethnicity, etc.) and other background or relevant medical history/ current 
medical conditions, transfusion/RBC history (within 6 months prior to study entry), disease 
history, prior chelation history at Visits 1 and/or 2.
To determine eligibility to be enrolled into the study, patients will also undergo assessments as 
per the inclusion and exclusion criteria which include vital signs, hematology and biochemistry 
evaluations, serum ferritin, serum creatinine and creatinine clearance (calculated by the central 
laboratory), [Egypt: Local laboratory will be used for analysis of all specimens collected], 
hepatitis viral testing, a known history of HIV positive test result (ELISA or Western blot)
which is documented in the source documents, serum pregnancy test and urinalysis.
Other assessments include ocular, audiometry, ECG, echocardiogram, and growth and 
development exams.
7.1.2
Treatment period
The study treatment duration is 48 weeks. Patient visits will occur weekly for the first 3 weeks 
of treatment and then every 4 weeks starting from Week 5 until Visit 777 (EOT). 
Having completed the screening period, patients who are eligible will be enrolled and 
randomized to receive either deferasirox DT or deferasirox granules. The target 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 either deferasirox DT 20 
mg/kg once daily or deferasirox granules 14 mg/kg once daily. All ICT pre-treated patients will 
use a deferasirox DT or an equivalent strength-adjusted granules starting dose corresponding to 
their pre-washout dose, please refer to Appendix 14.1.  
For details on study design and dose adjustments, see Section 4 and Section 6.2.
For details of assessments during the treatment periods, see Table 7-1 and Table 7-2.
After the core phase has ended, the patients who have participated and completed the 48 weeks 
core treatment phase as per protocol and do not have access to the new formulation will have 
the possibility to enter the optional extension treatment phase until there is local access to the 
new formulation (granules or FCT) or up to of 5 years, whichever occurs first. If the patient 
does not enter the optional extension phase they must complete the core EOT visit, 30 day safety 
follow up and EOS visit.


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
Patients who discontinue prior to Visit 17 will complete Visit 777 within 7 days of last 
dose of study drug. End of study (Visit 778) and safety follow-up will be performed 
within 30 days last dose was given in the core phase.

All patients who have completed the core treatment phase per protocol will have an EOT 
visit (Visit 777) at Week 49. Patients who opt to continue to the optional extension 
treatment phase will proceed to Table 7-2 to complete the Visit 17 assessments on the 
same day. At completion of the optional extension treatment phase, or should patients 
discontinue at any time after starting the extension treatment phase they will complete the 
End of Treatment of Optional Extension Phase (Visit 779) within 7 days of last dose of 
study drug. End of study (Visit 780) and safety follow-up will be performed within 30 
days last dose was given in the optional extension phase.
Patients who were on the DT arm during core phase of study will switch to granules in the 
optional extension phase at Visit 17. They will need to return weekly for the first month (visit 
18, 19 and 20) after beginning the optional extension phase (granules) for serum creatinine and 
creatinine clearance. Thereafter they will follow the same schedule as patients who were on the 
granules arm during the core phase.
7.1.3
Discontinuation of study treatment
Patients may voluntarily discontinue from the study treatment for any reason at any time. If a 
patient decides to discontinue from the study treatment, the investigator should make a 
reasonable effort (e.g. telephone, e-mail, letter) to understand the primary reason for this 
decision and record this information in the patient’s chart and on the appropriate CRF pages. 
They may be considered withdrawn if they state an intention to withdraw, fail to return for visits, 
or become lost to follow-up for any other reason.
The investigator should discontinue study treatment for a given patient if, he/she believes that 
continuation would be detrimental to the patient’s well-being.
Study treatment must be discontinued under the following circumstances:

Emergence of the following adverse events, please refer to Section 6.2

Any of the following laboratory abnormalities, please refer to Section 6.2

Pregnancy

Unwillingness to comply with the prescribed study treatment

Use of prohibited treatment refer to Section 6.3.2.

Any other protocol deviation that results in a significant risk to the patient’s safety
Patients who discontinue study treatment should undergo an end of study visit within 7 days of 
the last dose of the study treatment, at which time all the assessment listed for the End of 
Treatment (EOT) visit will be performed. An EOT eCRF page should be completed for all 
patients (for core or optional extension), giving the date and the reason for stopping the study 
treatment and then be discontinued from the trial.
The investigator must also contact the IRT to register the patient’s discontinuation from study.


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7.1.4
Withdrawal of consent
Patients may voluntarily withdraw consent to participate in the study for any reason at any time. 
Withdrawal of consent occurs only when a patient does not want to participate in the study any 
longer, and does not want any further visits or assessments, and does not want any further study 
related contact.
Novartis will continue to retain and use all research results that have already been collected for 
the study evaluation. All biological samples that have already been collected may be retained 
and analyzed at a later date (or as required by local regulations).
If a patient withdraws consent, the investigator should make a reasonable effort (e.g. telephone, 
e-mail, letter) to understand the primary reason for this decision and record this information.
Study treatment must be discontinued and no further assessments conducted.
Further attempts to contact the patient are not allowed unless safety findings require 
communication or follow up.
7.1.5
Follow up period
All patients must have safety evaluations for 30 days after the last dose of study treatment. If 
death occurs during this period, this will be collected in the Study Evaluation Completion 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.
7.2
Assessment types
7.2.1
Compliance with prescribed treatment
The stick pack/tablet count will be performed by investigator or study personnel every 4 weeks 
(week 5, 9, 13, 17, 21, 25, 29, 33, 37, 41, 45 and at EOT(core)/777 visits) during the core phase. 
Assessment of compliance using stick pack/tablet counts will be based on the actual count at 
the different time points, taking into account the amount of medication dispensed, returned and 
reported as lost/wasted by the patient in the core phase. Treatment prescribed will be recorded 
at every visit, including any dose adjustments performed in-between visits. Detailed 
information related to drug dispensation and returns will be captured in source documents (drug 
accountability logs) by the investigator or study personnel at each visit during the core phase. 
During the optional extension phase sites will only collect whether or not the stick pack(s) have 
been returned from the previous visit.
7.2.2
Serum Ferritin
Serum ferritin test will be performed during the core phase at Screening Visits 1 and 2 (in the 
absence of infection) to assess the eligibility of the patient. The baseline serum ferritin value is 
defined as the average of the two measurements obtained during the screening period. 
Thereafter serum ferritin testing will be performed at weeks 5, 9, 13, 17, 21, 25, 29, 33, 37, 41, 
45 and EOT(core)/777 visits to evaluate the clinical benefit related to improved compliance of 
the new formulation. This will be done monthly as per Exjade prescribing information during 


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the extension phase. A central laboratory will be used for analysis of all specimens collected. 
[Egypt: Local laboratory will be used for analysis of all specimens collected]
Details on the collections, shipment of samples and reporting of results by the central laboratory 
are provided to investigators in the [Laboratory Manual]. [Egypt: Details on the collections, 
shipment of samples and reporting of results by the local laboratory are provided to 
investigators in the local laboratory manual]
7.2.3
Patient / Observer Reported Outcomes
Patient satisfaction, palatability and compliance will be measured for both formulations using 
Patient / Observer Reported Outcomes (PRO/ObsRO) questionnaires.
For patients aged between 10 years and less than 18 years at enrollment, the PRO questionnaires 
will be completed by the patients themselves. The questionnaires for patients aged between 2 
years and less than 10 years have been designed as observations made by caregivers such as the 
parent or legal guardian (ObsRO).  For these patients the caregivers will continue completing 
the ObsRO questionnaires even after the patient turns 10 years for consistency in responses.  
Three questionnaires were developed to evaluate both formulations: the modified Satisfaction 
with Iron Chelation Therapy (SICT), a palatability questionnaire and a compliance diary. All 
questions will be translated into the patient’s native language.
All Patients/caregivers will complete the PRO/ObsRO questions via a handheld electronic 
device and they will receive training on the operation of this device. The device will be 
programmed to ensure that all relevant observations are recorded before submission. 
In case of malfunctioning devices (confirmed by vendor support helpdesk and only under this 
condition, the patients/caregivers will be authorized to use paper questionnaires until vendor 
fixes issue(s) of devices.  The back-up paper entry process in case of technical issues must be 
followed before any reporting in the database.   
The modified SICT questionnaire will be completed at Visits 4 (Week 2), 5 (Week 3), 11 (Week 
25), and 777 (within 7 days of the last dose of treatment for those not continuing to the extension 
phase). The Visit 4 assessment will be considered as baseline since the questionnaire asks for 
patient’s satisfaction with the iron chelation therapy received ‘in the past week’. The rationale 
for having the modified SICT completed also at Visit 5 is based on the need to conduct a test-
retest reliability within trial, meaning that patients need to complete the modified SICT 
questionnaire within 2-14 days after the baseline data collection to ensure the stability of the 
measure over a period of time where little change would be expected.
The palatability questionnaire will be completed at Visits 4 (Week 2), 5 (Week 3), 11 (Week 
25), and 777 (day of the last dose of treatment), in order to co-administer this questionnaire 
together with the modified SICT questionnaires. The Visit 4 palatability assessment will be 
considered as baseline and the Visit 5 assessment will allow to check the test-retest reliability 
within trial.
The handheld devices will be enabled with alarms that will remind the patient / caregiver to 
complete the modified SICT and the palatability questionnaires at the time points specified 
above.


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The compliance questionnaire will be completed daily, starting at Visit 3 until Visit 777 (day 
of the last dose of treatment). This questionnaire asks whether the study medication was taken 
by the patient / given by the caregiver and at what time it was ingested. Alarms and reminders 
will prompt patients to complete the compliance questionnaire every day.
Daily diary records will be used to calculate the rate of dosing instructions deviations in each 
study arm (doses missed completely or not taken at approximately the same time every day).
PRO/ObsRO questionnaires as well as the compliance diary will not be collected during 
optional extension phase.
7.2.4
Safety and tolerability assessments
Safety will be monitored by assessing physical examination, vital signs, laboratory evaluations, 
as well as collecting information on adverse events at every visit. For details on AE collection 
and reporting, refer to Section 8.
As per Section 4.5, during a Public Health emergency as declared by Local or Regional 
authorities i.e. pandemic, epidemic or natural disaster, that limits or prevents on-site study visits, 
regular phone or virtual calls can occur (every 4 weeks or more frequently if needed) for safety 
monitoring and discussion of the participant´s health status until it is safe for the participant to 
visit the site again.
7.2.4.1
Physical examination
A physical examination will be performed during the core phase at Screening visit 1, Visit 3 
and all subsequent visits. The physical examination at Visit 3 will serve as the Baseline physical 
examination for the entire study. The exam will entail an examination of general appearance, 
skin, neck (including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph 
nodes, extremities and nervous system. During the optional extension phase, physical exam will 
be done monthly as per Exjade prescribing information.
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.
7.2.4.2
Vital signs
Vital signs include body temperature, respiratory rate, blood pressure and pulse measurements 
and will be measured at all study visits (including EOT) at the core phase. During the optional 
extension phase, vital signs will be taken monthly as per Exjade prescribing information. 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 


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will be used. In case the cuff sizes available are not large enough for the patient’s arm 
circumference, a sphygmomanometer with an appropriately sized cuff may be used.
7.2.4.3
Height and weight
Height in centimeters (cm) and body weight (to the nearest 0.1 kilogram (kg) in indoor clothing, 
but without shoes) will be measured at each Visit). During the optional extension phase, 
assessments will be done monthly as per Exjade prescribing information.
7.2.4.4
Auditory examination.
Patients will undergo auditory examinations during the core phase at screening (core phase) and 
Visit 17, annually and at EOT visit (extension phase).
The auditory examination should include the following assessments:

Comprehensive audiometry threshold examination
Interpretation of the audiometry examinations must be made by a qualified physician and 
documented on the CRF page.
Information about the audiometry results must be present in the source documentation at study 
site. Significant findings of the audiometry examinations that meet the definition of an AE must 
be recorded in the adverse event summary page of the case report form.
7.2.4.5
Ocular Examination and Central Imaging Assessment
Patients will undergo ophthalmologic examinations during the core phase at Visit 1, 11, 777 
(EOT Core) and at unscheduled visits (if needed). During the optional extension phase, 
assessments will be done annually as per Exjade prescribing information and at EOT of 
Extension phase.
The ophthalmologic examination includes the following assessments:

Distance visual acuity test: in patients who don’t need correction with glasses or contact 
lenses, visual acuity test may be performed without correction. In patients who need 
correction (either wears prescription glasses/contact lenses or uncorrected visual acuity is 
not within normal limits), best corrected visual acuity should be tested. Information about 
visual acuity without correction, best corrected visual acuity and prescription/correction 
must be documented in the source records. 

Applanation tonometry

Slit Lamp exam and lens photography

Fundus exam and wide angle fundus photography of the retina and optic nerve
Interpretation of the ocular examinations must be made by a qualified physician and 
documented on the CRF page.
Information about the results of the ocular examinations, including the lens photographs and 
the wide angle fundus photographs of the retina and optic nerve, must be present in the source 
documentation at study site. Significant findings of the ocular examinations that meet the 
definition of an AE must be recorded in the adverse event summary page of the case report 
form. 


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All screening and on-study wide angle fundus photographs and lens photographs, including 
photography acquired prior to the release of Protocol Amendment 6, must be sent to an imaging 
Contract Research Organization (CRO) designated by Novartis for central assessment. 
Table 7-3
Central Imaging Assessments Collection Plan
Procedure
Screening/Baseline
During Treatment (core and extension 
phase)
Wide Angle Fundus Photography 
Required
Core phase: Visit 11 (Week 25),Visit 
777  (EOT Core) 
Optional Extension phase: Visit 33 
(Week 101), annually thereafter until 
EOT
Any unscheduled fundus photography 
during treatment 
Lens Photography
Required
Core Phase: Visit 11 (Week 25), Visit 
777 (EOT Core)  
Optional Extension phase: Visit 33 
(Week 101), annually thereafter until 
EOT
Any unscheduled lens photography 
during treatment
Details on transferring the fundus and lens photographs for reading by the imaging CRO are 
provided to investigators in the imaging CRO Site Operations Manual. All details of the central 
review methodology will be described in the Central Imaging Review Charter.
7.2.4.6
Laboratory evaluations
A central laboratory will be used for analysis of all specimens collected, except urinary dipstick 
analysis and urinary pregnancy test will be performed by the local lab. 
[Egypt: Local laboratory will be used for analysis of all specimens collected]
Details on the collections, shipment of samples and reporting of results by the central laboratory 
are provided to investigators in the [Central Laboratory Manual].
[Egypt: Details on the collections, shipment of samples and reporting of results by the 
local laboratory are provided to investigators in the local laboratory manual]
As per Section 4.5, during a Public Health emergency as declared by Local or Regional 
authorities i.e. pandemic, epidemic or natural disaster, that limits or prevents on-site study visits, 
if subjects cannot visit the site for safety lab assessments conducted through central labs, a local 
lab may be used. 
The results of the local laboratory will be recorded in the CRF if any of the following criteria 
are met: 

a treatment decision was made based on the local results , or

there are no concomitant central lab results available, or 


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
an AE was documented based on local lab result.
Table 7-4
Central Clinical laboratory parameters collection plan, [Egypt: Local 
Laboratory]
Test Category
Test Name
Hematology
Hematocrit, Hemoglobin, MCH, MCHC, MCV, Platelets, Red blood cells, White blood 
cells(WBC) count with differential, RBC Morphology with Differential (Basophils, 
Eosinophils, Lymphocytes, Monocytes, Neutrophils)
Biochemistry
Albumin, Alkaline phosphatase, ALT, AST, Bicarbonate, Calcium, Chloride, Creatinine, 
Creatine kinase, Direct (conjugated) 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): Color, Bilirubin, Blood, Glucose, Ketones, Leukocytes 
esterase, Nitrite, pH, Protein, Specific Gravity, Urobilinogen
Hepatitis markers
HbsAg, HbsAb, HbcAb, HCV RNA, Anti-HCV
Additional tests
Serum ferritin, creatinine clearance, urine protein/creatinine ratio, serum pregnancy test
7.2.4.6.1 Hematology
Hematology samples will be collected during the core phase at Screening Visits 1 and 2, Visit 
3, 5 - 16 and 777 (EOT) and will be sent to the central laboratory, [Egypt: Local laboratory]. 
During the optional extension phase, hematology samples will be collected every 3 months as 
per Exjade prescribing information. Hematology parameters monitored during the study are 
listed in Table 7-4.
7.2.4.6.2 Clinical chemistry
Clinical chemistry samples will be collected during the core phase at Screening Visits 1 and 2, 
at Visit 3, 5-16, and 777 (EOT) and will be sent to the central laboratory, [Egypt: Local 
laboratory]. During the optional extension phase, monthly assessments will be done as per 
Exjade prescribing information as per Table 7-2. Patients who were on the DT arm during core 
phase of study and decided to switch to granules as part of the optional extension phase will 
need to return weekly for the first month of the optional extension phase at Visits 18, 19 and 20 
for serum creatinine and creatinine clearance monitoring. Thereafter they will follow the same 
schedule as patients who were on granules arm during the core phase. Clinical chemistry 
parameters to be measured are listed in Table 7-4.
In accordance with the deferasirox label, serum creatinine, creatinine clearance, alkaline 
phosphatase, ALT/SGPT, AST/SGOT, direct (conjugated) bilirubin, indirect bilirubin, total 
bilirubin must be assessed in duplicate before the initiation of therapy to establish a reliable pre-
treatment baseline.
In addition, serum creatinine will be measured weekly during the first three weeks (after the 
first study drug administration and at Visits 4, 5) and monthly thereafter (starting with Visit 6) 
till Visit 777 (EOT). During the optional extension phase, monthly assessments will be done as 
per Exjade prescribing information for patients previously on the granules arm of the core phase. 
Patients on the DT arm for the core phase of the study who have decided to switch to granules 
as part of the optional extension phase will need to return weekly for the first month at Visits 


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18, 19 and 20. Creatinine clearance will be calculated by the central lab [Egypt: Local 
laboratory] using the Schwartz formula for patients 17 years and younger and the Cockcroft-
Gault formula for patients who turn 18 years old during the study, each time serum creatinine 
is collected.
7.2.4.6.3 Urinalysis
Urinalysis samples will be collected during the core phase at every study visit, from Screening 
until Visit 777 (EOT). During the optional extension phase, monthly assessments will be done 
as per Exjade prescribing information. A midstream, second voided morning urine sample will 
be obtained as this will provide the best results. Urinalysis parameters assessed are listed in 
Table 7-4.
The microscopic urinalysis will be performed only in case of positive dipstick. Dipsticks will 
be supplied by the central lab, [Egypt: Local laboratory].
At Screening Visits 1 and 2, a urine sample (at least 15 ml) will be collected and sent to the 
central lab [Egypt: Local laboratory] for urinary protein/creatinine (UPC) ratio to assess the 
eligibility of the patient. Thereafter UPC ratio will be assessed at every visit, till EOT, as 
described in the [Central Laboratory Manual], [Egypt: Local Laboratory Manual]. 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 Table 6-2.
7.2.4.6.4 Pregnancy and assessments of fertility
Females of child-bearing potential are defined as all females physiologically capable of 
becoming pregnant. This includes female pediatric patients who are menarchal or who become 
menarchal during the study.
All menarchal girls and their parents/caregivers should be informed about the potential risks of 
pregnancy and the need to prevent pregnancy during the study. It is important to be sensitive in 
introducing this issue, as understanding and comprehension of puberty, sexual activity, 
pregnancy and contraception is influenced by age, as well as factors such as precocity, socio 
(educational) economic and familial background. These discussions with the patient and her 
parents/caregivers are therefore best performed by investigators familiar with the pediatric 
subject and her family and should be guided by requirements of the local regulatory authorities. 
These discussions should take into account the socio-economic, cultural factors and religious 
beliefs of the adolescent participant and her family.
The investigator should also discuss the management of the pregnancy test results with the 
patient and her parents/caregivers. The privacy of the patient should be considered in 
accordance with the local law and ethics.
Serum and/or urine pregnancy tests will be performed for all females of child-bearing potential 
according to the schedule in Table 7-1 for the core phase. Urine pregnancy tests will be at the 
EOT visit (777) and then at Investigator’s discretion during the optional extension phase 
treatment period as per schedule in Table 7-2. Urine pregnancy tests will also be performed at 


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the end of treatment in the extension phase as per Novartis guidelines for pregnancy testing in 
clinical trials when basic contraception is requested.
Additional pregnancy tests may be performed at the investigator’s discretion during the study. 
Patients becoming pregnant or breastfeeding must be discontinued from study drug.
However, a patient may choose to remain in the study should she become pregnant, and be 
followed according to the protocol-defined study visits.
Female patients of child-bearing potential, who are or might become sexually active, must be 
informed of the need to prevent pregnancy during the study.
The basic contraception methods are:

Barrier method: Condom or Occlusive cap (diaphragm or cervical/vault caps). [For UK: 
with spermicidal foam/gel/film/cream/vaginal suppository].

Placement of an intrauterine device (IUD) or intrauterine system (IUS).
The decision on the contraceptive method should be reviewed at least every 3 months to 
evaluate the individual need and compatibility of the method chosen.
Please note that deferasirox may reduce the efficacy of hormonal contraception thus it is 
recommended to use alternative methods of contraception as described above.
See Section 8.4 for pregnancy reporting and follow-up requirements.
7.2.4.6.5 Hepatitis Viral tests
Hepatitis Viral testing consists of the following items: Hepatitis B Surface Antibody (Anti-
HBs), Hepatitis B core Antibody (HbcAb), Hepatitis C Antibody (Anti-HCV), Hepatitis B 
surface Antigen (HBsAg), Qualitative w/confirmation, HCV PCR (Quantitative). Hepatitis 
Viral testing will be conducted at Screening Visit 1 (core phase) to assess trial eligibility.
7.2.4.7
Cardiac assessments
7.2.4.7.1 Electrocardiogram (ECG)
A standard 12 lead ECG will be performed and interpreted by site personnel during the core 
phase at the following visits:

at screening Visit 1

at visit 777 (EOT)
During the optional extension phase, ECG will be performed when clinically indicated.
Interpretation of the tracing must be made by a qualified physician and documented on the ECG 
CRF page. Each ECG tracing should be labeled with the study number, patient’s initials (where 
regulations permit), patient number, date and kept in the source documents at the study site. 
Clinically significant abnormalities present when the patient signed informed consent should 
be reported on the Medical History 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.


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7.2.4.7.2 Echocardiography
A standard echocardiogram will be performed and interpreted by the site personnel during the 
core phase at the following visits:

at screening Visit 1

at visit 777 (EOT)
During the optional extension phase, echocardiography assessments will be done when 
clinically indicated.
Interpretation of the echocardiogram must be made by a qualified physician and documented 
on the CRF page. Each echocardiography should be labeled with the study number, patient’s 
initials (where regulations permit), patient number, date and kept in the source documents at 
the study site. Clinically significant abnormalities present when the patient signed informed 
consent should be reported on the Medical History 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.
7.2.4.8
Growth and Development
7.2.4.8.1 Growth velocity assessment in pediatric patients
At the end of core phase, the growth velocity will be assessed from the difference between the 
end of-core phase and the baseline height measurements during the core phase. 
During the optional extension phase, growth assessment will be performed annually as per 
Exjade prescribing information.
7.2.4.8.2 Pubertal stage
Pubertal stage will be scored at baseline and end of core phase according to Tanner staging 
system. 
During the optional extension phase, pubertal stage assessment will be performed annually as 
per Exjade prescribing information.
7.2.5
Pharmacokinetics
Detailed instructions for the collection, handling, and shipment of PK samples will be presented 
in the [CICL670F2202 Pharmacokinetics Laboratory Manual]. PK sampling will only be 
performed during the core phase.
7.2.5.1
PK blood sample collection and handling
7.2.5.1.1 Blood collection plan
PK blood samples will be collected in all patients [Egypt: no PK samples will be collected] at 
weeks 1, 3, 5, 9, 13, 17, 21, 25, 29, 33, 37, 41 and 45 visits to support the assessment of 
compliance (see Table 7-5). Patients / caregivers will be instructed that study drug should not 
be administered in the morning of these visits.


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Table 7-5
PK blood collection log (all patients)
Visit
Week
Day
Scheduled time point
PK collection 
number
PK 
Sample No
Sample 
volume [mL]
3
1
1
Pre-dose
1
1
2
5
3
1
Pre-dose
2
102
6***
2
6
5
1
Pre-dose
3
103
7
2
6
5
1
Post-dose 3 hour (+/- 1 hour)
3
9
2
7
9
1
Pre-dose
4
104
12
2
7
9
1
Post-dose 3 hour (+/- 1 hour)*
4
13
2
8
13
1
Pre-dose
5
105
14
2
9
17
1
Pre-dose
6
106
15
2
10
21
1
Pre-dose
7
107
16
2
11
25
1
Pre-dose
8
108
17
2
12
29
1
Pre-dose
9
109
18
2
13
33
1
Pre-dose
10
110
19
2
14
37
1
Pre-dose
11
111
20
2
15
41
1
Pre-dose
12
112
21
2
16
45
1
Pre-dose
13
113
22
2
999
Unscheduled**
--
--
1001+
2
Total
30
PK collection numbers 1 to 13 correspond to the dose taken on the day of the visit.
PK collection numbers 102 to 113 correspond to the dose taken the day before each study visit.
*One PK blood sample should be collected between 2 and 4 hours post-dose
** Each unscheduled PK blood sample will be uniquely numbered with sample number 100X (e.g., 1001, 1002, 
etc.) and will add 2 mL of blood to the total quantity collected
*** Certain PK samples have been removed as part of Protocol Amendment V.01 so PK sample numbers are no 
longer consecutive. Please follow numbering convention in Table 7-5.
On the days of visit 6 (Week 5) and visit 7 (Week 9) deferasirox should be administered at the 
study site under supervision of the investigator/site staff. This is to ensure appropriate draws of 
pre- and post-dose administration blood samples for PK assessments.
At Week 1, the pre-dose sample should be obtained before the first drug administration. At 
Week 5 and Week 9, the pre-dose PK sample should be obtained within 24 ± 2 hours from the 
previous dose, and one post-dose PK sample should be obtained between 2 and 4 hours post-
dose administration.
The time of all blood draws will be recorded on the PK blood collection page in the eCRF. All 
samples will be taken by either direct venipuncture or indwelling cannula inserted in a forearm 
vein.
Blood samples (2 mL each sample) will be collected at each sampling time into a Vacutainer™ 
tube containing lithium heparin provided by central lab [Egypt: No PK samples will be 
collected].Immediately after each tube of blood is drawn, it should be inverted gently several 
times to ensure the mixing of tube contents with the anticoagulant (avoiding prolonged contact 
with the rubber stopper). Samples must be cooled immediately by placing the tube upright in a 
test tube rack sitting in an ice-water bath or cryoblock until placed in the centrifuge. Within 30 
minutes of sample draw, the samples are centrifuged at about 5°C for 15 minutes at 2000 g (to 
be adapted according to the radius of the centrifuge). Within 10 minutes after centrifugation, 


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the upper plasma sample will be transferred into two separate 2 mL, tapered, polypropylene 
screw-cap tubes labeled as primary sample and back-up sample. The tube A should have at least 
0.5 mL of plasma and the tube B contains the remaining plasma. Both samples will be stored 
frozen at -70°C +/- 15°C within 60 min of collection.
Each sample will be given a unique sample number as indicated in Table 7-5. The exact clock 
time of dosing on each PK sampling day, as well as the actual sample collection date and time 
must be captured on the appropriate source documents for PK sample collection at Week 5 and 
Week 9.  Issues with obtaining samples will be noted in the comments field of the documents.
7.2.5.1.2 PK sample labeling
The sample labels must be completed in water proof ink and attached to the tube. The labels 
should include the information indicated below (Table 7-6)
Table 7-6
PK sample labels
Study number
CICL670F2202
Subject ID
xxxx_xxxxx
Subject initials
ABC
Treatment Arm
Arm 1, Arm 2
Visit
W1, W3, W5, W9, W13, W17, W21, W25, W29, W33, W37, W41, W45
Study day
D1 
PK time point
00:00 (taken pre-dose), 03:00 (taken post-dose)
PK sample number
1, 2, 3, etc.
Sample aliquot
Primary or Back-up 
7.2.5.2
PK analytical method
Deferasirox concentration will be measured in plasma using a validated liquid chromatography-
mass spectrometry/mass spectrometry (LC-MS/MS) method with an anticipated lower limit of 
quantification of 0.670 µmol/L by a Novartis Qualified external Service Provider.
Other assessments
No additional tests will be performed on patients entered into this study.
7.2.6
Resource utilization
Not Applicable.
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.


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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 
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 in this trial as mild, moderate, severe and life-
threatening, (corresponding to CTCAE Grades 1 – 4). CTCAE Grade 5 (death) will not be used 
in this study; rather, information about deaths will be collected though an EOT form during 
treatment period. Deaths that occur within the 30 day safety follow up after last study drug dose 
will be collected on the Study Evaluation Completion eCRF (visit 778 in the core phase or visit 
780 in the optional extension phase).
The occurrence of adverse events should be sought by non-directive questioning of the patient 
(subject) during the screening process after signing informed consent and at each visit during 
the study. Adverse events also may be detected when they are volunteered by the patient 
(subject) during the screening process or between visits, or through physical examination, 
laboratory test, or other assessments. As far as possible, each adverse event should be evaluated 
to determine:

The severity grade (mild, moderate, severe and life-threatening corresponding to CTCAE 
Grades 1 – 4)

Its duration (Start and end dates or Ongoing at End of Study )

Its relationship to the study treatment (Reasonable possibility that AE is related: No, Yes)

Action taken with respect to study or investigational treatment (none, dose adjusted, 
temporarily interrupted, permanently discontinued, unknown, not applicable)

Whether medication or therapy was given (no concomitant medication/non-drug therapy, 
concomitant medication/non-drug therapy)

Whether it is serious, where a serious adverse event (SAE) is defined as in Section 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) 
of any changes in severity, the suspected relationship to the study treatment, the interventions 
required to treat it, and the outcome.


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8.1.2
Laboratory test abnormalities
8.1.2.1
Definitions and reporting
Laboratory abnormalities that constitute an Adverse event in their own right (are considered 
clinically significant, induce clinical signs or symptoms, require concomitant therapy or require 
changes in study treatment), should be recorded on the Adverse Events 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 (CTCAE Grade 3) 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

Requires inpatient hospitalization or prolongation of existing hospitalization,

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

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, and whether the patient continued or withdrew from study 
participation.
If the SAE is not previously documented in the [Investigator’s Brochure] (new occurrence) and 
is thought to be related to the Novartis study treatment, an oncology Novartis Chief Medical 
Office and Patient Safety (CMO&PS) 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
Serum and urine pregnancy tests will be performed for all females of child-bearing potential 
according to the schedule in Table 7-1 for the core phase. Urine pregnancy tests will be at the 
Investigator’s discretion during the optional extension phase treatment phase as per schedule in 
Table 7-2 and will also be performed at the end of treatment in the optional extension phase as 
per Novartis guidelines for pregnancy testing in clinical trials when basic contraception is 
requested.
To ensure patient safety, each pregnancy in a patient after signing the informed consent 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. The study drug must be 
discontinued, though the patient may choose to remain in the study, if she wishes to do so. If 
the patient chooses to remain in the study, all assessments that are considered as a risk during 
pregnancy must not be performed. The patient may continue all other protocol assessments.
Pregnancy must be recorded on a Pharmacovigilance Pregnancy Form and reported by the 
investigator to the local Novartis Chief Medical Office and Patient Safety (CMO&PS) 
Department.
Pregnancy follow-up should be recorded on the same form and should 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.
After consent is provided, the pregnancy reporting will occur up to one year after the estimated 
date of delivery.
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
Not applicable.


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9
Data collection and management
9.1
Data confidentiality
Information about study subjects will be kept confidential and managed under the applicable 
laws and regulations. Those regulations require a signed subject authorization informing the 
subject of the following:

What protected health information (PHI) will be collected from subjects in this study

Who will have access to that information and why

Who will use or disclose that information

The rights of a research subject to revoke their authorization for use of their PHI
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization. For subjects that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect follow-up safety information (e.g. has the subject 
experienced any new or worsened AEs) at the end of their scheduled study period.
The data collection system for this study uses built-in security features to encrypt all data for 
transmission in both directions, preventing unauthorized access to confidential participant 
information. Access to the system will be controlled by a sequence of individually assigned 
user identification codes and passwords, made available only to authorized personnel who have 
completed prerequisite training.
9.2
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, Novartis 
personnel (or designated CRO) will review the protocol and 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/caregiver).
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/assent, 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.


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9.3
Data collection
This study is using Electronic Data Capture (EDC), the designated investigator staff will enter 
the data required by the protocol into the Electronic Case Report Forms (eCRF). The eCRFs 
have been built using fully validated secure web-enabled software that conforms to 21 CFR Part 
11 requirements, Investigator site staff will not be given access to the EDC system until they 
have been trained. Automatic validation programs check for data discrepancies in the eCRFs 
and, allow modification or verification of the entered data by the investigator staff.
The Principal Investigator is responsible for assuring that the data entered into eCRF is complete, 
accurate, and that entry and updates are performed in a timely manner. Samples for Central lab, 
PK and ocular examination photographs should be sent to the vendors on timely manner, [Egypt: 
only safety samples will be sent to Local laboratory, no PK samples will be collected]. 
Please refer to the corresponding section for more information.
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 staff are required to 
respond promptly to queries and to make any necessary changes to the data.
Concomitant treatments and prior medications entered into the database will be coded using the 
WHO Drug Reference List, which employs the Anatomical Therapeutic Chemical classification 
system. Medical history/current medical conditions and adverse events will be coded using the 
Medical dictionary for regulatory activities (MedDRA) terminology.
Data for PK, Laboratories sampling and ocular examination photographs will be processed 
centrally and the results will be sent electronically to Novartis (or a designated CRO). [Egypt: 
For Egypt sites, data for laboratories sampling will be processed locally and the results 
will be sent electronically to Novartis (or a designated CRO) including normal ranges].
ObsRO/PRO questionnaires and diary data will be entered into an electronic 
questionnaire/paper questionnaire (only in case of ePRO malfunctioning) by the 
patient/caregiver. The system will be supplied by a vendor(s), who will also manage the 
database. The database will be sent electronically to Novartis personnel (or designated CRO).
Randomization codes and data about all study treatments dispensed to the patient and all IRT 
assigned dosage changes will be tracked using an Interactive Response Technology. The system 
will be supplied by a vendor(s), who will also manage the database. The data will be sent 
electronically to Novartis personnel (or designated CRO).
The occurrence of any protocol violations will be determined. After these actions have been 
completed and the data has been verified to be complete and accurate, the database will be 
declared locked. Authorization is required prior to making any database changes to locked data, 
by joint written agreement between the Global Head of Biostatistics and Data Management and 
the Global Head of Clinical Development.
After database lock, the investigator will receive a CD-ROM or paper copies of the patient data 
for archiving at the investigational site.


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10
Statistical methods and data analysis
This is a randomized, open-label, multicenter, two arm, phase II study to investigate the 
treatment compliance, efficacy and safety of an improved deferasirox granule formulation in 
pediatric patients with iron overload.
Data from all centers participating in this study will be aggregated for analyses.
Standard descriptive analyses will include:

Frequencies and percentages for categorical data;

n, mean, standard deviation, minimum, median, 25th and 75th percentiles (as appropriate) 
and maximum for continuous data.
In PK analysis, geometric mean, CV%, CV% of geometric-mean will be included besides the 
analyses mentioned above. Additional information for analysis methods will be available in 
Statistical Analysis Plan. Statistical analysis will be performed according to treatment 
formulation groups: DT and deferasirox granule formulation.
The handling of any potential impact due to a Public Health emergency (e.g. pandemic, 
epidemic or natural disaster etc.) on the analyses will be detailed in the SAP.
10.1
Analysis sets
10.1.1
Full Analysis Set
The Full Analysis Set 1 (FAS-1) comprises all ICT naïve patients to whom study treatment has 
been assigned by randomization during the core phase.
The Full Analysis Set 2 (FAS-2) comprises all ICT pre-treated patients to whom study treatment 
has been assigned by randomization during the core phase.
The Full Analysis Set 3 (FAS-3) comprises all ICT pre-treated and naïve patients to whom study 
treatment has been assigned by randomization during the core phase.
According to the intent to treat principle, patients will be analyzed according to the treatment 
and stratification factors they have been assigned to during the randomization procedure.
10.1.2
Safety Set
The Safety Set 1 includes all ICT naïve patients who received at least one dose of study 
medication during the core phase.
The Safety Set 2 includes all ICT pre-treated patients who received at least one dose of study 
medication during the core phase.
The Safety Set 3 includes all ICT pre-treated and naïve patients who received at least one dose 
of study medication during core phase.
The Safety Set 4 will consist of all patients who received at least one dose of granule formulation 
during the core or extension phase.


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Patients will be analyzed according to the study treatment they actually received. A precise 
definition of “actually received” and of the analysis set used for pre-dose PK data analyses will 
be added in the SAP.
10.1.3
Per protocol Set
The Per Protocol Set consists of all ICT naïve patients from the FAS-1 without any major 
protocol deviation.
The protocol deviations that will lead to exclusion of patients from the PPS will be detailed in 
the SAP.
10.1.4
Pharmacokinetic Analysis Set
The Pharmacokinetic Analysis Set (PAS) consists of all patients who have at least one evaluable 
pre- or post-dose PK concentration (deferasirox).
A PK concentration is considered evaluable if it fulfills all of the following criteria:

The actual dose or leading dose prior to pre-dose sampling must be as planned by 
protocol. In addition, the patient should have received the same dose during the last 4 days 
prior to sampling (except for Week 1 Day 1).

The elapsed time between dose administration and PK concentration is documented.

