Clinical trial NCT03372083
Conditions: Iron Overload
Keywords: Iron Chelation Therapy Deferasirox Asunra Jadenu Exjade ICL 670 Pediatric
Sponsor: Novartis Pharmaceuticals
Start date: 2018-01-16; Completion date: 2019-12-05
Enrollment: 44 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study employed a prospective, single-arm, global multi-center interventional open-label, non-randomized design to identify and assess safety profile of the crushed deferasirox FCT when administered up to 24 weeks in pediatric patients aged ≥2 to \<6 years with transfusional hemosiderosis. The study was designed to enroll a minimum of 40 patients. Forty-four patients were treated and analyzed.

Detailed description:
The study included a screening period (from Day 0-14) with two visits at least 7 days apart to assess eligibility of patients that were chelation naïve or on a prior iron chelator treatment other than DFX. For Patients on DFX treatment prior to study entry only one screening visit (screening visit 1) were to occur to determine eligibility. Any current chelation therapy except deferasirox were to be discontinued to undergo a 5-day washout period prior to commencing a 24 week treatment period with crushed deferasirox FCT.

All patients were to have weekly visits for the first month to monitor renal function. Hepatic function were to be assessed biweekly during the first month. Thereafter, monthly safety assessments were to be performed, including the monitoring of serum ferritin values and trends in order to adapt patient treatment.

Eligibility, application of dosing standards and adjustments, as well as safety and serum ferritin assessments as specified in the protocol.

The planned duration of treatment was 24 weeks followed by a 30-day safety follow up.

Arms: arm 1: Crushed deferasirox (ICL670) FCT for oral use daily. Deferasirox FCT dosing was based on subject's weight.
Interventions: intervention 1: Deferasirox
Intervention descriptions: intervention 1: Deferosirox was provided in tablet forms of 90, 180 and 360mg. Tablets were crushed in the home environment and administered by sprinkling the full dose on to soft food to be consumed immediately.

Protocol documents:
Prot_000.pdf: 
Clinical Development 
Deferasirox FCT (ICL670) 
Oncology Clinical Protocol CICL670F2429 / NCT03372083
A single-arm interventional Phase IV, post-authorisation 
study evaluating the safety of pediatric patients with 
transfusional hemosiderosis treated with deferasirox 
crushed film coated tablets 
Authors 
 
Document type 
Amendment Protocol Version 
EUDRACT number 
2016-003482-25 
Version number 
01 Amended Protocol (Clean) 
Development phase 
IV 
Document status 
Final 
Release date 
25-Apr-2018
Property of Novartis 
Confidential 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 
Template version 15-Jan-2017 


Novartis 
Amended Protocol Version No. 01 (Clean) 
Confidential 
Page 20 
Protocol No. CICL670F2429 
 
 
Table of contents 
Table of contents ................................................................................................................. 2 
List of tables ........................................................................................................................ 6 
List of abbreviations ............................................................................................................ 7 
Glossary of terms ............................................................................................................... 10 
Amendment 1 (25-Apr-2018) ............................................................................................ 11 
Protocol summary .............................................................................................................. 15 
1 
Background ........................................................................................................................ 18 
1.1 
Overview of disease pathogenesis, epidemiology and current treatment .............. 18 
1.2 
Introduction to investigational treatment(s) and other study treatment(s) ............. 18 
1.2.1 
Overview of deferasirox film-coated tablet (FCT)................................ 19 
2 
Rationale ............................................................................................................................ 22 
2.1 
Study rationale and purpose ................................................................................... 22 
2.2 
Rationale for the study design ............................................................................... 22 
2.3 
Rationale for dose and regimen selection .............................................................. 23 
2.4 
Rationale for choice of combination drugs ............................................................ 23 
2.5 
Rationale for choice of comparators drugs ............................................................ 23 
2.6 
Risks and benefits .................................................................................................. 23 
3 
Objectives and endpoints ................................................................................................... 24 
4 
Study design ...................................................................................................................... 26 
4.1 
Description of study design ................................................................................... 26 
4.2 
Timing of interim analyses and design adaptations ............................................... 26 
4.3 
Definition of end of study ...................................................................................... 26 
4.4 
Early study termination .......................................................................................... 27 
5 
Population .......................................................................................................................... 27 
5.1 
Patient population .................................................................................................. 27 
5.2 
Inclusion criteria .................................................................................................... 27 
5.3 
Exclusion criteria ................................................................................................... 27 
6 
Treatment ........................................................................................................................... 28 
6.1 
Study treatment ...................................................................................................... 28 
6.1.1 
Dosing regimen ..................................................................................... 30 
6.1.2 
Ancillary treatments .............................................................................. 31 
6.1.3 
Rescue medication ................................................................................ 31 
6.1.4 
Guidelines for continuation of treatment .............................................. 31 
6.1.5 
Treatment duration ................................................................................ 31 
6.2 
Dose escalation guidelines ..................................................................................... 32 


Novartis 
Amended Protocol Version No. 01 (Clean) 
Confidential 
Page 30 
Protocol No. CICL670F2429 
 
6.2.1 
Starting dose rationale ........................................................................... 32 
6.2.2 
Provisional dose levels .......................................................................... 32 
6.2.3 
Definitions of dose limiting toxicities (DLTs) ...................................... 32 
6.3 
Dose modifications ................................................................................................ 32 
6.3.1 
Dose modification and dose delay ........................................................ 32 
6.3.2 
Dose adjustments for QTcF prolongation ............................................. 41 
6.3.3 
Follow-up for toxicities ......................................................................... 42 
6.3.4 
Anticipated risks and safety concerns of the study drug ....................... 43 
6.4 
Concomitant medications ...................................................................................... 43 
6.4.1 
Blood transfusion .................................................................................. 43 
6.4.2 
Permitted concomitant therapy requiring caution and/or action ........... 43 
6.4.3 
Prohibited concomitant therapy ............................................................ 44 
6.4.4 
Use of Bisphosphonates (or other concomitant agents) ........................ 44 
6.5 
Patient numbering, treatment assignment or randomization ................................. 44 
6.5.1 
Patient numbering ................................................................................. 44 
6.5.2 
Treatment assignment or randomization ............................................... 44 
6.5.3 
Treatment blinding ................................................................................ 44 
6.6 
Study drug preparation and dispensation ............................................................... 44 
6.6.1 
Study treatment packaging and labeling ............................................... 45 
6.6.2 
Drug supply and storage ........................................................................ 46 
6.6.3 
Study drug compliance and accountability ........................................... 46 
6.6.4 
Disposal and destruction ....................................................................... 47 
7 
Visit schedule and assessments ......................................................................................... 47 
7.1 
Study flow and visit schedule ................................................................................ 47 
7.1.1 
Molecular pre-screening ........................................................................ 51 
7.1.2 
Screening ............................................................................................... 51 
7.1.3 
Run-in period......................................................................................... 52 
7.1.4 
Treatment period ................................................................................... 52 
7.1.5 
Discontinuation of study treatment ....................................................... 52 
7.1.6 
Withdrawal of consent .......................................................................... 53 
7.1.7 
Follow up for safety evaluations ........................................................... 53 
7.1.8 
Lost to follow-up ................................................................................... 54 
7.1.9 
Unscheduled visits................................................................................. 54 
7.2 
Assessment types ................................................................................................... 54 
7.2.1 
Efficacy assessments ............................................................................. 54 
7.2.2 
Safety and tolerability assessments ....................................................... 54 


Novartis 
Amended Protocol Version No. 01 (Clean) 
Confidential 
Page 40 
Protocol No. CICL670F2429 
 