The PK concentration must NOT be associated with any vomiting within 4 hours of 
dosing.
10.2
Patient demographics/other baseline characteristics
Demographic and other background data will be summarized descriptively by formulations and 
overall separately for the FAS-1, FAS-2 and the FAS-3.
Demographic data included age, age categories (2 to <10 years and 10 to <18 years), gender, 
race. Other background data included weight, weight group (<20 kg, 20-<35 kg, 35-<55 kg, 55-
<75 kg, ≥75 kg), height, main underlying disease, history of splenectomy (Yes/No), prior iron 
chelation therapy (Yes/No), prior deferasirox (Yes/No), type of last chelation therapy prior to 
the study, hepatitis B and C status, medical history by MedDRA primary SOC and preferred 
term, abnormality in baseline ECG (Yes/No) and (clinically significant/non-significant), 
abnormality in baseline echocardiogram (Yes/No) and (clinically significant/non-significant), 
abnormality in baseline audiometric test (Yes/No) and (clinically significant/non-significant), 
abnormality in baseline ocular exam (Yes/No) and (clinically significant/non-significant, 
baseline creatinine, baseline creatinine group (≤upper limit of normal range (ULN), >ULN-
≤1.5*ULN and >1.5*ULN), baseline creatinine clearance, baseline creatinine clearance group 
(<40, ≥40-<60, , ≥60-<90 and ≥90 mL/min), baseline ALT, baseline ALT group 
(≤ULN, >ULN-≤3*ULN, >3*ULN-≤5*ULN and >5*ULN), baseline AST, baseline AST group 
(≤ULN, >ULN-≤3*ULN, >3*ULN-≤5*ULN and >5*ULN), urine protein/creatinine ratio (≤0.2 
mg/mg,>0.2-≤0.5, >0.5-≤1 mg/mg and >1 mg/mg), baseline serum ferritin and baseline serum 
ferritin group (<1000, ≥1000 to ≤2500, >2500 to ≤5000, >5000 ng/mL).


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Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, 25th and 75th percentiles, minimum, and maximum will be 
presented.
10.3
Treatments (duration of exposure, concomitant therapies, 
percentage of planned dose taken)
The following variables will be summarized with descriptive measures separately for the Safety 
Set-1, Safety Set-2, Safety Set-3 and Safety Set-4 by formulation: duration of exposure, in 
weeks and in categories (core phase: <4 weeks, 4-<12 weeks, 12-<20 weeks, 20-<28 weeks, 
28-<36 weeks, 36-<44 weeks, ≥44 weeks and extension phase: <6 months, 6-<12 months, 12-
<24 months, 24-<36 months, 36-<48 months, >48 months); average planned (mg/kg/day) and 
average actual daily dose; cumulative planned (mg/kg) and total actual dose (mg/kg); 
percentage of planned dose taken; frequency of interruptions, decreases and increases in 
planned dose, overall and by reason for change as recorded in the eCRF.
The total patient-years while on treatment, calculated as the sum of (overall drug exposure) / 
365.25 will be provided by formulation.
The duration of exposure, defined as the number of weeks (core phase) / months (extension 
phase) between the start and end of study medication, will be summarized by formulation and 
by phase. 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, excluding 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).
Prior and concomitant medications and significant non-drug therapies will be summarized 
through frequency tables according to their WHO ATC class and WHO generic term by phase. 
Prior medications are defined to be drugs taken prior to the first dose of study medication. 
Concomitant medications are medications taken between the first day of study medication and 
up to 30 days after the last day with study medication or medications starting prior to the first 
day of study medication and continuing after the start date of study medication. 
10.4
Primary objective
The primary objective of this study is to evaluate patient compliance with study treatment, as 
measured by the count of deferasirox granules stick packs/dispersible tablets and to evaluate 
the change in serum ferritin over time for both formulations of deferasirox in pediatric ICT 
naive patients with iron overload during core phase, after 24 weeks of treatment.
10.4.1
Variables and analysis set
All analyses for the primary objective will be performed on the FAS-1 and presented by 
treatment group: deferasirox DT and deferasirox granule formulation.


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The co-primary efficacy variables are:

Compliance measured by stick pack /tablet count based on amount of medication 
dispensed, returned and reported as lost/wasted by the patient or caregiver, over 24 weeks 
of treatment (i.e. assessed at week 25 visit). Compliance will be calculated 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 over 24 weeks of treatment (i.e. assessed at week 25 visit);

total count prescribed is cumulative prescribed count over 24 weeks of treatment (i.e. 
assessed at week 25 visit).

Change from baseline in serum ferritin after 24 weeks of treatment (i.e. assessed at the 
week 25 visit).
10.4.2
Statistical method of analysis
The primary efficacy analysis will be the comparison of means between the two treatment arms 
of change from baseline after 24 weeks of treatment in SF and mean relative consumed stick 
pack /tablet count over 24 weeks of treatment.
The trial will be claimed successful if the superiority of granule formulation relative to DT 
formulation could be demonstrated with regard to both endpoints. Therefore, no adjustment for 
multiplicity of the type I error (alpha) is required.
The primary inferential analysis described below will be based on the FAS-1.
Let μSF,G and μSF,DT denote the mean change from baseline in SF to week 25 visit for granule 
and DT formulations, respectively. Let μC,G and μC,DT be similarly defined for compliance 
measured by stick pack /tablet count.
The null and the alternative hypothesis are defined as follows:
H0,SF: μSF,G= μSF,DT
no effect of granule formulation with regard to change in SF, and/or
H0,C: μC,G= μC,DT
no effect of granule formulation with regard to compliance
versus
H1,SF: μSF,G < μSF,DT 
mean change in SF favorable for granule formulation compared to DT 
formulation, and
H1,C: μC,G > μC,DT 
mean compliance favorable for granule formulation compared to DT 
formulation
Analysis of covariance (ANCOVA) will be performed for comparison between both treatment 
groups. The ANCOVA model for compliance endpoint will include treatment group and age 
group (2 to<10 years, 10 to <18 years) as factors. The model for serum ferritin endpoint will 
also include the serum ferritin value at baseline as covariate.
For each of the endpoint the following estimates from the ANCOVA will be provided:

the least squares mean with 2-sided 95% confidence interval for each treatment arm

the least squares means with 2-sided 95% confidence interval, p-value for the difference 
between treatment arms


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10.4.3
Handling of missing values/discontinuations
In case of missing serum ferritin value after 24 weeks of treatment, the last available post-
baseline serum ferritin value will be used in the calculation of the primary endpoint. Patients 
without post-baseline serum ferritin value will be excluded from the analysis. 
10.4.4
Supportive analyses
The following supportive and supplementary analyses will be provided:

The primary analysis will be repeated for the FAS-2 and FAS-3.

The primary analysis will also be provided for the PPS;

If more than 10% of patients have no serum ferritin value after 24 weeks of treatment, 
supplementary analyses will be performed for the primary analysis for serum ferritin using 
imputation techniques. Details will be provided in the study SAP.
Other supportive analyses may be detailed in the SAP.
10.5
Secondary objectives 
10.5.1
To evaluate both formulations on change in serum ferritin and 
compliance measured by stick pack /tablet count after 48 weeks of 
treatment in ICT naïve patients
Descriptive analyses will be performed after 48 weeks of treatment for the FAS-1. Absolute 
and relative change from baseline in serum ferritin for core phase will be summarized after 48 
weeks of treatment using standard descriptive statistics by treatment arm.
In addition at the time of primary analysis if more than 10% of patients have no serum ferritin 
value after 48 weeks of treatment or missing compliance measured by stick pack/tablet count
over 48 weeks of treatment, a supplementary analysis will be performed using multiple 
imputation method. Details will be provided in the study SAP.
10.5.2
To evaluate both formulations on change in serum ferritin in ICT naïve 
and pre-treated patients
Absolute and relative change from baseline in serum ferritin for core phase will be summarized 
after 24 weeks (i.e. assessed at week 25 visit) and 48 weeks of treatment using standard
descriptive statistics by treatment arm for the FAS-1 and FAS-2. The 95% confidence intervals 
for mean will additionally be provided.
A forest plots will be presented with change in SF after 24 weeks and 48 weeks of treatment 
and the corresponding exact 95%CI. Point estimates and 95% CI will be generated for the FAS-
1, FAS-2 and FAS-3.
Furthermore, the mean and standard deviation values of serum ferritin will be plotted by 
treatment group and week.


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10.5.3
To evaluate both formulations on patient satisfaction and palatability 
using PRO/ObsRO questionnaires
The FAS-1, FAS-2 and the FAS-3 will separately be used for the analysis of patient satisfaction 
and palatability using a PRO/ObsRO questionnaire for the core phase.
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 for each domain score at Week 2, Week 3, Week 25 and the EOT (core)/777 visits 
as well as their absolute changes at Week 25 and EOT (core)/777 visits from Week 2. The 
standard descriptive analyses include: n, mean, standard deviation, minimum, median and 
maximum. The 95% confidence intervals for the absolute changes in all domains at Week 25 
and EOT (core)/777 visits from Week 2 will be presented for both formulations.
For the palatability questionnaire the overall score will be constructed using a scoring matrix 
from the score of items. Standard descriptive analyses will be performed for both formulations 
for the overall score at the Week 2, Week 3, Week 25 visits, and last day of study drug intake 
and the absolute changes of the overall score at the Week 25 visit and last day of study drug 
from Week 2. The standard descriptive analyses include: n, mean, standard deviation, minimum, 
median and maximum. The 95% confidence interval for the absolute change of the overall score 
at the Week 25 visit and last day of study drug from Week 2 will be presented for both 
formulations.
Details about scoring and analyses will be included in the SAP.
10.5.4
To evaluate both formulations on overall safety, measured by 
frequency and severity of adverse events and changes in laboratory 
values
The Safety Set 1, Safety Set 2 and the Safety Set-3 will separately be used. 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 31 after last dose of study medication.
10.5.4.1 Adverse events (AEs)
Summary tables for adverse events (AEs) have to include only AEs that started or worsened 
during the on-treatment period, the treatment-emergent AEs. However, all safety data 
(including those from the pre and post-treatment periods) will be listed and those collected 
during the pre-treatment and post-treatment period are to be flagged.
The incidence of treatment-emergent adverse events (new or worsening from baseline) will be 
summarized by system organ class and/or preferred term, severity, type of adverse event, 
relation to study treatment by formulation group. Exposure-adjusted adverse event incidence, 
defined as number of patients with new or worsened AEs during period/[total number of days 
patient was on treatment summed for all patients/365.25 days], will be presented.


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An overall summary of type of AEs (e.g. serious, leading to study drug discontinuation, 
requiring dose adjustment or/and interruption) will be presented by severity and formulation 
group.
Specific groupings of adverse events of special interest will be considered and the number of 
patients with at least one event in each grouping will be reported. Such groups consist of adverse 
events for which there is a specific clinical interest in connection with Deferasirox treatment or 
adverse events which are similar in nature (although not identical). Note that certain adverse 
events may be reported within multiple groupings/AESIs.
AESIs are defined by MedDRA terms. All AESI definitions or AE groupings are specified in 
the Novartis electronic Case Retrieval Strategy (eCRS). The latest version of the eCRS available 
at the time of the analysis will be used.
Incidence of AESI will be summarized by grouping, preferred term and treatment arm.
Summary tables for adverse events (AEs) will be repeated for the optional extension phase on 
the Safety Set 4.
10.5.4.2 Laboratory abnormalities
All laboratory values will be converted into SI units and the severity grade calculated using the 
low/normal/high classifications based on laboratory normal ranges and for selected parameters 
(see Table 10-1 below) by notable/extended ranges.
The following summaries will be generated separately for hematology, biochemistry and 
urinary laboratory tests:

shift tables using normal/notable/extended ranges to compare baseline to the worst on-
treatment value

listing of all laboratory data with values flagged to show the corresponding 
normal/notable/extended ranges (see Table 10-1 below).
For laboratory parameters observed values (and changes from baseline), and per subsequent 
quarter will be summarized by descriptive statistics overtime (n, mean, standard deviation, 
minimum, lower quartile, median, upper quartile and maximum).
Laboratory abnormalities will be described for the optional extension phase on the Safety Set 
4.
In addition to the above mentioned tables and listings, other exploratory analyses, for example 
figures plotting time course of raw or change in laboratory tests over time or box plots might 
be specified in the SAP.


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Table 10-1
Definition of notable/extended ranges for laboratory tests
Laboratory test
Criteria for notable ranges
Platelet count
< 100 x 109/L (extended range <50×109/L)
Absolute neutrophils
< 1.5 x 109/L (extended range <0.5×109/L)
Serum creatinine
> 33% increase from baseline and > ULN at two consecutive 
measurements at least 7 days apart
Creatinine clearance
<60 mL/min at two consecutive measurements at least 7 days apart 
(extended range <40 mL/min at two consecutive measurements at 
least 7 days apart)
Urinary protein/urinary creatinine ratio
≥ 1.0 (mg/mg) at two consecutive measurements at least 7 days 
apart
ALT and AST
>5 x ULN and >2 x baseline value (extended range >10×ULN 
and >2×baseline value)
10.5.5
To evaluate compliance using a daily PRO/ObsRO questionnaire
Patient adherence to medication regimen instructions will be assessed via daily diary records 
(PRO / ObsRO questionnaire) providing information on two dimensions: whether the study 
medication is consumed and the time of medication intake. These data will be summarized over 
time by descriptive statistics for both formulations. The rate of dosing instructions deviations 
(doses missed completely or not taken at approximately the same time every day) will be 
calculated for each study arm.
The FAS-1, FAS-2 and FAS-3 will separately be used for the analysis of compliance using a 
daily PRO/ObsRO questionnaire.
Details about scoring and analyses will be included in the SAP.
10.5.6
Pharmacokinetics
The PAS will be used to summarize (pre-dose) Cmin and (post-dose) Cmax concentrations and 
to assess  patients’ compliance and analysis of PK concentrations. PK/PD (PK/safety and 
PK/Efficacy) analyses will be based on the Safety Set or FAS accordingly. Other analyses and 
listings of PK concentration will use the FAS.
10.5.6.1 To evaluate pre-dose PK data to support the assessment of 
compliance
Pre-dose PK concentrations (Cmin) from the PAS will be analyzed to support the assessment 
of compliance. Predicted individual Cmin concentrations will be derived from a power model 
considering dose and potential other covariates, such as body weight. Predicted individual Cmin 
concentrations will be compared to respective observed pre-dose concentrations at steady-state 
of all patients. Distributions of the difference between predicted and observed Cmin values will 
be shown graphically by boxplots for both treatment groups and visit.
10.5.6.2 Description of individual PK concentrations and parameters
PK concentrations will be summarized by treatment, visit and time point. PK parameters will 
be summarized by treatment and visit.


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Descriptive statistics of PK concentration and PK parameters will include arithmetic and 
geometric means, median, SD, CV%, CV% of the geometric mean, minimum and maximum. 
Zero concentrations will not be included in the geometric mean calculation.
All analyses will be based on the PAS.
10.5.6.3 To explore PK/PD relationship
Serum ferritin change from baseline will be fitted by a linear mixed effect model with log-
transformed matching pre-dose concentrations as covariates and subject as random effect.
Serum creatinine change from baseline, serum creatinine clearance change from baseline and
urine protein creatinine ratio change from baseline will be fitted by a linear mixed effect model 
with log-transformed matching pre-dose and post-dose concentrations respectively as 
covariates and subject as random effect.
Incidence of notable serum creatinine events as defined in Table 10-1 will be analyzed by a 
logistic regression fitted by GEE methods as appropriate including matching log-transformed 
pre- and post-dose concentrations, respectively.
Incidence of notable serum creatinine clearance events as defined in Table 10-1 will be analyzed 
by a logistic regression fitted by GEE as appropriate methods including matching log-
transformed pre- and post-dose concentrations, respectively.
For all statistical models other covariates such as demographic characteristics may be included 
if appropriate.
Other non-linear mixed effect models, such as effect-compartment models, may be established 
if appropriate to further explore exposure efficacy or safety relationship and will be reported 
separately.
10.5.6.4 Data handling principles
Biofluid concentrations will be expressed in mass per volume units. All concentrations below 
the limit of quantitation or missing data will be reported as such in the concentration data listings. 
Concentrations below the limit of quantitation will be treated as zero in summary statistics.
10.6
Other analyses
10.6.1
Other safety data
Data from vital signs, body weight, ECG, echocardiogram, ocular, and auditory examinations 
will be listed and summarized with descriptive statistics as appropriate separately for each 
Safety Set. All new or worsened abnormalities will be recorded on the AE eCRF page.
10.6.1.1 Cardiac evaluation
ECG and Echocardiogram will be performed at baseline and EOT in the core phase. ECG will 
be performed when clinically indicated during the optional extension phase. Abnormalities will 
be reported together with an overall interpretation of the findings. Any abnormalities at baseline 
will be summarized. At post-baseline assessment, the investigator will flag all abnormalities 
s will be recorded 


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on the AE eCRF page. All findings of patients with new or worsened clinically significant 
abnormalities will be listed.
10.6.1.2 Vital signs and body weight
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 pulse rate and weight values 
are flagged. The criteria for notably abnormal pulse rate and weight are displayed in Table 10-
2.
Table 10-2
Definition of notable ranges for pulse rate and weight
Parameter
Weight
High 
Increase from baseline ≥ 10%
Low
Decrease from baseline ≥ 10%
Pulse rate (beats per minute)
High1
12-18 months
18-24 months
2-3 years
3-4 years
4-6 years
6-8 years
8-12 years
12-15 years
15-18 years
> 140
> 135
> 128
> 123
> 117
> 111
> 103
> 96
> 92
Low1
12-18 months
18-24 months
2-3 years
3-4 years
4-6 years
6-8 years
8-12 years
12-15 years
15-18 years
< 103
< 98
< 92
< 86
< 81
< 74
< 67
< 62
< 58
1: Fleming et al 2011.
10.6.1.3 Auditory and ocular assessment evaluations
Auditory evaluations will be performed at baseline, visit 17 if entering the optional extension 
phase and annually during the optional extension phase and ocular evaluations at baseline, 
Week 25 visit (Visit 11) and at EOT(core) visit (Visit 777) during the core phase and annually 


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during the optional extension phase. 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.
10.6.1.4 Growth and Development
For pediatric patients, growth velocity and pubertal stage will be listed at baseline, at EOT visit 
777 and annually during the optional extension phase and summarized using descriptive 
statistics as appropriate.
10.6.1.5 Serum ferritin during the optional extension phase
Change from baseline in serum ferritin at every year will be described for the Safety Set 4.
10.7
Interim analysis
One interim analysis has been added to allow for early analysis of the core phase data if 
requested by the health authority.  All chelation-naïve patients randomized in the study and who 
have completed a minimum of 12 weeks of treatment exposure or discontinued from treatment 
core phase at the time of the cutoff date will be included in the interim analysis.
All the analyses included in the interim analysis will be descriptive. Testing of hypotheses will 
not be performed and no decisions regarding the future course of the trial is anticipated at the 
time of the IA and the trial will continue. Therefore adjustment for multiplicity is not performed.  
Descriptive statistics will be provided by treatment arm on the primary endpoints (i.e. change 
from baseline in serum ferritin and compliance measured by stick pack /tablet count) and key 
safety data. 
Details on the analyses will be described in the statistical analysis plan.
10.8
Sample size calculation
The primary objective of this study is to evaluate patient compliance (using stick packs or 
tablets counts) and change in serum ferritin (SF) over time for both formulations of deferasirox 
in pediatric ICT naïve patients with iron overload.
The sample size was estimated to demonstrate superiority and statistical significance for both 
co-primary endpoints.
The assumptions made for this study were:

For serum ferritin:
An expected improvement between both formulations in SF change from baseline after 24 
weeks of treatment of −450ng/mL with a standard deviation (SD) of 900 ng/mL based on 
results from study CICL670A0107 in pediatric patients treated with Exjade on ≥25 
mg/kg/day after 24 weeks of treatment.


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
For compliance using stick packs or tablets counts:
An expected improvement between both formulations in mean relative consumed tablet 
count of 10% with a SD equal to 17.625% based on the pooled analysis on pediatric 
patients (77) from Exjade studies [ICL670A2206] (39), [ICL670A2204] (24) and 
[ICL670A2214] (14).
The sample size, driven by the calculation of serum ferritin, has been determined to obtain 76% 
power at a one-sided 5% level of significance for showing superiority of granule formulation 
over DT formulation with respect to change from baseline after 24 weeks  of treatment in serum 
ferritin.
A sample size of 45 in each group will have 76% power to detect a difference in means of 400.0 
ng/mL assuming that the common SD is 800.0 ng/mL using a two group t-test with a 0.050 one-
sided significance level. With 45 patients per arm, the power to detect a difference of 10% or 
more in mean compliance is about 84%.
Considering a potential of 5% dropout rate patients, the required sample size to achieve the 
primary objective is 48 chelation naïve patients for each treatment group (96 patients in total).
In addition, the clinical trial will enroll patients previously treated with iron chelation patients. 
Considering that a direct comparison of granule and DT formulations in terms of efficacy is not 
foreseen in previously chelated patients, the required sample size is not based on power 
calculations as usual. The selection of number of patients is based on the precision in the 
estimate of SF change after 48 weeks of treatment and on practical considerations.
A maximum of 120 (60 patients will be in each formulation group) previously chelated patients 
will be enrolled. Sixty patients will provide an estimate of SF change with precision (half-width 
of 95% confidence interval) equal to 303.6.
Table 10-3 below lists the precisions in the estimates of SF change for different numbers of 
patients using the estimated SD obtained from the [CICL670A0107] study results in pediatric 
patients treated with Exjade on ≥25 mg/kg/day at week 48 of treatment.
Table 10-3
Precision in the estimate of the serum ferritin change
Number of patients
Half-width of 95% confidence interval in the estimate of the SF change
40
371.8
45
350.6
50
332.6
55
317.1
60
303.6
The total required sample size for this clinical trial is up to 108 patients for each treatment group 
(up to 216 patients in total), including 48 iron chelation naive patients per group (96 patients in 
total).


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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.
As per Section 4.5, during a Public Health emergency as declared by Local or Regional 
authorities i.e. pandemic, epidemic or natural disaster, that may challenge the ability to obtain 


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a standard written informed consent due to limits that prevent an on-site visit, Investigator may 
conduct the informed consent discussion remotely (e.g. telephone, videoconference) if 
allowable by a local Heath Authority. 
Guidance issued by local regulatory bodies on this aspect prevail and must be implemented and 
appropriately documented (e.g. the presence of an impartial witness, sign/dating separate ICFs 
by trial participant and person obtaining informed consent, etc.).
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.


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The investigator/institution should maintain the trial documents as specified in Essential 
Documents for the Conduct of a Clinical Trial (ICH E6 Section 8) and as required by applicable 
regulations and/or guidelines. The investigator/institution should take measures to prevent 
accidental or premature destruction of these documents.
Essential documents (written and electronic) should be retained for a period of not less than 
fifteen (15) years from the completion of the Clinical Trial unless Sponsor provides written 
permission to dispose of them or, requires their retention for an additional period of time 
because of applicable laws, regulations and/or guidelines.
11.7
Confidentiality of study documents and patient records
The investigator must ensure anonymity of the patients; patients must not be identified by names 
in any documents submitted to Novartis. Signed informed consent/assent 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 prior to study start by study personnel who are directly 
involved in the treatment or evaluation of patients at the site.
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)
Borgna-Pignatti C, Rugolotto S, De Stefano P et al (2004) Survival and complications in 
patients with thalassemia major treated with transfusion and deferoxamine. Haematologica; 
89:1187-1193Cappellini MD, Cohen A, Piga A, et al. (2006) A Phase III study of deferasirox 
(ICL670), a once-daily oral iron chelator, in patients with ß-thalassemia. Blood; 107:3455-62
Cappellini MD (2008a) Long-term efficacy and safety of deferasirox. Blood Rev; Suppl 
2:S35-41
Cappellini MD, Elalfy M, Kattamis J, et al. (2008b) Efficacy and safety of once-daily, oral 
iron chelator deferasirox (Exjade) in a large group of regularly transfused patients with β-
thalassemia major. ASH, San Francisco, USA, 6-9 December 2008; Poster III-960
Fleming S, Thompson M, Stevens R, et al (2011) Normal ranges of heart rate and respiratory 
rate in children from birth to 18 years of age: a systematic review of observational studies. 
Lancet; 377:1011-8. 
Gabutti V, Piga A. (1996) Results of long-term iron-chelating therapy. Acta Haematol ; 
95:26-36
Haghpanah S, Zarei T, Zahed Zi,et al. (2014) Compliance and satisfaction with deferasirox 
(Exjade®) compared with deferoxamine in patients with transfusion-dependent beta-
thalassemia. Hematology; 19: 187-191
Inati A, Khoriaty E, Musallam KM (2011) Iron in Sickle-Cell Disease: What Have We 
Learned Over the Years? Pediatr Blood Cancer; 56:182-190
Kushner J, Porter J, and Olivieri N (2001) Secondary Iron Overload. Hematology; 47-61
Mednick LM, Braunstein J, Neufeld E (2010) Oral Chelation: Should It Be Used With Young 
Children? Pediatr Blood Cancer; 55:603-605
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
Osterberg L, Blaschke T (2005) Adherence to Medication. N Engl J Med; 353:487-97
Partridge AH, Avorn J, Wang PS, Winer EP (2002) Adherence to Therapy With Oral 
Antineoplastic Agents. Journal of the National Cancer Institute; 94( 9):652-661
Rudd P, Byyny RL, Zachary V et al (1989) The natural history of medication compliance in a 
drug trial: Limitations of pill counts. Clin Pharmacol Ther, Vol 46, No 2: 169-
176Trachtenberg F, Vichinsky E,  Haines, D, et al (2011) Iron chelation adherence to 
deferoxamine and deferasirox in thalassemia.  Am J Hematol;  86(5): 433–436  
Tuleu C (2011) Acceptability and Palatability – methods available for assessment.
Vichinsky E (2008) Oral Iron Chelators and the Treatment of Iron Overload in Pediatric 
Patients With Chronic Anemia.Pediatrics;121;1253-1256
Vichinsky et al (2012) Standards of Care Guidelines for Thalassemia (Internet) Available
from: http://thalassemia.com/documents/SOCGuidelines2012.pdf (Accessed 29 Jan 2015).
Weatherall DJ (2010) The inherited diseases of hemoglobin are an emerging global health 
burden. Blood; 115: 4331-4336.


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Workshop on Paediatric Formulations II for Assessors in National Regulatory Agencies, Nov 
8, 2011, EMA/432389/2011, Human Medicines Development and Evaluation.


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14
Appendices
14.1
Equivalent dose guidance
All iron chelation pre-treated patients well-managed on treatment with deferasirox will use the 
same starting DT dose or an equivalent granules dose (see Table 14-1).
For patients pre-treated with deferoxamine, a starting dose of DT or an equivalent granules 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 granules), see Table 14-2.
Dose equivalence between deferiprone and deferasirox is not established in clinical studies. For 
patients pre-treated with deferiprone (DFP), investigators should decide on the starting dose of 
DT or granules in the study, taking into consideration the iron overload status of the patients 
and their transfusional regimen.
Table 14-1
Patients pre-treated with deferasirox
Previous dose of
Deferasirox DT (mg/kg/day)
Equivalent dose to be used
Deferasirox DT (mg/kg/day)
Deferasirox granules (mg/kg/day)
5
5
3.5
10
10
7
15
15
10.5
20
20
14
25
25
17.5
30
30
21
35
35
24.5
40
40
28
Table 14-2
Patients pre-treated with deferoxamine
Previous dose of
Deferoxamine (mg/kg/day)
Equivalent dose to be used
Deferasirox DT (mg/kg/day)
Deferasirox granules (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


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Table 14-3
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 hummuus 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


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Example 5:
amount
kcal
g total 
fats
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
skim milk
1 cup
83
0
Total:
502
2
Example 6:
amount
kcal
g total 
fats
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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14.2
Dosing tables (Deferasirox DT, Deferasirox granules)
For each patient the investigator and/or pharmacist will calculate a target daily dose taking into 
account patient’s body weight at randomization. When the calculated dose cannot be reached 
with the deferasirox tablet / stick pack strengths available, the closest daily dose available will 
be prescribed. The following dosing tables provide an efficient combination of tablet / stick 
pack strengths reaching a certain daily dose for each body weight range.  
Examples illustrating this approach are provided below:

For a patient with a body weight of 46 kg and a deferasirox DT dose of 20 mg/kg/day, the 
calculated daily dose is 920 mg. Taking into account the available DT strengths of 125, 
250 and 500 mg deferasirox, the closest daily dose the patient can receive is 875 mg, by 
taking 3 deferasirox tablets: 1 x 125 mg + 1 x 250 mg + 1 x 500 mg. This combination can 
be found in the ‘Tablets’ column, for patients receiving 20 mg/kg/day of deferasirox DT 
and with a body weight between 41-46 kg.

For a patient with a body weight of 46 kg and a deferasirox granules dose of 14 
mg/kg/day, the calculated daily dose is 644 mg. Taking into account the available stick 
pack strengths of 90, 180 and 360 mg deferasirox, the closest daily dose the patient can 
receive is 630 mg, by taking 3 stick packs: 1 x 90 mg + 1 x 180 mg + 1 x 360 mg. This 
combination can be found in the ‘Stick packs’ column, for patients receiving 14 
mg/kg/day of deferasirox granules and with a body weight between 42-48 kg.
These dosing tables have been constructed for each dosing group using lower and upper body 
weight limits of 5 and 140 kg, respectively. This is taking into account that the study will enroll 
male or female children and adolescents, ≥ 2 and < 18 years. However, for some patients with 
a low body weight (e.g. below 19 kg in the 5 mg/kg/day dosing group) the dosing requirements 
given in Section 6.1.1 will not allow for the use of the smallest strength available (Eg: 125 mg 
for DT, or 90 mg for granules). In such cases a written request will be sent to Novartis, to advise 
on the individual patient enrolment / dose adjustments options.


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Table 14-4
Dosing table for deferasirox DT
Body weight ranges per dosing group (kg)
Tablets
5 mg/kg/day
[kg]
10 mg/kg/day 
[kg]
15 mg/kg/day 
[kg]
20 mg/kg/day 
[kg]
25 mg/kg/day 
[kg]
30 mg/kg/day 
[kg]
35 mg/kg/day 
[kg]
40 mg/kg/day 
[kg]
125 mg
250 mg 500 mg
19 - 37
10 - 18
9 - 12
5 – 9
5 - 7
5 - 6
5
1
38 - 62
19 - 31
13 - 20
10 - 15
8 - 12
7 - 10
6 - 8
5 - 7
1
63 - 87
32 - 43
21 - 29
16 - 21
13 - 17
11 - 14
9 - 12
8 - 10
1
1
88 - 112
44 - 56
30 - 37
22 - 28
18 - 22
15 - 18
13 - 16
11 - 14
1
113 - 137
57 - 68
38 - 45
29 - 34
23 - 27
19 - 22
17 - 19
15 - 17
1
1
138 - 140
69 - 81
46 - 54
35 - 40
28 - 32
23 - 27
20 - 23
18 - 20
1
1
82 - 93
55 - 62
41 - 46
33 - 37
28 - 31
24 - 26
21 -23
1
1
1
94 - 106
63 - 70
47 - 53
38 - 42
32 - 35
27 - 30
24 - 26
2
107 - 118
71 - 79
54 - 59
43 - 47
36 - 39
31 - 33
27 - 29
1
2
119 - 131
80 - 87
60 - 65
48 - 52
40 - 43
34 - 37
30 - 32
1
2
132 - 140
88 - 95
66 - 71
53 - 57
44 - 47
38 - 41
33 - 35
1
1
2
96 - 104
72 - 78
58 - 62
48 - 52
42 - 44
36 - 39
3
105 - 112
79 - 84
63 - 67
53 - 56
45 - 48
40 - 42
1
3
113 - 120
85 - 90
68 - 72
57 - 60
49 - 51
43 - 45
1
3
121 - 129
91 - 96
73 - 77
61 - 64
52 - 55
46 - 48
1
1
3
130 - 137
97 - 103
78 - 82
65 - 68
56 - 58
49 - 51
4
138 - 140
104 - 109
83 - 87
69 - 72
59 - 62
52 - 54
1
4
110 - 115
88 - 92
73 - 77
63 - 66
55 - 57
1
4
116 - 121
93 - 97
78 - 81
67 - 69
58 - 60
1
1
4
122 - 128
98 - 102
82 - 85
70 - 73
61 - 64
5
129 - 134
103 - 107
86 - 89
74 - 76
65 - 67
1
5
135 - 140
108 - 112
90 - 93
77 - 80
68 - 70
1
5
113 - 117
94 - 97
81 - 83
71 - 73
1
1
5
118 - 122
98 - 102
84 - 87
74 - 76
6
123 - 127
103 -106
88 - 91
77 - 79
1
6


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Body weight ranges per dosing group (kg)
Tablets
5 mg/kg/day
[kg]
10 mg/kg/day 
[kg]
15 mg/kg/day 
[kg]
20 mg/kg/day 
[kg]
25 mg/kg/day 
[kg]
30 mg/kg/day 
[kg]
35 mg/kg/day 
[kg]
40 mg/kg/day 
[kg]
125 mg
250 mg 500 mg
128 - 132
107 - 110
92 - 94
80 - 82
1
6
133 - 137
111 - 114
95 - 98
83 - 85
1
1
6
138 - 140
115 - 118
99 - 101
86 - 89
7
119 - 122
102 -105
90 - 92
1
7
123 - 127
106 -108
93 - 95
1
7
128 - 131
109 - 112
96 - 98
1
1
7
132 - 135
113 - 116
99 - 101
8
136 - 139
117 - 119
102 - 104
1
8
140
120 - 123
105 - 107
1
8
124 - 126
108 - 110
1
1
8
127 - 130
111 - 114
9
131 - 133
115 - 117
1
9
134 - 137
118 - 120
1
9
138 - 140
121 - 123
1
1
9
124 - 126
10
127 - 129
1
10
130 - 132
1
10
133 -135
1
1
10
136 - 139
11
140
1
11


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Table 14-5
Dosing table for deferasirox granules
Body weight ranges per dosing group (kg)
Stick packs
3.5 mg/kg/day 
[kg]
7 mg/kg/day 
[kg]
10.5 
mg/kg/day [kg]
14 mg/kg/day 
[kg]
17.5 
mg/kg/day [kg]
21 mg/kg/day 
[kg]
24.5 
mg/kg/day [kg]
28 mg/kg/day 
[kg]
90 mg
180 mg 360 mg
19 - 38
10 - 19
7 - 12
5 – 9
5 - 7
5 - 6
5
1
39 - 64
20 - 32
13 - 21
10 - 16
8 - 12
7 - 10
6 - 9
5 - 8
1
65 - 90
33 - 45
22 - 30
17 - 22
13 - 18
11 - 15
10 - 12
9 - 11
1
1
91 - 115
46 - 57
31 - 38
23 - 28
19 - 23
16 - 19
13 - 16
12 - 14
1
116 - 140
58 - 70
39 - 47
29 - 35
24 - 28
20 - 23
17 - 20
15 - 17
1
1
71 - 83
48 - 55
36 - 41
29 - 33
24 - 27
21 - 23
18 - 20
1
1
84 - 96
56 - 64
42 - 48
34 - 38
28 - 32
24 - 27
21 -24
1
1
1
97 - 109
65 - 72
49 - 54
39 - 43
33 - 36
28 - 31
25 - 27
2
110 - 122
73 - 81
55 - 61
44 - 48
37 - 40
32 - 34
28 - 30
1
2
123 - 135
82 - 90
62 - 67
49 - 54
41 - 45
35 - 38
31 - 33
1
2
136 - 140
91 - 98
68 - 73
55 - 59
46 - 49
39 - 42
34 - 36
1
1
2
99 - 107
74 - 80
60 - 64
50 - 53
43 - 45
37 - 40
3
108 - 115
81 - 86
65 - 69
54 - 57
46 - 49
41 - 43
1
3
116 - 124
87 - 93
70 - 74
58 - 62
50 - 53
44 - 46
1
3
125 - 132
94 - 99
75 - 79
63 - 66
54 - 56
47 - 49
1
1
3
133 - 140
100 - 106
80 - 84
67 - 70
57 - 60
50 - 52
4
107 - 112
85 - 90
71 - 75
61 - 64
53 - 56
1
4
113 - 118
91 - 95
76 - 79
65 - 67
57 - 59
1
4
119 - 125
96 - 100
80 - 83
68 - 71
60 - 62
1
1
4
126 - 131
101 - 105
84 - 87
72 - 75
63 - 65
5
132 - 138
106 - 110
88 - 92
76 - 78
66 - 69
1
5
139 - 140
111 - 115
93 - 96
79 - 82
70 - 72
1
5
116 - 120
97 - 100
83 - 86
73 - 75
1
1
5
121 - 126
101 - 105
87 - 90
76 - 78
6
127 - 131
106 -109
91 - 93
79 - 81
1
6
132 - 136
110 - 113
94 - 97
82 - 85
1
6


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Body weight ranges per dosing group (kg)
Stick packs
3.5 mg/kg/day 
[kg]
7 mg/kg/day 
[kg]
10.5 
mg/kg/day [kg]
14 mg/kg/day 
[kg]
17.5 
mg/kg/day [kg]
21 mg/kg/day 
[kg]
24.5 
mg/kg/day [kg]
28 mg/kg/day 
[kg]
90 mg
180 mg 360 mg
137 - 140
114 - 117
98 - 101
86 - 88
1
1
6
118 - 122
102 - 104
89 - 91
7
123 - 126
105 -108
92 - 94
1
7
127 - 130
109 -112
95 - 98
1
7
131 - 135
113 - 115
99 - 101
1
1
7
136 - 139
116 - 119
102 - 104
8
140
120 - 123
105 - 107
1
8
124 - 126
108 - 110
1
8
127 - 130
111 - 114
1
1
8
131 - 134
115 - 117
9
135 - 137
118 - 120
1
9
138 - 140
121 - 123
1
9
124 - 126
1
1
9
127 - 130
10
131 - 133
1
10
134 - 136
1
10
137 -139
1
1
10
140
11

SAP_001.pdf: 
Official Title: A randomized, open-label, multicenter, two arm, phase II study 
 to evaluate treatment compliance, efficacy and safety of an 
improved deferasirox formulation (granules) in pediatric patients 
with iron overload
NCT Number: NCT02435212
Document Date: Statistical Analysis Plan (Final Version): 21-February-2024
SAP-End of Core Phase (Final Version): 23-June-2021 
SAP Version 5.0: 26-March-2018


Clinical Development
ICL670/deferasirox
Study Number: CICL670F2202 / NCT02435212
A randomized, open-label, multicenter, two arm, phase II 
study to evaluate treatment compliance, efficacy and safety 
of an improved deferasirox formulation (granules) in 
pediatric patients with iron overload
Statistical Analysis Plan (SAP)
Detailed Statistical Methodology
Authors:
Document type:
RAP Documentation
Document status:
Final version 5.0
Release date:
26-Mar-2018
Number of pages:
54
Property of Novartis
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


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SAP – Amendment 3
ICL670F2202
Document History – Changes compared to previous version of SAP.
Version
Date
Changes
2.0
12 March 2015
Final version
Version based on Protocol dated of 06-Feb-2015
3.0
01 Feb 2017
Final version – Amendment 1 
This amendment reflects changes based on the study 
protocol amendments 1 and 2.
Section 1 – Introduction
- Study design (Section 1.1): addition of an optional 
extension phase, inclusion of ICT pre-treated patients
- Study objectives (Section 1.2): new secondary objectives 
for the extension phase as well as for ICT naïve versus pre-
treated patients. Update on PK objective based on the 
change of PK samples collection timepoints.
- Statistical analysis timepoints (Section 1): clarifications on 
the planned CSRs. Primary CSR at the end of the core 
phase and final CSR at the end of the extension phase
Section 2 – Statistical methods
- Data analysis (Section 2.1): 
Addition of the definition for the analysis cut-off of the 
primary analysis. Addition of the definition of the core and 
extension phases
- Analysis sets (Section 2.2):
Addition of Safety Sets 1, 2, 3, 4 and FASs 1, 2, 3 and 4 to 
align with study objectives. Clarification/update of the PPS 
based on the VAP module 3.
Clarification/update of the PAS-1 and addition of the PAS-2. 
- Patient demographics and other baseline characteristics 
(Section 2.3):
Update on the analysis sets.
Addition of summaries for DSURs/PSURs.
Addition of prior chelation therapy summary. 
Removal of time since last blood transfusion summary.
Update of creatinine clearance, serum creatinine, UPCR 
and serum ferritin categories at baseline. 
- Protocol deviations (Section 2.4): 
Update on analyzed Update on the analysis sets.
- Patient disposition (Section 2.5):
Update on the analysis sets.
Update of disposition summary for the core phase. 
Addition of disposition summary for the entire granule 
period.
- Treatment (Section 2.6):
Update on the analysis sets.
Removal of final dose summary. 
Addition of new categories for duration of exposure 


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Changes
analysis. 
Update of dose reduction, increase and interruption 
definitions.
- Baseline (Section 2.7):
Removal of baseline definition for mSICT and palatability 
questionnaires.
Addition of baseline definition for the entire granule period.
- Analysis of the primary variable (Section 2.8):
Update on the analysis sets.
Removal of compliance summary and graph by timepoint 
(supportive analysis). 
Addition of subgroups for supportive analyses. 
Addition of a supportive analysis: forest plot to present 
absolute change in serum ferritin at 48 week of treatment 
and the corresponding exact 95%CI including the defined 
subgroups. 
Addition of secondary and other analyses of the primary 
variables (serum ferritin and compliance).
- Analysis of secondary variables (section 2.9):
Update on the analysis sets.
Patient reported outcomes/Observer reported outcomes
(Section 2.9.1): Clarification on ObsRO/PRO data analysis: 
by type of questionnaire. Correction of the scoring rule to 
derive domain score from item responses for the mSICT 
questionnaire. Removal of waterfall and cumulative 
distribution plots. Addition of descriptive analysis (n, %) for 
all items. Modification of mean score plots by visit: change 
of 95%CI by SD. Addition of dose violation rate summary by 
visit. Removal of the plot presenting weekly average of 
medication intake
Safety evaluations: Observation periods definition for the 
entire granule period. Addition of safety outputs required for 
ClinicalTrial.gov and EudraCT. Addition of overall summary 
of type of AEs. Removal of exposure adjusted AEs 
analysis. Addition of ocular data analysis by evaluation 
(visual acuity, slit lamp, tonometry and fundus occuli). 
Clarification of growth velocity data analysis. Addition of an 
analysis regarding pubertal stage assessment.
Pharmacokinetics parameters: Clarification on the analysis 
sets to use for the PK analyses. Clarification added on PK 
analyses to support the assessment of compliance.
Removal of the section about the derivation of PK 
parameters. Clarification added on PK/PD analyses.
- Subgroup analysis (Section 2.10):
Clarification on subgroups definition. 
Addition of underlying disease subgroup.
- Sample size (Section 2.11): Update of the sample size 
section to add the enrolment of up to 120 pre-treated 
patients.
Section 3 - Change to protocol specified analyses: 


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Version
Date
Changes
Section updated to reflect the planned analyses in the SAP 
versus the protocol amendment 2 planned analyses.
Section 4 - Additional details on implementation of 
statistical methodology 
- Time windows (Section 4.1): 
Update of study periods for drug exposure and lab data 
analysis as well as for compliance ObsRO/PRO analysis by 
week. 
Removal of time window definition for pill count data
analysis.
- Other baseline characteristics: 
Addition of medical history PTs for baseline characteristics. 
Removal of dose interruption, change definitions.
- Stratification (Section 4.5): Clarification on stratification 
factors. 
- Efficacy endpoints (section 4.6): Addition of sas 
procedures for model-based analyses (primary and PK 
analyses). 
- Handling of missing or partial dates (section 4.8): Addition 
of analysis rules for incomplete dates.
Section 5 – References 
Section updated.
4.0
08 Dec 2017
Final version – Amendment 2
This amendment reflects changes based on the study 
protocol amendments 3 and 4.
Section 1 – Introduction
- Addition of an interim analysis (Section1) of the core 
phase data for which a CSR will be written.
- Study objectives (Section 1.2): 
Update on PK objectives to align with the protocol.
Section 2 – Statistical methods 
- Data analysis (Section 2.1):
Addition of interim analysis population definition.
Clarification of core phase definition.
- Analysis sets (Section 2.2):
Addition of one criterion to the PAS-1 and clarification that 
only evaluable PK samples from PAS-1 and PAS-2 will be 
considered. 
- Analysis of the primary variable (Section 2.8):
Clarification of the variable to be used for the forest plot 
(Section 2.8.4).
- Analysis of the secondary variables (Section 2.9):
Patient reported outcomes/Observer reported outcomes 
(Section 2.9.1): Correction of the response format for Items 
9 and 10 from mSICT PRO questionnaire to align with the 
PRO/ObsRO Data Transfer Specifications and addition of 
scoring rules to derive domain scores for the mSICT 
ObsRO questionnaire (Section 2.9.1.1). To clarify the 


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Version
Date
Changes
scoring rule to derive domain scores for the Palatability 
questionnaire (Section 2.9.1.2). To clarify the formula to 
compute the weekly average of dose violation rate (Section 
2.9.1.3). 
Pharmacokinetics parameters (Section 2.9.2): To update 
the pharmacokinetic analyses to align with the protocol. To 
update the time-windows criterion for the pre-dose PK data 
analysis to align with the PAS-1 definition (Section 2.9.3.2). 
To clarify the dose-adjusted PK concentrations/ parameters 
calculation (Section 2.9.3.3).
- Interim analysis (Section 2.12):
To add details about the interim analysis.
Section 3 – Change to protocol specified analyses
- Removal of the changes to protocol specified analyses to 
align with the protocol.
- ObsRO/PRO not analyzed at the time of the IA as per 
protocol amendment 4, rational provided.
Section 4 – Additional details on implementation of 
statistical methodology
- Time windows (Section 4.1): 
Addition of time windows for ocular data analysis.
Clarification of EOT time window (Section 4.1.2).
- Stratification (Section 4.5):
Clarification on the stratification ID numbers for ICT naïve 
patients. 
- Removal of SAS codes (Sections 4.6.1 and 4.6.2)
- Addition of method of calculation of probability of success 
(Section 4.6.3)
- Efficacy evaluations (Section 4.6):
- Handling of missing or partial dates (Section 4.8):
To clarify that only the date of last dose of study drug can 
be imputed from DAR eCRF records (Section 4.8.5).
5.0
26 Mar 2017
Final version – Amendment 3
This amendment reflects changes based on the study 
protocol amendment 5.
Section 1 – Introduction 
- Study objectives (Section 1.2): 
Update on primary and secondary objectives to align with 
the protocol.
Section 2 – Statistical methods
- Data analysis (Section 2.1): 
Clarification on cut-off definition for the primary analysis.
- Analysis sets (Section 2.2): 
Correction of ID for major protocol deviations for PPS to 
reflect the last VAP. 
- Analysis sets (Section 2.3): 
Removal of Safety Set 1, 2, FAS-1 and FAS-2 populations 
for the laboratory parameters description’ at baseline.


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Version
Date
Changes
- Treatments (Section 2.6): 
Clarification on dose reduction and increase flag derivation.
- Baseline (Section 2.7): 
Clarification on baseline definition: the last available 
assessment i.e. non-missing assessment.
- Analysis of the primary variable (Section 2.8):
Modification of the primary analysis variables and analysis 
as well as supportive analysis to align with protocol
(Sections 2.8.1 to 2.8.4).
Addition of secondary analyses to align with the protocol
(Section 2.8.5). 
- Analysis of the secondary variables (Section 2.9):
Addition of FAS-1 and FAS-2 populations for ObsRO/PRO 
data analysis to align with protocol (Section 2.9.1).
Addition of AESI descriptive summaries by severity, SAE,
relationship, etc. (Section 2.9.2). 
Correction of the visit numbers for pharmacokinetics 
analyses under PAS-2 (Section 2.9.3). 
- Sample size (Section 2.11):
Modification of sample size for the primary analysis to align 
with protocol.
Section 3 – Change in protocol specified analyses
Removal of changes to protocol specified analysis to align 
with the protocol.
Section 4 – Additional details on implementation of 
statistical methodology
- Time windows (Section 4.1)
Clarification of time-windows derivation for drug exposure, 
laboratory data and ocular data analysis
- Efficacy evaluations (Section 4.6)
Clarification on SAS procedures for primary and sensitivity 
analysis.
- Safety evaluations (Section 4.7)
Removal of eGFR formula: NA 
- Handling of missing or partial dates (Section 4.8)
Clarification of imputation rule for incomplete date of last 
dose of study drug.


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Table of contents
Table of contents .................................................................................................................7
List of tables ........................................................................................................................9
List of figures ......................................................................................................................9
List of abbreviations..........................................................................................................10
1
Introduction .......................................................................................................................12
1.1
Study design...........................................................................................................12
1.2
Objectives ..............................................................................................................13
2
Statistical methods.............................................................................................................14
2.1
Data analysis..........................................................................................................14
2.2
Analysis sets ..........................................................................................................16
2.3
Patient demographics and other baseline characteristics.......................................18
2.4
Protocol deviations ................................................................................................20
2.5
Patient disposition..................................................................................................20
2.6
Treatments (study drug exposure, concomitant therapies)....................................21
2.7
Baseline..................................................................................................................23
2.8
Analysis of the primary variables..........................................................................24
2.8.1
Variable.................................................................................................24
2.8.2
Statistical hypothesis, model, and method of analysis..........................25
2.8.3
Handling of missing values/discontinuations........................................25
2.8.4
Supportive analyses...............................................................................26
2.8.5
Secondary and other analyses of the primary variables........................26
2.9
Analysis of secondary variables ............................................................................26
2.9.1
Patient reported outcomes/Observer reported outcomes.......................27
2.9.2
Safety evaluations .................................................................................34
2.9.3
Pharmacokinetics parameters................................................................40
2.10
Subgroup analysis..................................................................................................43
2.11
Sample size............................................................................................................43
2.12
Interim analysis......................................................................................................44
3
Change to protocol specified analyses ..............................................................................45
4
Additional details on implementation of statistical methodology.....................................45
4.1
Time windows .......................................................................................................45
4.1.1
Study drug exposure..............................................................................45
4.1.2
Laboratory data and vital signs .............................................................46
4.1.3
Compliance diary ..................................................................................47


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4.1.4
Ocular data ............................................................................................48
4.2
Month/year derivation ...........................................................................................48
4.3
Body mass index....................................................................................................48
4.4
Other baseline characteristics ................................................................................48
4.5
Stratification ..........................................................................................................49
4.6
Efficacy evaluations...............................................................................................49
4.6.1
Primary endpoint...................................................................................49
4.6.2
Pharmacokinetics endpoint ...................................................................49
4.6.3
Calculation of predictive probability of success for serum ferritin 
change from baseline.............................................................................50
4.7
Safety evaluations..................................................................................................51
4.7.1
Multiple assessments within post-baseline visits..................................51
4.7.2
Baseline.................................................................................................51
4.8
Handling of missing or partial dates......................................................................52
4.8.1
AE date imputation ...............................................................................52
4.8.2
Concomitant medication date imputation .............................................53
4.8.3
Incomplete date of diagnosis of main underlying disease ....................53
4.8.4
Incomplete date for last iron chelation therapy.....................................53
4.8.5
Incomplete date of last dose of study drug............................................53
5
References .........................................................................................................................54


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List of tables
Table 1-1
Objectives and related endpoints ..........................................................13
Table 2-1
Definition of core and extension phases ...............................................15
Table 2-2
Deferasirox: Study drug exposure.........................................................22
Table 2-3
Scoring Matrix ......................................................................................33
Table 2-4
Definition of notable/extended ranges for key safety laboratory 
parameters .............................................................................................37
Table 2-5
Pharmacokinetic Parameters (NCA and CA)........................................40
Table 2-6
Subgroups definition and use................................................................43
Table 2-7
Precision in the estimate of the serum ferritin change ..........................44
Table 3-1
Changes to protocol specified analysis or descriptions and rationale...45
Table 4-1
Study periods for drug exposure ...........................................................46
Table 4-2
Time windows for laboratory data, vital signs, weight and BMI..........47
Table 4-3
Week periods for compliance diaries....................................................47
Table 4-4
Time windows for ocular data...............................................................48
Table 4-4
Medical history terms for other baseline characteristics.......................48
Table 4-5
AE start date imputation example scenarios .........................................52
List of figures
Figure 2-1
Core and extension phases ....................................................................15
Figure 2-2
Conceptual model for the Modified Satisfaction with Iron 
Chelation Therapy questionnaire ..........................................................28
Figure 2-3
Conceptual model for Item 7 of the modified SICT .............................29
Figure 2-4
Conceptual Model for the Modified Satisfaction with Iron 
Chelation Therapy Questionnaire .........................................................30
Figure 2-5
Conceptual model for item 6 and item 15 of the modified SICT.........31


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List of abbreviations
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALT
Alanine aminotransferase/glutamic pyruvic transaminase/GPT
AST
Aspartate aminotransferase/glutamic oxaloacetic transaminase/GOT
ATC
Anatomical Therapeutic Classification
AUC
Area under concentration-time curve
BMI
Body mass index
BP
Blood Pressure
CA
Compartmental Analyses
CI
Confidence Interval
CrCl
Creatinine Clearance
CRF
Case Report/Record Form
CSR
Clinical Study Report 
CV
Coefficient of Variation
DAR
Dosage Administration Record
DBP
Diastolic Blood Pressure
DRL
Drug Reference Listing
DT
Dispersible Tablet 
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
PRO/ObsRO
Patient Reported Outcomes/Observer Reported Outcomes
EOT
End of Treatment
FAS
Full Analysis Set
FCT
Film Coated Tablet
FU
Follow Up
GCP
Good Clinical Practice
GGT
Gamma-glutamyltransferase
HLT
High Level Terms
IA
Interim Analysis
ICT
Iron Chelation Therapy
IRT
Interactive Response Technology 
ITT
Intention To Treat
Kg
Kilogram
LLOQ
Lower Limit of Quantitation
MDRD
Modification of Diet in Renal Disease
MDS
Myelodysplastic syndrome
MedDRA
Medical Dictionary for Regulatory Activities


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NA
Not Applicable
NCA
Non-Compartmental Analyses
NEU
Neutrophils
NMQ
Novartis MedDRA Queries
PAS
Pharmacokinetic Analysis Set
PDS
Programming Datasets Specifications
PK
Pharmacokinetic
PPS
Per-Protocol Set
PT
Preferred Terms
RBC
Red Blood Cell
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SD
Standard Deviation
SCIT
Satisfaction with Iron Chelation Therapy
SI
International System 
SMQ
Standardized MedDRA Queries
SOC
System Organ Classes
SCr
Serum Creatinine
TBL
Total Bilirubin
TEAE
Treatment Emergent Adverse Event
TFL
Tables Figures Listings
ULN
Upper Limit of Normal
UNK
Unknown
WBC
White Blood Cell
WHO
World Health Organization


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1
Introduction
This document details the planned statistical analysis for data collected in the study 
CICL670F2202. 
Clinical Study Report (CSR) deliverables (tables, figures, listings - TFLs) and further 
programming specifications are described in separate documents namely TFL Shells and 
Programming Datasets Specifications (PDS), respectively. This analysis plan describes the 
primary analysis for the primary CSR planned at the end of the core phase and the analyses 
for the final CSR planned at the end of the extension phase. One interim analysis is planned to 
allow for early analysis of the core phase if requested by Health Authority. This document 
also details the statistical methods to be used for reporting results in the interim CSR.
1.1
Study design
This is a randomized, open-label, multicenter, two arm, phase II study to evaluate treatment
compliance and change in serum ferritin of a deferasirox granule formulation and a
Dispersible Tablet (DT) formulation in children and adolescents aged ≥ 2 and < 18 years at 
enrollment with any transfusion-dependent anemia requiring chelation therapy due to iron 
overload, and having a treatment goal to reduce iron burden as measured by serum ferritin.
Patients whose eligibility is confirmed will be enrolled prior to commencing a 48-week
randomized treatment period in the core phase with either deferasirox DT (taken as per local 
label) or deferasirox granule formulation (taken with or without a light meal) beginning on 
Day 1. 
Randomization will be stratified by age groups (2 to <10 years, 10 to <18 years) and by prior 
Iron Chelation Therapy (ICT) (Yes/No). Up to 240 naïve and pre-treated patients (120 ICT 
naïve and up to 120 pre-treated) will be randomized. 
There will be two study phases which include a 1 year core phase where patients will be 
randomized to a 48 week treatment period to either Deferasirox DT or granules, and an 
optional extension phase where all patients will receive the granules up to 5 years. Patients 
who demonstrate benefit to granules or DT in the core phase, and/or wish to continue in the 
optional extension phase on granules, will be offered this possibility until there is local access 
to the new formulation (granules or FCT) or up to 5 years, whichever occurs first.
During the 48 week treatment period in the core phase, patients will return to the site for study 
assessments weekly for the first 3 weeks and then every 4 weeks starting from week 5 (weeks 
9, 13, 17, 21, 25, 29, 33, 37, 41 and 45) until the core End Of Treatment (EOT) visit. 
Patients who discontinue study treatment before completing the core or optional extension 
phase should be scheduled for an end of treatment visit within 7 days of the last dose of study 
treatment, at which time all of the assessments listed for the core end of treatment visit or 
extension end of treatment visit will be performed. 
All patients, regardless if they discontinue the study treatment early or per protocol, will be 
contacted for safety evaluations 30 days after the last dose of study treatment.


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1.2
Objectives
The study objectives as outlined in the [protocol Section 3] are as follows (Table 1-1).
Table 1-1
Objectives and related endpoints
Objective
Endpoint
Analysis
Primary

To evaluate both formulations on patient 
compliance, using stick pack/tablet 
count over 24 weeks of treatment in ICT 
naïve patients during core phase

To evaluate the change from baseline in 
serum ferritin after 24 weeks of 
treatment for both formulations in ICT 
naïve patients

Compliance measured by stick pack/tablet 
count over 24 weeks of treatment (i.e. 
assessed at week 25 visit)

Change from baseline in serum ferritin after 
24 weeks of treatment (i.e. serum ferritin 
at week 25 visit)
Refer to
Protocol Section 
10.4 / SAP 
Section 2.8
Secondary (Core phase)
To evaluate both formulations on change in 
serum ferritin and compliance in ICT naive 
patients, after 48 weeks of treatment
● Compliance measured by stick pack/tablet 
count after 48 weeks of treatment
● Change from baseline in serum ferritin after 
48 weeks of treatment
Refer to 
Protocol Section 
10.5 / SAP 
Section 2.8.5
To evaluate both formulations on change in 
serum ferritin after 24 weeks and 48 weeks 
of treatment in ICT naïve and pre-treated 
patients
Change from baseline in serum ferritin after 24 
weeks (i.e. assessed at week 25 visit) and 48 
weeks of treatment
Refer to
Protocol Section 
10.5.1 / SAP
Section 2.8.5
To evaluate both formulations on patient 
satisfaction and palatability using Patient / 
Observer Reported Outcomes 
(PRO/ObsRO) questionnaires
Domain scores of treatment satisfaction and 
palatability over time
Refer to
Protocol Section 
10.5.2 / SAP 
Section 2.9.1
To evaluate both formulations on overall 
safety
Overall safety, as measured by frequency and 
severity of adverse events (including active 
monitoring for renal toxicity; including renal 
failure, hepatic toxicity; including hepatic 
failure, and gastrointestinal hemorrhage), and 
changes in laboratory values from baseline 
(serum creatinine, creatinine clearance, ALT, 
AST, RBC and WBC). In addition, vital signs, 
physical, ophthalmological, audiometric, 
cardiac, and growth and development 
evaluations will be assessed.
Refer to 
Protocol Section 
10.5.3 / SAP 
Section 2.9.2
To evaluate compliance using a daily 
PRO/ObsRO questionnaire
Rate of dosing instructions deviations (doses 
missed / not taken at the same time every day)
Refer to 
Protocol Section 
10.5.4 / SAP 
Section 2.9.1
To evaluate pre-dose PK data to support the 
assessment of compliance
Pre-dose deferasirox concentrations in all 
patients [except Egypt] at weeks  1, 3, 5, 9, 13, 
17, 21, 25, 29, 33, 37, 41 and 45 (13 samples)
Refer to 
Protocol Section 
10.5.5.1 / SAP 
Section 2.9.3
Post-dose data to be analyzed along with 
pre-dose PK data
Post-dose deferasirox concentrations between 
2 and 4 hours post-dose at Weeks 5 and 9 (2 
samples)
Refer to 
Protocol Section 
10.5.5.2 / SAP 
Section 2.9.3
To explore exposure-response relationships 
for measures of safety and effectiveness 
Serum creatinine change from baseline, 
notable serum creatinine events, serum 
creatinine clearance change from baseline and 
notable serum creatinine clearance events, 
Refer to 
Protocol Section 
10.5.5.3 / SAP 
Section 2.9.3


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Objective
Endpoint
Analysis
urine protein creatinine ratio change from 
baseline and serum ferritin change from 
baseline, in relationship to pre- and post-dose 
deferasirox concentrations.
Secondary (Optional Extension phase)
To assess additional safety data about new 
formulation (granules) in pediatric population 
Overall safety, as measured by frequency and 
severity of adverse events (including active 
monitoring for renal toxicity; including renal 
failure, hepatic toxicity; including hepatic 
failure, and gastrointestinal hemorrhage), and 
changes in laboratory values from baseline 
(serum creatinine, creatinine clearance, ALT, 
AST, RBC and WBC). In addition, vital signs, 
physical, ophthalmological, audiometric, and 
growth and development evaluations will be 
assessed.
Protocol 
sections 10.5.3
and 10.6.1 / 
SAP Section 
2.9.2
2
Statistical methods
This section will be imported to section 9.7 of the CSR after the analyses have been
conducted and follows the CSR template structure as of the release date of the first final 
version of this document.
Section 4_Additional_details_on
of the SAP provides statistical and programming 
conventions. 
2.1
Data analysis
Data will be analyzed by Novartis Oncology Biostatistics and Statistical Programming 
personnel according to the data analysis section 10 of the study protocol as detailed in this 
analysis plan. 
SAS® version 9.4 (or later version if available at time of database lock) will be used for all 
analyses.
Data from all patients who signed informed consent will be used in the analysis. The analysis 
cut-off date for the primary analysis of study data will be established 24 weeks after 
approximatively 96 ICT naïve patients have been randomized. For the interim analysis a cut-
off date will be established. All randomized iron chelation naïve patients who have completed 
a minimum of 12 weeks of treatment exposure or discontinued from treatment core phase at 
the time of the cut-off date will be included in the interim analysis (see Section 2.12). 
All statistical analyses will be performed using all data collected in the database up to the data
cutoff date. All data with an assessment date or event start date (e.g. vital sign assessment
date or start date of an adverse event) prior to or on the cut-off date will be included in the
analysis. Any data collected beyond the cut-off date will not be included in the analysis and 
will not be used for any derivations.
All events with a start date before or on the cut-off date and an end date after the cut-off date 
will be reported as ‘ongoing. The same rule will be applied to events starting before or on the 
cut-off date and not having documented end date. This approach applies, in particular, to 


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adverse event and concomitant medication reports. For these events, the end date will not be 
imputed and therefore will not appear in the listings.
Subsequent to the primary analysis, the study will remain open to collect efficacy and safety 
data from core phase and safety data from the extension phase until the end of the study has 
been declared (all patients have completed the safety follow-up period of the extension phase).
The primary and interim statistical analyses will be performed using the data from the core 
phase: the core phase is defined as the time period from start of the trial up to the stop date of 
the core phase as defined in Table 2-1.
Table 2-1
Definition of core and extension phases
Core phase
Extension phase
Treatment
Start date
Stop date
Treatment 
Start date
Stop date
Granules
Date of first IC 
signed
Minimum[Date of latest 
administration of 
Granules in core phase 
+ 30 days, cut-off date, 
Visit 17 date – 1 day]
Granules
Visit 17 date
Date of the last
administration of
Granules in extension 
+ 30 days
DT
Date of first IC 
signed
Minimum[Date of latest 
administration of DT + 
30 days, cut-off date, 
Visit 17 date – 1 day]
Granules
Date of first 
administration of 
Granules
Date of the last 
administration of 
Granules in extension 
+ 30 days
Only data with an assessment date or event start date (e.g. vital sign assessment date or start 
date of an adverse event) in the core phase will be summarized in the interim and primary 
analysis.
Summaries will be based on:

Core phase comparing data for Granules versus DT formulations (blue rectangle in 
Figure 2-1).

Entire granule period of patients randomized to Granule combining core and 
extension phases (dark green rectangle in Figure 2-1) side-by-side with Granules for 
patients randomized to DT who switched to Granules in extension phase (light green 
rectangle in Figure 2-1).Cross-over treatment group corresponds to the patients 
randomized to DT who switched to Granules in the extension phase. 
Figure 2-1
Core and extension phases


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General analysis conventions
Pooling of centers: Unless specified otherwise, data from all study centers will be pooled for 
the analysis. Due to expected small number of patients enrolled at centers, no center effect 
will be assessed.
Qualitative/categorical data (e.g., sex, race) will be summarized by frequency counts and 
percentages. Percentages will be calculated using the number of patients in the relevant 
treatment arm or subgroup as the denominator.  
Continuous data (e.g., age, body weight) will be summarized using appropriate descriptive 
statistics (i.e. mean, standard deviation, median, minimum, and maximum) by treatment arm.
Lower and upper quartiles will also be presented when applicable.
2.2
Analysis sets
All screened patients 
A patient is considered to be screened into the study if they have signed the study informed 
consent/assent form. Only patients who have signed informed consent will be included in the
All screened patients analysis set.
Screen failures
Screen failures analysis set includes all patients who have been screened and who failed to be 
randomized for any reason (i.e. failing to meet inclusion or exclusion criteria or any other 
screening procedure).
Safety Set
The Safety Set 1 will consist of all ICT naïve patients (as per eCRF) who received at least one 
dose of the study drug during the core phase.
The Safety Set 2 will consist of all ICT pre-treated patients (as per eCRF) who received at 
least one dose of study drug during the core phase. 
The Safety Set 3 will consist of all patients who received at least one dose of study drug
during the core phase. 
The Safety Set 4 will consist of all patients who received at least one dose of granule 
formulation during the core or extension phase.
Patients will be analyzed according to the treatment actually received and strata information 
recorded in the eCRF. 
Treatment actually received is defined as the treatment the patient received at the first day of 
study medication in the core phase.
Full Analysis Set
Full Analysis Set (FAS) is defined according to the Intention to Treat (ITT) principle. 


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The Full Analysis Set 1 (FAS-1) consists of all ICT naïve (as per IRT, see Section 4.5)
randomized patients. 
The Full Analysis Set 2 (FAS-2) consists of all ICT pre-treated (as per IRT) randomized 
patients. 
The Full Analysis Set 3 (FAS-3) consists of all randomized patients. 
Following the intent-to-treat principle patients are analyzed according to the treatment and 
stratification factors they were assigned to at randomization during the core phase.
Per-protocol set
The Per-Protocol Set (PPS) will consist of all ICT naïve patients from the FAS-1 without any 
major protocol deviation. 
The major protocol deviations that will lead to exclusion of patients from the PPS are listed 
below: 

No transfusion dependent anemia (ID=I05);

Serum ferritin ≤1000 µg/L at Screening (ID=I07);

First administered study medication different from medication assigned by randomization
(ID=S02);

Absence of serum ferritin assessment at baseline and at least 1 post-baseline assessment
(ID=G28);

Any safety-related exclusion criteria met (ID= E01A3,  E02A3,  E03A3, E05, E06, E07, 
E08, E09, E10, E11, E13, E14, E18A4 or E19);

No dose-adjustment for efficacy due to change in serum ferritin at weeks 13 and 25 
(ID=S11 at weeks 13 or 25);

Intake of any prohibited concomitant medication (ID= M01, M03, M04 or M05).

Strata assigned for randomization differs from strata reported by investigator on CRF
(ID=G32). 
Pharmacokinetic Analysis Set
The Pharmacokinetic Analysis Set 1 (PAS-1) consists of all patients who have at least one 
evaluable pre- or 3 hours post-dose PK concentration (deferasirox) regardless of whether the 
pre-dose was taken under the original or current protocol instructions.
A PK concentration is considered evaluable if it fulfills all of the following criteria:

The actual dose or leading dose prior to pre-dose or post-dose sampling must be as 
planned by protocol and be documented. In addition, the patient should have received the 
same dose during the last 4 days prior to the PK sampling (except for Week 1 Day 1).

The elapsed time between dose administration and PK concentration is documented.

The pre-dose sample should be within 24 ± 4 hours from the previous dose. The 3h post-
dose sample should be obtained between 2 and 4 hours post-dose administration.


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
The PK concentration must NOT be associated with any vomiting within 4 hours of 
dosing.
For statistical analysis based on PAS-1, only evaluable PK samples from patients in PAS-1 
will be considered.
The Pharmacokinetic Analysis Set 2 (PAS-2) consists of all patients enrolled under the 
original protocol who have an evaluable PK profile. PK parameters will be calculated by the 
clinical pharmacologist if a minimum of 12 patients with evaluable PK profile are available. 

An evaluable PK profile is assessed as such by the Clinical Pharmacologist.
For statistical analysis based on PAS-2, only evaluable PK samples from patients in PAS-2 
will be considered
Reporting
Frequency counts and percentages (using FAS-3 or Safety Set 4 as denominator) of patients in 
each of the above defined analysis sets will be summarized. In addition, listings of patients 
excluded from each of the analysis sets will be provided.
2.3
Patient demographics and other baseline characteristics
The FAS-1, FAS-2, FAS-3 and Safety Set 4 will be used for all patient demographic and 
baseline characteristic summaries, unless otherwise specified. Summaries will be produced by 
treatment arm and overall. Listings will be produced by treatment arm for the FAS-3 and 
Safety Set 4.
Enrollment status
The number of patients screened and randomized will be summarized respectively by region, 
country, center and treatment arm on the FAS-3 and Safety Set 4. The number of patients 
randomized will also be summarized by stratification factor (age group: 2 to <10 years versus 
10 to <18 years and prior ICT: Yes versus No) and treatment arm on the FAS-3. IRT versus 
eCRF stratification factors will be tabulated on the FAS-3.
Basic demographic and other baseline characteristics
Basic demographic data
Categorical data (sex, age groups, weight group, race, and ethnicity) will be summarized by 
frequency counts and percentages. Continuous data (age, weight and height) will be 
summarized by descriptive statistics.
The following variables will be summarized as a continuous and categorical data:

Age  (years) will be categorized as: 2 to <10 years and 10 to < 18

Weight (kg) will be categorized as: <20, 20 to <35, 35 to <55, 55 to <75 and ≥75
The number of patients by sex and age categories and the number of patients by race will be 
tabulated on the Safety Set 3 and Safety Set 4.


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History of disease 
The main underlying disease as well as the time since the diagnosis date will be summarized
by treatment arm.
Time since the diagnosis (years) = (Screening visit 1 date – date of diagnosis + 1) / 365.25. 
Prior iron chelation therapy 
Frequency counts and percentages will be tabulated by treatment arm, for prior Iron Chelation 
Therapy (ICT) prior to start of study drug (yes or no), prior Deferasirox (yes or no) and type 
of last ICT received. Time since last dose of prior ICT will be summarized by descriptive 
statistics.
Time since last dose of prior iron chelation therapy (days) = (Screening visit 1 date – stop date 
+ 1). 
History of blood transfusion
Descriptive statistics will be tabulated by treatment arm, for total number of blood 
transfusions received.
Other baseline characteristics
Descriptive statistics, frequency counts and percentages will be tabulated by treatment arm, as 
appropriate, for history of splenectomy (yes or no), for hepatic B and C status (see Table 4-4). 
In addition, clinically significant abnormality in ECG (yes or no), overall interpretation in 
echocardiogram (normal or clinically significant or insignificant abnormality), overall 
interpretation in audiometric test (normal or clinically significant or insignificant abnormality), 
overall interpretation in ocular exam (normal or clinically significant or insignificant 
abnormality) will be summarized on the Safety set 3 and 4. 
The following continuous variables will be summarized categorically on the Safety Set 3 and 
4, and on the FAS-3 and Safety Set 4 for serum ferritin:

Creatinine will be categorized as: ≤ULN, >ULN - ≤1.5*ULN, >1.5*ULN

Recalculated Creatinine Clearance (CrCl) will be categorized as: <40, 40 to <60, 60 to 
<90 and ≥90mL/min

ALT and AST will be categorized as: ≤ULN, >ULN-≤3*ULN, >3*ULN-≤5*ULN 
and >5*ULN

Urine protein/creatinine ratio: ≤0.2 mg/mg,>0.2- ≤0.5, >0.5-≤1 mg/mg, >1 mg/mg

Serum ferritin will be categorized as: <1000, ≥1000 to 2500, >2500 to 5000, >5000 ng/
mL.
Medical history
Medical history and ongoing conditions will be summarized and listed by treatment arm on 
the FAS-3 and Safety Set 4. Separate summaries will be presented for ongoing and historical 
medical conditions. The summaries will be presented by primary system organ class, 


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preferred term and treatment arm. Medical history and current medical conditions will be 
coded using the Medical Dictionary for Regulatory Activities (MedDRA) terminology.
Data presented for screen failure patients
The total number and the reasons for screen failure (based on reasons recorded in ‘Screening 
log’ page) will be summarized.
The following listings will be provided for screen failure patients:

Patient demographics (age, sex, race and ethnicity)

Patient disposition

Serious Adverse Events (SAE)
2.4
Protocol deviations
Frequency counts and percentages of patients with any protocol deviation (selection criteria 
not met, patient not withdrawn as per protocol, treatment deviation, prohibited concomitant 
medication, other Good Clinical Practice (GCP) deviation) will be tabulated by the deviation 
type category and treatment arm on the FAS-3 for the core phase and on the Safety Set 4 for 
the entire granule period. Protocol deviations leading to exclusion of patients from the PPS 
will be tabulated separately by treatment arm on the FAS-1. 
The full list of protocol deviations is documented in the Validation And Planning (VAP)
Module 3 document.
All protocol deviations will be listed on the FAS-3 and Safety Set 4. 
2.5
Patient disposition
Listings will be produced on the FAS-3 and Safety Set 4. 
The summaries of patient disposition during the core phase by treatment arm on the FAS-1, 
FAS-2 and FAS-3 will show:

Number (%) of randomized patients who were not treated;

Number (%) of randomized patients who were treated;

Number (%) of patients who completed the core phase;

Number (%) of patients who discontinued the core phase;

Number (%) for each reasons for core phase discontinuation;
The summaries of patient disposition during the entire granule period by treatment arm on the 
Safety Set 4 will show in addition:

Number (%) of patients who entered in the optional extension phase;

Number (%) of patients who were not treated during the optional extension phase;

Number (%) of patients who were treated during the optional extension phase;

Number (%) of patients who completed the optional extension phase;

Number (%) of patients who discontinued the optional extension phase;

Number (%) for each reasons for optional extension phase discontinuation;


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2.6
Treatments (study drug exposure, concomitant therapies)
The Safety Set 1, Safety Set 2, Safety Set 3 and Safety Set 4 will separately be used for 
medication data summaries unless otherwise specified. Listings will be produced by treatment 
arm on the Safety Set 3 and Safety Set 4. 
Study drug and study treatment
The terms study drug and study treatment are equivalent and will refer both to deferasirox DT 
or deferasirox granule.  
Date of first/last administration of study drug
The date of first administration of study drug is derived as the first date when a non-zero 
actual dose of study drug was administered as recorded on Dosage Administration Record 
(DAR) Electronic Case Report Form (eCRF). The date of first administration of study drug 
will also be referred as ‘start of study treatment’.
The date of last administration of study drug is defined as the last date when a non-zero actual 
dose of study drug was administered as recorded on DAR eCRF. This date will also be 
referred as ‘last date of study treatment’.
Study day
The study day for safety and pharmacokinetics assessments (e.g. adverse event onset, 
laboratory abnormality occurrence, vital sign measurement, Electrocardiogram (ECG), PK 
concentration, etc.) will be calculated using the start date of study treatment as the reference. 
For assessments occurring 

on or after the start date of study treatment, the study day will be calculated as (date of 
safety assessment) – (start date of study treatment) + 1. Study day 1 will therefore be the 
first day of study treatment.

before the start date of study treatment, the study day will be calculated as (date of 
safety assessment) – (start date of study treatment). 
For example, if an adverse event starts 3 days before the start of study treatment the study day 
displayed on the listing will be negative, i.e. -3. 
The study day for efficacy assessments (e.g. serum ferritin, PRO) will be calculated using the 
randomization date as the reference. For assessments occurring

on or after randomization date, the study day will be calculated as (date of non-safety
assessment) – (date of randomization) + 1. Then study day 1 will be the day of 
randomization. 

before randomization date, the study day will be calculated as (date of non-safety 
assessment) – (date of randomization). 
The study day will be displayed in the data listings. 