7.2.3 
Limitations of the study ........................................................................ 58 
7.2.4 
Pharmacokinetics .................................................................................. 58 
7.2.5 
Biomarkers ............................................................................................ 58 
7.2.6 
Other assessments ................................................................................. 59 
7.2.7 
Resource utilization ............................................................................... 59 
7.2.8 
Patient reported outcomes ..................................................................... 59 
8 
Safety monitoring and reporting ........................................................................................ 59 
8.1 
Adverse events ....................................................................................................... 59 
8.1.1 
Definitions and reporting ...................................................................... 59 
8.1.2 
Laboratory test abnormalities ................................................................ 60 
8.1.3 
Adverse events of special interest ......................................................... 61 
8.2 
Serious adverse events ........................................................................................... 61 
8.2.1 
Definitions ............................................................................................. 61 
8.2.2 
Reporting ............................................................................................... 62 
8.3 
Emergency unblinding of treatment assignment ................................................... 62 
8.4 
Pregnancies ............................................................................................................ 62 
8.5 
Warnings and precautions ...................................................................................... 63 
8.6 
Data Monitoring Committee .................................................................................. 63 
8.7 
Steering Committee ............................................................................................... 63 
9 
Data collection and management ....................................................................................... 63 
9.1 
Data confidentiality ............................................................................................... 63 
9.2 
Site monitoring ...................................................................................................... 64 
9.3 
Data collection ....................................................................................................... 64 
9.4 
Database management and quality control ............................................................ 64 
10 Statistical methods and data analysis ................................................................................. 65 
10.1 
Analysis sets .......................................................................................................... 65 
10.1.1 
Full Analysis Set ................................................................................... 65 
10.1.2 
Safety set ............................................................................................... 65 
10.1.3 
Per-Protocol set ..................................................................................... 65 
10.1.4 
Dose-determining analysis set ............................................................... 65 
10.1.5 
Pharmacokinetic analysis set ................................................................. 65 
10.1.6 
Other analysis sets ................................................................................. 65 
10.2 
Patient demographics/other baseline characteristics .............................................. 66 
10.3 
Treatments (study treatment, concomitant therapies, compliance) ....................... 66 
10.4 
Primary objective ................................................................................................... 66 
10.4.1 
Variable ................................................................................................. 66 


Novartis 
Amended Protocol Version No. 01 (Clean) 
Confidential 
Page 50 
Protocol No. CICL670F2429 
 
10.4.2 
Statistical hypothesis, model, and method of analysis .......................... 66 
10.4.3 
Handling of missing values/censoring/discontinuations ....................... 67 
10.4.4 
Supportive and Sensitivity analyses ...................................................... 67 
10.5 
Secondary objectives ............................................................................................. 67 
10.5.1 
Key secondary objective(s) ................................................................... 67 
10.5.2 
Other secondary efficacy objectives ..................................................... 67 
10.5.3 
Safety objectives ................................................................................... 67 
10.5.4 
Pharmacokinetics .................................................................................. 69 
10.5.5 
Biomarkers ............................................................................................ 69 
10.5.6 
Resource utilization ............................................................................... 69 
10.5.7 
Patient-reported outcomes ..................................................................... 69 
10.6 
Exploratory objectives ........................................................................................... 70 
10.7 
Interim analysis ...................................................................................................... 70 
10.7.1 
Progression free survival (PFS)............................................................. 70 
10.7.2 
Key secondary endpoint: Overall survival (OS) ................................... 70 
10.8 
Sample size calculation .......................................................................................... 71 
11 Ethical considerations and administrative procedures ...................................................... 71 
11.1 
Regulatory and ethical compliance ........................................................................ 71 
11.2 
Responsibilities of the investigator and IRB/IEC/REB ......................................... 71 
11.3 
Informed consent procedures ................................................................................. 71 
11.4 
Discontinuation of the study .................................................................................. 72 
11.5 
Publication of study protocol and results ............................................................... 72 
11.6 
Study documentation, record keeping and retention of documents ....................... 73 
11.7 
Confidentiality of study documents and patient records ....................................... 73 
11.8 
Audits and inspections ........................................................................................... 74 
11.9 
Financial disclosures .............................................................................................. 74 
12 Protocol adherence ............................................................................................................ 74 
12.1 
Amendments to the protocol .................................................................................. 74 
13 References (available upon request) .................................................................................. 75 
14 Appendices ........................................................................................................................ 76 
14.1 
mSICT (Modified Satisfaction with Iron Chelation Therapy) - crushed FCT........... 76 
14.2 
Palatability (taste and ability to consume medicine) Questionnaire ....................... 81 
14.3 
GI Symptom Questionnaire ................................................................................... 82 
14.4 
Deferasirox FCT Weight Dose Table ..................................................................... 84 
14.5 
Examples of light meals with soft foods ................................................................ 85 


Novartis 
Amended Protocol Version No. 01 (Clean) 
Confidential 
Page 60 
Protocol No. CICL670F2429 
 
 
List of tables 
Table 3-1 
Objectives and related endpoints ........................................................... 25 
Table 6-1 
Deferasirox FCT Weight Dosing Table ................................................ 29 
Table 6-2 
Equivalent dose of deferasirox FCT...................................................... 30 
Table 6-3 
Dose and treatment schedule ................................................................. 30 
Table 6-4 
Criteria for dose reduction / interruption and re-initiation of 
deferasirox treatment for adverse drug reactions .................................. 37 
Table 6-5 
Preparation and dispensing .................................................................... 45 
Table 6-6 
Packaging and labeling .......................................................................... 46 
Table 6-7 
Supply and storage of study treatments ................................................. 46 
Table 7-1 
Visit evaluation schedule ...................................................................... 48 
Table 7-2 
Local Clinical laboratory parameters collection plan ........................... 55 
Table 10-1 
Clopper-Pearson 95% CI for different incidence of AEs and the 
corresponding probability to observe at least one AE ............................. 71 
Table 14-1 
Examples of light meals with soft foods ............................................... 85 


Novartis 
Amended Protocol Version No. 01 (Clean) 
Confidential 
Page 70 
Protocol No. CICL670F2429 
 
 
List of abbreviations 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase/glutamic pyruvic transaminase/GPT 
AST 
Aspartate aminotransferase/glutamic oxaloacetic transaminase/GOT 
ATC 
Anatomical Therapeutic Classification 
CHMP 
Committee for Medicinal Products for Human Use 
CI 
Confidence interval 
cm 
Centimeters 
CMO&PS 
Chief Medical Office and Patient Safety 
CMV 
Cytomegalovirus 
CrCl 
Creatinine clearance 
CRF 
Case Report/Record Form; the term CRF can be applied to either EDC or Paper 
CRO 
Contract Research Organization 
CSR 
Clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DFP 
Deferiprone 
DFO 
Deferoxamine 
DFX 
Deferasirox 
DILI 
Drug-induced liver injury 
DRESS 
Drug reaction with eosinophilia and systemic symptoms 
DT 
Dispersible tablet 
EBV 
Epstein-Barr virus 
EC 
European Commission 
ECG 
Electrocardiogram 
EDC 
Electronic data capture 
ELISA 
Enzyme linked immunosorbent assay 
EM 
Erythema multiforme 
EMA 
European Medicines Agency 
EoT 
End of study treatment 
EU 
European Union 
FAS 
Full Analysis Set 
FCT 
Film-coated tablet 
FDA 
Food & Drug Administration 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transferase 
GI 
Gastrointestinal 
HBsAb 
Hepatitis B surface antibodies 
HBsAg 
Hepatitis B surface antigen 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
HSV 
Herpes simplex virus 
IB 
Investigators brochure 
IBD 
Development International Birth Date 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 


Novartis 
Amended Protocol Version No. 01 (Clean) 
Confidential 
Page 80 
Protocol No. CICL670F2429 
 
 
ICMJE 
International Committee of Medical Journal Editors 
ICT 
Iron chelation therapy 
IEC 
Independent Ethics Committee 
IN 
Investigator notification 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
IPSS-R 
Revised International Prognostic Scoring System 
IRT 
Interactive Response Technology 
L 
Liter 
LFT 
Liver function tests 
LIC 
Liver iron concentration 
LLN 
Lower limit of normal 
LPLV 
Last patient last visit 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular volume 
MDS 
Myelodysplastic Syndrome 
MedRA 
Medical dictionary for regulatory activities 
mg 
Milligrams 
mL 
Milliliters 
MRI 
Magnetic resonance imaging 
MRI T*2 
Magnetic resonance T*2 imaging 
mSICT 
Modified Satisfaction with Iron Chelation Therapy 
MUGA 
Multiple gated acquisition 
ng 
Nanogram 
ObsRO 
Observer reported outcomes 
o.d. 
omnia die/once a day 
PASS 
Post-Authorization Safety Study 
PCR 
Polymerase chain reaction 
PHI 
Protected Health Information 
PK 
Pharmacokinetic 
p.o. 
Per os/by mouth/orally 
PRAC 
Pharmacovigilance Risk Assessment Committee 
PRO 
Patient reported outcomes 
PT 
Prothrombin time 
PTY 
Patient-years 
q.d. 
Once daily 
RBC 
Red blood cells 
REB 
Research Ethics Board 
RNA 
Ribonucleic acid 
R Value 
ALT/ALP in x ULN 
SAE 
Serious Adverse Event 
SAP 
Statistical analysis plan 
SCr 
Serum creatinine 
SF 
Serum ferritin 
SI 
International system of units 
SJS 
Stevens-Johnson Syndrome 


Novartis 
Amended Protocol Version No. 01 (Clean) 
Confidential 
Page 90 
Protocol No. CICL670F2429 
 
 
SOC 
System organ class 
SOP 
Standard Operating Procedure 
SUSAR 
Suspected unexpected serious adverse reaction 
TBIL 
Total bilirubin 
TDT 
Transfusion dependent thalassemia 
TEAE 
Treatment-emergent adverse events 
TEN 
Toxic epidermal necrolysis 
UGT 
UDP glucuronosyltransferase 
UK 
United Kingdom 
ULN 
Upper limit of normal 
UPCR 
Urine protein/creatinine ratio 
WBC 
White blood cell 
WHO 
World Health Organization 


Novartis 
Amended Protocol Version No. 01 (Clean) 
Confidential 
Page 10
0 Protocol No. 
 
 
Glossary of terms 
Assessment 
A procedure used to generate data required by the study 
Baseline 
The first visit on study following the screening period 
Biologic Samples 
A biological specimen including, for example, blood (plasma, serum), saliva, 
tissue, urine, stool, etc. taken from a study subject or study patient 
Dose level 
The dose of drug given to the patient (total daily or weekly etc.) 
End of study treatment (EoT) 
The visit at which patients will have permanently discontinued study 
treatment 
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 
Screening 
An assessment that determines study eligibility against defined inclusion 
and exclusion criteria 
Stop study participation 
Point/time at which the patient came in for a final evaluation visit or when 
study treatment was discontinued whichever is later 
Study treatment 
Includes any drug or combination of drugs in any study arm administered to 
the patient (subject) as part of the required study procedures, including 
placebo and active drug run-ins. 
In specific examples, it is important to judge investigational treatment 
component relationship relative to a study treatment combination; study 
treatment in this case refers to the investigational and non-investigational 
treatments in combination. 
Study treatment discontinuation 
Point/time when patient permanently stops taking study treatment for any 
reason 
Subject Number 
(Subject No.) 
A unique identifying number assigned to each patient/subject/healthy 
volunteer who enrolls in the study 
Treatment emergent adverse 
events 
Adverse events that a subject experiences within 30d after last dose of 
study treatment 
Variable 
Identifier used in the data analysis; derived directly or indirectly from data 
collected using specified assessments at specified timepoints 
Withdrawal of consent 
Withdrawal of consent 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 
Amended Protocol Version No. 01 (Clean) 
Confidential 
Page 11
0 Protocol No. 
 
 
Amendment 1 (25-Apr-2018) 
Amendment rationale 
 
As of 25-Apr-2018, seven patients have been enrolled into the study. 
Deferasirox FCT 90 mg, 180 mg, and 360 mg (Deferasirox FCT), is commercially available in 
some participating countries but not in all countries. 
The purpose of this amendment is to enable Novartis Drug Supply Management to supply 
labeled study drug to countries where Deferasirox FCT is not commercially available and also 
to enable countries where Deferasirox FCT is commercially available to follow their local 
processes for using commercial products in clinical trials. 
Two guidance were provided related to collection of Observer Reported Outcomes (ObsROs) 
• The GI symptom questionnaire was removed from the Week 1 day 1 visit because for all 3 
questionnaires, the Screening visit 1 ObsRO will be considered baseline. Additionally, 
patients who are on prior chelation therapy other than deferasirox are not able to complete 
the GI questionnaires at Week 1 day 1 because of the 5 day washout period required. The 
questionnaires investigate the impact of chelation treatment received 7 days prior to the 
visit. 
• Chelation naïve patients and patients treated with chelation therapy who stopped treatment 
more than 7 days prior to Screening visit 1 (SV1) will not complete ObsROs 
questionnaires at SV1. The questionnaires investigate impact of chelation treatment 
received within 7 days prior to SV1 and as such are not applicable to naive patients and 
patients treated with chelation therapy who stopped treatment more than 7 days prior to 
SV1. 
In addition, some updates have been made to provide further clarification on some aspects of 
the study as listed below. 
 
Changes to the protocol 
• Section 1.2.1.2: The cumulative world-wide exposure with commercial deferasirox was 
updated. 
• Section 6.6: Additional clarification provided for drug dispensation to be registered in 
IRT. 
• Section 6.3.1.6.1: Guidance provided on skin reactions was moved from section 6.3.1.6.2 
to this section. 
• Section 6.3.1.6.2: Guidance on skin reaction deleted and moved to section 6.3.2.6.1. 
• Section 6.4.1: Clarification provided that history of transfusion must be collected for the 
last 3 months prior to Screening visit 1 and during the study. 
• Section 6.6: Guidance provided that “All drug dispensation will be registered in IRT. 
Countries with commercially available deferasirox will register only the quantity 
dispensed as there are no unique kit numbers on commercial drugs.” 
• Section 6.6.1.1: Drug supply process clarified, indicating that Novartis will supply labeled 
drug to countries where deferasirox FCT is not commercially available. 


Novartis 
Amended Protocol Version No. 01 (Clean) 
Confidential 
Page 12
0 Protocol No. 
 
 
• Section 6.6.1.2: Drug supply process clarified, indicating that countries where deferasirox 
is commercially available will use commercially available deferasirox FCT as study drug 
and follow their local processes for using commercial products for clinical trials. 
• Section 6.6.2: Drug supply and storage process was clarified, indicating that countries 
where deferasirox FCT is not commercially available will be supplied centrally with study 
drug (ICL670) and upon receipt, the investigator or designee will confirm study drug 
receipt in IRT and store as appropriate. Countries with commercially available deferasirox 
FCT will use commercial deferasirox FCT. 
• Table 6-6: For countries where Deferasirox FCT is not commercially available, “study 
treatment” and “labeled drug” was changed from “Deferasirox FCT” to “ ICL670” 
• Table 6-7: For countries where Deferasirox FCT is not commercially available, “study 
treatment” was changed from “Deferasirox FCT” to “ ICL670” and “bulk medication” 
was changed to “labeled medication” 
• Section 6.6.3.2: Drug accountability clarified that all drug dispensation will be registered 
in IRT. 
• Table 7.1: Visit window of ± 3 days provided for visits Week 2, Week 3 and Week 4 and 
visit window of ± 7 days is provided for visits Week 8, Week 12, Week 16, Week 20, 
Week 24 (End of Treatment). 
• Table 7.1: Clarification is provided to indicate in which visits IRT will be used. 
• Table 7.1: “Study drug administration” was changed to “study drug dispensation” for 
better clarity. Drug dispensation is removed from Week 2 visit and Week 3 visit because 
each study drug bottle contains 35 tablets and is sufficient for treatment for 1 months. If 
study drug is dispensed at Week 1 visit, it should be sufficient for treatment for one 
months and additional drug dispensation at Week 2 and Week 3 visits are not required. 
• Table 7.1: The GI symptom questionnaire was removed from the Week 1 day 1 visit 
because for all 3 questionnaires, the Screening visit 1 ObsROs assessment will be 
considered the baseline. 
• Table 7.1: Three footnotes were added to provide further clarification: 
• SV2 is applicable only to patients who are chelation naïve or are currently treated 
with chelation therapy other than deferasirox. 
• Chelation naïve patients and patients treated with chelation therapy who stopped 
treatment more than 7 days prior to Screening visit 1 (SV1) will not complete 
ObsROs questionnaires at SV1. 
• The choice of method for ocular and auditory assessments will be at the discretion of 
the investigators. 
• Section 7.1.2: Guidance added that the investigator or responsible site personnel will 
register Screening visit 1 in IRT. 
• Section 7.1.2.1: Statement that “the investigator or responsible site personnel will register 
the patient in IRT once eligibility is confirmed” was deleted and moved to section 7.1.4 
• Section 7.1.4: Clarification provided to indicate that once patients have completed the 
screening period, patients will be enrolled and eligibility registered in IRT. 


Novartis 
Amended Protocol Version No. 01 (Clean) 
Confidential 
Page 13
0 Protocol No. 
 