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Study drug exposure
Definitions of duration of exposure, total patient-years exposure, average daily dose, 
cumulative total dose as well as percentage of planned dose taken are defined in Table 2-2:
Table 2-2
Deferasirox: Study drug exposure 
Overall duration of exposure (day):
[(date of last study treatment) – (date of first study 
treatment) + 1]
Drug exposure on dose X (days)
[(date of last study treatment on dose X) – (date of first 
study treatment on dose X) + 1] 
Average dose (planned and actual, 
in mg/kg/day):
Mean dose over all days between first and last dose, 
including interruptions: sum of all (X dose * corresponding 
duration of exposure on dose X) / overall duration of
exposure
Cumulative dose (planned and
actual, in mg/kg):
Sum over daily doses of all days between first and last dose
Total patient-years (years):  
Overall duration of exposure (days) / 365.25 
Percentage of planned dose taken:
100 × [Cumulative actual dose / Cumulative planned dose]
The actual dose in mg/kg/day will be obtained by dividing the actual total daily dose 
administered in the DAR eCRF page by the last available weight at the time of dose 
administration reported in the vital signs eCRF page.
Overall duration of exposure, average planned and actual daily dose, cumulative actual dose, 
total patient-years and percentage of planned dose taken will be summarized by treatment arm
for the core phase and for the entire granule period. 
The following variables will also be summarized by treatment arm and for each phase as 
appropriate as:  

Duration of exposure will be categorized in the core phase as: <4 weeks, 4 to <12 weeks,
12-<20 weeks 20-<28 weeks, 28-<36 weeks, 36-<44 weeks, ≥44 weeks; and in the entire 
granule period as: <6 months, 6-<12 months, 12-<24 months, 24-<36 months, 36-<48 
months, ≥48 months).

Deferasirox DT average dose will be categorized as: <15, 15 to <25, 25 to <35 and ≥35 
mg/kg/day

Deferasirox granule average dose will be categorized as: <10.5, 10.5 to <17.5, 17.5 to 
<24.5 and ≥24.5 mg/kg/day
In addition, the number of patients who have dose reduction, increase or dose interruption, 
with corresponding reasons and the average length of dose interruptions will be summarized.
Dose reduction will be considered if the actual dose is not equal to 0 (or not counted as 
interruption) and [the planned dose level is lower than the previous non-missing planned dose 
level Or the dose change is equal to ’yes’ and the actual total daily dose administered (mg) is 
lower (> 15%) than the calculated dose amount based on the planned dose (mg)]. Any dose 
change to correct a dosing error will not be considered a dose reduction (patient goes back to 
the previous planned/actual dose after a dose change due to dosing error). Number of 
reductions will be derived programmatically.


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Dose increase will be considered if the actual dose is not equal to 0 (or not counted as 
interruption) and [the planned dose level is higher than the previous non-missing planned dose 
level Or the dose change is equal to ’yes’ and the actual total daily dose administered (mg) is 
higher (> 15%) than the calculated dose amount based on the planned dose (mg)]. Note that a 
dose rechallenge i.e when a patient goes back to the previous planned dose after an 
interruption or a dose reduction is not considered as an increase. 
Dose interruption will be considered if an actual dose of zero in a unit of time between two 
non-zero actual dosing records. Any rest period as part of the schedule is not considered as an 
interruption. For the purpose of summarizing interruptions and reasons, in case multiple 
entries for interruption that are entered on consecutive days with different reasons will be 
counted as separate interruptions. However, if the reason is the same in this mentioned 
multiple entries on consecutive days, then it will be counted as one interruption.
Furthermore, box plot of average actual daily dose will be plotted by month and treatment
(see Table 4-1 for month definition) on the core phase only.
For each patient, listings of each dose of the study drug administered along with dose change
reasons will be produced.  
Concomitant therapy
Prior and concomitant therapies are defined as any medication, and significant non-drug 
therapies administered to a subject preceding or coinciding with the study assessment period.
Medications will be coded using the World Health Organization (WHO) Drug Reference 
Listing (WHO DRL) dictionary that employs the WHO Anatomical Therapeutic Chemical 
(WHO ATC) classification system. 
Concomitant therapies will include medications and significant non-drug therapies taken 
between the first and last day with study medication, excluding medications start on the last 
day of study medication. Prior therapies will include medications or significant non-drug 
therapies starting and ending prior to the start of study treatment.
Concomitant and prior therapies will be summarized by ATC class, preferred term and 
treatment arm for the Safety Set 3 and Safety Set 4. Medications starting prior to the start of 
study treatment and continuing after the start of study treatment will be counted in both 
summaries.
All prior and concomitant therapies will be listed.
2.7
Baseline
Baseline is considered as the result of an investigation describing the ‘true’ uninfluenced state 
of the patient.
For efficacy evaluations, (e.g. serum ferritin), the last available (i.e. non-missing) assessment 
before or on the date of randomization is taken as ‘baseline’ value or ‘baseline’ assessment. 
For safety evaluations (e.g. laboratory, vital signs, etc.) the last available (i.e. non-missing)
assessment before or on the date of start of study treatment is taken as ‘baseline’ value or 
‘baseline’ assessment.


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If patients have no value as defined above, the baseline result will be missing.
If an assessment is planned to be performed prior to the first dose of study drug in the protocol 
and the assessment is performed on the same day as the first administration of study drug, it 
will be assumed that it was performed prior to study drug administration, if assessment time
point is not collected or is missing. Unscheduled assessments will be considered in the 
determination of baseline. 
Patients who start treatment and discontinue from the study on the same day may have 2 
different sets of data collected on study Day 1, one being reported to the week 1 visit, the 
other reported to the End Of Treatment (EOT) visit. Data reported at the EOT visit are not 
eligible for baseline selection.
For analyses of the extension phase (entire granule period) requiring comparison to baseline 
value (e.g. lab shift tables) the baseline is defined as follows. For patients randomized to DT 
formulation who switched to granule formulation in the extension phase, the last assessment 
prior or equal to the start date of granules in the extension phase will be defined as pre-
granule value which will be reference value for changes in the extension time. For patients
randomized to granules continuing in extension phase the initial baseline value at study start 
will be taken.
2.8
Analysis of the primary variables
The primary objectives of this study are to evaluate patient compliance with study treatment, 
as measured by the count of deferasirox granule stick packs/dispersible tablets and to evaluate 
the change in serum ferritin after 24 weeks of treatment for both formulations of deferasirox 
in pediatric ICT naive patients with iron overload during core phase.
2.8.1
Variable
All analyses for the primary objective will be performed on the FAS-1 and presented by 
treatment group: deferasirox DT and deferasirox granule formulation.
The co-primary efficacy variables are:

Compliance  measured by stick pack /tablet count based on amount of medication
dispensed, returned and reported as lost/wasted by the patient or caregiver in the eCRF, 
over 24 weeks of treatment (i.e. assessed at week 25 visit). Compliance will be calculated 
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 over 24 weeks of treatment (i.e. assessed at week 25 visit);
-
total count prescribed is derived from cumulative prescribed count over 24 weeks of 
treatment (i.e. assessed at week 25 visit).
The prescribed count corresponds to the count prescribed by the investigator for the 
relevant visit 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 granule), the prescribed count for the relevant visit period is 
calculated from the daily prescribed count at the beginning of this period multiply by the 
duration (days) of this period. The duration of a period will be calculated as (end date of 


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the period) – (start date of the period) + 1. The total count prescribed is the sum of counts 
prescribed per strength.

Change from baseline in serum ferritin after 24 weeks of treatment (i.e. assessed at week 
25 visit). 
2.8.2
Statistical hypothesis, model, and method of analysis
The primary efficacy analysis will be the comparison of means between the two treatment 
arms of change from baseline after 24 weeks of treatment in serum ferritin and mean relative 
consumed stick pack /tablet count over 24 weeks of treatment. 
The trial will be claimed successful if the superiority of granule formulation relative to DT 
formulation could be demonstrated with regard to both endpoints. Therefore no adjustment for 
multiplicity of the type I error (alpha) is required.
The primary inferential analysis described below will be based on the FAS-1.
Let μSF,G and μSF,DT denote the mean change from baseline in Serum Ferritin (SF) to week 25 
visit for granule and DT formulations, respectively. Let μC,G and μC,DT be similarly defined for 
compliance  measured by stick pack /tablet count.
The null and the alternative hypothesis are defined as follows: 
H0,SF: μSF,G= μSF,DT
no effect of granule formulation with regard to change in SF, 
and/or
H0,C: μC,G= μC,DT
no effect of granule formulation with regard to compliance
versus
H1,SF: μSF,G < μSF,DT
mean change in SF favorable for granule formulation compared 
to DT formulation, and
H1,C: μC,G > μC,DT
mean compliance favorable for granule formulation compared 
to DT formulation
Analysis of covariance (ANCOVA) will be performed for comparison between both treatment 
groups. The ANCOVA model for compliance endpoint will include treatment group and the 
age group as per stratification (2 to <10 years versus 10 to <18 years), as factors. The model 
for serum ferritin endpoint will also include the serum ferritin value at baseline as covariate.
2.8.3
Handling of missing values/discontinuations
In case of missing serum ferritin after 24 weeks of treatment, the last available post-baseline 
serum ferritin value will be used in the calculation of the primary endpoint. Patients without 
post-baseline serum ferritin value will be excluded from the analysis. 
No imputation will be performed for the compliance endpoint calculation. However, patient 
who discontinued before the week 25 visit will be included in the compliance endpoint 
calculation.


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2.8.4
Supportive analyses
The following supportive analyses will be provided:

The primary analysis as described in Section 2.8.2 & Section 2.8.3 will be also performed
for the PPS, FAS-2 and FAS-3 as supportive efficacy analyses;

In addition, descriptive summaries will be provided for the FAS-1 by treatment arm:
• Summary of absolute and relative change from baseline values in serum ferritin assessed 
at week 25 visit and 95% confidence intervals for means (see Table 4-2 for time window 
definition);
• Summary statistics of overall compliance measured by stick pack/tablet count assessed at 
week 25 visit and 95% confidence intervals for means. Patient who discontinued before 
the week 25 visit will be included in the compliance endpoint calculation.
These descriptive analyses will be repeated by the age stratification factor, by average 
actual daily dose category, by baseline serum ferritin category, and underlying disease 
(see Table 2-6).
• A forest plot of mean difference between treatments will be presented with absolute 
change in serum ferritin after 24 weeks of treatment and the corresponding exact 95%CI
including these subgroups. Point estimates and 95% CI will be generated. 

If more than 10% of patients have no serum ferritin value after 24 weeks of treatment, 
sensitivity analysis will be performed for the primary analysis for serum ferritin using 
multiple imputation method. This analysis will be performed for the FAS-1.
2.8.5
Secondary and other analyses of the primary variables
Secondary analyses of the primary variables
Descriptive summaries as specified in Section 2.8.4 will be repeated:

For the FAS-1 after 48 weeks of treatment. In addition, if more than 10% of patients have 
no serum ferritin value after 48 weeks of treatment or missing compliance measured by 
stick pack/tablet count over 48 weeks of treatment, a sensitivity analysis will be performed 
using multiple imputation method. 

For the FAS-2 and FAS-3, after 24 and 48 weeks of treatment (as for the FAS-1). 
Furthermore, a graphical presentation of mean and standard deviation of absolute value in 
serum ferritin will be plotted by treatment arm and time-window (see Table 4-2 for time-
window definition) for FAS-1, FAS-2 and FAS-3. 
Other analyses of the primary variable 
Relative and absolute change from baseline in serum ferritin at every year visit during the 
entire granule period will be described for the Safety Set 4.
2.9
Analysis of secondary variables
Secondary variables include patient reported outcomes/observer reported outcomes, safety 
assessments 
(i.e. 
adverse 
events, 
laboratory 
parameters, 
vital 
signs, 
etc.) 
and 


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Pharmacokinetics (PKs) parameters. All secondary variables will be analyzed by treatment 
group.
2.9.1
Patient reported outcomes/Observer reported outcomes
Patient satisfaction, palatability and compliance with study drug will be evaluated for both 
treatment groups
using Patient
Reported Outcomes/Observer Reported Outcomes
(PRO/ObsRO).
Three PRO/ObsRO questionnaires have been developed: the modified SICT questionnaire, a 
palatability questionnaire and a compliance diary. Patients/caregiver will complete all 
PRO/ObsRO questions via a handheld electronic device (exceptionally paper could be used in 
specific situation). The diaries will be completed daily at home and the palatability and 
modified SICT will be completed at pre-determined site visits.
The three questionnaires were developed using patient input in one on one interview. The 
PRO questionnaires were validated for their psychometric properties, and the ObsRO 
questionnaires will be validated in a within-trial data for validation that will be conducted by 
Adelphi Value. The statistical analysis plan, the data analysis as well as the results report for 
ObsRO psychometric validation will be done and provided by Adelphi Value.
The FAS-1, FAS-2 and FAS-3 will be used for the three PRO/ObsRO questionnaires analysis
for the core phase, unless otherwise specified.
2.9.1.1
Modified SICT questionnaire
Patient reported outcomes
The Modified SICT questionnaire consists of 13 items that represent 3 domains; Adherence, 
Preference and Concerns (see Figure 2-2).


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Figure 2-2
Conceptual model for the Modified Satisfaction with Iron Chelation 
Therapy questionnaire
Adherence domain consists of 7 items, 6 of which are measured using a 5 point response 
scale. 
Items 4 and 5 use the response format 1 “Never””, 2 “Rarely” 3 “Sometimes” 4 ” Most of the 
time” and 5 “Always”; item 6 uses the response format 1 “Always”, 2 “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 or hard”, 4 “Hard” and 5 “Very hard”; Items 9 and 10 use the response 
format 5 “Very bothered”, 4”Bothered” 3”Moderately bothered”, 2 “A little bothered” and 1
“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 of 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 (Figure 
2-3). Each response category will be coded as binary item, for example taste will be an item 
with the response format 0 “Not endorsed” 1 “Endorsed”. 


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Figure 2-3
Conceptual model for Item 7 of the modified SICT
Satisfaction/preference domain consists of 3 items, 2 (Items 11 and 12) 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 (Item 13) asks the patient to assess which medication for iron overload they 
prefer.
Concerns domain consists of 3 items (Items 1, 2 and 3) 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.
Observer reported outcomes
The modified SICT consists of 17 items that represent 3 domains: Adherence, Preference, and 
Concerns (see Figure 2-4).


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Figure 2-4
Conceptual Model for the Modified Satisfaction with Iron Chelation 
Therapy Questionnaire
The conceptual framework consists of 2 separate scales to capture the child’s and caregiver’s 
perspective; these are further broken into 3 domains for the child: Concerns, Preference, and 
Adherence and 2 domains for the caregiver: Concerns and Adherence. 
Adherence domain will be captured from 2 perspectives: 

Child’s perspective (a Domain score + a Checklist for reasons for non-adherence) 

Caregiver’s perspective (a Domain score + a Checklist for reasons for non-adherence)
There will be 2 separate domain scores for overall adherence, the caregiver’s perspective of 
adherence domain consists of 6 items (Items 12, 13, 14, 16 and 17), while the child’s 
perspective of adherence domain consists of 7 items (Items 3, 4, 5, 7, 8 and 9). 
Child’s perspective of Adherence: Items 3 and 5 are measured using a 5-point response scale: 
“Always” =1, “Most of the time” =2, “Sometimes” =3, “Rarely” =4, and “Never” =5.  Item 4 
is measured on a scale from “Always” =5, “Most of the time” =4, “Sometimes” =3, “Rarely” 
=2, and “Never” =1.  Two items (Item 7 and 8) use different response options. Item 7 focuses 
on “How easy/hard did your child tell you it was to take his/her medicine” and uses the 
response scale “Very easy” =1, “Easy” =2, “Neither easy or hard” =3, “Hard” =4, and “Very 
hard” =5. Similarly, Item 8 captures bother expressed by child for amount of time he/she had 
to wait to eat food after taking medication. The response scale for Item 8 is “Very bothered” 
=5, “Bothered” =4, “Moderately bothered” =3, “A little bothered” =2, and “Not bothered at 
all” =1. Item 9 reports “how happy your child appeared” and is scored on a scale from 1=Very 
happy and 5=Very unhappy. 
Caregiver’s perspective of Adherence: Items 12 and 14 are measured using a 5-point response 
scale: “Always” =1, “Most of the time” =2, “Sometimes” =3, “Rarely” =4, and “Never” =5. 
Conversely, Item 13 is scored as “Always” =5, “Most of the time” =4, “Sometimes” =3, 
“Rarely” =2, and “Never” =1. Two items (Item 16 and 17) use different response options. 
Item 16 focuses on “How easy/hard was it to give your child his/her medicine” and uses the 


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response scale “Very easy” =1, “Easy” =2, “Neither easy or hard” =3, “Hard” =4, and “Very 
hard” =5. Similarly, Item 17 captures “bothered by the amount of time it took to prepare 
medication” and uses the response scale “Very bothered” =5, “Bothered” =4, “Moderately 
bothered” =3, “A little bothered” =2, and “Not bothered at all” =1. 
Separate adherence domain score for the child’s and caregiver’s perspective will be calculated. 
A domain score will be calculated by summing item scores on respective domains. Overall, a 
lower domain score will indicate better adherence. 
The checklist item from each perspective will evaluate the reason for non-adherence. Only 
respondents who, at Item 5 (for the child's perspective) and Item 14 (for the caregiver's 
perspective), indicate that they did not “Always” take their medication as instructed, are 
expected to give the reasons for non-adherence. For both perspectives the respondent can 
check all the reasons that apply (Figure 2-5).  For the child‘s perspective (item 6), each of the 
5 response options (i.e. taste, aftertaste, inconvenience, prepared medicine incorrectly, and 
other) will be coded as binary item, for example taste will be an item with the response format 
0 “Not endorsed” 1 “Endorsed”. Similarly, for the caregiver perspective (item 15), each of the 
7 response options (i.e. child refuse to take, forgot, inconvenient, side-effect, not prepare 
medication per doctor’s instruction, did not give full amount, and others) will be coded as 
binary item (0/1).
Figure 2-5
Conceptual model for item 6 and item 15 of the modified SICT
Preference of the Child: This domain consists of 1 item (Item 10), to assess which 
medication they prefer (like). The item is to be considered a single item domain. 
Concerns domain will be captured from 2 perspectives: 

Child’s perspective (Item 1 and 2) 

Caregiver’s perspective (Item 11) 
The concerns domain for the child’s perspective has 2 items which focus on “limiting child’s 
activity” (Item 1) and “getting upset about the side-effects” (Item 2). Both the items are 


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measured using a 5-point response scale from “Always” =1, “Most of the time” =2, 
“Sometimes” =3, “Rarely” =4, and “Never” =5. A sum score for a Concerns domain for the 
child's perspective will be created. A higher score will indicate lesser concerns.
There is only a single item to capture concern in regards to caregiver’s perspective. The item 
11 captures “worry if the child is swallowing enough medication” and is scored on a 5-point 
response scale from “Always” =1, “Most of the time” =2, “Sometimes” =3, “Rarely” =4, and 
“Never” =5.  A higher score on the single item domain will indicate lesser caregiver concern.
Adherence, satisfaction/preference and concerns domain scores will be summarized using 
standard descriptive statistics by treatment arm, type of questionnaire (ObsRO questionnaire 
versus PRO questionnaire) and week (weeks 2, 3, 25 and core EOT). Additionally, absolute 
change from week 2 to week 25 and core EOT in the domain scores will be summarized 
including 95% confidence intervals for mean.
Graphical representation of PRO scores over weeks will be provided by domain by type of 
questionnaire and treatment. The y-axis will be the mean and SD for the domain score and the 
x-axis will be the week number.
In addition, all items from adherence, satisfaction/preference and concerns domains will be 
summarized by treatment arm by type of questionnaire and week using frequency counts and 
percentages for the FAS-3.
The number of patients completing the modified SICT questionnaire and the number of 
missing or incomplete assessments will be summarized by treatment arm, type of 
questionnaire and week for the FAS-3.
2.9.1.2
Palatability questionnaire 
The palatability questionnaire consists of 4 items. Two items measure the taste (item 1) and 
aftertaste (item 2) of the medication and are scored on a 5 point response scale with the 
response format 1 “Very good”, 2 ”Good”, 3 “Not good or bad” for PRO/ 3 “Neither good nor 
bad” for ObsRO, 4 “Bad’ and 5 “Very bad”. The PRO 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. 
Note for ObsRO:  Item 1 the response format for 3 refers to “Neither good nor bad” and for 
Item 3 the response format 1 refers to “Swallowed and retained ALL of the medicine”. Same 
scoring rule will be used for both ObsRO and PRO.
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 3 
Swallowed ALL of the medicine =1


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Spat out SOME of the medicine & Spat out ALL of the medicine and 
swallowed none =2
Vomited within 30 minutes after swallowing the medicine = 3
Recode Item 4  
Not enough liquid & Too much liquid = 1
Just enough liquid = 2
No missing data will be imputed when calculating the palatability summary score. 
The Table 2-3 presents the Items 1, 3 and 4 scoring matrix leading to the palatability summary 
score:
Table 2-3
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, type of questionnaire (ObsRO questionnaire versus PRO questionnaire) and week (weeks 
2, 3, 25 and core EOT). Additionally, absolute change from week 2 to week 25 and core EOT
will be summarized including 95% confidence intervals for mean.
Graphical representation of this 11 point response scale will be provided over weeks by 
treatment and type of questionnaire. The y-axis will be the mean and SD and the x-axis will 
be the week number.
In addition, all of the 4 Items from the palatability questionnaire will be summarized using 
descriptive statistics by treatment arm, type of questionnaire and week using frequency counts 
and percentages for the FAS-3.


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The number of patient completing the palatability questionnaire and the number of missing 
assessments will be summarized by treatment arm, type of questionnaire and week for the 
FAS-3.
2.9.1.3
Compliance diary
The Compliance questionnaire consists of 2 items. Item 1 assessed whether the medication 
was taken (yes/no) and Item 2 is a record of the time when the medication was taken with a 
not applicable option for patients who did not take their ICT. 
The daily compliance questionnaire diary records will also be used to calculate the rate of 
dose violations. For a given day, a dose violation is defined as a dose that is either missed 
completely or not taken in accordance with the timing instruction (no later than 12:00 pm). 
The dose violation rate is calculated as: 
[Number of dose violations / Drug exposure (days)] *100
Weekly average of dose violation rate will be calculated and summarized using descriptive 
statistics by treatment arm, type of questionnaire (ObsRO questionnaire versus PRO 
questionnaire) and week (weeks 1, 13, 25, 37 and core EOT). Additionally, absolute change 
from week 1 will be tabulated including 95% confidence intervals for mean. A graphical 
representation will be provided over all week periods by treatment arm and type of 
questionnaire. The y-axis will be the mean and SD and the x-axis will be the corresponding 
week period (see Table 4-3 for week periods definition).
Due to the use of ePRO there will be no individual items missing. The weekly average rates
will be calculated when there are at least four non missing daily responses. For a given week 
the denominator will be the number of non-missing days. No additional imputation will be 
carried out. 
The number of patients completing the compliance diary and the number of expected and 
missing days will be summarized by each treatment arm and type of questionnaire for the 
FAS-3.
2.9.2
Safety evaluations
Unless otherwise specified, the following analyses will be performed separately for the Safety 
Set 1, Safety Set 2, Safety Set 3 for the core phase and the Safety Set-4 for the entire granule 
period. Listings will be provided for the Safety Set 3 and the Safety Set-4.
On-treatment period
For the core phase, the overall observation period will be divided into three mutually 
exclusive segments taking into account stop rules as per Table 2-1:

Pre-treatment period: from day of patient’s first  informed consent to the day before first 
dose of study drug;

On-treatment period: from day of first dose of study drug to 30 days after last dose of 
study drug;

Post-treatment period: starting at day 30+1 after last dose of study treatment.


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For the entire granule period, the following conventions will be taken into account while 
deriving the three observation periods: 

For patients enrolled in DT formulation in the core phase, the pre-treatment period will 
not be derived;

For patients enrolled in Granule formulation in the core phase, the first dose of study drug 
will be the day of first dose in the core phase.
Unless otherwise specified, the safety summary tables will include only assessments from the 
on-treatment period.
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.
Adverse events
AEs will be coded using the latest version of Medical Dictionary for Regulatory Activities
(MedDRA) available prior to clinical database lock. 
Any information collected (e.g. relatedness to study drug, action taken etc.) will be listed. 
The following adverse event summaries will be produced by treatment arm:

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

Serious adverse events (overall and severe), with suspected 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

Deaths (all and on-treatment) by primary system organ class and preferred term (Safety 
Set 3 and 4 only). 
For the legal requirements of ClinicalTrials.gov and EudraCT, two required tables will be 
produced for the Safety Set 3 on combined core and extension phases at the time of the final 
CSR:

Non-serious adverse events with an incidence greater than 5%; 


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
Serious adverse events (SAE) and SAE suspected to be related to study treatment will be 
provided by system organ class and preferred term. The number of deaths resulting from 
SAEs suspected to be related to study treatment and SAEs irrespective will also be 
provided.
If for a same patient, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same SOC and PT:

a single occurrence will be counted if there is ≤ 1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE

more than one occurrence will be counted if there is > 1 day gap between the end date of 
the preceding AE and the start date of the consecutive AE
For occurrence, the presence of at least one SAE / SAE suspected to be related to study 
treatment / non SAE has to be checked in a block e.g., among AE's in a ≤ 1 day gap block, if 
at least one SAE is occurring, then one occurrence is calculated for that SAE.
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, severity and 
relation to study drug by treatment arm. A patient with multiple occurrences of an AE will be 
counted only once in the AE category. 
An overall summary of type of AEs (e.g. serious, leading to study drug discontinuation, 
requiring dose adjustment or/and interruption) will be presented by severity and treatment arm.
All AEs will be listed. Any information collected (e.g. regardless to study drug, action taken 
etc.) will be listed as well as the duration of the AE. The listings of all deaths, serious adverse 
events, adverse events leading to study drug discontinuation, and adverse events requiring 
dose adjustment or interruption will also be provided. 
Adverse events of special interest 
Specific groupings of AESI will be considered and the number of patients with at least one 
event in each grouping will be reported. Note that certain adverse events 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 MedDRA 
terms to be used are defined in an independent AESI search table which is located in the 
document management system in the “CREDI Projects/I/ICL670A/Integrated Medical Safety”
folder. The latest AESI search table has to be used.
The AESI search table will be used to map reported adverse events to the AESI groupings. 
The list of adverse events of special interest may be updated during the course of the trial 
based on accumulating safety data.  Therefore clinical study report will list the AE groupings 
used and provide a listing of the corresponding AESI search table. AESI will be summarized
by grouping, preferred term and treatment arm (specifying severity, SAE, relationship, 
leading to treatment discontinuation, leading to dose adjustment/interruption and requiring 
additional therapy). 


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Laboratory data
Laboratory data from all sources (central and local laboratories) will be combined. All 
laboratory values will be converted into International System (SI) units.
Raw values as well as absolute and relative change from baseline values for hematology, 
biochemistry and urinalysis laboratory parameters will be summarized descriptively per time 
window and treatment arm on the Safety Set 3 and 4 (see Table 4-2 for time windows
definition). 
Shift tables based on normal ranges to compare baseline to the worst post-baseline value will 
be provided by parameter and treatment arm for hematology, biochemistry and urinary 
laboratory data. Same shift table will be provided based on notable/extended ranges for key 
safety laboratory parameters defined in Table 2-4. 
Table 2-4
Definition of notable/extended ranges for key safety laboratory 
parameters
Laboratory parameters
Criteria for notable/extended 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
Recalculated 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/AST
>5 x ULN and 2 x baseline (extended range >10×ULN and
>2×baseline value)
Recalculated creatinine clearance will be calculated using the Schwartz formula (for pediatric 
population at baseline) described in Section 3.6.3. The Modification of Diet in Renal 
Disease (MDRD) derivation will be provided in the derived datasets only for possible future 
requests.
A listing of all laboratory values with values flagged to show the corresponding range
classifications relative to the laboratory reference ranges will be provided by laboratory data
and treatment arm. Assessment day relative to first dose of study drug will be included and all 
laboratory assessments collected outside of the on-treatment period will be flagged. 
A listing of patients with laboratory abnormalities based on normal ranges and
notable/extended ranges will also be provided.
Normal ranges by laboratory parameter will also be provided in a separate listing. 
In addition to the above mentioned tables and listings, box plots of absolute value and the 
absolute change from baseline value for key safety laboratory parameters per time window 
and treatment arm will be provided as appropriate.


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Vital signs, weight and body mass index
The following criteria define clinically notable abnormalities for vital signs and weight values:

Clinically notable elevated values

Systolic Blood Pressure (BP): 180 mmHg and an increase 20 mmHg from 
baseline

Diastolic BP: 105 mmHg and an increase 15 mmHg from baseline.

Pulse rate: 120 bpm with increase from baseline of 15 bpm

Weight: increase from baseline of 7%

Clinically notable low values

Systolic BP: ≤90 mmHg with decrease from baseline of 20 mmHg   

Diastolic BP: ≤50 mmHg with decrease from baseline of 15 mmHg   

Pulse rate: ≤50 bpm with decrease from baseline of 15 bpm 

Weight: 7% decrease from baseline
Descriptive statistics will be tabulated per time window and treatment arm using absolute 
change from baseline values for each vital sign measure, weight and BMI (see Table 4-2 for 
time windows definition) separately for Safety Set 3 and 4.
All vital sign assessments, weight and BMI will be listed by treatment arm, patient and 
parameter. In the listings, clinically notable values will also be flagged.
Cardiac evaluations
Cardiac evaluations include ECG and echocardiogram. Any abnormalities at baseline will be 
summarized as described in Section 2.3. All findings of patients with new or worsened 
abnormalities since baseline will be listed separately for Safety Set 3 and Safety Set 4.
Ocular evaluations
The number of patients with available assessment for each type of ocular evaluation and eye 
side will be provided by treatment group.
Visual acuity
Visual acuity will be measured using the Snellen visual acuity. This is determined by
establishing the smallest optotypes that can be identified correctly by the patient at a given
observation distance. Snellen visual acuity can be reported as a Snellen fraction (m/M) in
which the numerator (m) indicates the test distance and the denominator (M) indicates the 
distance at which the gap of the equivalent Landolt ring subtends 1 minute of arc. For each 
timepoint, the LogMAR score will be calculated as –log(m/M).
Descriptive statistics of the LogMAR scores at baseline, at each post-baseline visit and 
changes from baseline at each post-baseline visit will be presented, for each eye by treatment 
group provided that for a given patient, the assessment was done in the same condition 
(with/without correction) as done at baseline.


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The LogMAR value will be compared at baseline and worst post-baseline based on the 
identifying clinically meaningful deterioration in LogMAR of ≤0, >0 to <0.1, 0.1 to <0.2, 0.2 
to <0.3 and ≥0.3, for each eye side by treatment group.
Number and percentage of patients with clinically relevant LogMAR change from baseline
more or equal than 0.2 and more or equal than 0.3 will be summarized by treatment arm. For
patients with such values, a listing will also be provided.
Slit lamp
For each considered evaluation type and eye, the number of patients with and without
abnormality (normal, insignificant, significant and any) will be provided by treatment arm. In 
addition, a shift table will present any changes in interpretation compared to baseline. A 
listing of patients with any abnormality will be provided.
Tonometry
Descriptive statistics of the intraocular pressure at baseline, at each post-baseline visit and 
changes from baseline at each post-baseline visit will be presented, by eye and treatment 
group. 
The number of patients with clinically relevant changes from baseline intraocular pressure 
above 5 mmHg and 10 mmHg will be summarized by treatment arm. For patients with such 
values, a listing will also be provided.
Intraocular pressure will also be summarized in shift table (baseline and worst post baseline 
value) for each eye side considering the following categories: <22, ≥ 22 and <30 and ≥ 30
mmHg.
Fundus occuli
For each eye, the number of patients with and without abnormality (normal, insignificant, 
significant and any) will be provided by treatment arm. In addition, shift table will be done to 
present any changes in interpretation compared to baseline. A listing of patients with any 
abnormality will be provided.
Growth and Development
Growth velocity will be listed at baseline and core EOT visit and summarized using 
descriptive statistics by sex and age group during the core phase for the Safety Set 3. 
Summaries and listing will be repeated for the entire granule period on the Safety Set 4.
The growth velocity in height which evaluates the rate of growth per year will be calculated 
on the difference with the previous measure of height (in cm) and the time period (in days) as: 
Growth velocity (cm / year) =
(with Vx = actual visit ; Vx-1 = previous visit ;  F = 365.25).
1
1 *
)
(




x
x
x
x
V
date
V
date
F
V
height
V
height


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Pubertal stage assesses the stage of physical development of sex characteristics. The 
characteristics breast development, pubic hair, testes and penis size are evaluated based on the 
Tanner scale: for each characteristic there are 5 classes (Tanner stage 1 to 5) indicating the 
level of development of that specific characteristic. 
The age will be summarized descriptively at baseline and core EOT visit for the core phase by
sex, characteristic, Tanner stage and treatment arm. For the entire granule period, the same 
summary will be repeated at baseline and at each annual assessment. 
A listing will be provided including the Tanner stage as well as the individual records for 
each sex characteristic by visit. 
Other safety data
All data from auditory evaluation, hepatitis testing, and pregnancy test will be listed. 
Patients with clinically significant abnormal interpretations or abnormal values will be 
flagged as well as positive pregnancy test results.  
Data related to blood transfusion during treatment phase will be listed by treatment arm.
2.9.3
Pharmacokinetics parameters 
2.9.3.1
General considerations
Pharmacokinetic (PK) analyses will be based on PK parameters derived by Non-
Compartmental Analyses (NCA) and Compartmental Analyses (CA) (Table 2-5) and on PK 
concentrations. PK concentrations and Parameters are based on serum Exjade concentrations.
Table 2-5
Pharmacokinetic Parameters (NCA and CA)
NCA 
Parameters
AUClast 
The AUC from time zero to the last measurable concentration sampling time (tlast) (mass x time x 
volume-1)
AUCinf
The area under the plasma concentration-time curve extrapolated to infinity (mass x time x 
volume-1)
AUCtau
The AUC calculated to the end of a dosing interval (tau) at steady-state (mass x time x volume-1)
Cmax
The maximum (peak) observed plasma, blood, serum, or other body fluid drug concentration 
(mass x volume-1)
Tmax
The time to reach maximum (peak) plasma drug concentration after dose administration (time)
R
Accumulation index calculated as (AUC0-24h at steady state)/(AUC0-24h after the first dose)
CA 
Parameters
ka
absorption rate constant (hr-1)
CL/F
apparent clearance for ICL670 and where F is the bioavailability (L/h)
V1/F
apparent volume of the central compartment for ICL670 (L)
Q/F
apparent distributional clearance for ICL670 (L/h)
V2/F
apparent peripheral volume for ICL670 (L)


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Note: PK parameters are defined assuming a two compartment disposition model with first 
order absorption. In the unexpected case, the structure of the compartmental model require a 
change (e.g. for concentrations after granule application) PK parameter may change.
The daily dose categories defined in Table 2-6 will be used. 
The PAS-1 will be used for the analysis of PK concentrations and characterization of Cmin 
and Cmax. The PAS-2 will be used to summarize PK parameters and visualize PK profiles.
PK/safety analyses will be based on the Safety Set 3 and PK/efficacy analyses on the FAS-3
patients who also belonged to the PAS-1.
Descriptive statistics of dose-adjusted PK concentration by visit and time point and PK 
parameters by visit will include arithmetic and geometric means, median, SD, CV%, CV% of 
the geometric mean, minimum and maximum. Zero concentrations will not be included in the 
geometric mean calculation. 
Coefficient of variation CV (%) is calculated as follows: 100*(SD/arithmetic mean). 
Geometric CV (%) is calculated as follows: CV(%)=100√(exp (σ ̂^2 )-1) where σ2 denotes 
the variance of the log-transformed values.
Unscheduled samples will not be included in the descriptive analysis by time point but these 
samples will be flagged in the corresponding concentration listing.
Missing concentrations will not be imputed. Concentrations below the Lower Limit of 
Quantification (LLOQ) will be labeled as such in the concentration data listings.
Concentrations below the limit of quantitation will be treated as zero in summary statistics 
and excluded from geometric mean and geometric Coefficient of Variation (CV%) 
computation.
All individual data will be listed on the FAS-3 and those excluded from the analysis will be 
flagged.
2.9.3.2
Evaluation of pre-dose PK data to support the assessment of 
compliance
Pre-dose (Cmin) PK data from patients in the PAS-1 will be analyzed to assess variability of 
individual patient’s compliance. The following approach will be used: 
A linear mixed effect power model to pre-dose samples which fulfill compliance criteria in 
terms of steady state (4 consecutive same doses prior to the PK drawn), time-windows (PK 
sample drawn 20 to 28 hours after previous dose) and without any vomiting episodes within 
the 4 hours prior to the PK sample will be fitted. The model will consider dose, treatment 
group, stratification factors and potential other factors, such as body weight as covariates.
Predicted pre-dose concentrations will be compared with observed pre-dose concentrations 
considering all patients and pre-dose samples in PAS-1. Distributions of the difference 
between predicted and observed Cmin values will be shown graphically by boxplots for both 
treatment groups and visit. 


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2.9.3.3
Pharmacokinetics analyses 
Dose-adjusted PK concentrations will be summarized by treatment, visit and time point based 
on PAS-1. The individual dose-adjusted pre-dose concentration will be plotted for Week 1, 
Week 3, Week 5, Week 9, Week 13, Week 17, Week 21, Week 25, Week 29, Week 33, Week, 
37, Week 41 and Week 45 based on data from all patients. In addition arithmetic mean dose-
adjusted pre-dose concentration will be plotted over time by treatment. These analyses will be 
based on the PAS-1.
Dose- adjusted PK parameters will be summarized by treatment for Week 1 and Week 5based 
on PAS-2. In addition, dose-adjusted PK concentrations will be summarized by treatment and 
time point for Week 1 and Week 5 on the PAS-2. Dose-adjusted individual concentration-time 
profiles will be plotted for Week 1 and Week 5. These analyses will be based on the PAS-2.
The dose-adjusted PK concentration and dose-adjusted PK parameter will be calculated as 
follows:

For patients taking deferasirox DT: 
Dose-adjusted PK concentration or parameter = (PK concentration or parameter/actual 
dose)*20

For patients taking deferasirox granules: 
Dose-adjusted PK concentration or parameter = (PK concentration or parameter/actual 
dose)*14 
2.9.3.4
Exploration of PK/PD relationship
To characterize the exposure-efficacy relationship, serum ferritin change from baseline will be 
fitted by a linear mixed effect model with log- transformed matching pre-dose concentrations 
and post-dose concentrations as covariates and subject as random effect.
To characterize the exposure-safety relationship: Serum creatinine change from baseline, 
creatinine clearance change from baseline and urine protein creatinine ratio change from 
baseline will be fitted by a linear mixed effect model with log-transformed matching pre-dose 
and post-dose concentrations as covariates and subject as random effect. A model on post-
baseline measurement and adjusted by corresponding baseline as covariate might be 
considered if improves the model fit. 
Incidence of notable serum creatinine and incidence of notable serum creatinine clearance 
events will be analyzed by a logistic regression fitted by GEE methods as appropriate 
including log-transformed pre- and post-dose concentrations (see Table 2-4 for notable range 
definition). These analyses will be conducted if notable events were reported for a minimum 
of 20 patients. If notable events were reported for less than 20 patients a descriptive approach 
will be followed.
For all statistical models other covariates such as demographic characteristics may be 
included if appropriate (e.g. underlying disease).
PK/PD listing will be provided.
All PK/safety and PK/efficacy analyses will be based on the Safety Set 3 and on the FAS-3,
respectively. 