 
• Section 7.1.6: The text “All biological samples that have already been collected may be 
retained and analyzed at a later date (or as required by local regulations)” was removed 
from the protocol because the study will use local labs only and therefore there will be no 
collection or retention of biological samples by Novartis. 
• Section 7.1.9: A new section has been added to indicate that, unscheduled safety 
assessments may be performed as clinically indicated at the discretion of the investigator 
at any time during the study. 
• Section 7.2.2.5: References made to blood sample collection, sample shipment, reporting 
of results and local laboratory manuals were deleted. Blood samples will be analyzed in 
the local laboratories and not shipped to Novartis so the statement regarding shipment to 
Novartis is not applicable. Additionally statement that investigator will be provided with 
local laboratory manual is not applicable. 
• Table 7-2: The following parameters that were omitted in the original protocol have been 
added to the chemistry panel in line with other Exjade protocols: Uric acid, Total protein, 
Bicarbonate, Albumin, Chloride, Glucose, Inorganic phosphate, Potassium, Sodium, 
Calcium and Magnesium. 
• Section 7.2.2.5.2 Clinical Chemistry: The additional parameters specified below were 
added at Screening visit 1, Week1, 3, 4, 8, 12, 16, 20 and End of Treatment visits: Uric 
acid, Total protein, Bicarbonate, Albumin, Chloride, Glucose, Inorganic phosphate, 
Potassium, Sodium, Calcium and Magnesium.. 
• Section 7.2.2.6: Clarification provided that ocular assessments will be according to 
institution’s practice. 
• Section 7.2.2.7: Clarification provided that auditory assessments will be according to 
institution’s practice. 
• Section 7.2.8: ObsRO assessments schedules updated to indicate that GI symptom 
questionnaire will not be completed at Week 1 day 1. Further to that, guidance is provided 
that, chelation naïve patients and patients treated with chelation therapy who stopped 
treatment more than 7 days prior to Screening visit 1 (SV1) will not complete 
questionnaires at SV1. Additionally, guidance is provided that ObsRO questionnaires will 
be completed at study site (during study visits). 
• Section 10.5.7: Section update to indicate that GI symptom questionnaire will not be 
completed at Week 1 day 1 visit. For all questionnaires, Screening visit 1 PRO will be 
considered baseline so there is no added value to complete another questionnaire at Week 
1 day 1 prior to study treatment. 
Additionally, analyses were updated as follows: 
• Clarified that for mSICT and palatability questionnaires, only descriptive statistics 
will be provided for the chelation naïve patients. 
• GI symptoms analysis updated as below: 
• 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. 


Novartis 
Amended Protocol Version No. 01 (Clean) 
Confidential 
Page 14
0 Protocol No. 
 
 
IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities where applicable / 
required. 
The changes described in this amended protocol are non-substantial and do not 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. 


Novartis 
Amended Protocol Version No. 01 (Clean) 
Confidential 
Page 15
0 Protocol No. 
 
 
Protocol summary: 
Title 
A single-arm interventional Phase IV, post-authorisation study evaluating the safety 
of pediatric patients with transfusional hemosiderosis treated with deferasirox 
crushed film coated tablets 
Brief title 
Phase IV safety study of crushed deferasirox film coated tablets in pediatric patients 
with transfusional hemosiderosis 
Sponsor and Clinical 
Phase 
Novartis 
Phase IV 
Investigation type 
Drug 
Study type 
Interventional 
Purpose and 
rationale 
During the evaluation of the film-coated tablet (FCT) application for deferasirox, the 
European Health Authorities (CHMP/PRAC) have expressed that the safety in the 
youngest children (particularly those <6 years) need further evaluation, especially 
when the tablets are crushed. The authorities have requested Novartis to conduct 
an additional post-authorization safety study (PASS) to characterize the pediatric 
safety profile of deferasirox and to provide safety data on selected gastrointestinal 
adverse events (esophagitis, stomatitis, mouth ulceration, gastric ulcers, 
hemorrhage, abdominal pain, diarrhea, nausea, and vomiting). 
Primary Objective 
● To assess the safety of crushed deferasirox FCT with respect to selected 
gastrointestinal (GI) disorders in pediatric patients aged ≥2 to < 6 years with 
transfusional iron overload up to 24 weeks including 30 days safety follow up 
● The primary endpoint is the number and percentage of patients with selected 
gastrointestinal disorders (esophagitis, stomatitis, mouth ulceration, gastric ulcers, 
haemorrhage, abdominal pain, diarrhea, nausea and vomiting) up to 24 weeks 
including 30 days safety follow-up. 
Secondary 
Objectives 
To evaluate adverse events (AEs) suspected to be related to the crushed deferasirox 
FCT during the study 
● To assess the overall safety of crushed FCT of deferasirox 
● To assess the efficacy of deferasirox FCT treatment 
● To evaluate patient treatment satisfaction, palatability and gastrointestinal (GI) 
symptoms with Observer Reported Outcomes (ObsROs) 
Study design 
● The study employs an interventional, prospective, single arm, open label, global, 
multi-center, non-randomized trial design to monitor and assess the safety profile of 
the crushed deferasirox FCT in pediatric patients between age ≥2 to <6 with 
transfusional hemosiderosis over 24 weeks. This study will aim to enroll at least 40 
patients. 
● The study will include a screening period (from Day 0-14) with two visits at least 7 
days apart to assess eligibility of patients that are chelation naïve or on a prior iron 
chelator treatment other than DFX. For Patients on DFX treatment prior to study 
entry only one screening visit (screening visit 1) will occur to determine eligibility. Any 
current chelation therapy except deferasirox will be discontinued to undergo a 5-day 
washout period prior to commencing a 24 week treatment period with crushed 
deferasirox FCT. 
● All patients will have weekly visits for the first month to monitor renal function. 
Hepatic function will be assessed biweekly during the first month. Thereafter, 
monthly safety assessments will be performed, including the monitoring of serum 
ferritin values and trends in order to adapt patient treatment. 
Eligibility, application of dosing standards and adjustments, as well as safety and 
serum ferritin assessments as specified in the protocol, will occur in accordance with 
the EU label throughout the study. 
● Patients will continue therapy up to 24 weeks. 
Population 
Pediatric patients between the age ≥2 to <6 years with transfusional hemosiderosis 
that are candidates for treatment with deferasirox. 
Inclusion criteria 
Patients that are candidates for treatment with deferasirox 
● Patients ≥2 to <6 years old diagnosed with transfusional hemosiderosis 
● Documented history of red blood cell transfusions 
● Written informed consent/assent before any study-specific procedures. The 


Novartis 
Amended Protocol Version No. 01 (Clean) 
Confidential 
Page 16
0 Protocol No. 
 
 
consent will be obtained from caregiver(s) or patient’s legal representative. 
Investigators will also obtain assent of patients according to local, regional, or national 
regulations. 
● For patient on prior DFX: Serum ferritin (SF) >500 ng/mL, measured at screening 
visit 1 and requiring a DFX daily dose equivalent to FCT ≥ 7mg/kg/day 
● For patients on a prior iron chelator other than DFX or iron chelation naïve: Serum 
ferritin (SF) >1000 ng/mL measured at screening visits 1 and 2 
Exclusion criteria 
● Patients that receive more than one iron chelator at the same time as current iron 
chelation treatment. (Patients who have received combination therapy in their 
medical history but are currently being treated with a single ICT agent are eligible). 
● Patients continuing on deferoxamine or deferiprone in addition to study treatment. 
(Patients switching to or continuing on deferasirox are eligible). 
● Unresolved adverse event if the patient was previously treated with deferiprone or 
deferoxamine or deferasirox 
● Significant proteinuria as indicated by a urinary protein/creatinine ratio > 0.5 mg/mg 
in a non-first void morning urine measured at screening visit 1 
● Serum creatinine ˃age adjusted ULN measured at any screening visit 
● Creatinine clearance below 90 mL/minute measured at any screening visit. 
Creatinine clearance will be estimated from serum creatinine measured at each 
respective visit 
● Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) >2.5 x 
ULN measured at screening visit 1 
● Total Bilirubin (TBIL) >1.5 x ULN measured at screening visit 1. 
● Patients with chronic or acute significant impaired gastrointestinal (GI) function or 
GI disease that may significantly alter the absorption of oral deferasirox FCT (e.g. 
ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption 
syndrome, or small bowel resection) 
● History of and/or prior laboratory evidence of active Hepatitis B or Hepatitis C 
(Hepatitis B surface antigen [HBsAg] in the absence of hepatitis B surface antibodies 
[HBsAb] OR Hepatitis C virus [HCV] antibody positive with HCV RNA positive) 
● Liver disease with severity of Child-Pugh Class B or C 
● History of hypersensitivity to any of the study drugs or excipients 
● Patients participating in another clinical trial or receiving an investigational drug 
● Patients with a known history of human immunodeficiency virus (HIV) seropositivity 
● Patients unwilling or unable to comply with the protocol 
● 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 
past 5 years whether or not there is evidence of local recurrence or metastases, with 
the exception of localized basal cell carcinoma of the skin 
● 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.) 
● Female patients who reach menarche and they or their caregivers refuse 
pregnancy testing and/or if there is a positive pregnancy test result 
Investigational and 
reference therapy 
After the screening period, chelation-naïve patients will be dispensed deferasirox 
FCT at a starting dose of 14 mg/kg/day, refer to Table 6-2. Dose should be adjusted 
for efficacy and safety parameters with a maximum dose of 28mg/kg/day. 
For patients already well-managed on any prior iron chelation treatment (ICT) 
including deferoxamine or deferasirox dispersible tablet (DT), a starting dose of 
crushed deferasirox FCT is outlined in the table: 
ICT dose prior to enrollment 
Equivalent dose of deferasirox FCT on 
study 
Deferoxamine 
(mg/kg/day) 
Deferasirox DT 
(mg/kg/day) 
Deferasirox FCT (mg/kg/day) 
10 
5 
3.5 
20 
10 
7 
30 
15 
10.5 


Novartis 
Amended Protocol Version No. 01 (Clean) 
Confidential 
Page 17
0 Protocol No. 
 
 
40 
20 
14 
50 
25 
17.5 
60 
30 
21 
70 
35 
24.5 
80 
40 
28 
Dose equivalence between deferiprone (DFP) and deferasirox (DFX) has not been 
established in clinical studies. For patients pre-treated with deferiprone, the starting 
dose of deferasirox should be 14 mg/kg/day. 
For the first month after treatment initiation, weekly safety assessments of renal 
function and biweekly assessments of hepatic function will be performed. Thereafter, 
monthly safety assessments will be performed during the duration of the study. 
Monthly serum ferritin values and trends will be used to adapt the treatment of the 
patients together with safety data. 
Efficacy 
assessments 
Serum ferritin 
Safety assessments 
Adverse events and in particular selected gastrointestinal AEs (esophagitis, 
stomatitis, mouth ulceration, gastric ulcers, hemorrhage, abdominal pain , diarrhea, 
nausea, and vomiting) 
Hematology, blood chemistry (including renal and hepatic parameters) and urinalysis 
● Electrocardiogram (ECG) 
● Vital signs 
● Auditory and ocular examination 
Other assessments 
Deferasirox FCT treatment using ObsROs: 
● Modified Satisfaction with Iron Chelation Therapy (mSICT) 
● Palatability 
● GI symptoms 
Data analysis 
● Descriptive statistics (n, mean, standard deviation, median, minimum, and 
maximum) will be used to summarize continuous variables (e.g., laboratory 
assessments) and frequency counts and percentages will be provided for categorical 
variables. 
● For the primary endpoint, 95% confidence interval (CI) for percentage will also be 
computed based on Clopper-Pearson (Exact) method. 
Key words 
Children, iron chelation therapy, transfusional hemosiderosis, deferasirox, film- 
coated tablet, gastrointestinal 


Novartis 
Amended Protocol Version No. 01 (Clean) 
Confidential 
Page 18
0 Protocol No. 
 
 
1 
Background 
1.1 
Overview of disease pathogenesis, epidemiology and current 
treatment 
Transfusion-dependent  hemoglobinopathies  represent  a  major  global   health   burden   with 
>300,000 born annually with thalassemia or sickle cell disease. Iron overload is an inevitable 
clinical consequence for these patients. Iron chelation therapy is, therefore, an important and 
integral part of their supportive care. 
Humans are unable to actively eliminate body iron. This becomes clinically relevant when there 
is accumulation of toxic quantities of iron due to repeated blood transfusions as in transfusion 
dependent anemias, or when there is excessive uptake of dietary iron as in hereditary 
hemochromatosis. Excess iron is deposited as insoluble hemosiderin mainly in the liver, 
endocrine organs and myocardium. The exact mechanism of iron damage is unknown, but organ 
failure correlates closely with tissue iron burden. Excess iron deposition, especially in the liver, 
heart and endocrine organs, results in progressive tissue damage and organ failure, and is linked 
to iron-related promotion of free hydroxyl radical formation. In addition, the risk of some 
complications increases with age (Taher 2010). Serum ferritin (SF) has been traditionally used 
to assess transfusional iron overload with a well -established correlation to liver iron 
concentration, a more direct measurement of liver tissue iron. 
Complications of chronic iron overload (cardiac, hepatic and endocrine failure) represent the 
major causes of morbidity and mortality in patients with transfusional hemosiderosis who 
receive regular blood transfusions without appropriate chelation therapy. Iron chelators 
gradually mobilize iron most probably by continuously binding tiny amounts of soluble iron 
present in a ‘transit pool’ which is in equilibrium with hemosiderin. Solubilized, chelated iron 
can then be excreted in the urine and/or feces. Adherence to iron chelation therapy is crucial to 
reduce or prevent iron overload and has been correlated with improved patient survival 
(Kushner 2001, Borgna-Pignatti 2004, Gabutti and Piga 1996). The goal of chelation is to 
maintain SF <1000 ng/mL; however many patients live with significantly higher levels due to 
compliance issues with 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) 
 
1.2 
Introduction to investigational treatment(s) and other study 
treatment(s) 
Clinical studies have shown deferasirox to effectively chelate iron in patients with transfusional 
iron overload as demonstrated by decreases in liver iron concentration (LIC), serum ferritin 
(SF) and cardiac iron (MRI T2*) at adequate doses. The most common adverse reactions that 
are associated with drug administration in patients of all ages were gastrointestinal events, rash, 
and mild non-progressive increases in serum creatinine. 
To further characterize the safety of deferasirox dispersible tablet (DT) in children two large 
observational studies were conducted: 
Study CICL670A2411: A 5 year observational study on the safety of deferasirox (DT) in a 
pediatric patient population aged 2 years to 6 years at enrollment with transfusional iron 


Novartis 
Amended Protocol Version No. 01 (Clean) 
Confidential 
Page 19
0 Protocol No. 
 
 
overload. The study enrolled 267 patients that received at least one dos e of deferasirox. The 
median and mean duration of exposure to deferasirox was 59.9 months and 44.1 months 
respectively in this pediatric population. Almost half of the patients completed 5 years of 
observation on treatment with deferasirox. 
Study CICL670A2301: A non-interventional international sentinel site surveillance of patients 
with transfusional hemosiderosis treated with Exjade® (deferasirox) DT in actual practice 
setting. Study CICL670A2301 enrolled adult and pediatric patients ≥2 years old with chronic 
transfusional iron overload treated with deferasirox. Patients were followed for 3 years. There 
were 69 pediatric and 51 adult patients enrolled. The median duration of exposure to deferasirox 
DT was 29.9 months; 10 months in the adult study population and 30.6 months in the <18 years 
group. In the pediatric subpopulation 65.2% completed 3 years of observation on deferasirox 
treatment. 
In the pediatric population of these observational studies the most commonly affected primary 
system organ classes (SOCs) were gastrointestinal disorders and infections and infestations. GI 
related disorders occurred in about 40% of patients and less than half of them were suspected 
to be related to study drug by the investigator. AE related to the upper GI tract were rarely 
reported in the group of AE which occurred in more than 5%. 
Both recently completed long term safety studies indicated no new or unexpected safety 
findings in a pediatric population with transfusional iron overload. In accordance with the 
previous clinical studies, the data confirmed that deferasirox was generally well-tolerated with 
a clinically manageable safety profile. 
This trial will use crushed deferasirox film coated tablets (FCT). Deferasirox FCT was approved 
by the FDA in March 2015 and by EMA in March, 2016. 
 
1.2.1 
Overview of deferasirox film-coated tablet (FCT) 
Deferasirox is an orally active tridentate iron chelator and is indicated for the treatment of 
chronic iron overload due to blood transfusions (transfusional hemosiderosis) in adult and 
pediatric patients (aged 2 years and older) as well as in patients with non -transfusional 
dependent thalassemia syndromes aged 10 years and older. 
Deferasirox FCT received first approvals in March 2015 by the US FDA and by EMA in March 
2016. Deferasirox FCT, is an immediate release solid oral dosage form, is based on wet 
granulation technology with a higher drug load of 54.0%. The FCT does not contain lactose, 
and sodium lauryl sulfate surfactant was replaced by Polaxamer 188. 
In the EU label of Exjade FCT, crushing of the film coated tablet is allowed. 
In this study deferasirox FCT must be crushed and administered by sprinkling the full dose on 
soft food (e.g. yogurt or apple sauce) and consumed immediately and completely. Three dosage 
strengths of deferasirox FCT are available: 90 mg, 180 mg, and 360 mg. The use of crushed 
deferasirox FCT is supported by the in-vitro dissolution, stability and delivered dose data which 
indicated that no significant difference between intact and crushed deferasirox FCT. 
The film -coated tablets (FCT) are of the same qualitative and quantitative composition as 
deferasirox granules that are currently being investigated worldwide; both FCT and granules 
are using the same active ingredients at the same doses, and the same excipients (with exception 


Novartis 
Amended Protocol Version No. 01 (Clean) 
Confidential 
Page 20
0 Protocol No. 
 
 
of the film-coating ingredients only used in the FCT). The recommendations how patients 
should be taking the crushed deferasirox film-coated tablet and the recommendations for 
application of the Deferasirox Granules in ongoing clinical trials are similar. 
 