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2.10
Subgroup analysis
Table 2-6 provides details on the subgroups definition and planned analyses.
Table 2-6
Subgroups definition and use
Subgroup
Categories
Definition/identification 
method
Use
Age categories
2 to <10 versus 10 to <18
Based on IRT
Supportive 
analysis
Average actual 
daily dose 
categories
- Deferasirox DT average dose 
will be categorized as: <15, 15 to 
<25, 25 to <35 and ≥35 
mg/kg/day
- Deferasirox granule average 
dose will be categorized as: 
<10.5, 10.5 to <17.5, 17.5 to 
<24.5 and ≥24.5 mg/kg/day 
Based on DAR eCRF 
page
Supportive 
analysis
Baseline 
serum ferritin 
categories
≥1000 to 2500 versus >2500 to 
5000 versus >5000 ng/mL
Based on laboratory 
datasets
Supportive 
analysis
Underlying 
disease
- Thalassemia: Beta-thalassemia 
major, Beta-thalassemia 
intermedia
- Sickle cell disease
- Other
Based on history of 
disease eCRF
Supportive 
analysis
2.11
Sample size
The primary objective of this study is to evaluate patient compliance (using stick packs or 
tablet counts) and change in serum ferritin over time for both formulations of deferasirox in 
pediatric ICT naïve patients with iron overload.
The sample size was estimated to demonstrate superiority and statistical significance for both 
co-primary endpoints.
The assumptions made for this study were:  

For serum ferritin:
An expected improvement between both formulations in serum ferritin change from 
baseline after 24 weeksof treatment of −450ng/mL with a standard deviation (SD) of 900 
ng/mL based on results from study CICL670A0107 in pediatric patients treated with 
Exjade on ≥25 mg/kg/day after 24weeks of treatment

For compliance using stick packs or tablets counts:
An expected improvement between both formulations in mean relative consumed tablet 
count of 10% with a SD equal to 17.625% based on the pooled analysis on pediatric 
patients (n=77) from Exjade studies [ICL670A2206] (n=39), [ICL670A2204] (n=24) and 
[ICL670A2214] (14).


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The sample size, driven by the calculation of serum ferritin, has been determined to obtain 
76% power at a one-sided 5% level of significance for showing superiority of granule 
formulation over DT formulation with respect to change from baseline after 24 s of treatment 
in serum ferritin. 
A sample size of 45 in each group will have 76% power to detect a difference in means of 450
ng/mL assuming that the common SD is 900 ng/mL using a two group t-test with a 0.050 one-
sided significance level. With 45 patients per arm, the power to detect a difference of 10% or 
more in mean compliance is about 84%.
Considering a potential of 5% dropout rate patients, the required sample size to achieve the 
primary objective is 48 chelation naïve patients for each treatment group (96 patients in total).
In addition, the clinical trial will enroll patients previously treated with iron chelation patients. 
Considering that a direct comparison of granule and DT formulations in terms of efficacy is 
not foreseen in previously chelated patients, the required sample size is not based on power 
calculations as usual. The selection of number of patients is based on the precision in the 
estimate of SF change at 48 weeks of treatment and on practical considerations.
A maximum of 120 (60 patients will be in each formulation group) previously chelated 
patients will be enrolled. Sixty patients will provide an estimate of SF change with precision 
(half-width of 95% confidence interval) equal to 303.6. 
Table 2-7 below lists the precisions in the estimates of SF change for different numbers of 
patients using the estimated SD obtained from the [CICL670A0107] study results in pediatric 
patients treated with Exjade on ≥25 mg/kg/day at week 48 of treatment.
Table 2-7
Precision in the estimate of the serum ferritin change
Number of patients
Half-width of 95% confidence interval in the estimate of the SF change
40
371.8
45
350.6
50
332.6
55
317.1
60
303.6
The total required sample size for this clinical trial is up to 108 patients for each treatment 
group (up to 216 patients in total), including 48 iron chelation naive patients per group (96
patients in total).
2.12
Interim analysis
At the time of the Interim Analysis (IA) safety and efficacy data will be provided on all 
randomized iron chelation naïve patients (ICT naïve based on either in IRT or CHY eCRF 
page) who have completed a minimum of 12 weeks (≥84 days) of treatment exposure or 
discontinued from treatment core phase at the time of the cut-off date.
Unless otherwise specified, the FAS-1 will be used for the analysis of efficacy endpoints as 
well as for patient demographic and baseline characteristic, patient disposition and protocol 
deviations summaries. Similarly, the Safety Set 1 will be used for all safety data summaries.
All analyses will be presented by treatment arm. Only descriptive analysis will be performed. 


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There is no intent to stop (neither for futility nor for efficacy) or to modify the design of the 
study as a consequence of this look. Therefore no alpha will be spent at this interim look. At 
the time of the IA data from approximately 74% of the patients expected to be enrolled will be 
available.
The primary endpoints, i.e. serum ferritin change from baseline and overall compliance 
measured by stick pack /tablet count, and key safety data will be summarized descriptively.
The Interim CSR deliverables are specified in the TFL Shells document. 
In addition, two supportive analyses will be performed: 

Descriptive summary of serum ferritin change from baseline will be provided after 
imputing missing values using multiple imputation method (see Section 4.6.1).

Predictive probability of success of the primary analysis for serum ferritin change from 
baseline will be assessed using normal approximation based on observed interim analysis 
data.
3
Change to protocol specified analyses
Table 3-1
Changes to protocol specified analysis or descriptions and rationale
Protocol section
Protocol description
Change
Rationale
NA
4
Additional details on implementation of statistical 
methodology
The sections below contain additional details on statistical methodology that will be included 
in Appendix 16.1.9 (Documentation of Statistical Methods) of the CSR as well as programing 
rules that will be followed to implement the analyses described in Section 2.
4.1
Time windows
4.1.1
Study drug exposure 
Study drug will be dispensed at randomization (week 1), then every four weeks. Dose 
adjustments based on safety are allowed at any time point during the study.
Information on study drug strength will be collected on the Dose Administration Record 
(DAR) eCRF and includes the planned dose (mg/kg/day), actual total daily dose (mg) taken, 
reason for the dose change, start date and end date.
Table 4-1 shows the defined study periods for drug exposure.
All assessments within a time period will be used to calculate the drug exposure for the 
corresponding period. 


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Table 4-1
Study periods for drug exposure
Period
Visit Period Definition
Month 1
Study Day 1 – 28
Month 2
Study Days 29 – 56
Month y** (with y=3, 4, 5,…)
Study Days (y-1)*28+1 to (y)*28
Etc.
*Study Day 1 = first day of study treatment
** For the core phase data analysis: y=1 to k=12 
4.1.2
Laboratory data and vital signs
Laboratory data (biochemistry, hematology and urinary parameters as well as serum 
creatinine, creatinine clearance and proteinuria) and vital signs will be collected at screening 
visits, at each regularly patient visit and at end of treatment visit.
If two or more assessments are performed within a time window then the assessment closest 
to the planned visit is used in analyses by time window. When two values are equidistant from 
the planned assessment, the later one is used in analyses. When multiple values are reported 
on the same day then the average value is used in analyses. For parameters with categorical 
results, the one from central laboratory is used in analyses.
For worst post-baseline assessment, all on-treatment values are considered regardless of time 
windows.
Table 4-2 shows the defined time windows.


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Table 4-2
Time windows for laboratory data, vital signs, weight and BMI
Time Window
Planned Visit Timing 
Time Window Definition
On treatment
Baseline
On or before Study Day 1*
≤ Study Day 1
Week 2**
Study Day* 8
Study Days 2 – 11 (excluded 
baseline assessment)
Week 3**
Study Day* 15
Study Days 12 – 18
Week 4**
Study Day* 22
Study Days 19 – 25
Week 5 
Study Day* 29
Study Days 26 – 42
Every 4 weeks thereafter 
Week y=5+4*k 
(with k*** = 1, 2, 3, 4, 5, 6, 7, 
8, 9, 10, 11,…)
Study Day (5+4*k-1)*7+1 
Study Days 
(5+4*k-1)*7+1-14 to 
(5+4*k-1)*7+1+13
Notes: 
- EOT data visit are included if 
obtained within 7* days of last 
non-0 dose intake or within 14*
days for ocular assessments
(*NA for patients continuing in 
extension phase).
*Study Day 1 = first day of study treatment
** where appropriate (e.g. week 2 time-window NA for serum ferritin)
*** For the core phase data analysis: k=1 to k=11 with EOT_Core corresponding to week 49 time-
window
4.1.3
Compliance diary
Patients will be asked to fill-out the PRO compliance questionnaire daily from Week 1 Day 1 
visit to end of treatment visit.
Table 4-3 shows the defined week periods for this two PRO questionnaire.
All daily assessments within a week period will be used in analysis by week. 
Table 4-3
Week periods for compliance diaries 
Week Period
Week Period Definition
Week 1 period
Study Day 1 – 7
Week 2 period
Study Days 8 – 14
Week 3 period
Study Days 15 – 21
Week y period (with y=4, 5, 
6,…)
Study Days  (y-1)*7+1 to y*7
Etc.
Study Day 1 = first day of study treatment


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4.1.4
Ocular data 
Ocular data will be collected at screening visit, at patient visit 11 and at end of treatment visit
during the core phase and annually during the extension phase.
Table 4-4 shows the defined time windows.
Table 4-4
Time windows for ocular data
Time Window
Planned Visit Timing 
Time Window Definition
On treatment
Baseline 
On or before Study Day 1*
≤ Study Day 1
Week 25
Study Day 169
Study Days 140 – 197
EOT_Core
NA
Data collected at the EOT visit; if 
no data were collected at the EOT 
visit the last post-baseline available 
data obtained before EOT will be 
used
*Study Day 1 = first day of study treatment
4.2
Month/year derivation
For all derivations, a year will be defined as 365.25 days and a month will be calculated as 
(365.25 / 12) = 30.4375 days. If duration is to be reported in months, duration in days will be 
divided by 30.4375.
4.3
Body mass index 
Body mass index, in kg/m2, is a measure of relative weight based on an individual's mass and 
height.
It is calculated using the following formula, where weight is in kilograms and height is in 
meter:
BMI = Weight / Height2
Baseline BMI will be determined using the last available height and weight prior to start of 
study drug.
4.4
Other baseline characteristics
Table 4-4
Medical history terms for other baseline characteristics
Disease
Terms (PT)
Splenectomy
SPLENECTOMY 
Hepatic B
HEPATITIS B
HEPATITIS B CORE ANTIGEN POSITIVE
HEPATITIS B SURFACE ANTIGEN POSITIVE
HEPATITIS B VIRUS TEST POSITIVE
HEPATITIS B E ANTIGEN POSITIVE
HEPATITIS B ANTIGEN POSITIVE


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Disease
Terms (PT)
Hepatic C
HEPATITIS C
HEPATITIS C ANTIBODY POSITIVE
HEPATITIS C RNA POSITIVE
HEPATITIS C VIRUS TEST POSITIVE
4.5
Stratification
In this study, two randomization lists have been developed:

Patients enrolled in the initial protocol will be randomized using a central stratified 
block randomization with the following stratification factor: age group (2 to <10 years 
versus 10 to <18 years).

Patients enrolled after protocol amendment 1 will be randomized using a central 
stratified block randomization with the following stratification factors: age group (2 to 
<10 years versus 10 to <18 years) and prior ICT (Yes versus No).
Therefore, the FAS-1, considering only ICT naïve patients as per IRT, will include patients 
randomized in the following strata: 2 years to <10 years (stratification id=1), 2 to < 10 years + 
PICT No (stratification id=4) and 10 to < 18 years (stratification id=2) 10 to < 18 years + 
PICT No (stratification id=6).
4.6
Efficacy evaluations
4.6.1
Primary endpoint
An ANCOVA will be used for comparison between both treatment groups. PROC GLM 
procedure in SAS will be used for the primary analysis.
For each of the endpoint the following estimates from the ANCOVA will be provided:

the least squares mean with 2-sided 95% confidence interval for each treatment arm

the least squares means with 2-sided 95% confidence interval, p-value for the difference 
between treatment arms
Multiple imputation technique will be used for sensitivity analysis for the primary analysis for 
serum ferritin if more than 10% of the patients have no serum ferritin value after 24 weeks of 
treatment. PROC MI procedure in SAS will be used for this analysis.
4.6.2
Pharmacokinetics endpoint
4.6.2.1
Elapsed time
For pre-dose the elapsed time is calculated as the difference between the PK sampling time 
and the dosing time on the day prior to the PK draw.
For post-dose, the elapsed time is calculated as the difference between the dosing time on the 
day of the PK draw and the PK sampling time.


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4.6.2.2
Model-based analyses
A linear mixed model will be used to evaluate pre-dose PK data to support the assessment of 
compliance and to characterize exposure-efficacy and exposure-safety relationships as 
described in Section 2.9.3.4. PROC MIXED procedure in SAS will be used for this analysis.
Further statistical details of those analyses will be described in Appendix 16.1.9.
A logistic regression model will evaluate the potential effect of PK pre and post-dose 
concentration on odds of having renal safety events as described in Section 2.9.3.4. PROC 
GENMOD procedure in SAS will be used for this analysis. Further statistical details of those 
analyses will be described in Appendix 16.1.9.
4.6.3
Calculation of predictive probability of success for serum ferritin 
change from baseline 
The predictive probability of observing a significant treatment effect at the end of study will 
be calculated and provided as supportive information at the time of the interim analysis.
We will use the following notations:

PoS is the probability of success

μ denotes the true (unknown) mean difference between the treatment arms in serum 
ferritin change from baseline at week 25, respectively

	
 is the mean difference between treatment arms in serum ferritin change from 
baseline at week 25 at the primary analysis, 

	 is the observed mean difference between treatment arms in serum ferritin 
change from baseline at week 25 at the interim analysis,

Yc the critical value for the primary analysis

σ is the “outcome standard deviation” of the observed mean difference

Φis the cumulative distribution function of the standard normal distribution

n1, n2 and n are the number of patients at the interim analysis, between the interim and 
the primary analysis, and the total number of patients, respectively.
Assuming a normal likelihood, i.e. 
	
 ~  (μ,

 )
and a non-informative (improper) prior for μ
μ ∝1


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This implies:
μ ¦ 	 ~  (	,

√)
	
 ¦ 	 ~  (	, 
2 !
1(1 + 2))
PoS = 
#$	
 > & ¦ 	'
=
#((()!)
!
$	
 −	' > (()!)
!
$& −	')
=
1 −Φ ((()!)
!
$& −	'
For the actual calculation, 	 and σ will be obtained from an ANCOVA adjusted for the 
stratification factor age. Specifically, 	 is the corresponding point estimate from the 
ANCOVA and σ = √1,-(	) , where ,-(	) is the standard error from the 
ANCOVA.
4.7
Safety evaluations
The text below gives more detailed instructions and rules needed for programming of the 
safety analyses described in Section 2.
4.7.1
Multiple assessments within post-baseline visits
For all analyses regarding abnormal assessments or analyses based on worst post-baseline 
value (e.g. laboratory, ECGs, vital signs), all post-baseline values will be included (scheduled, 
unscheduled, repeat). All unscheduled and repeat measurements will be included in listings.
4.7.2
Baseline
As defined in Section 2.7, for safety evaluations, the last available assessment before or on the 
date of start of study drug is defined as ‘baseline’ value or ‘baseline’ assessment. Recalculated 
creatinine clearance
The recalculated creatinine clearance will be calculated using the Schwartz formula (pediatric 
population at baseline). The MDRD derivation will be provided in the derived datasets only 
for possible future requests.
In the formulae below, CrCl denotes Creatinine Clearance, SCr denotes Serum Creatinine in 
µmol/L; age in years is calculated from date of birth and date of the relevant blood sample. 
Weight and height are the last available measurements at the time of the relevant blood 
sample.
Schwartz formula (<18 years of age at beginning of the study), 


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CrCl (mL/min)=(k×height)/(SCr×0.01131) with
k = 0.45 for children <1 year based on current age
k = 0.55 for children from 1 to 12 years based on current age
k = 0.55 for girls ≥13 years based on current age
k = 0.70 for boys ≥13 years based on current age
4.8
Handling of missing or partial dates
A date is considered as missing when no information at all is available, i.e. the day, the month 
and the year are missing.
A partial (or incomplete) date is a date for which part of date information is missing, i.e. either 
the day or the day and month are not available. Partial dates, if left partial, would possibly 
mean an event cannot be placed in time, treatment/dosage at the time of the event is unknown 
and the event cannot be reported/summarized appropriately – if at all. Therefore it is 
important to perform date imputation for selected dates to ensure that as many data events are 
represented as correctly as possible.
Date imputation is the creation of a new, complete date from the partial information available 
according to an agreed and acceptable algorithm. 
4.8.1
AE date imputation
Missing and partial date for AE will be handled according to rules specified below. 
There will be no attempt to impute the following:

Completely Missing AE start dates 

AE start dates missing the year.

Partial/missing AE end dates
For partial AE start date, the date imputation will be based on the temporal relation between 
the partial date and start of treatment date.
Table 4-5 provides examples of the different considered imputations for AE start date. 
The full description will be provided in the PDS.
Table 4-5
AE start date imputation example scenarios
Partial
AE start date
Treatment
start date
Temporal 
relationship 
compared to 
treatment start 
Imputed Date
12mmyyyy
20OCT2001
Uncertain
<blank>
ddmmm2000
20OCT2001
Before
01JUL2000
ddmmm2002
20OCT2001
After
01JAN2002
ddmmm2001
20OCT2001
Uncertain
21OCT2001
ddSEP2001
20OCT2001
Before
15SEP2001
ddOCT2001
20OCT2001
Uncertain
21OCT2001
ddNOV2001
20OCT2001
After
01NOV2001


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4.8.2
Concomitant medication date imputation
The imputation of the start date of concomitant medication will follow the same conventions 
as for AE start date. Partial concomitant medication end dates will not be imputed.
4.8.3
Incomplete date of diagnosis of main underlying disease
Incomplete dates for date of diagnosis of main underlying disease will be imputed with the 
earliest possible date, provided that at least the year of diagnosis is known and that imputed 
diagnosis date occurred before screening visit 1.  
4.8.4
Incomplete date for last iron chelation therapy
Stop date:
Imputed date = min (randomization date-1, last day of the month), if day is missing;
Imputed date = min (randomization date-1, 31DEC), if month and day are missing.
4.8.5
Incomplete date of last dose of study drug
The following rule should be used for the imputation of date of last administration:
Scenario 1: If the date of last administration is completely missing and there is no EOT eCRF 
page, the patient is considered as on-going. The patient should be treated as on-going and the 
cut-off date should be used as the last dosing date.
Scenario 2: If the date of last administration is completely or partially missing and the EOT 
eCRF page is available (prior to any death date or withdrawal of consent date, if available): 
Case 1: The date of last administration is completely missing, and the EOT visit date is 
complete, then the EOT date should be used.  
Case 2: Only Year(yyyy) of the dose end date is available and yyyy < the year of EOT date:  
Use Dec31yyyy
Case 3: Only Year(yyyy) of the dose end date is available and yyyy  = the year of EOT date: 
Use EOT date
Case 4: Both Year(yyyy) and Month (mm) are available for the date of last administration, 
and yyyy  = the year of EOT date and 

mm < the month of EOT visit:  
Use last day of the Month (mm)

mm = the month of EOT visit:  
Use EOT day.
After imputation, compare the imputed date with the start date of that specific record, if the 
imputed date is < start date of that record
Use the start date of that record.


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Patients with missing start dates are to be considered missing for all study treatment 
component related calculations and no imputation will be made. If the date of first 
administration is missing, then the date of last administration should not be imputed.
There will be no attempt to impute any other date from eCRF DAR page.
5
References
Food and Drug Administration. Guidance for Industry. Patient-Reported Outcome Measures: 
Use in Medical Product Development to Support Labeling Claims Establishment and
Operation of Clinical Trial Data Monitoring Committees. December 2009.
International Conference on Harmonization. E9: Statistical Principles for Clinical Trials.
Schwartz GJ, Brion LP, Spitzer A (1987) The use of plasma creatinine concentration for 
estimating glomerular filtration rate in infants, children, and adolescents. Pediatr Clin North 
Am; 34(3):571-90.
Tanner JM. Growth at adolescence. Oxford: Blackwell Scientific Publications, 1962.


Clinical Development
ICL670/deferasirox
Study Number: CICL670F2202 / NCT02435212
A randomized, open-label, multicenter, two arm, phase II 
study to evaluate treatment compliance, efficacy and safety 
of an improved deferasirox formulation (granules) in 
pediatric patients with iron overload
Statistical Analysis Plan (SAP) – End of Core Phase 
Detailed Statistical Methodology
Authors:
 Statistician; 
 Statistician
Document type:
RAP Documentation
Document status:
Final version 1.0
Release date:
23-Jun-2021
Number of pages:
41
Property of Novartis
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


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Document History – Changes compared to previous version of SAP.
Version
Date
Changes
1.0
23 June 2021
Initial version (based on the SAP Amendment 3 (dated 
26Mar2018))


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Table of contents
Table of contents .................................................................................................................3
List of tables ........................................................................................................................5
List of figures ......................................................................................................................5
List of abbreviations............................................................................................................6
1
Introduction .........................................................................................................................8
1.1
Study design.............................................................................................................8
1.2
Objectives ................................................................................................................8
2
Statistical methods.............................................................................................................10
2.1
Data analysis..........................................................................................................10
2.2
Analysis sets ..........................................................................................................12
2.3
Patient demographics and other baseline characteristics.......................................13
2.4
Protocol deviations ................................................................................................13
2.5
Patient disposition..................................................................................................13
2.6
Treatments (study drug exposure, concomitant therapies)....................................14
2.7
Baseline..................................................................................................................17
2.8
Analysis of the primary variables..........................................................................18
2.8.1
Variable.................................................................................................18
2.8.2
Statistical hypothesis, model, and method of analysis..........................18
2.8.3
Handling of missing values/discontinuations........................................18
2.8.4
Supportive analyses...............................................................................19
2.9
Analysis of secondary variables ............................................................................19
2.9.1
Compliance after 48 weeks of treatment during core phase .................19
2.9.2
Changes from baseline in serum ferritin after 24 weeks of 
treatment during core phase ..................................................................19
2.9.3
Changes from baseline in serum ferritin after 48 weeks of 
treatment during core phase ..................................................................19
2.9.4
Other analyses of change from baseline in serum ferritin.....................19
2.9.5
Patient reported outcomes/Observer reported outcomes.......................20
2.9.6
Safety evaluations .................................................................................27
2.9.7
Pharmacokinetics parameters................................................................33
2.10
Sample size............................................................................................................33
2.11
Interim analysis......................................................................................................33
3
Change to protocol specified analyses ..............................................................................33
4
Additional details on implementation of statistical methodology.....................................34
4.1
Time windows .......................................................................................................34


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4.1.1
Study drug exposure..............................................................................34
4.1.2
Laboratory data and vital signs .............................................................35
4.1.3
Compliance diary ..................................................................................36
4.1.4
Ocular data ............................................................................................36
4.2
Month/year derivation ...........................................................................................38
4.3
Body mass index....................................................................................................38
4.4
Stratification ..........................................................................................................38
4.5
Efficacy evaluations...............................................................................................38
4.5.1
Primary endpoint...................................................................................38
4.6
Safety evaluations..................................................................................................38
4.6.1
Multiple assessments within post-baseline visits..................................39
4.6.2
Baseline.................................................................................................39
4.6.3
Recalculated creatinine clearance .........................................................39
4.7
Handling of missing or partial dates......................................................................39
4.7.1
AE date imputation ...............................................................................39
4.7.2
Concomitant medication date imputation .............................................40
4.7.3
Incomplete date of first/last dose of study drug....................................40
5
References .........................................................................................................................41


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List of tables
Table 1-1
Objectives and related endpoints ............................................................8
Table 2-1
Definition of core and extension phases ...............................................11
Table 2-2
Deferasirox: Study drug exposure.........................................................15
Table 2-3
Scoring Matrix ......................................................................................26
Table 2-4
Definition of notable/extended ranges for key safety laboratory 
parameters .............................................................................................29
Table 2-5
Definition of clinically notable abnormalities for vital signs and 
weight values.........................................................................................30
Table 3-1
Changes to protocol specified analysis or descriptions and rationale...33
Table 4-1
Study periods for drug exposure ...........................................................34
Table 4-2
Time windows for laboratory data, vital signs, weight and BMI..........36
Table 4-3
Week periods for compliance diaries....................................................36
Table 4-4
Time windows for ocular data in core phase ........................................37
Table 4-5
Time windows for ocular data in extension phase................................37
Table 4-6
AE start date imputation example scenarios .........................................40
List of figures
Figure 2-1
Core and extension phases ....................................................................11
Figure 2-2
Conceptual model for the Modified Satisfaction with Iron 
Chelation Therapy questionnaire ..........................................................21
Figure 2-3
Conceptual model for Item 7 of the modified SICT .............................22
Figure 2-4
Conceptual Model for the Modified Satisfaction with Iron 
Chelation Therapy Questionnaire .........................................................23
Figure 2-5
Conceptual model for item 6 and item 15 of the modified SICT.........24


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List of abbreviations
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALT
Alanine aminotransferase/glutamic pyruvic transaminase/GPT
AST
Aspartate aminotransferase/glutamic oxaloacetic transaminase/GOT
ATC
Anatomical Therapeutic Classification
AUC
Area under concentration-time curve
BMI
Body mass index
BP
Blood Pressure
CA
Compartmental Analyses
CI
Confidence Interval
CrCl
Creatinine Clearance
CRF
Case Report/Record Form
CSR
Clinical Study Report 
CV
Coefficient of Variation
DAR
Dosage Administration Record
DBP
Diastolic Blood Pressure
DRL
Drug Reference Listing
DT
Dispersible Tablet 
EoC
End of Core Phase
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
PRO/ObsRO
Patient Reported Outcomes/Observer Reported Outcomes
EOT
End of Treatment
FAS
Full Analysis Set
FCT
Film Coated Tablet
FU
Follow Up
GCP
Good Clinical Practice
GGT
Gamma-glutamyltransferase
HLT
High Level Terms
IA
Interim Analysis
ICT
Iron Chelation Therapy
IRT
Interactive Response Technology 
ITT
Intention To Treat
Kg
Kilogram
LLOQ
Lower Limit of Quantitation
MDRD
Modification of Diet in Renal Disease
MDS
Myelodysplastic syndrome


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MedDRA
Medical Dictionary for Regulatory Activities
NA
Not Applicable
NCA
Non-Compartmental Analyses
NEU
Neutrophils
NMQ
Novartis MedDRA Queries
PAS
Pharmacokinetic Analysis Set
PDS
Programming Datasets Specifications
PK
Pharmacokinetic
PPS
Per-Protocol Set
PT
Preferred Terms
RBC
Red Blood Cell
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SD
Standard Deviation
SCIT
Satisfaction with Iron Chelation Therapy
SI
International System 
SMQ
Standardized MedDRA Queries
SOC
System Organ Classes
SCr
Serum Creatinine
TBL
Total Bilirubin
TEAE
Treatment Emergent Adverse Event
TFL
Tables Figures Listings
ULN
Upper Limit of Normal
UNK
Unknown
WBC
White Blood Cell
WHO
World Health Organization


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1
Introduction
This document details the planned statistical analysis for data collected during the core and 
extension phases in the study CICL670F2202. The SAP from the primary analysis (CSR SAP 
Amendment 3, dated 26Mar2018) will be used as a reference for this SAP. The CSR SAP is 
located at the following CREDI location:
 
Clinical Study Report (CSR) deliverables (tables, figures, listings - TFLs) and further 
programming specifications are described in separate documents namely TFL Shells and 
Programming Datasets Specifications (PDS), respectively. An interim and the primary analysis 
were performed in the study. The data cut-off date for the interim analysis was 16-Nov-2017
and included all randomized ICT naïve patients who had completed a minimum of 12 weeks of 
treatment exposure or discontinued from the treatment core phase by the cut-off date. The 
primary analysis was performed when 96 randomized ICT naive patients had completed 24 
weeks of treatment or discontinued early (data cut-off date: 31-May-2018). All data collected 
within the core phase of the study at the time of the primary data cut-off date were reported in 
the primary analysis CSR.
This analysis plan describes the analyses for an End of Core Phase (EoC) CSR requested by the
CHMP that will include the cumulative data from the completed core phase and extension phase 
with a data cut-off date of 18-Jan-2021. This data cut-off date allows the inclusion of all patients 
who have completed a minimum of 3 years of treatment or discontinued from treatment in the 
core or extension phase. Only the analyses based on the core and extension phase described in 
this analysis plan will be performed for this EoC phase CSR. Analyses that were presented in 
the primary CSR and for which no additional data was collected after the primary analysis data 
cut-off date (e.g. baseline demographics) will not be repeated for the EoC phase analysis.
1.1
Study design
Refer to section 1.1 of CSR SAP Amendment 3. 
1.2
Objectives
The study objectives as outlined in the protocol version 5, Section 3 are as follows (Table 1-1).
Table 1-1
Objectives and related endpoints
Objective
Endpoint
To be reported in 
EoC CSR
Primary


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Objective
Endpoint
To be reported in 
EoC CSR

To evaluate both formulations on 
patient compliance, using stick 
pack/tablet count over 24 weeks of 
treatment in ICT naïve patients
during core phase

To evaluate the change from baseline 
in serum ferritin after 24 weeks of 
treatment for both formulations in 
ICT naïve patients

Compliance measured by stick 
pack/tablet count over 24 weeks of 
treatment (i.e. assessed at week 25
visit)

Change from baseline in serum ferritin 
after 24 weeks of treatment (i.e. serum 
ferritin at week 25 visit)
Primary analysis 
planned as per 
protocol was 
conducted in the 
primary analysis
CSR and the 
study did not meet 
its primary 
objective.
Analyses reported 
in the EoC CSR, 
will be descriptive 
and testing of 
hypothesis will not 
be performed 
Secondary (Core phase)
To evaluate both formulations on change 
in serum ferritin and compliance in ICT 
naive patients, after 48 weeks of 
treatment
● Compliance measured by stick pack/tablet 
count after 48 weeks of treatment
● Change from baseline in serum ferritin 
after 48 weeks of treatment
Yes
To evaluate both formulations on change 
in serum ferritin after 24 weeks and 48 
weeks of treatment in ICT naïve and pre-
treated patients
Change from baseline in serum ferritin after 
24 weeks (i.e. assessed at week 25 visit) 
and 48 weeks of treatment
Yes
To evaluate both formulations on patient 
satisfaction and palatability using Patient 
/ Observer Reported Outcomes 
(PRO/ObsRO) questionnaires
Domain scores of treatment satisfaction and 
palatability over time
Yes
To evaluate both formulations on overall 
safety
Overall safety, as measured by frequency 
and severity of adverse events (including 
active monitoring for renal toxicity; including 
renal failure, hepatic toxicity; including 
hepatic failure, and gastrointestinal 
hemorrhage), and changes in laboratory 
values from baseline (serum creatinine, 
creatinine clearance, ALT, AST, RBC and 
WBC). In addition, vital signs, physical, 
ophthalmological, audiometric, cardiac, and 
growth and development evaluations will be 
assessed.
Yes
To evaluate compliance using a daily 
PRO/ObsRO questionnaire
Rate of dosing instructions deviations (doses 
missed / not taken at the same time every 
day)
Yes
To evaluate pre-dose PK data to support 
the assessment of compliance
Pre-dose deferasirox concentrations in all 
patients [except Egypt] at weeks  1, 3, 5, 9, 
13, 17, 21, 25, 29, 33, 37, 41 and 45 (13 
samples)
No
Post-dose data to be analyzed along with 
pre-dose PK data 
Post-dose deferasirox concentrations 
between 2 and 4 hours post-dose at Weeks 
5 and 9 (2 samples)
No
To explore exposure-response 
relationships for measures of safety and 
effectiveness 
Serum creatinine change from baseline, 
notable serum creatinine events, serum 
creatinine clearance change from baseline 
and notable serum creatinine clearance 
No


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Objective
Endpoint
To be reported in 
EoC CSR
events, urine protein creatinine ratio change 
from baseline and serum ferritin change from 
baseline, in relationship to pre- and post-
dose deferasirox concentrations.
Secondary (Optional Extension phase)
To assess additional safety data about 
new formulation (granules) in pediatric 
population 
Overall safety, as measured by frequency 
and severity of adverse events (including 
active monitoring for renal toxicity; including 
renal failure, hepatic toxicity; including 
hepatic failure, and gastrointestinal 
hemorrhage), and changes in laboratory 
values from baseline (serum creatinine, 
creatinine clearance, ALT, AST, RBC and 
WBC). In addition, vital signs, physical, 
ophthalmological, audiometric, and growth 
and development evaluations will be 
assessed.
Yes
2
Statistical methods
This section describes the analysis for the Core and extension phase data. Refer to the CSR SAP 
Amendment 3 for additional details. 
Section 4 of the SAP provides statistical and programming conventions. 
2.1
Data analysis
Data will be analyzed by Novartis Oncology Biostatistics and Statistical Programming 
personnel according to the data analysis section 10 of the study protocol as detailed in this 
analysis plan. 
SAS® version 9.4 (or later version if available at time of database lock) will be used for all 
analyses. Data from all patients who signed informed consent will be used in the analysis. Data 
collected after patients’ withdrawal of informed consent for further participation in the study 
will not be reported (except for death date which might be obtained from public records per 
local laws).
All statistical analyses will be performed using all data collected in the database up to the data
cutoff date. All data with an assessment date or event start date (e.g. vital sign assessment date
or start date of an adverse event) prior to or on the cut-off date will be included in the analysis.
Any data collected beyond the cut-off date will not be included in the analysis and will not be 
used for any derivations.
All events with a start date before or on the cut-off date and an end date after the cut-off date 
will be reported as ‘ongoing’. The same rule will be applied to events starting before or on the 
cut-off date and not having documented end date. This approach applies, in particular, to 
adverse event and concomitant medication reports. For these events, the end date will not be 
imputed and therefore will not appear in the listings.
The time periods defined in Table 2-1 will be used to define the core and extension phases for 
the analysis.


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Table 2-1
Definition of core and extension phases
Core phase
Extension phase
Treatment
Start date
Stop date
Treatment 
Start date
Stop date
Granules
Date of first IC 
signed
Date of last treatment 
of granules + 30 days
No 
treatment
Nil
Nil
DT
Date of first IC 
signed
Date of last treatment 
of DT + 30 days
No 
treatment
Nil
Nil
Granules
Date of first IC 
signed
date of first 
administration of 
granules in extension 
phase*– 1 day
Granules
date of first 
administration of 
granules in 
extension 
phase*
Date of the last 
administration of 
Granules in extension 
+ 30 days
DT
Date of first IC 
signed
Date of first 
administration of 
granules* – 1 day
Granules
Date of first 
administration of 
Granules*
Date of the last 
administration of 
Granules in extension 
+ 30 days
*including 0 doses for patients to identify the extension start date only
Summaries will be based on:

Core phase* - comparing data for Granules versus DT formulations (blue rectangle 
in Figure 2-1).

Extension phase*: summaries will only display extension phase data from patients 
randomized to Granules (light blue rectangle in Figure 2-1) side-by-side with patients 
randomized to DT who switched to Granules in extension phase (light green rectangle
in Figure 2-1). Cross-over treatment group corresponds to the patients randomized to 
DT who switched to Granules in the extension phase.

Entire granule period - patients randomized to Granules combining core and 
extension phases (dark green rectangle in Figure 2-1) side-by-side with Granules for 
patients randomized to DT who switched to Granules in extension phase (light green 
rectangle in Figure 2-1). Cross-over treatment group corresponds to the patients 
randomized to DT who switched to Granules in the extension phase. 
*Note for exception to Table 2-1: For analyses by time point in patients who continue into 
extension phase, EOT-core assessments done at the beginning of extension phase will be 
displayed in core phase reports.
Figure 2-1
Core and extension phases


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General analysis conventions
Pooling of centers: Unless specified otherwise, data from all study centers will be pooled for 
the analysis. Due to expected small number of patients enrolled at centers, no center effect 
will be assessed.
Qualitative/categorical data (e.g., sex, race) will be summarized by frequency counts and 
percentages. Percentages will be calculated using the number of patients in the relevant 
treatment arm as the denominator.  
Continuous data (e.g., age, body weight) will be summarized using appropriate descriptive 
statistics (i.e. mean, standard deviation, median, minimum, and maximum) by treatment arm.
Lower and upper quartiles will also be presented when applicable.
2.2
Analysis sets
Safety Set
The Safety Set 1 will consist of all ICT naïve patients (as per eCRF) who received at least one 
dose of the study drug during the core phase.
The Safety Set 2 will consist of all ICT pre-treated patients (as per eCRF) who received at least 
one dose of study drug during the core phase. 
The Safety Set 3 will consist of all patients who received at least one dose of study drug during 
the core phase. 
The Safety Set 4 will consist of all patients who received at least one dose of granule formulation 
during the core or extension phase.
Patients will be analyzed according to the treatment actually received and strata information 
recorded in the eCRF. 
Treatment actually received is defined as the treatment the patient received at the first day of 
study medication in the core phase.
Full Analysis Set
Full Analysis Set (FAS) is defined according to the Intention to Treat (ITT) principle. 
The Full Analysis Set 1 (FAS-1) consists of all ICT naïve (as per IRT, see Section 4.4)
randomized patients. 
The Full Analysis Set 2 (FAS-2) consists of all ICT pre-treated (as per IRT) randomized patients. 
The Full Analysis Set 3 (FAS-3) consists of all randomized patients. 
Following the intent-to-treat principle patients are analyzed according to the treatment and 
stratification factors they were assigned to at randomization during the core phase.