1.2.1.1 
Non-clinical experience 
Preclinical studies revealed that deferasirox did not affect fertility and it is neither teratogenic 
nor carcinogenic. Detailed information regarding the preclinical evaluation of deferasirox is 
provided in the deferasirox Investigator’s Brochure. 
 
1.2.1.2 
Clinical experience 
The cumulative world-wide exposure with commercial deferasirox is estimated to be 383,491 
Patient Years (PTY) as of October 31, 2017, and approximately 8,110 patients have been treated 
with deferasirox in Novartis-sponsored investigational clinical trials cumulatively since the 
Development International Birth Date (IBD). 
Clinical studies have shown deferasirox to effectively chelate iron in patients with transfusional 
iron overload as demonstrated by decreases in liver iron concentration (LIC), serum ferritin, and 
cardiac iron (as assessed by magnetic resonance imaging [MRI] T2*) in patients with various 
underlying anemias ( Nick 2003, Cappellini 2006, Vichinsky 2007, Porter 2008, Pennell 2010). 
Furthermore, deferasirox has been shown in various studies (ICL670A108, 2409, US02, US03, 
etc.…) to be efficacious in reducing the iron overload in lower-risk MDS patients as measured 
by SF and/or LIC. 
Deferasirox has demonstrated acceptable safety and tolerability in adult and pediatric patients 
with transfusional iron overload (Piga 2006, Cappellini 2006, Cappellini 2011). The most 
frequent reactions reported during chronic treatment with deferasirox in adult and pediatric 
patients included gastrointestinal disturbances in about 26% of patients (mainly nausea, 
vomiting, diarrhea, or abdominal pain) and skin rash in approximately 7% of patients. These 
reactions were dose-dependent, mostly mild to moderate, generally transient, and mostly 
resolve even if treatment is continued. Deferasirox can cause gastrointestinal hemorrhages, 
which can be fatal, especially in elderly patients who have advanced hematologic malignancies 
and/or low platelet counts. 
Mild, nonprogressive increases in serum creatinine, mostly within the normal range, occurred 
in approximately 36% of patients. These were dose-dependent, often resolved spontaneously 
and some were alleviated by reducing the dose. Acute renal failure and increases in serum 
creatinine (≥2x upper limit of normal ULN), have been reported following prescription use of 
deferasirox; these were usually reversible after treatment interruption. Renal tubulopathy has 
been reported with deferasirox. The majority of patients were children and adolescents with 
beta-thalassemia and serum ferritin levels <1,500 microgram/L. 
Elevations of liver function transaminases were reported as an adverse reaction in 
approximately 2% of patients. These were not dose dependent and most of these patients had 
elevated levels prior to receiving deferasirox due to a high background incidence of chronic 
viral hepatitis and of liver damage secondary to chronic iron overload. Elevations of 
transaminases >10 x ULN, suggestive of hepatitis, were uncommon (0.3%). There have been 


Novartis 
Amended Protocol Version No. 01 (Clean) 
Confidential 
Page 21
0 Protocol No. 
 
 
post-marketing reports of hepatic failure; most involved patients with significant comorbidities 
including liver cirrhosis and multi-organ failure. 
In a 1-year, randomized, double-blind, placebo-controlled study in patients with non- 
transfusion-dependent thalassemia syndromes and iron overload (CICL670A106), diarrhea 
(9.1%), rash (9.1%) and nausea (7.3%) were the most frequent study drug-related adverse events 
reported by patients receiving 10 mg/kg/day deferasirox. Abnormal serum creatinine and 
creatinine clearance values were reported in 5.5% and 1.8%, respectively of patients receiving 
10 mg/kg/day deferasirox. Elevations of liver transaminases >2x baseline and 5x ULN were 
reported in 1.8% of patients treated with 10 mg/kg/day deferasirox. 
There have been post-marketing reports of Stevens-Johnson syndrome, hypersensitivity 
vasculitis, urticaria, alopecia, toxic epidermal necrolysis, and hypersensitivity reactions 
(including anaphylaxis and angioedema). Rare cases of erythema multiforme have been 
reported during deferasirox treatment. There have also been post-marketing reports (both 
spontaneous and from clinical trials) of cytopenias including neutropenia, thrombocytopenia, 
and aggravated anemia in patients treated with deferasirox. Most of these patients had pre - 
existing hematologic disorders that are frequently associated with bone marrow failure. The 
relationship of these episodes to deferasirox is uncertain. Cases of serious acute pancreatitis 
were observed with and without documented underlying biliary conditions. 
In a 5-year observational study (CICL670A2411) in which 267 children aged 2 to <6 years (at 
enrollment) with transfusional hemosiderosis received deferasirox DT, there were no 
unexpected safety findings regarding AEs or laboratory abnormalities. Increases in serum 
creatinine of >33% and above the upper limit of normal (ULN) on ≥2 consecutive occasions 
were observed in 3.1% of children and elevation of alanine aminotransferase (ALT) greater than 
5 times the ULN was reported in 4.3% of children. The most frequently observed AEs with 
reported suspected relationship to study drug were increase in ALT (21.1%), increase in 
aspartate aminotransferase (AST, 11.9%), vomiting (5.4%), rash (5.0%), increase in blood 
creatinine (3.8%), abdominal pain (3.1%) and diarrhea (1.9%). Overall growth and development 
were not affected in this pediatric population. 
Because of the importance of tolerability and patient compliance, a new deferasirox 
formulation, film-coated tablet (FCT), for once daily (q.d.) oral administration has been 
developed with improved palatability. 
A randomized study CICL670F2201 was designed to investigate the safety and outcomes of 
patients treated with deferasirox dispersible tablets (DT) or deferasirox FCT. In total, 173 
patients were randomized 1:1 to DT (n = 86) or FCT (n = 87; Table I). Most patients had TDT 
(n = 70 in each arm); 16 patients in each arm had MDS and most had IPSS-R low-risk MDS 
(DT, n = 8 [9.3%]; FCT, n = 10 [11.5%]). The primary endpoints were Treatment Emergent 
Adverse Events (TEAEs) and changes from baseline during on -treatment period for the 
following laboratory assessments: serum creatinine, recalculated creatinine clearance, alanine 
aminotransferase (ALT), aspartate aminotransferase (AST), red blood cells (RBC), platelets, 
and white blood cells (WBC). Key secondary endpoints included the percentages of selected 
gastrointestinal events, pharmacokinetic (PK) analysis and Patient Reported Outcomes (PRO). 
Investigator-reported AEs regardless of relationship to deferasirox were reported in 77 (89.5%) 
patients on DT and 78 (89.7%) patients on FCT). The most frequently reported AEs were 


Novartis 
Amended Protocol Version No. 01 (Clean) 
Confidential 
Page 22
0 Protocol No. 
 
 
diarrhea, nausea, and abdominal pain, with similar proportions of patients experiencing these 
events in each treatment arm. AEs with a suspected relationship to deferasirox were reported in 
54 (62.8%) patients on DT and 41 (47.1%) patients on FCT, and were predominantly (≥10%) 
diarrhea (DT 19.8%; FCT 13.8%), increased UPCR (DT 10.5%; FCT 17.2%), 
abdominal pain (DT 16.3%; FCT 8.0%), vomiting (DT 15.1%; FCT 4.6%) and nausea (DT 
12.8%; FCT 9.2%). The exposure-adjusted incidence for GI related events was lower in the 
FCT group (137 per 100 patient years) as compared to the DT group (153 per 100 patient years). 
In summary, deferasirox is a once-daily oral iron chelator that has been approved for treating 
chronic iron overload, with demonstrated efficacy in the reduction or maintenance of body iron 
stores, and an acceptable safety profile with dispersible and non-dispersible formulations. 
 
2 
Rationale 
2.1 
Study rationale and purpose 
During the evaluation of the FCT application, the European Health Authorities (CHMP/PRAC) 
have expressed that the safety in the youngest children (particularly < 6 years) is not known, 
especially when the tablets are crushed, and have requested Novartis to conduct an additional 
post-authorization safety study (PASS) to characterize the pediatric safety profile and to provide 
safety data on selected AEs (esophagitis, stomatitis, mouth ulceration, gastric ulcers, 
haemorrhage, abdominal pain, diarrhea, nausea, and vomiting). 
A PASS is defined in Directive 2001/83/EC (DIR) Art 1(15) as any study relating to an 
authorized medicinal product conducted with the aim of identifying, characterizing or 
quantifying a safety hazard, confirming the safety profile of the medicinal product, or of 
measuring the effectiveness of risk management measures. 
Study CICL670F2429 will serve to fulfill the post-authorization measure imposed by the 
European Health Authority. 
 
2.2 
Rationale for the study design 
This study employs a prospective, single-arm, global multi-center, interventional open-label, 
non- randomized design to identify and assess AEs suspected to be related to study drug when 
administered up to 24 weeks in pediatric patients age ≥2 to <6 years with transfusional 
hemosiderosis. 
This design requires crushing the study medication, deferasirox FCT, and a detailed safety 
assessment mandated by the study protocol. Crushing the deferasirox FCT is mandatory. The 
selected age category addressed the need to investigate the safety in younger children. 
The single-arm, open-label study design is well established for this type of request and the 
schedule of assessment is appropriate for this study and according to the current standards of 
care and as suggested by the Health Authority. 


Novartis 
Amended Protocol Version No. 01 (Clean) 
Confidential 
Page 23
0 Protocol No. 
 
 
2.3 
Rationale for dose and regimen selection 
Deferasirox FCT dosing will be calculated for pediatric patients and the investigator’s overall 
clinical assessment of the subject at each study visit in accordance with the protocol. The initial 
dose of deferasirox will be determined by the subjects prior history of chelation (iron chelation 
naïve or prior DFX or any other prior iron chelator other than DFX) from a standardized 
conversion of prior iron chelation therapy to deferasirox FCT. DFX FCT dosing is based on 
body weight (mg DFX/ kg body weight); please refer to Table 6-1. 
 
2.4 
Rationale for choice of combination drugs 
Not applicable 
 
2.5 
Rationale for choice of comparators drugs 
Not applicable 
 
2.6 
Risks and benefits 
The goal of iron chelation therapy is to remove the amount of iron administered in transfusion 
and as required, to reduce the existing iron burden. The decision to initiate iron chelation therapy 
should be individualized and based on anticipated clinical benefits and risks. 
The risks associated with the use of deferasirox in this population of subjects with transfusional 
hemosiderosis are well described in clinical trials. As with other iron chelator treatment, the risk 
of toxicity of deferasirox  may be increased  when  inappropriately high doses are given in 
patients with a low iron burden or with serum ferritin levels that are only slightly elevated. In 
patients with no LIC assessment, caution should be taken during chelation therapy to minimize 
the risk of over-chelation. 
Chelation should be regularly adjusted to meet a patient’s specific needs, based on transfusion 
requirements (i.e., decreased or increased for patients with low or high iron intake, respectively), 
severity of iron overload, and treatment goal (i.e., to maintain or reduce iron body levels). 
Patients with pre-existing renal conditions or patients who are receiving medicinal products that 
may depress renal function may be more at risk of complications and weekly monitoring of 
serum creatinine and/or creatinine clearance is recommended in the first month after initiation 
or modification of therapy and monthly thereafter. Concomitant administration of deferasirox 
with drugs that have known ulcerogenic potential, such as non-steroidal anti- inflammatory 
drugs, corticosteroids, or oral bisphosphonates, and use of deferasirox in patients receiving 
anticoagulants may increase the risk of gastrointestinal irritation. 
The risk to subjects in this trial may be minimized by compliance with the eligibility criteria 
and study procedures including, close clinical monitoring, safety assessment and dose 
adjustment. 
As with other iron chelator treatment, the risk of toxicity of deferasirox FCT may be increased 
when inappropriately high doses are given in patients with a low iron burden or with serum 
ferritin levels that are only slightly elevated. 


Novartis 
Amended Protocol Version No. 01 (Clean) 
Confidential 
Page 24
0 Protocol No. 
 
 
Benefits to eligible subjects include the removal of excess iron and decrease in the risks 
associated with transfusional hemosiderosis. 
 
3 
Objectives and endpoints 
Objectives and related endpoints are described in Table 3-1 below. 


 
 
 
Novartis 
Confidential 
 
Page 25 
Amended Protocol Version No. 01 (Clean) 
 
Protocol No. CICL670F2429 
 
 
Table 3-1 
Objectives and related endpoints 
Objective 
Endpoint 
Analysis 
 
Primary 
Refer to Section 10.4 
To assess the safety of crushed deferasirox FCT with 
respect to selected gastrointestinal (GI) disorders in 
pediatric patients aged ≥2 to < 6 years with 
transfusional iron overload up to 24 weeks including 
30 days safety follow up 
Number and percentage of patients with selected 
gastrointestinal disorders (esophagitis, stomatitis, 
mouth ulceration, gastric ulcers, haemorrhage, 
abdominal pain, diarrhea, nausea, and vomiting) up 
to 24 weeks including 30 days safety follow-up 
 
Secondary 
Refer to Section 10.5 
Evaluate AEs suspected to be related to the crushed 
deferasirox FCT 
 
 
To assess the overall safety of crushed FCT of 
deferasirox 
Number and percentage of patients who experienced 
AEs suspected to be related to study drug up to 24 
weeks including a 30 day follow up overall and by 
SOC. 
Overall safety up to 24 weeks including 30 days 
safety follow-up as measured by frequency and 
severity of adverse events, serious adverse events 
(SAEs) and AEs leading to discontinuation and 
absolute change from baseline over time (shift tables 
will also be provided) for serum creatinine, creatinine 
clearance, UPCR, total bilirubin, ALP, ALT, AST). 
Other safety data (e.g., ECGs, vital signs, ocular, 
auditory examinations) will also be summarized. 
 
To assess the efficacy of deferasirox FCT treatment 
Change from baseline over time in SF up to 24 weeks 
of treatment 
To evaluate patient treatment satisfaction, palatability, 
and GI symptoms with Observer-reported Outcomes 
(ObsROs) 
Domain scores with ObsROs (Modified Satisfaction 
with Iron Chelation Therapy [mSICT], palatability, and 
GI symptom) questionnaires 
 
Other secondary 
Refer to Section 10.5.2 
None 
 
Exploratory 
Refer to Section 10.6 
None 
 


Novartis 
Amended Protocol Version No. 01 (Clean) 
Confidential 
Page 26
6 Protocol No. 
 
 
 
4 
Study design 
4.1 
Description of study design 
The study employs an interventional, prospective, single arm, open label, global multi-center, 
non-randomized trial design to monitor and assess the safety profile of the crushed deferasirox 
FCT in pediatric patients between age ≥ 2 to < 6 years with transfusional hemosiderosis over 
24 weeks. 
This study will enroll at least 40 patients worldwide. 
The study will include a screening period (from Day 0-14) with two visits at least 7 days apart 
to assess eligibility of patients that are chelation naïve or on a prior iron chelator treatment other 
than DFX. For Patients on DFX treatment prior to study entry only one screening visit 
(screening visit 1) will occur to determine eligibility and monitoring will be monthly after 
baseline assessments (day1). (For additional details refer to Section 8.1). Any current chelation 
therapy except deferasirox will be discontinued to undergo a 5-day washout period prior to 
commencing a 24 weeks treatment period with crushed deferasirox FCT, refer to Section 8.2 
for additional details. 
All patients will have weekly visits for the first month. 
Safety assessments will be performed weekly after treatment initiation and thereafter monthly 
during the study. Monthly serum ferritin values and trends will be used to adapt the treatment 
of the patients together with safety data. 
Patients will continue therapy for up to 24 weeks. 
 
30-day follow-up 
All patients must be followed for AEs and SAEs for 30 days after the last dose of study 
treatment to determine any potential treatment emergent adverse event regardless of whether 
the patient continues prescribed iron chelation treatment after last dose of study medication. 
Patients who discontinue study drug before week 24 should be scheduled for a visit within 7 
days of ending treatment at which time all of the assessments listed for the final visit will be 
performed (end of treatment visit). At a minimum, all patients who discontinue study treatment, 
including those who refuse to return for a final visit, will be contacted for safety evaluations 
during the 30 days following the last dose of study drug. 
 