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Reporting
Frequency counts and percentages (using FAS-3 or Safety Set 4 as denominator) of patients in 
each of the above defined analysis sets will be summarized. In addition, listings of patients 
excluded from each of the analysis sets will be provided.
2.3
Patient demographics and other baseline characteristics
All patient demographic and baseline characteristics summaries were presented by FAS-1, 
FAS-2 and FAS-3 in the primary analysis CSR and will not be repeated for the EoC CSR. 
Enrollment status
The number of patients screened and randomized was summarized respectively by region, 
country, center and treatment arm on the FAS-3 in the primary CSR analysis and will not be 
repeated for the EoC CSR.
2.4
Protocol deviations
Frequency counts and percentages of patients with any protocol deviation (selection criteria not 
met, patient not withdrawn as per protocol, treatment deviation, prohibited concomitant 
medication, other Good Clinical Practice (GCP) deviation) will be tabulated by the deviation 
type category and treatment arm on the FAS-3 for the core phase and on the Safety Set 4 for the 
entire granule period. Patients with COVID-19 related protocol deviations will be presented 
separately in the table and listing for Safety Set 4 by category and relationship. 
The full list of protocol deviations is documented in the Validation And Planning (VAP) 
Module 3 document. The COVID-related protocol deviations and relationship to pandemic will 
be identified and maintained in an independent tracker located in the document management 
system in the “CREDI Studies/ICL670F2202/TMF (Study Level)/Protocol Deviations” folder.
The latest available tracker prior to database lock will be used. 
All protocol deviations will be listed on the FAS-3 and COVID related protocol deviations on 
Safety Set 4. 
2.5
Patient disposition
Listings will be produced on the FAS-3 with a flag for extension phase data.
The summaries of patient disposition during the core phase by treatment arm on the FAS-1, 
FAS-2 and FAS-3 will show:

Number (%) of randomized patients who were not treated;

Number (%) of randomized patients who were treated;

Number (%) of patients who completed the core phase;

Number (%) of patients who discontinued the core phase;

Number (%) for each reasons for core phase discontinuation;
The summaries of patient disposition during the extension phase by treatment arm on the Safety 
Set 4 will show in addition:


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
Number (%) of patients who entered in the optional extension phase;

Number (%) of patients who were not treated during the optional extension phase;

Number (%) of patients who were treated during the optional extension phase;

Number (%) of patients who are ongoing in the optional extension phase;

Number (%) of patients who completed the optional extension phase;

Number (%) of patients who discontinued the optional extension phase;

Number (%) for each reasons for optional extension phase discontinuation;
2.6
Treatments (study drug exposure, concomitant therapies)
The Safety Set 1, Safety Set 2, Safety Set 3 and Safety Set 4 will separately be used for 
medication data summaries unless otherwise specified. Listings will be produced by treatment 
arm on the Safety Set 3 and Safety Set 4. 
Study drug and study treatment
The terms study drug and study treatment are equivalent and will refer both to deferasirox DT 
or deferasirox granule.  
Date of first/last administration of study drug
The date of first administration of study drug is derived as the first date when a non-zero actual 
dose of study drug was administered as recorded on Dosage Administration Record (DAR) 
Electronic Case Report Form (eCRF). The date of first administration of study drug will also 
be referred as ‘start of study treatment’.
The date of last administration of study drug is defined as the last date when a non-zero actual 
dose of study drug was administered as recorded on DAR eCRF. This date will also be referred 
as ‘last date of study treatment’.
Study day
The study day for safety and pharmacokinetics assessments (e.g. adverse event onset, 
laboratory abnormality occurrence, vital sign measurement, Electrocardiogram (ECG), PK 
concentration, etc.) will be calculated using the start date of study treatment as the reference. 
For assessments occurring 

on or after the start date of study treatment, the study day will be calculated as (date of 
safety assessment) – (start date of study treatment) + 1. Study day 1 will therefore be the 
first day of study treatment.

before the start date of study treatment, the study day will be calculated as (date of safety 
assessment) – (start date of study treatment). 
For example, if an adverse event starts 3 days before the start of study treatment the study day 
displayed on the listing will be negative, i.e. -3. 
The study day for efficacy assessments (e.g. serum ferritin, PRO) will be calculated using the 
randomization date as the reference. For assessments occurring


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
on or after randomization date, the study day will be calculated as (date of non-safety 
assessment) – (date of randomization) + 1. Then study day 1 will be the day of 
randomization. 

before randomization date, the study day will be calculated as (date of non-safety 
assessment) – (date of randomization). 
The study day will be displayed in the data listings. 
Study drug exposure
Definitions of duration of exposure, total patient-years exposure, average daily dose, 
cumulative total dose as well as percentage of planned dose taken are defined in Table 2-22:
Table 2-2
Deferasirox: Study drug exposure 
Overall duration of exposure (day):
[(date of last exposure) – (date of first study treatment) + 1]
Drug exposure on dose X (days)
[(date of last exposure on dose X) – (date of first study 
treatment on dose X) + 1] 
Average dose (planned and actual, 
in mg/kg/day):
Mean dose over all days between first and last dose, 
excluding interruptions: sum of all (X dose * corresponding 
duration of exposure on dose X) / overall number of dosing 
days
Cumulative dose (planned and
actual, in mg/kg):
Sum over daily doses of all days between first and last dose
Total patient-years (years):  
Overall duration of exposure (days) / 365.25 
Percentage of planned dose taken:
100 × [Cumulative actual dose / Cumulative planned dose]
For the core phase only where patients do not enter the extension phase, date of the first 
administration and last exposure of study drug refer to the first and last dates respectively when 
a non-zero actual dose of study drug was administered during the study core phase as defined 
in Table 2-1.
For patients who switch from DT to granules in the extension phase, date of last exposure of 
study drug in core phase refers to the day prior to the date of the first administration of granules 
in extension phase (including a zero actual dose) as defined in Table 2-1. 
For patients who switch from DT to granules, the date of the first administration of study drug 
(granules) refers to the first date of granules in the extension phase (including a zero actual dose) 
to account for treatment interruptions due to efficacy and safety reasons. The last exposure of 
the granules refers to the last date when a non-zero actual dose of granules was administered 
during the study extension phase as defined in Table 2-1. 
For patients receiving granules throughout the study, the date of the first administration and last 
exposure of study drug refer to the first and last dates respectively when a non-zero actual dose 
of study drug (granules) was administered during the study.
The actual dose in mg/kg/day will be obtained by dividing the actual total daily dose 
administered in the DAR eCRF page by the last available weight at the time of dose 
administration reported in the vital signs eCRF page.


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Overall duration of exposure, average planned and actual daily dose, cumulative actual dose, 
total patient-years and percentage of planned dose taken will be summarized by treatment arm
for the core phase and for the entire granule period. 
The following variables will also be summarized by treatment arm and for each phase as 
appropriate as:  

Duration of exposure will be categorized in the core phase as: <4 weeks, 4 to <12 weeks,
12-<20 weeks 20-<28 weeks, 28-<36 weeks, 36-<44 weeks, ≥44 weeks; and in the entire 
granule period as: <6 months, 6-<12 months, 12-<24 months, 24-<36 months, 36-<48 
months, ≥48 months).

Deferasirox DT average dose will be categorized as: <15, 15 to <25, 25 to <35 and ≥35 
mg/kg/day

Deferasirox granule average dose will be categorized as: <10.5, 10.5 to <17.5, 17.5 to 
<24.5 and ≥24.5 mg/kg/day
In addition, the number of patients who have dose reduction, increase or dose interruption, with
corresponding reasons and the average length of dose interruptions will be summarized.
Dose reduction will be considered if the actual dose is not equal to 0 (or not counted as 
interruption) and [the planned dose level is lower than the previous non-missing planned dose 
level Or the dose change is equal to ’yes’ and the actual total daily dose administered (mg) is 
lower (> 15%) than the calculated dose amount based on the planned dose (mg)]. Any dose 
change to correct a dosing error will not be considered a dose reduction (patient goes back to 
the previous planned/actual dose after a dose change due to dosing error). Number of reductions 
will be derived programmatically. The first dose in the extension phase for patient’s switching
from DT to granules will not be considered as reduction as per protocol section 14.1 (Equivalent 
dose guidance).
Dose increase will be considered if the actual dose is not equal to 0 (or not counted as 
interruption) and [the planned dose level is higher than the previous non-missing planned dose 
level Or the dose change is equal to ’yes’ and the actual total daily dose administered (mg) is 
higher (> 15%) than the calculated dose amount based on the planned dose (mg)]. Note that a 
dose rechallenge i.e when a patient goes back to the previous planned dose after an interruption 
or a dose reduction is not considered as an increase. 
Dose interruption will be considered if an actual dose of zero in a unit of time between two non-
zero actual dosing records. For the purpose of summarizing interruptions and reasons, in case 
multiple entries for interruption that are entered on consecutive days with different reasons will 
be counted as separate interruptions. However, if the reason is the same in this mentioned 
multiple entries on consecutive days, then it will be counted as one interruption.
For each patient, listings of each dose of the study drug administered along with dose change
reasons will be produced.  
Concomitant therapy
Prior and concomitant therapies are defined as any medication, and significant non-drug 
therapies administered to a subject preceding or coinciding with the study assessment period.


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Medications will be coded using the World Health Organization (WHO) Drug Reference 
Listing (WHO DRL) dictionary that employs the WHO Anatomical Therapeutic Chemical 
(WHO ATC) classification system. 
Concomitant therapies will include medications and significant non-drug therapies taken 
between the first day of study medication and up to 30 days after the last day of study medication
(see section 2.9.6 for the on-treatment period definitions).
Concomitant therapies will be summarized by ATC class, preferred term and treatment arm for 
the Safety Set 3 and Safety Set 4. Medications starting prior to the start of study treatment and 
continuing after the start of study treatment will be included in this summary for the core phase 
and entire granule period as defined in Table 2-1.
Prior therapies will include medications or significant non-drug therapies starting and ending 
prior to the start of study treatment. Prior therapies were summarized in the primary CSR 
analysis and will not be repeated for the EoC CSR.
All prior and concomitant therapies will be listed.
2.7
Baseline
Baseline is considered as the result of an investigation describing the ‘true’ uninfluenced state 
of the patient.
For efficacy evaluations, (e.g. serum ferritin), the last available (i.e. non-missing) assessment 
before or on the date of randomization is taken as ‘baseline’ value or ‘baseline’ assessment. 
For safety evaluations (e.g. laboratory, vital signs, etc.) the last available (i.e. non-missing)
assessment before or on the date of start of study treatment is taken as ‘baseline’ value or 
‘baseline’ assessment.
If patients have no value as defined above, the baseline result will be missing. Unscheduled 
assessments will be considered in the determination of baseline for both safety and efficacy 
evaluations.
For safety assessments, if an assessment is planned to be performed prior to the first dose of 
study drug in the protocol and the assessment is performed on the same day as the first 
administration of study drug, it will be assumed that it was performed prior to study drug 
administration, if assessment time point is not collected or is missing. 
Patients who start treatment and discontinue from the study on the same day may have 2 
different sets of data collected on study Day 1, one being reported to the week 1 visit, the other 
reported to the End Of Treatment (EOT) visit. Data reported at the EOT visit are not eligible 
for baseline selection.
For analyses of the extension phase or entire granule period requiring comparison to baseline 
value (e.g. lab shift tables) the baseline is defined as follows. For patients randomized to DT 
formulation who switched to granule formulation in the extension phase, the date of the last 
assessment prior or equal to the start date of granules in the extension phase will be defined as 
pre-granule value which will be reference value for changes in the extension time. For patients
randomized to granules continuing in extension phase the initial baseline value at study start 
will be taken.


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2.8
Analysis of the primary variables
The primary objectives of this study are to evaluate patient compliance with study treatment, as
measured by the count of deferasirox granule stick packs/dispersible tablets and to evaluate the 
change in serum ferritin after 24 weeks of treatment for both formulations of deferasirox in 
pediatric ICT naive patients with iron overload during core phase. Cumulative data up to week 
24 from all ICT naive patients will be analyzed in the EoC CSR and reported descriptively. 
2.8.1
Variable
All analyses for the primary objective will be performed on the FAS-1 and presented by 
treatment group: deferasirox DT and deferasirox granule formulation.
The co-primary efficacy variables are:

Compliance  measured by stick pack /tablet count based on amount of medication
dispensed, returned and reported as lost/wasted by the patient or caregiver in the eCRF, 
over 24 weeks of treatment (i.e. assessed at week 25 visit). Compliance will be calculated 
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 over 24 weeks of treatment (i.e. assessed at week 25 visit);
-
total count prescribed is derived from cumulative prescribed count over 24 weeks of 
treatment (i.e. assessed at week 25 visit).
The prescribed count corresponds to the count prescribed by the investigator for the 
relevant visit 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 granule), the prescribed count for the relevant visit period is calculated from 
the daily prescribed count at the beginning of this period multiply by the duration (days) of 
this period. The duration of a period will be calculated as (end date of the period) – (start 
date of the period). The total count prescribed is the sum of counts prescribed per strength. 
The end date of the period is defined as the date of next assessment. 

Change from baseline in serum ferritin after 24 weeks of treatment (i.e. assessed at week 
25 visit). 
2.8.2
Statistical hypothesis, model, and method of analysis
For the EoC CSR, there will be no formal testing of hypotheses. 
Analysis of covariance (ANCOVA) will be performed for comparison between both treatment 
groups. The ANCOVA model for compliance endpoint will include treatment group and the 
age group as per stratification (2 to <10 years versus 10 to <18 years), as factors. The model for 
serum ferritin endpoint will also include the serum ferritin value at baseline as covariate.
2.8.3
Handling of missing values/discontinuations
In case of missing serum ferritin after 24 weeks of treatment, the last available post-baseline 
serum ferritin value will be used in the calculation of the primary endpoint. Patients without 
post-baseline serum ferritin value will be excluded from the analysis. 


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No imputation will be performed for the compliance endpoint calculation. However, patient 
who discontinued before the week 25 visit will be included in the compliance endpoint 
calculation.
2.8.4
Supportive analyses
The supportive analyses for the primary endpoint were presented in the primary CSR and will 
not be repeated for the EoC CSR. 
2.9
Analysis of secondary variables
Secondary variables include compliance after 48 weeks of treatment, changes in SF from 
baseline after 24 weeks in ICT pre-treated patients and after 48 weeks of treatment in ICT-naive 
and pre-treated patients, patient reported outcomes/observer reported outcomes and safety 
assessments (i.e. adverse events, laboratory parameters, vital signs, etc.). All secondary 
variables will be analyzed by treatment group.
2.9.1
Compliance after 48 weeks of treatment during core phase
Summary statistics of overall compliance measured by stick pack/tablet count assessed at week 
48 visit and 95% confidence intervals for means will be provided for FAS-1, FAS-2 and FAS-
3. Patient who discontinued before the week 48 visit (end of core phase) will be included in the 
compliance endpoint calculation. End-of-core visit for patients who continue into extension 
phase will be calculated based on their last visit before the initiation of treatment of extension 
phase. 
2.9.2
Changes from baseline in serum ferritin after 24 weeks of treatment
during core phase
Summary of absolute and relative change from baseline values in serum ferritin assessed at 
week 24 (week 25 visit) and 95% confidence intervals for means (see Table 4-2 for time window 
definition) will be provided by FAS-2 and FAS-3. 
2.9.3
Changes from baseline in serum ferritin after 48 weeks of treatment
during core phase
Summary of absolute and relative change from baseline values in serum ferritin assessed at 
week 48 visit and 95% confidence intervals for means (see Table 4-2 for time window 
definition) will be provided for FAS-1, FAS-2 and FAS-3. 
Furthermore, a graphical presentation of mean and standard deviation of absolute value in serum 
ferritin will be plotted by treatment arm and time-window (see Table 4-2 for time-window 
definition) for FAS-1, FAS-2 and FAS-3. 
2.9.4
Other analyses of change from baseline in serum ferritin
Relative and absolute change from baseline in serum ferritin at every year visit during the entire 
granule period will be described for the Safety Set 4.


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2.9.5
Patient reported outcomes/Observer reported outcomes
Patient satisfaction, palatability and compliance with study drug will be evaluated for both 
treatment groups
using Patient Reported Outcomes/Observer Reported Outcomes
(PRO/ObsRO). For patients aged between 10 years and less than 18 years at enrollment, the 
PRO questionnaires will be completed by the patients themselves. The questionnaires for 
patients aged between 2 years and less than 10 years have been designed as observations made 
by caregivers such as the parent or legal guardian (ObsRO). For these patients the caregivers 
will continue completing the ObsRO questionnaires even after the patient turns 10 years for 
consistency in responses.
Three PRO/ObsRO questionnaires have been developed: the modified SICT questionnaire, a 
palatability questionnaire and a compliance diary. Patients/caregiver will complete all 
PRO/ObsRO questions via a handheld electronic device (exceptionally paper could be used in 
specific situation). The diaries will be completed daily at home and the palatability and modified 
SICT will be completed at pre-determined site visits.
The three questionnaires were developed using patient input in one on one interview. The FAS-
1, FAS-2 and FAS-3 will be used for the three PRO/ObsRO questionnaires analysis for the core 
phase, unless otherwise specified.
2.9.5.1
Modified SICT questionnaire
Patient reported outcomes
The Modified SICT questionnaire consists of 13 items that represent 3 domains; Adherence, 
Preference and Concerns (see Figure 2-2).


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Figure 2-2
Conceptual model for the Modified Satisfaction with Iron Chelation 
Therapy questionnaire
Adherence domain consists of 7 items, 6 of which are measured using a 5 point response scale. 
Items 4 and 5 use the response format 1 “Never””, 2 “Rarely” 3 “Sometimes” 4 ” Most of the 
time” and 5 “Always”; item 6 uses the response format 1 “Always”, 2 “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 or hard”, 4 “Hard” and 5 “Very hard”; Items 9 and 10 use the response 
format 5 “Very bothered”, 4”Bothered” 3”Moderately bothered”, 2 “A little bothered” and 1
“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 of 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 (Figure 
2-3). Each response category will be coded as binary item, for example taste will be an item 
with the response format 0 “Not endorsed” 1 “Endorsed”. 


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Figure 2-3
Conceptual model for Item 7 of the modified SICT
Satisfaction/preference domain consists of 3 items, 2 (Items 11 and 12) 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 (Item 13) asks the patient to assess which medication for iron overload they 
prefer.
Concerns domain consists of 3 items (Items 1, 2 and 3) 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.
Observer reported outcomes
The modified SICT consists of 17 items that represent 3 domains: Adherence, Preference, and 
Concerns (see Figure 2-4).


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Figure 2-4
Conceptual Model for the Modified Satisfaction with Iron Chelation 
Therapy Questionnaire
The conceptual framework consists of 2 separate scales to capture the child’s and caregiver’s 
perspective; these are further broken into 3 domains for the child: Concerns, Preference, and 
Adherence and 2 domains for the caregiver: Concerns and Adherence. 
Adherence domain will be captured from 2 perspectives: 

Child’s perspective (a Domain score + a Checklist for reasons for non-adherence) 

Caregiver’s perspective (a Domain score + a Checklist for reasons for non-adherence)
There will be 2 separate domain scores for overall adherence, the caregiver’s perspective of 
adherence domain consists of 6 items (Items 12, 13, 14, 16 and 17), while the child’s perspective 
of adherence domain consists of 7 items (Items 3, 4, 5, 7, 8 and 9). 
Child’s perspective of Adherence: Items 3 and 5 are measured using a 5-point response scale: 
“Always” =1, “Most of the time” =2, “Sometimes” =3, “Rarely” =4, and “Never” =5.  Item 4 
is measured on a scale from “Always” =5, “Most of the time” =4, “Sometimes” =3, “Rarely” 
=2, and “Never” =1.  Two items (Item 7 and 8) use different response options. Item 7 focuses 
on “How easy/hard did your child tell you it was to take his/her medicine” and uses the response 
scale “Very easy” =1, “Easy” =2, “Neither easy or hard” =3, “Hard” =4, and “Very hard” =5. 
Similarly, Item 8 captures bother expressed by child for amount of time he/she had to wait to 
eat food after taking medication. The response scale for Item 8 is “Very bothered” =5, 
“Bothered” =4, “Moderately bothered” =3, “A little bothered” =2, and “Not bothered at all” =1. 
Item 9 reports “how happy your child appeared” and is scored on a scale from 1=Very happy 
and 5=Very unhappy. 
Caregiver’s perspective of Adherence: Items 12 and 14 are measured using a 5-point response 
scale: “Always” =1, “Most of the time” =2, “Sometimes” =3, “Rarely” =4, and “Never” =5. 
Conversely, Item 13 is scored as “Always” =5, “Most of the time” =4, “Sometimes” =3, “Rarely” 
=2, and “Never” =1. Two items (Item 16 and 17) use different response options. Item 16 focuses 
on “How easy/hard was it to give your child his/her medicine” and uses the response scale 


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“Very easy” =1, “Easy” =2, “Neither easy or hard” =3, “Hard” =4, and “Very hard” =5. 
Similarly, Item 17 captures “bothered by the amount of time it took to prepare medication” and 
uses the response scale “Very bothered” =5, “Bothered” =4, “Moderately bothered” =3, “A little 
bothered” =2, and “Not bothered at all” =1. 
Separate adherence domain score for the child’s and caregiver’s perspective will be calculated. 
A domain score will be calculated by summing item scores on respective domains. Overall, a 
lower domain score will indicate better adherence. 
The checklist item from each perspective will evaluate the reason for non-adherence. Only 
respondents who, at Item 5 (for the child's perspective) and Item 14 (for the caregiver's 
perspective), indicate that they did not “Always” take their medication as instructed, are 
expected to give the reasons for non-adherence. For both perspectives the respondent can check 
all the reasons that apply (Figure 2-5).  For the child‘s perspective (item 6), each of the 5 
response options (i.e. taste, aftertaste, inconvenience, prepared medicine incorrectly, and other) 
will be coded as binary item, for example taste will be an item with the response format 0 “Not 
endorsed” 1 “Endorsed”. Similarly, for the caregiver perspective (item 15), each of the 7 
response options (i.e. child refuse to take, forgot, inconvenient, side-effect, not prepare 
medication per doctor’s instruction, did not give full amount, and others) will be coded as binary 
item (0/1).
Figure 2-5
Conceptual model for item 6 and item 15 of the modified SICT
Preference of the Child: This domain consists of 1 item (Item 10), to assess which medication 
they prefer (like). The item is to be considered a single item domain. 
Concerns domain will be captured from 2 perspectives: 

Child’s perspective (Item 1 and 2) 

Caregiver’s perspective (Item 11) 
The concerns domain for the child’s perspective has 2 items which focus on “limiting child’s 
activity” (Item 1) and “getting upset about the side-effects” (Item 2). Both the items are 


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measured using a 5-point response scale from “Always” =1, “Most of the time” =2, “Sometimes” 
=3, “Rarely” =4, and “Never” =5. A sum score for a Concerns domain for the child's perspective 
will be created. A higher score will indicate lesser concerns.
There is only a single item to capture concern in regards to caregiver’s perspective. The item 
11 captures “worry if the child is swallowing enough medication” and is scored on a 5-point 
response scale from “Always” =1, “Most of the time” =2, “Sometimes” =3, “Rarely” =4, and 
“Never” =5.  A higher score on the single item domain will indicate lesser caregiver concern.
Adherence, satisfaction/preference and concerns domain scores will be summarized using 
standard descriptive statistics by treatment arm, type of questionnaire (ObsRO questionnaire 
versus PRO questionnaire) and week (weeks 2, 3, 25 and core EOT). Additionally, absolute 
change from week 2 to week 25 and core EOT in the domain scores will be summarized 
including 95% confidence intervals for mean.
Graphical representation of PRO scores over weeks will be provided by domain by type of 
questionnaire and treatment. The y-axis will be the mean and SD for the domain score and the 
x-axis will be the week number.
In addition, all items from adherence, satisfaction/preference and concerns domains will be 
summarized by treatment arm by type of questionnaire and week using frequency counts and 
percentages for the FAS-3.
The number of patients completing the modified SICT questionnaire and the number of missing 
or incomplete assessments will be summarized by treatment arm, type of questionnaire and 
week for the FAS-3.
2.9.5.2
Palatability questionnaire 
The palatability questionnaire consists of 4 items. Two items measure the taste (item 1) and
aftertaste (item 2) of the medication and are scored on a 5 point response scale with the response 
format 1 “Very good”, 2 ”Good”, 3 “Not good or bad” for PRO/ 3 “Neither good nor bad” for 
ObsRO, 4 “Bad’ and 5 “Very bad”. The PRO 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. 
Note for ObsRO:  Item 1 the response format for 3 refers to “Neither good nor bad” and for 
Item 3 the response format 1 refers to “Swallowed and retained ALL of the medicine”. Same 
scoring rule will be used for both ObsRO and PRO.
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 3 
Swallowed ALL of the medicine =1


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Spat out SOME of the medicine & Spat out ALL of the medicine and 
swallowed none =2
Vomited within 30 minutes after swallowing the medicine = 3
Recode Item 4  
Not enough liquid & Too much liquid = 1
Just enough liquid = 2
No missing data will be imputed when calculating the palatability summary score. 
The Table 2-3 presents the Items 1, 3 and 4 scoring matrix leading to the palatability summary 
score:
Table 2-3
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, type of questionnaire (ObsRO questionnaire versus PRO questionnaire) and week (weeks 
2, 3, 25 and core EOT). Additionally, absolute change from week 2 to week 25 and core EOT
will be summarized including 95% confidence intervals for mean.
Graphical representation of this 11 point response scale will be provided over weeks by 
treatment and type of questionnaire. The y-axis will be the mean and SD and the x-axis will be 
the week number.
In addition, all of the 4 Items from the palatability questionnaire will be summarized using 
descriptive statistics by treatment arm, type of questionnaire and week using frequency counts 
and percentages for the FAS-3.


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The number of patient completing the palatability questionnaire and the number of missing 
assessments will be summarized by treatment arm, type of questionnaire and week for the FAS-
3.
2.9.5.3
Compliance diary
The Compliance questionnaire consists of 2 items. Item 1 assessed whether the medication was 
taken (yes/no) and Item 2 is a record of the time when the medication was taken with a not 
applicable option for patients who did not take their ICT. 
The daily compliance questionnaire diary records will also be used to calculate the rate of dose 
violations. For a given day, a dose violation is defined as a dose that is either missed completely 
or not taken in accordance with the timing instruction (no later than 12:00 pm). The dose 
violation rate is calculated as: 
[Number of dose violations / Drug exposure (days)] *100
Weekly average of dose violation rate will be calculated and summarized using descriptive 
statistics by treatment arm, type of questionnaire (ObsRO questionnaire versus PRO 
questionnaire) and week (weeks 1, 13, 25, 37 and core EOT). Additionally, absolute change 
from week 1 will be tabulated including 95% confidence intervals for mean. A graphical 
representation will be provided over all week periods by treatment arm and type of 
questionnaire. The y-axis will be the mean and SD and the x-axis will be the corresponding 
week period (see Table 4-3 for week periods definition).
Due to the use of ePRO there will be no individual items missing. The weekly average rates
will be calculated when there are at least four non missing daily responses. For a given week 
the denominator will be the number of non-missing days. No additional imputation will be 
carried out. 
The number of patients completing the compliance diary and the number of expected and 
missing days will be summarized by each treatment arm and type of questionnaire for the FAS-
3.
2.9.6
Safety evaluations
Unless otherwise specified, the following analyses will be performed separately for the Safety 
Set 1, Safety Set 2, Safety Set 3 for the core phase and the Safety Set-4 for the entire granule 
period. Listings will be provided for the Safety Set 3 and the Safety Set-4.
On-treatment period
For the core phase, the overall observation period will be divided into three mutually exclusive 
segments taking into account stop rules as per Table 2-1:

Pre-treatment period: from day of patient’s first  informed consent to the day before first 
dose of study drug;

On-treatment period: from day of first dose of study drug to 30 days after last dose of 
study drug for patients who do not enter the extension phase; from day of first dose of 
study drug in the core phase to one day prior to the start of the first dose of study drug in 
the extension phase for patients who enter the extension phase.


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
Post-treatment period: starting at day 30+1 after last dose of study treatment.
For the entire granule period, the following conventions will be taken into account while 
deriving the three observation periods above: 

For patients enrolled in DT formulation in the core phase, the pre-treatment period will 
not be derived;

For patients enrolled in Granule formulation in the core phase, the first dose of study drug 
will be the day of first dose in the core phase.
Unless otherwise specified, the safety summary tables will include only assessments from the 
on-treatment period.
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.
Any COVID-19 related safety events will be flagged in listings.
Adverse events
AEs will be coded using the latest version of Medical Dictionary for Regulatory Activities
(MedDRA) available prior to clinical database lock. 
Any information collected (e.g. relatedness to study drug, action taken etc.) will be listed. 
The following adverse event summaries will be produced by treatment arm:

Adverse events (overall and severe), regardless of study drug relationship by primary 
system organ class and preferred term

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

Serious adverse events (overall and severe), with suspected 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

Deaths (all and on-treatment) by primary system organ class and preferred term (Safety Set 
3 and 4 only). 
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, severity and relation 
to study drug by treatment arm. A patient with multiple occurrences of an AE will be counted 
only once in the AE category. 


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An overall summary of type of AEs (e.g. serious, leading to study drug discontinuation, 
requiring dose adjustment or/and interruption) will be presented by severity and treatment arm.
All AEs will be listed. Any information collected (e.g. regardless to study drug, action taken 
etc.) will be listed as well as the duration of the AE. The listings of all deaths, serious adverse 
events, adverse events leading to study drug discontinuation, and adverse events requiring dose 
adjustment or interruption will also be provided. 
Adverse events of special interest 
Specific groupings of AESI will be considered and the number of patients with at least one 
event in each grouping will be reported. Note that certain adverse events 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. All AESI definitions 
or AE groupings are specified in the electronic Case Retrieval Strategy (eCRS). The latest 
version of the eCRS available at the time of the analysis will be used.
AESI will be summarized by grouping, preferred term and treatment arm (specifying severity, 
SAE, relationship, leading to treatment discontinuation, leading to dose adjustment/interruption
and requiring additional therapy). 
Laboratory data
Laboratory data from all sources (central and local laboratories) will be combined. All 
laboratory values will be converted into International System (SI) units.
Raw values as well as absolute and relative change from baseline values for hematology, 
biochemistry and urinalysis laboratory parameters will be summarized descriptively per time 
window and treatment arm on the Safety Set 3 and 4 (see Table 4-2 for time windows definition). 
Shift tables based on normal ranges to compare baseline to the worst post-baseline value will 
be provided by parameter and treatment arm for hematology, biochemistry and urinary 
laboratory data. Same shift table will be provided based on notable/extended ranges for key 
safety laboratory parameters defined in Table 4-2. 
Table 2-4
Definition of notable/extended ranges for key safety laboratory 
parameters
Laboratory parameters
Criteria for notable/extended 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
Recalculated 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)


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Urinary protein/urinary 
creatinine ratio
> 1.0 (mg/mg) at two consecutive measurements at least 7 
days apart
ALT/AST
>5 x ULN and 2 x baseline (extended range >10×ULN and
>2×baseline value)
Recalculated creatinine clearance will be calculated using the Schwartz formula (for pediatric 
population at baseline) described in Section 4.6.3. The Modification of Diet in Renal 
Disease (MDRD) derivation will be provided in the derived datasets only for possible future 
requests.
A listing of all laboratory values with values flagged to show the corresponding range
classifications relative to the laboratory reference ranges will be provided by laboratory data
and treatment arm. Assessment day relative to first dose of study drug will be included and all 
laboratory assessments collected outside of the on-treatment period will be flagged. 
A listing of patients with laboratory abnormalities based on normal ranges and notable/extended 
ranges will also be provided.
Normal ranges by laboratory parameter will also be provided in a separate listing. 
Vital signs, weight and body mass index
The following criteria define clinically notable abnormalities for vital signs and weight values:
Table 2-5
Definition of clinically notable abnormalities for vital signs and weight 
values
Parameter1
Weight
High 
Increase from baseline ≥ 10%
Low
Decrease from baseline ≥ 10%
Pulse rate (beats per minute)
High2
12-18 months
18-24 months
2-3 years
3-4 years
4-6 years
6-8 years
8-12 years
12-15 years
15-18 years
> 140
> 135
> 128
> 123
> 117
> 111
> 103
> 96
> 92
Low2
12-18 months
18-24 months
2-3 years
3-4 years
4-6 years
6-8 years
8-12 years
12-15 years
15-18 years
< 103
< 98
< 92
< 86
< 81
< 74
< 67
< 62
< 58
1Systolic and diastolic blood pressure will be listed individually.


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2Fleming S, Thompson M, Stevens R, et al. Normal ranges of heart rate and respiratory rate in
children from birth to 18 years of age: a systematic review of observational studies. Lancet 2011;
published online March 15. DOI: 10.1016/S0140-6736(10)62226-X.
Descriptive statistics will be tabulated per time window and treatment arm using absolute 
change from baseline values for each vital sign measure, weight and BMI (see Table 4-2 for 
time windows definition) separately for Safety Set 3 and 4.
All vital sign assessments, weight and BMI will be listed by treatment arm, patient and 
parameter. In the listings, clinically notable values will also be flagged.
Cardiac evaluations
Cardiac evaluations include ECG and echocardiogram. Any abnormalities at baseline will be 
summarized as described in Section 2.3. All findings of patients with new or worsened 
abnormalities since baseline will be listed separately for Safety Set 3 and Safety Set 4.
Ocular evaluations
The number of patients with available assessment for each type of ocular evaluation and eye 
side will be provided by treatment group.
Visual acuity
Visual acuity will be measured using the Snellen visual acuity. This is determined by
establishing the smallest optotypes that can be identified correctly by the patient at a given
observation distance. Snellen visual acuity can be reported as a Snellen fraction (m/M) in which 
the numerator (m) indicates the test distance and the denominator (M) indicates the distance at 
which the gap of the equivalent Landolt ring subtends 1 minute of arc. The following formula 
for conversion from Snellen acuity results to the logMAR score (Holladay 1997) will be applied 
and the LogMAR score will be calculated for each timepoint.
logMAR score = –log10(m/M).
LogMAR scores will be categorized as follows: <0.1, ≥0.1 to <0.2, ≥0.2 to <0.3, ≥0.3 to <0.6, 
≥0.6. Shift tables using these categories to compare baseline to increases and decreases from 
baseline of logMAR score will be presented at each visit, for each eye side by treatment group
in the core phase. Number and percentage of patients with worst change from baseline for each 
logMAR category will be summarized by treatment arm. Changes from baseline at each visit
will be calculated for assessments done in the same condition (with/without correction) as at 
baseline. The shift tables and summaries will be repeated for the safety set 4.
A listing with the Snellen fraction and logMAR score will be provided for all patients with a 
flag for patients who have 0.2 or more increase in the post-baseline logMAR score. 
Slit lamp
For each considered evaluation type and eye, the number of patients with and without
abnormality (normal, insignificant, significant and any) will be provided by treatment arm. In 
addition, a shift table will present any changes in interpretation compared to baseline. A listing 
of patients with any abnormality will be provided.


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Tonometry
The number of patients with clinically relevant post-baseline value of less than or equal to 5 
mmHg and changes from baseline intraocular pressure above 5 mmHg and 10 mmHg will be 
summarized by treatment arm. For patients with such values, a listing will also be provided.
Intraocular pressure will also be summarized in shift tables (baseline and post baseline value
at each time point) for each eye side considering the following categories: ≤5, >5 to ≤21, >21 
to ≤30 and > 30 mmHg.
Fundus oculi
For each eye, the number of patients with and without abnormality (normal, insignificant, 
significant and any) will be provided by treatment arm. In addition, shift table will be done to 
present any changes in interpretation compared to baseline. A listing of patients with any 
abnormality will be provided.
Growth and Development
Growth velocity will be listed at baseline and core EOT visit and summarized using descriptive 
statistics by sex and age group during the core phase for the Safety Set 3. Summaries and listing 
will be repeated for the entire granule period on the Safety Set 4.
The growth velocity in height which evaluates the rate of growth per year will be calculated on 
the difference with the previous measure of height (in cm) and the time period (in days) as: 
Growth velocity (cm / year) =
(with Vx = actual visit ; Vx-1 = previous visit ;  F = 365.25).
Pubertal stage assesses the stage of physical development of sex characteristics. The 
characteristics breast development, pubic hair, testes and penis size are evaluated based on the 
Tanner scale: for each characteristic there are 5 classes (Tanner stage 1 to 5) indicating the level 
of development of that specific characteristic. 
The age will be summarized descriptively at baseline and core EOT visit for the core phase by
sex, characteristic, Tanner stage and treatment arm. For the entire granule period, the same 
summary will be repeated at baseline and at each annual assessment (core phase and extension 
phase displayed separately). 
A listing will be provided including the Tanner stage as well as the individual records for each 
sex characteristic by visit. Patients with delayed puberty will be flagged in the listing. Delayed
puberty in boys is defined as failure to attain Tanner Stage 2 (for both testis and pubic hair) by 
age 14 (Crowley and Pitteloud 2012) and in girls is defined as the failure to attain Tanner Stage 
2 (for both breast development and pubic hair) by age 13, or absence of menarche by age 15 or 
absence of menarche within 5 years of attainment of Tanner Stage 2 (Fenichel 2012).
Other safety data
All data from auditory evaluation, hepatitis testing, and pregnancy test will be listed. 
1
1 *
)
(




x
x
x
x
V
date
V
date
F
V
height
V
height


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Patients with clinically significant abnormal interpretations or abnormal values will be flagged 
as well as positive pregnancy test results.  
Data related to blood transfusion during treatment phase will be listed by treatment arm.
2.9.7
Pharmacokinetics parameters 
2.9.7.1
Pharmacokinetics analyses
The assessment of pharmacokinetic parameters was characterized in the primary CSR and will 
not be repeated for the EoC CSR. For details on this analysis, refer to the primary analysis SAP.
In the EoC CSR, all individual PK concentration data will be listed on the FAS-3.
2.9.7.2
Exploration of PK/PD relationship
The exposure-efficacy relationship was characterized in the primary CSR and will not be 
repeated for the EoC CSR since no additional data was collected for these endpoints after the 
primary CSR data cut-off. For details on this analysis, refer to the primary analysis SAP.
2.10
Sample size
Refer to Section 2.11 of the primary analysis SAP for details. 
2.11
Interim analysis
Refer to Section 2.12 of the primary analysis SAP for details.
3
Change to protocol specified analyses
Table 3-1
Changes to protocol specified analysis or descriptions and rationale
Protocol section
Protocol description
Change
Rationale
10.3
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).
Average daily dose
should be calculated 
excluding dose 
interruptions. (Table 
2-2 in this SAP)
Incorrectly defined in 
the study protocol and 
primary CSR.
10.3
Concomitant medications 
are medications taken 
between the first and last 
day with study 
medication, excluding 
medications start on the 
All concomitant 
medications taken 
between the first 
dose and up to 30 
days after the last 
dose will be 
summarized.
Concomitant 
medications are 
collected up to 30 
days after treatment 
discontinuation as per 
protocol. 


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Protocol section
Protocol description
Change
Rationale
last day of study 
medication.
(Section 2.6 of this 
SAP)
10.6.1.2
Table 10-2 Definition of
notable ranges for vital 
signs and weight
Table 2-5 in this 
SAP
The thresholds for 
clinically notable vital 
signs were incorrectly 
provided for adults in 
the study protocol.
4
Additional details on implementation of statistical 
methodology
The sections below contain additional details on statistical methodology that will be included 
in Appendix 16.1.9 (Documentation of Statistical Methods) of the CSR as well as programing 
rules that will be followed to implement the analyses described in Section 2.
The time windows are used for tables and figures where analysis is performed by timepoint. In 
case of listings, the visit name will be presented as collected in the database.
4.1
Time windows
Only core phase analysis windows will be defined for subjects discontinuing from the core 
phase except for exposure.   
4.1.1
Study drug exposure 
Study drug will be dispensed at randomization (week 1), then every four weeks. Dose 
adjustments based on safety are allowed at any time point during the study.
Information on study drug strength will be collected on the Dose Administration Record (DAR) 
eCRF and includes the planned dose (mg/kg/day), actual total daily dose (mg) taken, reason for 
the dose change, start date and end date.
Table 4-1 shows the defined study periods for drug exposure.
All assessments within a time period will be used to calculate the drug exposure for the 
corresponding period. 
Table 4-1
Study periods for drug exposure
Period
Visit Period Definition
Month 1
Study Day 1 – 28
Month 2
Study Days 29 – 56
Month y** (with y=3, 4, 5,…)
Study Days (y-1)*28+1 to (y)*28
Etc.
*Study Day 1 = first day of study treatment
** For the core phase data analysis: y=1 to k=12 


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4.1.2
Laboratory data and vital signs
Laboratory data (biochemistry, hematology and urinary parameters as well as serum creatinine, 
creatinine clearance and proteinuria) and vital signs will be collected at screening visits, at each 
regularly patient visit and at end of treatment visit.
If two or more assessments are performed within a time window then the assessment closest to 
the planned visit is used in analyses by time window. When two values are equidistant from the 
planned assessment, the later one is used in analyses. When multiple values are reported on the 
same day then the average value is used in analyses. For parameters with categorical results, 
the one from central laboratory is used in analyses.
For worst post-baseline assessment, all on-treatment values are considered regardless of time 
windows.
Table 4-2 shows the defined time windows.


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Table 4-2
Time windows for laboratory data, vital signs, weight and BMI
Time Window
Planned Visit Timing 
Time Window Definition
On treatment
Baseline
On or before Study Day 1*
≤ Study Day 1
Week 2**
Study Day* 8
Study Days 2 – 11 (excluded 
baseline assessment)
Week 3**
Study Day* 15
Study Days 12 – 18
Week 4**
Study Day* 22
Study Days 19 – 25
Week 5 
Study Day* 29
Study Days 26 – 42
Every 4 weeks thereafter 
Week y=5+4*k 
(with k*** = 1, 2, 3, 4, 5, 6, 7, 
8, 9, 10, 11, 12…)
Study Day (5+4*k-1)*7+1 
Study Days 
(5+4*k-1)*7+1-14 to 
(5+4*k-1)*7+1+13
Notes: 
- EOT data visit are included if 
obtained within the next 7* days 
of last non-0 dose intake (*NA for 
patients continuing in extension 
phase).
*Study Day 1 = first day of study treatment
** where appropriate (e.g. week 2 time-window NA for serum ferritin)
*** For the core phase data analysis: k=1 to k=11 with EOT_Core corresponding to week 49 time-
window for subjects who continue into the extension phase. 
4.1.3
Compliance diary
Patients will be asked to fill-out the PRO compliance questionnaire daily from Week 1 Day 1 
visit to end of treatment visit.
Table 4-3 shows the defined week periods for this two PRO questionnaire.
All daily assessments within a week period will be used in analysis by week. 
Table 4-3
Week periods for compliance diaries 
Week Period
Week Period Definition
Week 1 period
Study Day 1 – 7
Week 2 period
Study Days 8 – 14
Week 3 period
Study Days 15 – 21
Week y period (with y=4, 5, 
6,…)
Study Days  (y-1)*7+1 to y*7
Etc.
Study Day 1 = first day of study treatment
4.1.4
Ocular data
Ocular data will be collected at screening visit, at patient visit 11 and at end of treatment visit
during the core phase and annually during the extension phase. If two or more assessments are 


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performed within a time window then the assessment closest to the planned visit is used in 
analyses by time window. When two values are equidistant from the planned assessment, the 
later one is used in analyses. 
For worst post-baseline assessment, all on-treatment values are considered regardless of time 
windows.
Table 4-4 and Table 4-5 shows the defined time windows.
Table 4-4
Time windows for ocular data in core phase
Time Window
Planned Visit Timing 
Time Window Definition
On treatment
Baseline 
On or before Study Day 1*
≤ Study Day 1
Week 25
Study Day 169
Study Days 140 – 197
EOT_Core
NA
-
EOT-core visit are included if 
obtained within the next 14^
days of last non-0 dose intake
(^NA if patients continuing in 
extension phase).
-
Week 49 visit for patients 
continuing into extension
-
For the post-baseline 
assessments, if no data were 
collected at the EOT visit the 
last available post-baseline
data will be used for EOT -
Core. 
*Study Day 1 = first day of study treatment
Table 4-5
Time windows for ocular data in extension phase
Time Window
Planned Visit Timing 
Time Window Definition
On treatment
Baseline 
On or before Study Day 1*
≤ Study Day 1
Week# y=5+4*k 
with (k = 24, 37,…to 89 with
increments of 13)
Study Day (5+4*k-1)*7+1 
Study Days 
(5+4*k-1)*7+1-59 to 
(5+4*k-1)*7+1+58
EOT_Ext
NA
-
EOT-ext visit are included if 
obtained within the next 14^ 
days of last non-0 dose intake 
-
For the post-baseline 
assessments, if no data were 
collected at the EOT visit the 
last available post-baseline 
data will be used for EOT - Ext.
*Study Day 1 = first day of study treatment
# Every 52 weeks starting from Week 101


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4.2
Month/year derivation
For all derivations, a year will be defined as 365.25 days and a month will be calculated as 
(365.25 / 12) = 30.4375 days. If duration is to be reported in months, duration in days will be 
divided by 30.4375.
4.3
Body mass index 
Body mass index, in kg/m2, is a measure of relative weight based on an individual's mass and 
height.
It is calculated using the following formula, where weight is in kilograms and height is in meter:
BMI = Weight / Height2
Baseline BMI will be determined using the last available height and weight prior to start of 
study drug.
4.4
Stratification
In this study, two randomization lists have been developed:

Patients enrolled in the initial protocol will be randomized using a central stratified 
block randomization with the following stratification factor: age group (2 to <10 years 
versus 10 to <18 years).

Patients enrolled after protocol amendment 1 will be randomized using a central 
stratified block randomization with the following stratification factors: age group (2 to 
<10 years versus 10 to <18 years) and prior ICT (Yes versus No).
Therefore, the FAS-1, considering only ICT naïve patients as per IRT, will include patients 
randomized in the following strata: 2 years to <10 years (stratification id=1), 2 to < 10 years + 
PICT No (stratification id=4) and 10 to < 18 years (stratification id=2) 10 to < 18 years + PICT 
No (stratification id=6).
4.5
Efficacy evaluations
4.5.1
Primary endpoint
An ANCOVA will be used for comparison between both treatment groups. PROC GLM 
procedure in SAS will be used for the primary analysis.
For each of the endpoint the following estimates from the ANCOVA will be provided:

the least squares mean with 2-sided 95% confidence interval for each treatment arm

the least squares means with 2-sided 95% confidence interval, p-value for the difference 
between treatment arms
4.6
Safety evaluations
The text below gives more detailed instructions and rules needed for programming of the safety 
analyses described in Section 2.


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4.6.1
Multiple assessments within post-baseline visits
For all analyses regarding abnormal assessments or analyses based on worst post-baseline value 
(e.g. laboratory, ECGs, vital signs), all post-baseline values will be included (scheduled, 
unscheduled, repeat). All unscheduled and repeat measurements will be included in listings.
4.6.2
Baseline
As defined in Section 2.7, for safety evaluations, the last available assessment before or on the 
date of start of study drug is defined as ‘baseline’ value or ‘baseline’ assessment.
4.6.3
Recalculated creatinine clearance
The recalculated creatinine clearance will be calculated using the Schwartz formula (pediatric 
population at baseline). The MDRD derivation will be provided in the derived datasets only for
possible future requests.
In the formulae below, CrCl denotes Creatinine Clearance, SCr denotes Serum Creatinine in 
µmol/L; age in years is calculated from date of birth and date of the relevant blood sample. 
Weight and height are the last available measurements at the time of the relevant blood sample.
Schwartz formula (<18 years of age at beginning of the study), 
CrCl (mL/min)=(k×height)/(SCr×0.01131) with
k = 0.45 for children <1 year based on current age
k = 0.55 for children from 1 to 12 years based on current age
k = 0.55 for girls ≥13 years based on current age
k = 0.70 for boys ≥13 years based on current age
4.7
Handling of missing or partial dates
A date is considered as missing when no information at all is available, i.e. the day, the month 
and the year are missing.
A partial (or incomplete) date is a date for which part of date information is missing, i.e. either 
the day or the day and month are not available. Partial dates, if left partial, would possibly mean 
an event cannot be placed in time, treatment/dosage at the time of the event is unknown and the 
event cannot be reported/summarized appropriately – if at all. Therefore it is important to 
perform date imputation for selected dates to ensure that as many data events are represented 
as correctly as possible.
Date imputation is the creation of a new, complete date from the partial information available 
according to an agreed and acceptable algorithm. 
4.7.1
AE date imputation
Missing and partial date for AE will be handled according to rules specified below. 
There will be no attempt to impute the following:

Completely Missing AE start dates 

AE start dates missing the year.


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
Partial/missing AE end dates
For partial AE start date, the date imputation will be based on the temporal relation between the 
partial date and start of treatment date.
Table 4-6 provides examples of the different considered imputations for AE start date. 
The full description will be provided in the PDS.
Table 4-6
AE start date imputation example scenarios
Partial
AE start date
Treatment
start date
Temporal 
relationship 
compared to 
treatment start 
Imputed Date
12mmyyyy
20OCT2001
Uncertain
<blank>
ddmmm2000
20OCT2001
Before
01JUL2000
ddmmm2002
20OCT2001
After
01JAN2002
ddmmm2001
20OCT2001
Uncertain
21OCT2001
ddSEP2001
20OCT2001
Before
15SEP2001
ddOCT2001
20OCT2001
Uncertain
21OCT2001
ddNOV2001
20OCT2001
After
01NOV2001
4.7.2
Concomitant medication date imputation
The imputation of the start date of concomitant medication will follow the same conventions as 
for AE start date. Partial concomitant medication end dates will not be imputed.
4.7.3
Incomplete date of first/last dose of study drug
The following rule should be used for the imputation of date of last administration:
Scenario 1: If the date of last administration is completely missing and there is no EOT eCRF 
page, the patient is considered as on-going. The patient should be treated as on-going and the 
cut-off date should be used as the last dosing date.
Scenario 2: If the date of last administration is completely or partially missing and the EOT 
eCRF page is available (prior to any death date or withdrawal of consent date, if available): 
Case 1: The date of last administration is completely missing, and the EOT visit date is complete, 
then the EOT date should be used.  
Case 2: Only Year(yyyy) of the dose end date is available and yyyy < the year of EOT date:  
Use Dec31yyyy
Case 3: Only Year(yyyy) of the dose end date is available and yyyy  = the year of EOT date: 
Use EOT date
Case 4: Both Year(yyyy) and Month (mm) are available for the date of last administration, and 
yyyy  = the year of EOT date and 

mm < the month of EOT visit:  


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Use last day of the Month (mm)

mm = the month of EOT visit:  
Use EOT day.
After imputation, compare the imputed date with the start date of that specific record, if the 
imputed date is < start date of that record
Use the start date of that record.
Patients with missing start dates are to be considered missing for all study treatment component 
related calculations and no imputation will be made. If the date of first administration is missing, 
then the date of last administration should not be imputed.
Note: In order to handle partial start dates issue when identifying extension phase treatment 
start date, “record number” and “extension”variables will be used to identify the first DAR 
record in extension phase. More details in PDS.
There will be no attempt to impute any other date from eCRF DAR page.
5
References
Food and Drug Administration. Guidance for Industry. Patient-Reported Outcome Measures: 
Use in Medical Product Development to Support Labeling Claims Establishment and
Operation of Clinical Trial Data Monitoring Committees. December 2009.
Holladay JT 1997. Proper Method for Calculating Average Visual Acuity. Journal of
Refractive surgery;13:388-91.
International Conference on Harmonization. E9: Statistical Principles for Clinical Trials.
Schwartz GJ, Brion LP, Spitzer A (1987) The use of plasma creatinine concentration for 
estimating glomerular filtration rate in infants, children, and adolescents. Pediatr Clin North 
Am; 34(3):571-90.
Tanner JM. Growth at adolescence. Oxford: Blackwell Scientific Publications, 1962.
Crowley WF and Pitteloud N. (2012) Diagnosis and treatment of delayed puberty. 
Fenichel P (2012). Delayed puberty. Endocr Dev, 22, 138-59.


Clinical Development
ICL670/deferasirox/Exjade ®
CICL670F2202 / NCT02435212
A randomized, open-label, multicenter, two arm, phase II study to 
evaluate treatment compliance, efficacy and safety of an improved 
deferasirox formulation (granules) in pediatric patients with iron 
overload
Statistical Analysis Plan (SAP) - Final CSR 
Document type:
SAP Documentation
Document status:
Final
Release date:
21-Feb-2024
Number of pages:
35
Property of Novartis
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis
Template Version 6.0, Effective from 23-Nov-2022


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SAP – Final CSR
Study No. ICL670F2202
Document History – Changes compared to previous final version of SAP
Date
Time 
point
Reason for 
update
Outcome for update
Section and title 
impacted 
(Current)
21-
Feb-
2024
Prior 
to 
DB 
lock
Creation of 
final 
version
N/A - First version (based on SAP 
Amendment 3 (dated 26-Mar-2018) and 
CICL670F2202_SAP_End of Core Phase 
CSR)
NA


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SAP – Final CSR
Study No. ICL670F2202
Table of contents
Table of contents..................................................................................................................3
List of tables.........................................................................................................................4
List of figures.......................................................................................................................5
List of abbreviations ............................................................................................................6
1
Introduction..........................................................................................................................8
1.1
Study design.............................................................................................................8
1.2
Study objectives, endpoints and estimands..............................................................9
2
Statistical methods .............................................................................................................10
2.1
Data analysis general information..........................................................................10
2.1.1
General analysis conventions ................................................................11
2.1.2
Study drug and study treatment.............................................................12
2.1.3
Date of first/last administration of study drug.......................................12
2.1.4
Study day...............................................................................................12
2.1.5
Baseline .................................................................................................12
2.1.6
On-treatment period...............................................................................13
2.2
Analysis sets...........................................................................................................13
2.3
Patient disposition, demographics and other baseline characteristics....................14
2.3.1
Patient disposition .................................................................................14
2.3.2
Demographics and other baseline characteristics..................................15
2.4
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................15
2.4.1
Study treatment......................................................................................15
2.4.2
For each patient, listings of each dose of the study drug 
administered along with dose change reasons will be produced.  
Prior, concomitant and post therapies ...................................................16
2.5
Analysis supporting primary objective(s)..............................................................16
2.6
Analysis supporting secondary objectives.............................................................17
2.7
Safety analyses.......................................................................................................17
2.7.1
Adverse events (AEs)............................................................................17
2.7.2
Deaths....................................................................................................18
2.7.3
Disclosure related analysis ....................................................................18
2.7.4
Laboratory data......................................................................................19
2.7.5
Other safety data....................................................................................21
2.7.6
Ocular evaluations.................................................................................21
2.7.7
Growth and Development......................................................................23


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2.7.8
Other safety data....................................................................................25
2.8
Pharmacokinetic endpoints ....................................................................................26
2.9
PD and PK/PD analyses.........................................................................................26
3
Sample size calculation......................................................................................................26
4
Change to protocol specified analyses...............................................................................26
5
Appendix............................................................................................................................27
5.1
Imputation rules .....................................................................................................27
5.1.1
Study drug .............................................................................................27
5.1.2
AE, concomitant medication, and other safety assessment date 
imputation..............................................................................................28
5.2
Laboratory parameters ...........................................................................................29
5.2.1
Derivations ............................................................................................29
5.2.2
Handling of Special character in Laboratory data.................................29
5.3
Time windows........................................................................................................30
5.3.1
Study drug exposure..............................................................................30
5.3.2
Laboratory data and vital signs..............................................................30
5.3.3
Growth data ...........................................................................................31
5.3.4
Ocular data.............................................................................................32
5.4
Month/year derivation............................................................................................33
5.5
Body mass index....................................................................................................33
5.6
Growth data............................................................................................................33
6
Reference ...........................................................................................................................34
List of tables
Table 1-1
Objectives and related endpoints.............................................................9
Table 2-1
Definition of core and extension phases................................................11
Table 2-2
Deferasirox: Study drug exposure.........................................................15
Table 2-4
Definition of notable/extended ranges for key safety laboratory 
parameters..............................................................................................19
Table 2-2
Standard grades for LOCSIII assessment..............................................23
Table 2-5
Definition of clinically notable abnormalities for vital signs and 
weight values.........................................................................................25
Table 4-1
Changes to protocol specified analysis or descriptions and rationale ...26
Table 5-1
Imputation of start dates (Adverse events, Concomitant 
Medications, etc.) ..................................................................................28
Table 5-2
Imputation of end dates (Concomitant Medications) ............................28


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Table 4-3
Study periods for drug exposure............................................................30
Table 5-4
Time windows for laboratory data, vital signs, weight and BMI..........30
Table 5-5
Time windows for growth data..............................................................31
Table 5-6
Time windows for ocular data in core phase.........................................32
Table 5-7
Time windows for ocular data in extension phase ................................32
List of figures
Figure 2-1
Core and extension phases.....................................................................11


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List of abbreviations
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALT
Alanine aminotransferase/glutamic pyruvic transaminase/GPT
AST
Aspartate aminotransferase/glutamic oxaloacetic transaminase/GOT
ATC
Anatomical Therapeutic Classification
AUC
Area under concentration-time curve
BMI
Body mass index
BP
Blood Pressure
CrCl
Creatinine Clearance
CRF
Case Report/Record Form
CSR
Clinical Study Report 
DAR
Dosage Administration Record
DBP
Diastolic Blood Pressure
DRL
Drug Reference Listing
DT
Dispersible Tablet 
EoC
End of Core Phase
ECG
Electrocardiogram
eCRF
Electronic Case Report Form 
PRO/ObsRO
Patient Reported Outcomes/Observer Reported Outcomes
EOT
End of Treatment
FAS 
Full Analysis Set
FU
Follow Up
GCP
Good Clinical Practice
HLT
High Level Terms
IA
Interim Analysis
ICT
Iron Chelation Therapy
IRT
Interactive Response Technology 
ITT
Intention To Treat
Kg
Kilogram
MDRD
Modification of Diet in Renal Disease 
MedDRA
Medical Dictionary for Regulatory Activities
NA
Not Applicable
NEU
Neutrophils
NMQ
Novartis MedDRA Queries
PAS
Pharmacokinetic Analysis Set
PDS
Programming Datasets Specifications
PK
Pharmacokinetic


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PPS
Per-Protocol Set
PT
Preferred Terms
RBC
Red Blood Cell
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SD
Standard Deviation
SCIT
Satisfaction with Iron Chelation Therapy
SI
International System 
SMQ
Standardized MedDRA Queries
SOC
System Organ Classes
SCr
Serum Creatinine
TBL
Total Bilirubin
TEAE
Treatment Emergent Adverse Event
TFL
Tables Figures Listings
ULN
Upper Limit of Normal
WBC
White Blood Cell
WHO
World Health Organization


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1
Introduction
This document details the planned statistical analysis for the final CSR. The SAP from the 
primary analysis (CSR SAP Amendment 3, dated 26-Mar-2018) and end of core CSR 
(CICL670F2202_SAP_End of Core Phase CSR dated 25-Jun-2021) will be used as a reference 
for this SAP. The SAPs are located at the following CREDI locations:
 
 
Clinical Study Report (CSR) deliverables (tables, figures, listings - TFLs) and further 
programming specifications are described in separate documents namely TFL Shells and 
Programming Datasets Specifications (PDS), respectively. 
An interim and the primary analysis as well as an End of Core Phase (EoC) CSR were already 
performed for this study. 
The data cut-off date for the interim analysis was 16-Nov-2017 and included all randomized 
ICT naïve patients who had completed a minimum of 12 weeks of treatment exposure or 
discontinued from the treatment core phase by the cut-off date. The primary analysis was 
performed when 96 randomized ICT naive patients had completed 24 weeks of treatment or 
discontinued early (data cut-off date: 31-May-2018). All data collected within the core phase 
of the study at the time of the primary data cut-off date were reported in the primary analysis 
CSR. 
The analyses for an EoC CSR requested by the CHMP included the cumulative data from the 
completed core phase and extension phase with a data cut-off date of 18-Jan-2021. This data 
cut-off date allowed the inclusion of all patients who have completed a minimum of 3 years of 
treatment or discontinued from treatment in the core or extension phase. 
Completion of this study as a whole will occur upon the availability and accuracy verification 
of the last data point required for statistical analysis of the optional extension phase. Data 
collection will terminate and End of Study will be declared after all patients have completed the 
treatment phase of the optional extension phase (up to 305 weeks) including the safety follow-
up period (30 days after treatment discontinuation). The final CSR will be based on the core 
and extension phase using the entire granule treatment unless mentioned otherwise. Analyses 
that were presented in the primary CSR or EoC CSR and for which no additional data was 
collected since previous analysis data cut-off date (e.g. baseline demographics) will not be 
repeated for the final analysis. Any analyses already presented in the primary or EoC CSR 
will only be repeated in the final CSR in case of any additional data or data changes.
1.1
Study design
Refer to section 1.1 of CSR SAP Amendment 3.


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1.2
Study objectives, endpoints and estimands 
The study objectives as outlined in the protocol version 6, Section 3 are as follows (Table 1-1). 
Any analyses already presented in the primary or EoC CSR will only be repeated in the 
final CSR in case of any additional data or significant data changes. 
Table 1-1
Objectives and related endpoints
Objective
Endpoint
To be reported in 
final CSR
Primary
•
To evaluate both formulations on 
patient compliance, using stick 
pack/tablet count over 24 weeks of 
treatment in ICT naïve patients 
during core phase
•
To evaluate the change from baseline 
in serum ferritin after 24 weeks of 
treatment for both formulations in 
ICT naïve patients
•
Compliance measured by stick 
pack/tablet count over 24 weeks of 
treatment (i.e. assessed at week 25 
visit)
•
Change from baseline in serum ferritin 
after 24 weeks of treatment (i.e. serum 
ferritin at week 25 visit)
No, as it is already 
presented in 
primary CSR 
Secondary (Core phase) 
To evaluate both formulations on change 
in serum ferritin and compliance in ICT 
naive patients, after 48 weeks of 
treatment
● Compliance measured by stick pack/tablet 
count after 48 weeks of treatment
● Change from baseline in serum ferritin 
after 48 weeks of treatment
No (presented in 
EoC CSR)
To evaluate both formulations on change 
in serum ferritin after 24 weeks and 48 
weeks of treatment in ICT naïve and pre-
treated patients
Change from baseline in serum ferritin after 
24 weeks (i.e. assessed at week 25 visit) 
and 48 weeks of treatment
No (presented in 
EoC CSR)
To evaluate both formulations on patient 
satisfaction and palatability using Patient 
/ Observer Reported Outcomes 
(PRO/ObsRO) questionnaires
Domain scores of treatment satisfaction and 
palatability over time
No (presented in 
EoC CSR, no 
extension data)
To evaluate both formulations on overall 
safety
Overall safety, as measured by frequency 
and severity of adverse events (including 
active monitoring for renal toxicity; including 
renal failure, hepatic toxicity; including 
hepatic failure, and gastrointestinal 
hemorrhage), and changes in laboratory 
values from baseline (serum creatinine, 
creatinine clearance, ALT, AST, RBC and 
WBC). In addition, vital signs, physical, 
ophthalmological, audiometric, cardiac, and 
growth and development evaluations will be 
assessed.
 No (presented in 
EoC CSR except 
for 
Ophthalmological 
assessments 
[LOCSIII and 
Color fundus 
photographs] 
which will be 
presented in this 
CSR) 
To evaluate compliance using a daily 
PRO/ObsRO questionnaire
Rate of dosing instructions deviations (doses 
missed / not taken at the same time every 
day)
No (presented in 
EoC CSR, no 
extension data)
To evaluate pre-dose PK data to support 
the assessment of compliance
Pre-dose deferasirox concentrations in all 
patients [except Egypt] at weeks 1, 3, 5, 9, 
13, 17, 21, 25, 29, 33, 37, 41 and 45 (13 
samples)
No (presented in 
EoC CSR, no 
extension data)


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Objective
Endpoint
To be reported in 
final CSR
Post-dose data to be analyzed along with 
pre-dose PK data 
Post-dose deferasirox concentrations 
between 2 and 4 hours post-dose at Weeks 
5 and 9 (2 samples)
No (presented in 
EoC CSR, no 
extension data)
To explore exposure-response 
relationships for measures of safety and 
effectiveness 
Serum creatinine change from baseline, 
notable serum creatinine events, serum 
creatinine clearance change from baseline 
and notable serum creatinine clearance 
events, urine protein creatinine ratio change 
from baseline and serum ferritin change from 
baseline, in relationship to pre- and post-
dose deferasirox concentrations.
No (presented in 
EoC CSR, no 
extension data)
Secondary (Optional Extension phase) 
To assess additional safety data about 
new formulation (granules) in pediatric 
population 
Overall safety, as measured by frequency 
and severity of adverse events (including 
active monitoring for renal toxicity; including 
renal failure, hepatic toxicity; including 
hepatic failure, and gastrointestinal 
hemorrhage), and changes in laboratory 
values from baseline (serum creatinine, 
creatinine clearance, ALT, AST, RBC and 
WBC). In addition, vital signs, physical, 
ophthalmological, audiometric, and growth 
and development evaluations will be 
assessed. 
Yes
2
Statistical methods
This section describes the analysis of the final CSR based for the entire granule treatment data. 
Refer to the CSR SAP Amendment 3 for additional details. Any analyses already presented 
in the primary or EoC CSR will not be repeated, unless significant data changes impacting 
the primary and secondary analysis results presented in the primary and the EOC CSR, 
respectively, have occurred with the final CSR cut-off.
Section 5 of the SAP provides statistical and programming conventions.
2.1
Data analysis general information
Data will be analyzed by Novartis Oncology Biostatistics and Statistical Programming 
personnel according to the data analysis section 10 of the study protocol as detailed in this 
analysis plan. 
SAS® version 9.4 (or later version if available at time of database lock) will be used for all 
analyses. Data from all patients who signed informed consent and who received granule 
treatment will be used in the analysis. Data collected after patients’ withdrawal of informed 
consent for further participation in the study will not be reported (except for death date which 
might be obtained from public records per local laws).
All statistical analyses will be performed using all data (for patients who received granule 
treatment) collected in the database up to the last patient last visit (LPLV) date. 


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All events with a start date before or on the LPLV date and not having documented end date 
will be reported as ‘ongoing’. This approach applies to adverse event and concomitant 
medication reports. For these events, the end date will not be imputed and therefore will not 
appear in the listings.
The time periods defined in Table 2-1 will be used to define the extension phase for the analysis.
Table 2-1
Definition of core and extension phases
Core phase
Extension phase
Treatment
Start date
Stop date
Treatment 
Start date
Stop date
Granules
Date of first IC 
signed
Date of last treatment 
of granules + 30 days
No 
treatment
Nil
Nil
DT
Date of first IC 
signed
Date of last treatment 
of DT + 30 days
No 
treatment
Nil
Nil
Granules
Date of first IC 
signed
date of first 
administration of 
granules in extension 
phase*– 1 day
Granules
date of first 
administration of 
granules in 
extension 
phase*
Date of the last 
administration of 
Granules in extension 
+ 30 days
DT
Date of first IC 
signed
Date of first 
administration of 
granules* – 1 day
Granules
Date of first 
administration of 
Granules* 
Date of the last 
administration of 
Granules in extension 
+ 30 days
*including 0 doses for patients to identify the extension start date only
Summaries will be based on:
•
Entire granule period - patients randomized to Granules combining core and extension 
phases (dark green rectangle in Figure 2-1) side-by-side with Granules for patients 
randomized to DT who switched to Granules in extension phase (light green rectangle 
in Figure 2-1). Cross-over treatment group corresponds to the patients randomized to 
DT who switched to Granules in the extension phase.
Figure 2-1
Core and extension phases
2.1.1
General analysis conventions
Pooling of centers: Unless specified otherwise, data from all study centers will be pooled for 
the analysis. Due to expected small number of patients enrolled at centers, no center effect will 
be assessed.


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Qualitative/categorical data (e.g., sex, race) will be summarized by frequency counts and 
percentages. Percentages will be calculated using the number of patients in the relevant 
treatment arm as the denominator.  
Continuous data (e.g., age, body weight) will be summarized using appropriate descriptive 
statistics (i.e. mean, standard deviation, median, minimum, and maximum) by treatment arm. 
Lower and upper quartiles will also be presented when applicable.
2.1.2
Study drug and study treatment
The terms study drug and study treatment are equivalent and will refer to deferasirox granule.  
2.1.3
Date of first/last administration of study drug
The date of first administration of study drug is derived as the first date when a non-zero actual 
dose of study drug was administered as recorded on Dosage Administration Record (DAR) 
Electronic Case Report Form (eCRF). The date of first administration of study drug will also 
be referred as ‘start of study treatment’.
The date of last administration of study drug is defined as the last date when a non-zero actual 
dose of study drug was administered as recorded on DAR eCRF. This date will also be referred 
as ‘last date of study treatment’.
2.1.4
Study day
The study day for safety (e.g. adverse event onset, laboratory abnormality occurrence, vital 
sign measurement, Electrocardiogram (ECG), etc.) will be calculated using the start date of 
study treatment as the reference. For assessments occurring 
•
on or after the start date of study treatment, the study day will be calculated as (date of 
safety assessment) – (start date of study treatment) + 1. Study day 1 will therefore be the 
first day of study treatment.
•
before the start date of study treatment, the study day will be calculated as (date of safety 
assessment) – (start date of study treatment). 
For example, if an adverse event starts 3 days before the start of study treatment the study day 
displayed on the listing will be negative, i.e. -3. 
The study day will be displayed in the data listings. 
2.1.5
Baseline
Baseline is considered as the result of an investigation describing the ‘true’ uninfluenced state 
of the patient.
For safety evaluations (e.g. laboratory, vital signs, etc.) the last available (i.e. non-missing) 
assessment before or on the date of start of study treatment is taken as ‘baseline’ value or 
‘baseline’ assessment.
If patients have no value as defined above, the baseline result will be missing. Unscheduled 
assessments will be considered in the determination of baseline.


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For safety assessments, if an assessment is planned to be performed prior to the first dose of 
study drug in the protocol and the assessment is performed on the same day as the first 
administration of study drug, it will be assumed that it was performed prior to study drug 
administration, if assessment time point is not collected or is missing. 
Patients who start treatment and discontinue from the study on the same day may have 2 
different sets of data collected on study Day 1, one being reported to the week 1 visit, the other 
reported to the End Of Treatment (EOT) visit. Data reported at the EOT visit are not eligible 
for baseline selection.
For analyses of the entire granule period requiring comparison to baseline value (e.g. lab shift 
tables, pubertal staging etc.) the baseline is defined as follows. For patients randomized to DT 
formulation who switched to granule formulation in the extension phase, the date of the last 
assessment prior or equal to the start date of granules in the extension phase will be defined as 
pre-granule value which will be reference value for changes in the extension time. For patients 
randomized to granules continuing in extension phase the initial baseline value at study start 
will be taken.
2.1.6
On-treatment period
The overall observation period will be divided into three mutually exclusive segments taking 
into account stop rules as per Table 2-1:
•
Pre-treatment period: from day of patient’s first informed consent to the day before first 
dose of study drug;
•
On-treatment period: from day of first dose of study drug to 30 days after last dose of 
study drug.
•
Post-treatment period: starting at day 30+1 after last dose of study treatment.
For the entire granule period, the following conventions will be taken into account while 
deriving the three observation periods above: 
•
For patients enrolled in DT formulation in the core phase, the pre-treatment period will 
not be derived, and their entire granule period starts from Extension phase start date 
mentioned in Table 2-1
•
For patients enrolled in Granule formulation in the core phase, the first dose of study drug 
will be the day of first dose in the core phase.
2.2
Analysis sets 
The Safety Set 1 will consist of all ICT naïve patients (as per eCRF) who received at least one 
dose of the study drug during the core phase. 
The Safety Set 2 will consist of all ICT pre-treated patients (as per eCRF) who received at least 
one dose of study drug during the core phase. 
The Safety Set 3 will consist of all patients who received at least one dose of study drug during 
the core phase. 
Safety set 1 to 3 will only be used for the analysis of lens photography (LOCSIII) and color 
fundus photography. Safety set 3 is only used for disclosure related analysis, deaths and drug 


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dispension lisitings. Both assessments were only collected since protocol amendment 6 which 
was implemented after the EoC CSR.
All analysis for the final CSR will be based on Safety Set 4.
The Safety Set 4 will consist of all patients who received at least one dose of granule formulation 
during the core or extension phase.
Patients will be analyzed according to the treatment actually received and strata information 
recorded in the eCRF. 
Treatment actually received is defined as the treatment the patient received at the first day of 
study medication in the core phase
Protocol deviations
Frequency counts and percentages of patients with any protocol deviation (selection criteria not 
met, patient not withdrawn as per protocol, treatment deviation, prohibited concomitant 
medication, other Good Clinical Practice (GCP) deviation) will be tabulated by the deviation 
type category and treatment arm on the Safety Set 4 for the entire granule period. Patients with 
COVID-19 related protocol deviations will be presented separately in the table.  
The full list of protocol deviations is documented in the Validation And Planning (VAP) 
Module 3 document. The COVID-related protocol deviations and relationship to pandemic will 
be identified and maintained in an independent tracker located in the document management 
system in the “CREDI Studies/ICL670F2202/TMF (Study Level)/Protocol Deviations” folder. 
The latest available tracker prior to database lock will be used. 
All protocol deviations and COVID related protocol deviations will be listed on Safety Set 4. 
2.3
Patient disposition, demographics and other baseline 
characteristics
2.3.1
Patient disposition
Listings will be produced on the Safety set 4 with a flag for extension phase data. 
The summaries of patient disposition during the extension phase by treatment arm on the Safety 
Set 4 will show:
•
Number (%) of patients who entered in the optional extension phase;
•
Number (%) of patients who were not treated during the optional extension phase;
•
Number (%) of patients who were treated during the optional extension phase;
•
Number (%) of patients who completed the optional extension phase;
•
Number (%) of patients who discontinued the optional extension phase;
•
Number (%) of patients for each reason for optional extension phase discontinuation


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2.3.2
Demographics and other baseline characteristics
All patients’ demographic and baseline characteristics as well as enrollment status by region, 
country, center and treatment arm were analyzed for the primary CSR analysis and will not be 
repeated for the final CSR. 
Demographics, disease characteristics and baseline characteristics will only be generated for 
safety set 4 subjects as defined in the SAP from primary analysis.
2.4
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance)
Safety Set 3 will be used for drug dispension listing.
2.4.1
Study treatment
Listings will be produced by treatment arm on the Safety Set 4. 
Definitions of duration of exposure, total patient-years exposure. average daily dose, 
cumulative total dose as well as percentage of planned dose taken are defined in Table 2-2:
Table 2-2
Deferasirox: Study drug exposure 
Overall duration of exposure (day):
[(date of last exposure) – (date of first study treatment) + 1]
Overall duration of exposure 
(months)
[(date of last exposure) – (date of first study treatment) + 
1]/30.4375
Drug exposure on dose X (days)
[(date of last exposure on dose X) – (date of first study 
treatment on dose X) + 1] 
Total patient-years (years):  
Overall duration of exposure (days) / 365.25 
Average dose (planned and actual, 
in mg/kg/day):
Mean dose over all days between first and last dose, 
excluding interruptions: sum of all (X dose * corresponding 
duration of exposure on dose X) / overall number of dosing 
days
Cumulative dose (planned and 
actual, in mg/kg):
Sum over daily doses of all days between first and last dose 
Percentage of planned dose taken:
100 × [Cumulative actual dose / Cumulative planned dose]
For patients who switch from DT to granules in the extension phase, date of last exposure of 
study drug in core phase refers to the day prior to the date of the first administration of granules 
in extension phase (including a zero actual dose) as defined in Table 2-1. 
For patients who switch from DT to granules, the date of the first administration of study drug 
(granules) refers to the first date of granules in the extension phase (including a zero actual 
dose) to account for treatment interruptions due to efficacy and safety reasons. The last exposure 
of the granules refers to the last date when a non-zero actual dose of granules was administered 
during the study extension phase as defined in Table 2-1. 
For patients receiving granules throughout the study, the date of the first administration and last 
exposure of study drug refer to the first and last dates respectively when a non-zero actual dose 
of study drug (granules) was administered during the study.


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Overall duration of exposure and total patient-years will be summarized by treatment arm for 
the entire granule period. 
The following variables will also be summarized by treatment arm and for each phase as 
appropriate as:  
•
Duration of exposure will be categorized in the entire granule period as: <6 months, 6-<12 
months, 12-<24 months, 24-<36 months, 36-<48 months and so on.
The actual dose in mg/kg/day will be obtained by dividing the actual total daily dose 
administered in the DAR eCRF page by the last available weight at the time of dose 
administration reported in the vital signs eCRF page. Average dose, average dose categories 
(<10.5 mg/kg/day Granule, 10.5-<17.5 mg/kg/day Granule, 17.5-<24.5 mg/kg/day Granule, 
≥24.5 mg/kg/day Granule), cumulative dose and percentage of planned dose taken will only be 
analyzed for patients with complete dates (for all records of the patient) in DAR panel. Patients 
with complete DAR start and end dates for all the records of the treatment within the granule 
formulation will be flagged in the listings.
In addition, the number of patients who have any dose interruptions or dose changes with the 
corresponding reasons will be summarized as collected in the DAR panel.
2.4.2
For each patient, listings of each dose of the study drug administered 
along with dose change reasons will be produced.  Prior, concomitant 
and post therapies
Prior and concomitant therapies are defined as any medication, and significant non-drug 
therapies administered to a subject preceding or coinciding with the study assessment period. 
Medications will be coded using the World Health Organization (WHO) Drug Reference 
Listing (WHO DRL) dictionary that employs the WHO Anatomical Therapeutic Chemical 
(WHO ATC) classification system.
Concomitant therapies will include medications and significant non-drug therapies taken 
between the first day of study medication and up to 30 days after the last day of study medication 
(see Section 2.1.6 for the on-treatment period definitions). 
Concomitant therapies will be summarized by ATC class, preferred term and treatment arm for 
the Safety Set 4. Medications starting prior to the start of study treatment and continuing after 
the start of study treatment will be included in this summary for the entire granule period as 
defined in Table 2-1. 
Prior therapies will include medications or significant non-drug therapies starting and ending 
prior to the start of study treatment. Prior therapies were summarized in the primary CSR 
analysis and will not be repeated for the final CSR.
All concomitant therapies will be listed for Safety Set 4.
2.5
Analysis supporting primary objective(s)
The primary objectives of this study are to evaluate patient compliance with study treatment, as 
measured by the count of deferasirox granule stick packs/dispersible tablets and to evaluate the 


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change in serum ferritin after 24 weeks of treatment for both formulations of deferasirox in 
pediatric ICT naive patients with iron overload during core phase. Cumulative data up to week 
24 from all ICT naive patients was analyzed in the primary CSR as well as EoC CSR (reported 
descriptively) and will not be repeated for final CSR. 
2.6
Analysis supporting secondary objectives 
Secondary variables include compliance after 48 weeks of treatment, changes in SF from 
baseline after 24 weeks in ICT pre-treated patients and after 48 weeks of treatment in ICT-naive 
and pre-treated patients, patient reported outcomes/observer reported outcomes and safety 
assessments (i.e. adverse events, laboratory parameters, vital signs, etc.). All secondary 
variables were analyzed in the EoC CSR and will not be repeated for the final CSR.
2.7
Safety analyses
All analyses will be performed on the Safety Set-4 for the entire granule period. Listings will 
be provided for the Safety Set-4.
Unless otherwise specified, the safety summary tables will include only assessments from the 
on-treatment period. For the definition of on-treatment period, please see section 2.1.6.
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. 
Any COVID-19 related safety events will be flagged in listings.
2.7.1
Adverse events (AEs)
AEs will be coded using the latest version of Medical Dictionary for Regulatory Activities 
(MedDRA) available prior to clinical database lock. 
All aEs will be listed. Any information collected (e.g. regardless to study drug, action taken 
etc.) will be listed as well as the duration of the AE. The listings of all, serious adverse events, 
adverse events leading to study drug discontinuation, and adverse events requiring dose 
adjustment or interruption will also be provided. 
The following adverse event summaries will be produced by treatment arm:
•
Adverse events (overall and severe), regardless of study drug relationship by primary 
system organ class and preferred term 
•
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
•
Serious adverse events (overall and severe), with suspected 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


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•
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
•
An overall summary of type of AEs (e.g. serious, leading to study drug discontinuation, 
requiring dose adjustment or/and interruption) will be presented overall and by severe AEs 
and treatment arm.
Adverse events of special interest / grouping of AEs
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. All AESI definitions 
or AE groupings are specified in the electronic Case Retrieval Strategy (eCRS). The latest 
version of the eCRS available at the time of the analysis will be used.
AESI will be summarized by grouping, preferred term and treatment arm (specifying severity, 
SAE, relationship, leading to treatment discontinuation, leading to dose adjustment/interruption 
and requiring additional therapy).
A listing of all grouping levels down to the MedDRA preferred terms used to define each AESI 
will be generated.
2.7.2
Deaths
Deaths occurring on-treatment (i.e. within 30 days after discontinuation of study drug) as well 
as all deaths will be summarized by primary system organ class and preferred term. All deaths 
will be listed using safety set 3.
2.7.3
Disclosure related analysis
In order to provide a cumulative summary of AEs by treatment arm and by phase (core, 
extension) during the studyfor disclosure, the following arms need to be generated within a 
single XML file based on safety set 3.
•
Deferasirox DT: CORE
•
Deferasirox granules: CORE
•
Deferasirox granules: Extension (including patients who already received granules in the 
core phase)
•
Crossover to Deferasirox granules: Extension (including patients who received DT in core 
phase but crossed over to deferasirox granules during the extension phase)
For the legal requirements of ClinicalTrials.gov and EudraCT, two required tables on on-
treatment adverse events which are not serious adverse events with an incidence greater than 5% 
and on on-treatment serious adverse events and SAE suspected to be related to study treatment 
will be provided by system organ class and preferred term on the safety set population.
If for a same patient, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same SOC and PT:


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•
a single occurrence will be counted if there is  ≤ 1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE
•
more than one occurrence will be counted if there is > 1 day gap between the end date 
of the preceding AE and the start date of the consecutive AE
For occurrence, the presence of at least one SAE / SAE suspected to be related to study 
treatment / non SAE has to be checked in a block e.g., among AE's in a ≤ 1 day gap block, if at 
least one SAE is occurring, then one occurrence is calculated for that SAE.
The number of deaths resulting from SAEs suspected to be related to study treatment and SAEs 
irrespective of study treatment relationship will be provided by SOC and PT.
2.7.4
Laboratory data
2.7.4.1
Serum ferritin
Relative and absolute change from baseline in serum ferritin at every year visit during the 
extension period will be described for the Safety Set 4. A graphical presentation of mean and 
standard deviation of absolute value in serum ferritin during the study will be plotted by 
treatment arm and timepoint for safety set 4. 
2.7.4.2
Other laboratory data
Laboratory data from all sources (central and local laboratories) will be combined. All 
laboratory values will be converted into International System (SI) units. 
Raw values as well as absolute and relative change from baseline values for hematology, 
biochemistry and urinalysis laboratory parameters will be summarized descriptively per time 
window and treatment arm on the Safety Set 4 (see Table 5-4 for time windows definition). 
Shift tables based on normal ranges to compare baseline to the worst post-baseline value will 
be provided by parameter and treatment arm for hematology, biochemistry and urinary 
laboratory data. Same shift table will be provided based on notable/extended ranges for key 
safety laboratory parameters defined in Table 2-4. 
For notable/extended ranges below for each laboratory parameter, all patients satisfying the 
condition will be considered. For the other post-baseline categories, a patient will be counted 
only in the worst category (ie., categories are mutually exclusive).
Table 2-4
Definition of notable/extended ranges for key safety laboratory 
parameters
Laboratory parameters
Criteria for notable/extended 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


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Laboratory parameters
Criteria for notable/extended ranges
Recalculated 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/AST
>5 x ULN and >2 x baseline (extended range >10×ULN and
>2×baseline value)
Recalculated creatinine clearance will be calculated using the Schwartz formula (for pediatric 
population at baseline) described in Section 5.2.1. The Modification of Diet in Renal 
Disease (MDRD) derivation will be provided in the derived datasets only for possible future 
requests. 
A listing of all laboratory values with values flagged to show the corresponding range 
classifications relative to the laboratory reference ranges will be provided by laboratory data 
and treatment arm based on Safety set 4. Assessment day relative to first dose of study drug 
will be included and all laboratory assessments collected outside of the on-treatment period will 
be flagged. 
A listing of patients with laboratory abnormalities based on normal ranges and notable/extended 
ranges will also be provided for Safety set 4.
Normal ranges by laboratory parameter will also be provided in a separate listing. 
Liver Function Parameters
Liver function parameters of interest are total bilirubin (TBL), Alanine aminotransferase (ALT), 
Aspartate aminotransferase (AST) and alkaline phosphatase (ALP). The number (%) of subjects 
with worst post-baseline values as per Novartis Liver Toxicity guidelines will be summarized.
The following summaries will be produced:
•
ALT > 3xULN 
•
ALT > 5xULN
•
ALT > 8xULN
•
ALT > 10xULN
•
ALT > 20xULN
•
AST > 3xULN 
•
AST > 5xULN
•
AST > 8xULN
•
AST > 10xULN
•
AST > 20xULN
•
ALT or AST > 3xULN 
•
ALT or AST > 5xULN
•
ALT or AST > 8xULN
•
ALT or AST > 10xULN
•
ALT or AST > 20xULN
•
TBL > 2xULN


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•
TBL > 3xULN
•
ALT or AST > 3xULN & TBL > 2xULN
•
ALT or AST > 3xULN & TBL > 2xULN & ALP >= 2xULN 
•
ALT or AST > 3xULN & TBL > 2xULN & ALP < 2xULN
2.7.5
Other safety data
2.7.6
Ocular evaluations
The number of patients with available assessment for each type of ocular evaluation and eye 
side will be provided for Safety Set 4 if not otherwise stated. The frequency and percentage of 
subjects with completed ocular assessments will be presented by eye side, evaluation type, 
timepoint, and treatment arm. Additionally, a summary for the number of ocular examinations 
performed at each time point will be presented by treatment arm. Overall interpretation for 
ocular will be listed. 
As color fundus photography and Lens opacification grading (LOCSIII) was only implemented 
with protocol amendment 6 and never reported so far, these analyses will also be provided for 
Safety set 1 to 3. A separate listing for subjects with available images of color fundus 
photography and LOCSIII will be provided.
2.7.6.1
Visual acuity
Visual acuity will be measured using the Snellen visual acuity. This is determined by 
establishing the smallest optotypes that can be identified correctly by the patient at a given 
observation distance. Snellen visual acuity can be reported as a Snellen fraction (m/M) in which 
the numerator (m) indicates the test distance and the denominator (M) indicates the distance at 
which the gap of the equivalent Landolt ring subtends 1 minute of arc. The following formula 
for conversion from Snellen acuity results to the logMAR score (Holladay 1997) will be applied 
and the LogMAR score will be calculated for each timepoint:
logMAR score = –log10(m/M).
The logMAR scores will be categorized as follows: < 0.1, ≥ 0.1 to < 0.2, ≥ 0.2 to < 0.3, ≥ 0.3 
to < 0.6, ≥ 0.6. The following shift tables will be generated using the above categories by 
treatment group:
•
Comparing baseline and increases from baseline in logMAR score category at each 
visit by eye side (right & left)
•
Comparing baseline and decreases from baseline in logMAR score category at each 
visit by eye side (right & left)
Change from baseline (logMAR) = Post Baseline Value (logMAR) – Baseline Value (logMAR) 
In case both values are negative, the absolute values of Post baseline & Baseline records will 
be used for the calculation. 
The number and percentage of subjects with the following change from baseline for logMAR 
categories (< 0.1, ≥ 0.1 to < 0.2, ≥ 0.2 to < 0.3, ≥ 0.3 to < 0.6, ≥ 0.6) will be summarized by 
treatment arm:


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•
the best change (decrease) in logMAR score category from baseline by eye side (right, 
left, best) 
•
the worst change (increase) in logMAR score category from baseline by eye side 
(right, left, worst)
The changes from baseline at each visit will be calculated for assessments done in the same 
correction method as at baseline.
The shift tables and summaries will be produced for the Safety set 4.
A listing with the Snellen fraction, logMAR score abnormalities and change from baseline 
categories will be provided for all subjects.
2.7.6.2
Slit lamp
For each considered evaluation type in the CRF page and eye side, the number & percentage of 
subjects with and without abnormality (normal, insignificant, clinically significant) will be 
provided by timepoint and treatment arm. In addition, for each slit lamp evaluation, shift tables 
will be generated to present the worst post-baseline changes compared to baseline by treatment 
arm and eye side. Further, shift tables will be generated by visit, treatment arm and eye side. A 
listing of patients with any abnormality will be provided. 
2.7.6.3
Tonometry
Descriptive statistics for the intraocular pressure at baseline, at each post-baseline visit and 
changes from baseline at each post-baseline visit will be presented, by eye and treatment arm. 
Box plot for intraocular pressure by eye side and treatment arm will be generated for the overall 
period. 
The number & percentage of subjects with post-baseline values listed below will be summarized 
by treatment arm
•
at least one post-baseline value ≤ 5 mmHg, > 5 to ≤ 21 mmHg, > 21 to ≤ 30 mmHg, 
and > 30mmHg by eye side (right, left, worst)
•
the Increase from baseline IOP ≥ 5mmHg to < 10 mmHg & ≥ 10mmHg by eye side 
(right, left, best) 
•
the Decrease from baseline IOP ≥ 5mmHg to < 10 mmHg & ≥ 10mmHg by eye side 
(right, left, worst)
A listing of patients will also be provided for this assessment. 
Intraocular pressure will also be summarized in shift table (baseline and post baseline value at 
each time point) for each eye side considering the following categories: ≤ 5, >5 to ≤ 21, >21 to 
≤ 30 and > 30 mmHg for each of the treatment arms. 
2.7.6.4
Lens photography
The lens photography was collected for central reading to determine LOCSIII grade. A decimal 
grade using 0.1 unit intervals were assigned to the opacity by the grader. These continuous 
values ranging from 0.1 (clear or colorless) to 5.9 (very opaque for Cortical and Posterior 


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Subcapsular) or 6.9 (very opaque or brunescent for Nuclear Color, Nuclear Opalescence) were 
converted to standard grades using the Table 2-2 (Chylack et al., 1993).
Table 2-2
Standard grades for LOCSIII assessment
Nuclear Color (NC)
Nuclear Opalescence (NO)
Cortical (C)
Posterior Subcapsular (P)
No Opacity is >=0.1 
to <1
No Opacity is >=0.1 to <1
No Opacity 
is >=0.1 to <1
No Opacity is >=0.1 to <1
NC1 is >=1 to <2
NO1 is >=1 to <2
C1 is >=1 to <2
P1 is >=1 to <2
NC2 is >=2 to <3
NO2 is >=2 to <3
C2 is >=2 to <3
P2 is >=2 to <3
NC3 is >=3 to <4
NO3 is >=3 to <4
C3 is >=3 to <4
P3 is >=3 to <4
NC4 is >=4 to <5
NO4 is >=4 to <5
C4 is >=4 to <5
P4 is >=4 to <5
NC5 is >=5 to <6
NO5 is >=5 to <6
C5 is >=5 to <=5.9
P5 is >=5 to <=5.9
NC6 is >=6 to <=6.9
NO6 is >=6 to <=6.9
The worst change in grade compared to baseline for each eye, evaluation type, and treatment 
arm will also be presented using shift tables. For each considered evaluation type and eye side, 
the number & percentage of subjects for image quality will be provided by timepoint and 
treatment arm. A listing of subjects will be provided, additionally, listings for the findings, 
general comments and confidence score comments will be presented for safety set 3. As data 
was not analyzed so far, the analysis will be repeated for safety set 1 to 3.
2.7.6.5
Fundus oculi
For each eye side, the number & percentage of subjects with and without abnormality (normal, 
insignificant, clinically significant) will be provided by timepoint, eye side and treatment arm. 
In addition, shift table will be generated to present the worst post-baseline changes compared 
to baseline by eye side and treatment arm. A listing of subjects with any abnormality will be 
provided. 
2.7.6.6
Color Fundus Photography
The Color Fundus Photography Assessment will be conducted by a central vendor though 
photographs. For each considered evaluation type and eye side, the number & percentage of 
subjects with and without abnormality will be provided by timepoint and treatment arm. For 
each considered evaluation type and eye side, the number & percentage of subjects for image 
quality will be provided by timepoint and treatment arm. A listing of subjects will be provided, 
additionally, listings for the findings, general comments and confidence score comments will 
be presented for safety set 3. As data was not analyzed so far, the analysis will be repeated for 
safety set 1 to 3.
2.7.7
Growth and Development
Growth velocity will be listed at EOT-extension visit and summarized using descriptive 
statistics by sex and age group during the entire granule period for the Safety Set 4. Listing will 
be produced for the entire granule period on the Safety Set 4.
The growth velocity in height which evaluates the rate of growth per year will be calculated on 
the difference with the previous measure of height (in cm) and the time period (in days) as: 


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Growth velocity (cm / year) =
(with Vx = actual visit ; Vx-1 = previous visit ;  F = 365.25).
2.7.7.1
SDS method 
Growth data collected during the study (both core and extension phases) for safety set 4 
subjects will also be summarized descriptively at each relevant time point. These data consist 
of BMI, height, height velocity, weight and weight velocity.
The baseline for this analysis will be the core phase baseline for both DT crossover and granule 
patients.
Height and BMI will be summarized at 6 months intervals, using the standard deviation scores 
(SDS, also called z-score), velocity and velocity SDS. The relevant height and weight values 
for each 6-month period are defined using time windows, as defined in Section 5.3.3. The z-
scores will allow identification of potential outliers.
The formula used to calculate the SDS and height and weight velocities are provided in Section 
5.6.
Note that BMI SDS are reported instead of weight SDS as no reference data for weight are 
provided by the WHO for age beyond 10.
Height/BMI SDS and height/weight velocity SDS will be summarized using descriptive 
statistics (mean, standard deviation, range) for each time window (at Baseline and thereafter 
allowing informal comparison of growth data), as well as by presenting number of patients with 
SDS values lower/higher than 5th/95th percentiles respectively. Box plots will also be plotted for 
each time window. In addition, a shift table to compare baseline SDS to the worst on-treatment 
SDS will be produced for height and BMI SDS. All height/BMI SDS, velocity and velocity 
SDS data will be listed, and values of SDS and velocity SDS outside of the central 95% of 
population values will be flagged as either High (SDS > 1.645) or Low (SDS < -1.645).
2.7.7.2
Pubertal Stage
Pubertal stage assesses the stage of physical development of sex characteristics. The 
characteristics breast development, pubic hair, testes and penis size are evaluated based on the 
Tanner scale: for each characteristic there are 5 classes (Tanner stage 1 to 5) indicating the level 
of development of that specific characteristic. 
The age will be summarized descriptively at baseline and each annual assessment for the entire 
granule period by sex, characteristic, Tanner stage and treatment arm (core phase and extension 
phase displayed separately). 
A listing will be provided including the Tanner stage as well as the individual records for each 
sex characteristic by visit. Patients with delayed puberty will be flagged in the listing. Delayed 
puberty in boys is defined as failure to attain Tanner Stage 2 (for both testis and pubic hair) by 
1
1 *
)
(




x
x
x
x
V
date
V
date
F
V
height
V
height


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age 14 (Crowley and Pitteloud 2012) and in girls is defined as the failure to attain Tanner Stage 
2 (for both breast development and pubic hair) by age 13, or absence of menarche by age 15 or 
absence of menarche within 5 years of attainment of Tanner Stage 2 (Fenichel 2012).
2.7.8
Other safety data
2.7.8.1
Cardiac evaluations
Cardiac evaluations include ECG and echocardiogram. Any abnormalities at baseline were 
analyzed for the primary CSR analysis and will not be repeated for the final CSR. All findings 
of patients with new or worsened abnormalities since baseline will be listed separately for 
Safety Set 4.
2.7.8.2
Vital signs
The following criteria define clinically notable abnormalities for vital signs and weight values:
Table 2-5
Definition of clinically notable abnormalities for vital signs and weight 
values
Parameter1
High 
Increase from baseline ≥ 10%
Weight
Low
Decrease from baseline ≥ 10%
High2
12-18 months    
18-24 months
2-3 years
3-4 years
4-6 years
6-8 years
8-12 years
12-15 years
15-18 years
> 140
> 135
> 128
> 123
> 117
> 111
> 103
> 96
> 92
Pulse rate (beats per minute)
Low2
12-18 months    
18-24 months
2-3 years
3-4 years
4-6 years
6-8 years
8-12 years
12-15 years
15-18 years
< 103
< 98
< 92
< 86
< 81
< 74
< 67
< 62
< 58
1 Systolic and diastolic blood pressure will be listed individually.
2 Fleming S, Thompson M, Stevens R, et al. Normal ranges of heart rate and respiratory rate in children 
from birth to 18 years of age: a systematic review of observational studies. Lancet 2011; published online 
March 15. DOI: 10.1016/S0140-6736(10)62226-X.


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Descriptive statistics will be tabulated per time window and treatment arm using absolute 
change from baseline values for each vital sign measure, weight and BMI (see Table 5-4 for 
time windows definition) separately for Safety Set 4. 
All vital sign assessments, weight and BMI will be listed by treatment arm, patient and 
parameter. In the listings, clinically notable values will also be flagged.
2.7.8.3
Other data
All data from auditory evaluation, hepatitis testing, and pregnancy test will be listed. 
Patients with clinically significant abnormal interpretations or abnormal values will be flagged 
as well as positive pregnancy test results.  
Data related to blood transfusion during treatment phase will be listed by treatment arm. 
2.8
Pharmacokinetic endpoints
The assessment of pharmacokinetic parameters was characterized in the primary CSR and will 
not be repeated for the final CSR. For details on this analysis, refer to the primary analysis SAP.
2.9
PD and PK/PD analyses
The exposure-efficacy relationship was characterized in the primary CSR and will not be 
repeated for the final CSR since no additional data was collected for these endpoints after the 
primary CSR data cut-off. For details on this analysis, refer to the primary analysis SAP. 
3
Sample size calculation
Refer to Section 2.11 of the primary analysis SAP for details 
4
Change to protocol specified analyses
Table 4-1
Changes to protocol specified analysis or descriptions and rationale
Protocol section
Protocol description
Change
Rationale
10.5.4.1
Exposure-adjusted 
adverse event incidence, 
defined as number of 
patients with new or 
worsened AEs during 
period/[total number of 
days patient was on 
treatment summed for all 
patients/365.25 days], 
will be presented
Exposure-adjusted 
AE incidence will 
not be presented
Core phase duration is 
same for both arms 
and hence not 
generated for safety 
set 3 in EoC CSR. 
No comparison 
planned between 
crossover to DFX 
Granule in DT arm 
and DFX Granule arm 
for entire granule 


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period in safety set 4 
irrespective of 
heterogenous follow-
up.
5
Appendix
5.1
Imputation rules
5.1.1
Study drug
The following rule should be used for the imputation of date of last administration:
Scenario 1: If the date of last administration is completely missing and there is no EOT eCRF 
page, the patient is considered as on-going. The patient should be treated as on-going and the 
cut-off date should be used as the last dosing date.
Scenario 2: If the date of last administration is completely or partially missing and the EOT 
eCRF page is available (prior to any death date or withdrawal of consent date, if available): 
Case 1: The date of last administration is completely missing, and the EOT visit date is complete, 
then the EOT date should be used.  
Case 2: Only Year(yyyy) of the dose end date is available and yyyy < the year of EOT date:  
Use Dec31yyyy
Case 3: Only Year(yyyy) of the dose end date is available and yyyy  = the year of EOT date: 
Use EOT date
Case 4: Both Year(yyyy) and Month (mm) are available for the date of last administration, and 
yyyy  = the year of EOT date and 
mm < the month of EOT visit: 
Use last day of the Month (mm)
mm = the month of EOT visit:
Use EOT day.
After imputation, compare the imputed date with the start date of that specific record, if the 
imputed date is < start date of that record 
Use the start date of that record.
Patients with missing start dates are to be considered missing for all study treatment component 
related calculations and no imputation will be made. If the date of first administration is missing, 
then the date of last administration should not be imputed.


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Note: In order to handle partial start dates issue when identifying extension phase treatment 
start date, “record number” and “extension”variables will be used to identify the first DAR 
record in extension phase. More details in PDS.
There will be no attempt to impute any other date from eCRF DAR page.
In the rare cases that there is missing EOT eCRF pages, EOT date will be imputed using the 
last non-zero DAR record.
5.1.2
AE, concomitant medication, and other safety assessment date 
imputation
Every effort will be made to get the missing information on partial dates. However, despite best 
efforts, some partial dates might still exist in the database. They will be listed as is. If needed 
in a calculation (e.g. duration), the standard Novartis Oncology imputation rules will be used. 
Table 5-1
Imputation of start dates (Adverse events, Concomitant Medications, 
etc.)
Missing 
Element
Rule
day, month, 
and year
•
No imputation will be done for completely missing dates
day, month
•
If available year = year of study treatment start date then 
o
If stop date contains a full date and stop date is earlier than 
study treatment start date then set start date = 01JanYYYY 
o
Else set start date = study treatment start date. 
•
If available year > year of study treatment start date then 01JanYYYY
•
If available year < year of study treatment start date then 01JulYYYY
day
•
If available month and year = month and year of study treatment start 
date then 
o
If stop date contains a full date and stop date is earlier than 
study treatment start date then set start date= 01MONYYYY. 
o
Else set start date = study treatment start date.
•
If available month and year > month and year of study treatment start 
date then 01MONYYYY  
•
If available month and year < month year of study treatment start date 
then 15MONYYYY  
Table 5-2
Imputation of end dates (Concomitant Medications) 
Missing 
Element
Rule 
*=last treatment date plus 30 days non > (death date, cut-off date)
day, month, 
and year
•
No imputation will be done for completely missing dates


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Missing 
Element
Rule 
*=last treatment date plus 30 days non > (death date, cut-off date)
day, month
•
If partial end date contains year only, set end date = earliest of 
31DecYYYY or end date of the on-treatment period* 
day
•
If partial end date contains month and year, set end date = earliest of 
last day of the month or end date of the on-treatment period*
Any AEs and ConMeds with partial/missing dates will be displayed as such in the data listings.
Any AEs and ConMeds which are continuing as per data cut-off will be shown as ‘continuing’ 
rather than the end date provided. 
5.2
Laboratory parameters 
5.2.1
Derivations
The recalculated creatinine clearance will be calculated using the Schwartz formula (pediatric 
population at baseline). The MDRD derivation will be provided in the derived datasets only for 
possible future requests.
In the formulae below, CrCl denotes Creatinine Clearance, SCr denotes Serum Creatinine in 
µmol/L; age in years is calculated from date of birth and date of the relevant blood sample. 
Weight and height are the last available measurements at the time of the relevant blood sample.
Schwartz formula (<18 years of age at beginning of the study), 
CrCl (mL/min) = (k × height)/(SCr × 0.01131) with
k = 0.45 for children <1 year based on current age
k = 0.55 for children from 1 to 12 years based on current age
k = 0.55 for girls ≥ 13 years based on current age
k = 0.70 for boys ≥ 13 years based on current age
The following rules will be applied for local lab data to derive the WBC differential counts 
when only percentages are available
Absolute value = (WBC count) * (Value (%) / 100)
The unit of this absolute value will be the unit of WBC count.
5.2.2
Handling of Special character in Laboratory data
If the values (results and ranges) of the laboratory parameters like Hematology, Biochemistry 
and urinalysis are provided as '<X' or '>X' (i.e. below limit of detection either lower or upper 
side), prior to conversion of laboratory values to SI unit, these numeric values are set to X for 
the analysis purposes, after removing the '<'/'>' symbol, when generating the tables and figures 
which are related to above mentioned laboratory parameters e.g., descriptive and shift tables of 
laboratory parameter. However, in case of listing actual values with '<'/'>' symbol will be 
reported.


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5.3
Time windows
5.3.1
Study drug exposure
Study drug will be dispensed at randomization (week 1), then every four weeks. Dose 
adjustments based on safety are allowed at any time point during the study.
Information on study drug strength will be collected on the Dose Administration Record (DAR) 
eCRF and includes the planned dose (mg/kg/day), actual total daily dose (mg) taken, reason for 
the dose change, start date and end date.
Table 4-3 shows the defined study periods for drug exposure.
All assessments within a time period will be used to calculate the drug exposure for the 
corresponding period. 
Table 4-3
Study periods for drug exposure
Period
Visit Period Definition
Month 1
Study Day 1 – 28
Month 2
Study Days 29 – 56
Month y (with y=3, 4, 5,…)
Study Days (y-1)*28+1 to (y)*28
Etc. 
*Study Day 1 = first day of study treatment
5.3.2
Laboratory data and vital signs 
If two or more assessments are performed within a time window then the assessment closest to 
the planned visit is used in analyses by time window. When two values are equidistant from the 
planned assessment, the later one is used in analyses. When multiple values are reported on the 
same day then the average value is used in analyses. For parameters with categorical results, 
the one from central laboratory is used in analyses. If multiple values are reported on the same 
day from local and central laboratory, the central laboratory value is used in analyses. If only 
local lab assessments are collected, then local lab values are considered for analyses.
For worst post-baseline assessment, all on-treatment values are considered regardless of time 
windows. 
Table 5-4 shows the defined time windows.
Table 5-4
Time windows for laboratory data, vital signs, weight and BMI 
Time Window
Planned Visit Timing 
Time Window Definition
On treatment
Baseline 
On or before Study Day 1*
≤ Study Day 1


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Time Window
Planned Visit Timing 
Time Window Definition
On treatment
Week 2** 
Study Day* 8
Study Days 2 – 11 (excluded 
baseline assessment)
Week 3** 
Study Day* 15
Study Days 12 – 18
Week 4** 
Study Day* 22
Study Days 19 – 25
Week 5 
Study Day* 29
Study Days 26 – 42
Every 4 weeks thereafter 
Week y=5+4*k 
(with k = 1, 2, 3, 4, 5, 6, 7, 8, 
9, 10, 11, 12…)
Study Day (5+4*k-1)*7+1 
Study Days 
(5+4*k-1)*7+1-14 to 
(5+4*k-1)*7+1+13
Notes: 
- EOT data visit are included if 
obtained within the next 7* days 
of last non-0 dose intake (*NA for 
patients continuing in extension 
phase).
* Study Day 1 = first day of study treatment
** where appropriate (e.g. week 2 time-window NA for serum ferritin)
5.3.3
Growth data
Table 5-5 summarizes the time windows for growth data, where windows are centered at every 
6 months after start of deferasirox. If there is more than one assessment within the time window, 
the last available assessment in that time window will be used. Although height and weight 
could be collected more frequently than every 6 months, this choice of time window length was 
made to reflect the degree of accuracy in the reference values (every 6 months) that will be used 
in the calculation of summary variables of growth (Section 2.7.7).
Table 5-5
Time windows for growth data
Assessment
Time window
Baseline
Treatment Days up to 1
Month 6 
Treatment Days 85 – 252 
Month 12
Treatment Days 253 – 420 
Month 18
Treatment Days 421 – 588 
Month 24
Treatment Days 589 – 756 
Month 30
Treatment Days 757 – 924 
Month 36
Treatment Days 924 – 1092 
Month 42
Treatment Days 1093 – 1260 
Month 48
Treatment Days 1261 – 1428
Month 54
Treatment Days 1429 – 1596 
Month 60
Treatment Days 1597 – 1764
etc.
Treatment Day 1 = date of first intake of deferasirox


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5.3.4
Ocular data 
Ocular data will be collected at screening visit, at patient visit 11 and at end of treatment visit 
during the core phase and annually during the extension phase. If two or more assessments are 
performed within a time window then the assessment closest to the planned visit is used in 
analyses by time window. When two values are equidistant from the planned assessment, the 
later one is used in analyses. 
For worst post-baseline assessment, all on-treatment values are considered regardless of time 
windows. 
Table 5-6 and Table 5-7 show the defined time windows.
Table 5-6
Time windows for ocular data in core phase 
Time Window
Planned Visit Timing 
Time Window Definition
On treatment
Baseline 
On or before Study Day 1*
≤ Study Day 1
Week 25 
Study Day 169
Study Days 140 – 197 
EOT_Core 
NA
-
EOT-core visit are included if 
obtained within the next 14^ 
days of last non-0 dose intake 
(^NA if patients continuing in 
extension phase).
-
Week 49 visit for patients 
continuing into extension
-
For the post-baseline 
assessments, if no data were 
collected at the EOT visit the 
last available post-baseline 
data on or before the last non-
zero dose will be used for EOT 
- Core. 
*Study Day 1 = first day of study treatment
Table 5-7
Time windows for ocular data in extension phase
Time Window
Planned Visit Timing 
Time Window Definition
On treatment
Baseline 
On or before Study Day 1*
≤ Study Day 1


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Time Window
Planned Visit Timing 
Time Window Definition
On treatment
Week# y=5+4*k 
with (k = 24, 37,…to 89 with 
increments of 13) 
Study Day (5+4*k-1)*7+1 
Study Days 
(5+4*k-1)*7+1-59 to 
(5+4*k-1)*7+1+58
EOT_Ext 
NA
-
EOT-ext visit are included if 
obtained within the next 14 
days of last non-0 dose intake 
-
For the post-baseline 
assessments, if no data were 
collected at the EOT visit the 
last available post-baseline 
data on or before the last non-
zero dose will be used for EOT 
- Ext.
*Study Day 1 = first day of study treatment
# Every 52 weeks starting from Week 101
5.4
Month/year derivation
For all derivations, a year will be defined as 365.25 days and a month will be calculated as 
(365.25 / 12) = 30.4375 days. If duration is to be reported in months, duration in days will be 
divided by 30.4375.
5.5
Body mass index 
Body mass index, in kg/m2, is a measure of relative weight based on an individual's mass and 
height.
It is calculated using the following formula, where weight is in kilograms and height is in meter:
BMI = Weight / Height2
Baseline BMI will be determined using the last available height and weight prior to start of 
study drug.
5.6
Growth data
SDS will be calculated using the current formulae provided by the WHO as follows:
1. Calculate zind = 
2. If | zind | ≤ 3, SDS = zind
If zind > 3,
SDS = 3 + (X – SD3pos) / SD23pos
If zind < -3,
SDS = -3 + (X – SD3neg) / SD23neg
where:
•
X is height in centimeters or BMI in kilograms/m2,
•
L, M and S are height or BMI-, sex- and age-specific reference values from the WHO 
Growth Charts.


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•
SD3pos is the cutoff 3SD calculated by the LMS method:
SD3pos = M * (1 + LS*3)1/L
•
SD3neg is the cutoff -3SD calculated by the LMS method:
SD3neg = M * (1 + LS*(-3))1/L
•
SD23pos if the difference between the cutoffs 3SD and 2SD:
SD23pos = M * (1 + LS*3)1/L - M * (1 + LS*2)1/L
•
SD23neg if the difference between the cutoffs -2SD and -3SD:
SD23neg = M * (1 + LS*(-2))1/L - M * (1 + LS*(-3))1/L
Height-for-age and BMI-for-age L, M and S reference values for males and females are 
available under http://www.who.int/childgrowth/standards/en/ (for patients aged between 0 to 
5 years old) and http://www.who.int/growthref/en/ (for patients aged between 5 to 19 years old). 
These correspond to the latest available international references available at this time and 
described in the 2007 Bulletin of the World Health Organization (Mercedes de Onis et al 2007). 
The age category immediately above the patient’s exact age should be used. SDS is actually a 
Z score that measures the distance from the population mean in units of standard deviations. 
That is, SDS < 0 refers to values lower than the population mean, and for example SDS ≤ -
1.645 refers to values in the lowest 5%. (The usual percentile more commonly used in the 
clinical practice can be derived from the z-score by a normal distribution).
Note that BMI is reported instead of weight as no reference data are provided by the WHO for 
age beyond 10.
Height velocity is defined as follows:
Height velocity (cm/6-months) = (height in time window k – height in time window k-1) ÷ 
([assessment date in time window k – assessment date in time window k-1] x [365.25/2]), 
and similarly for weight velocity. 
Velocity SDS is calculated as (velocity – mean) / SD, where mean and SD are obtained as the 
height-, weight-, sex- and age-specific values (Baumgartner et al 1986)), where the age category 
immediately above the patient’s exact age (at the assessment date in time window k) should be 
used. Velocity SDS will only be calculated for time window k if data also exists for time window 
k-1, since calculating across multiple units of 6 months requires more than one reference value 
to be taken into account. 
6
Reference
Baumgartner RN, Roche AF, Himes (1986). Incremental growth tables: supplementary to 
previously published charts. American Journal of Clinical Nutrition, 43, 711-22.
Chylack, L.T., JK Wolfe, DM Singer, MC Leske, MA Bullimore, IL Bailey, J Friend, D McCarthy, 
and SY Wu. “The Lens Opacities Classification System III. The Longitudinal Study of Cataract 
Study Group”. Arch Ophthalmol. (1993) 111(6):831-6.
Crowley WF and Pitteloud N. (2012) Diagnosis and treatment of delayed puberty. 
Fenichel P (2012). Delayed puberty. Endocr Dev, 22, 138-59.


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Food and Drug Administration. Guidance for Industry. Patient-Reported Outcome Measures: 
Use in Medical Product Development to Support Labeling Claims Establishment and 
Operation of Clinical Trial Data Monitoring Committees. December 2009.
Holladay JT 1997. Proper Method for Calculating Average Visual Acuity. Journal of 
Refractive surgery;13:388-91.
International Conference on Harmonization. E9: Statistical Principles for Clinical Trials.
De Onis M, Adelheid WO, Borghi E, et al (2007). Development of a WHO growth reference 
for school-aged children and adolescents.  Bull World Health Organ;85(9):660-7.
Schwartz GJ, Brion LP, Spitzer A (1987) The use of plasma creatinine concentration for 
estimating glomerular filtration rate in infants, children, and adolescents. Pediatr Clin North 
Am; 34(3):571-90.
Tanner JM. Growth at adolescence. Oxford: Blackwell Scientific Publications, 1962.
Fenichel P (2012). Delayed puberty. Endocr Dev, 22, 138-59.