4.2 
Timing of interim analyses and design adaptations 
Not Applicable 
 
4.3 
Definition of end of study 
Completion of this study as a whole will occur upon the availability of the last data point. 


Novartis 
Amended Protocol Version No. 01 (Clean) 
Confidential 
Page 27
6 Protocol No. 
 
 
4.4 
Early study termination 
The study can be terminated at any time for any reason due to an unavoidable event 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 discontinued or withdrawn 
patient. The investigator may be informed of additional procedures to be followed in order to 
ensure that adequate consideration is given to the protection of the patient’s interests. The 
investigator will be responsible for informing IRBs and/or ECs of the early termination of the 
trial. 
 
5 
Population 
5.1 
Patient population 
Pediatric patients ≥2 years old to <6 years old with transfusional hemosiderosis that are 
candidates for treatment with deferasirox. Patients enrolled in this study are not permitted to 
participate in additional parallel investigational drug or device studies. Patients who failed 
screening may be re-screened with Novartis confirmation. Patients who complete the study may 
not be re-enrolled for a second course of treatment. 
The investigator or designee must ensure that only patients who meet all the following inclusion 
and none of the exclusion criteria are offered treatment in the study. 
 
5.2 
Inclusion criteria 
Written informed consent must be obtained prior to any screening procedures. 
1. Patients ≥2 to <6 years old diagnosed with transfusional hemosiderosis 
2. Documented history of red blood cell transfusions 
3. Written informed consent/assent before any study-specific procedures. The consent will be 
obtained from caregiver(s) or patient’s legal representative. Investigators will also obtain 
assent of patients according to local, regional, or national regulations. 
4. For patients on prior DFX: Serum ferritin (SF) >500 ng/mL, measured at screening visit 1 
and requiring a DFX daily dose equivalent to FCT ≥ 7mg/kg/day. 
5. For patients on a prior chelator other than DFX (e.g. deferiprone or deferoxamine) or 
chelation naive: Serum ferritin (SF) >1000 ng/mL measured at screening visits 1 and 2. 
 
5.3 
Exclusion criteria 
Patients eligible for this study must not meet any of the following criteria: 
1. Patients that receive more than one iron chelator at the same time as current iron chelation 
treatment. (Patients who have received combination therapy in their medical history but 
are currently being treated with a single ICT agent are eligible.) 
2. Patients continuing on deferoxamine or deferiprone in addition to study treatment. 
(Patients switching to or continuing on deferasirox are eligible). 
3. Unresolved adverse events if the patient was previously treated with deferiprone or 
deferoxamine or deferasirox. 


Novartis 
Amended Protocol Version No. 01 (Clean) 
Confidential 
Page 28
6 Protocol No. 
 
 
4. Significant proteinuria as indicated by a urinary protein/creatinine ratio > 0.5 mg/mg in a 
non-first void sample urine measured at screening visit 1. 
5. Serum creatinine > age adjusted ULN measured at any screening visit 
6. Creatinine clearance below 90 mL/minute measured at any screening visit. Creatinine 
clearance using the Schwartz formula will be estimated from serum creatinine measured at 
each respective visit. 
7. ALT and/or AST > 2.5 x ULN measured at screening visit 1. 
8. Total bilirubin (TBIL) >1.5 x ULN measured at screening visit 1. 
9. Patients with significant impaired GI function or GI disease that may significantly alter the 
absorption of oral deferasirox FCT (e.g. ulcerative diseases, uncontrolled nausea, 
vomiting, diarrhea, malabsorption syndrome, or small bowel resection). 
10. History of and/or laboratory evidence of active Hepatitis B or Hepatitis C (HBsAg in the 
absence of HBsAb OR HCV Ab positive with HCV RNA positive. 
11. Liver disease with severity of Child-Pugh Class B or C. 
12. History of hypersensitivity to any of the study drug or excipients. 
13. Patients participating in another clinical trial or receiving an investigational drug. 
14. Patients with a known history of HIV seropositivity. 
15. Patients unwilling or unable to comply with the protocol. 
16. History of malignancy of any organ system, treated or untreated, within the past 5 years 
whether or not there is evidence of local recurrence or metastases, with the exception of 
localized basal cell carcinoma of the skin. 
17. Significant medical condition interfering with the ability to partake in this study (e.g. 
uncontrolled hypertension, unstable cardiac disease not controlled by standard medical 
therapy, systemic disease: cardiovascular, renal, hepatic, etc.). 
18. Female patients who reach menarche and they or their caregivers refuse pregnancy testing 
and/or if there is a positive pregnancy test result. 
 
6 
Treatment 
6.1 
Study treatment 
The investigational study drug for this trial is crushed deferasirox (ICL670) FCT for oral use. 
Deferasirox FCT dosing is based on subject’s weight, outlined below in Table 6-1. 
To guide the investigator and/or pharmacist/designee on the number of deferasirox FCT tablets 
of a given strength to prescribe/dispense to a given subject, taking into account the subject’s 
body weight and protocol specified dosing scheme, a dosing table (Table 6-1) has been 
provided. 
For each patient the investigator, pharmacist and/ or designee will calculate a target daily dose 
taking into account patient’s body weight. When the exact calculated dose cannot be reached 
with the deferasirox FCT strengths available, the closest daily dose available will be prescribed 
and dispensed. The following dosing Table 6-1 provides an efficient combination of FCT 
strengths reaching a certain daily dose for each body weight range. 


Novartis 
Amended Protocol Version No. 01 (Clean) 
Confidential 
Page 29
6 Protocol No. 
 
 
Example illustrating this approach is provided below: 
For a patient with a body weight of 20 kg and a deferasirox FCT dose of 14 mg/kg/day, the 
calculated daily dose is 280 mg. Taking into account the available deferasirox FCT strengths of 
90, 180 and 360 mg, the closest daily dose the patient can receive is 270 mg, by taking 2 crushed 
FCT tablets: 1 x 90 mg + 1 x 180 mg. This combination can be found in the # of Tablets to 
dispense column to the far right in Table 6-1, for patients receiving 14 mg/kg/day of deferasirox 
FCT with a body weight between 17-22 kg. 
 
Table 6-1 
Deferasirox FCT Weight Dosing Table 
 
Body weight ranges per dosing group (kg) 
# of Tablets to dispense 
3.5 
7 
10.5 
14 
17.5 
21 
24.5 
28 
mg/kg/ 
mg/kg/ 
mg/kg/ 
mg/kg/ 
mg/kg/ 
mg/kg/ 
mg/kg/ 
mg/kg/ 
day 
day 
day 
day 
day 
day 
day 
day 
[kg] 
[kg] 
[kg] 
[kg] 
[kg] 
[kg] 
[kg] 
[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 
33-45 
22-30 
17-22 
13-18 
11-15 
10-12 
9-11 
1 
1 
46-57 
31-38 
23-28 
19-23 
16-19 
13-16 
12-14 
1 
39-47 
29-35 
24-28 
20-23 
17-20 
15-17 
1 
1 
48-55 
36-41 
29-33 
24-27 
21-23 
18-20 
1 
1 
42-48 
34-38 
28-32 
24-27 
21-24 
1 
1 
1 
49-54 
39-43 
33-36 
28-31 
25-27 
2 
44-48 
37-40 
32-34 
28-30 
1 
2 
49-54 
41-45 
35-38 
31-33 
1 
2 
46-49 
39-42 
34-36 
1 
1 
2 
50-53 
43-45 
37-40 
3 
46-49 
41-43 
1 
3 
50-53 
44-46 
1 
3 
47-49 
1 
1 
3 
50-52 
4 
These dosing tables have been constructed for each dosing group considering lower (5th) and 
upper (98th) percentiles form weight charts for children aged ≥2 to <6 years. This is taking into 
account that the study will enroll male or female children, ≥ 2 and < 6  years  For patients  with 
a low body weight and lower daily DFX dosing requirements (e.g. below 19 kg body weight in 
the 3.5 mg/kg/day dosing group) the needs will not allow for the use of the smallest tablet 
strength available. In such cases a written request will be sent to Novartis, to advise on the 
individual patient enrolment / dose adjustments options. 
The patient will be dispensed deferasirox FCT in accordance with the protocol. For patients 
already well-managed on prior treatment with deferoxamine or deferasirox DT, a starting dose 
of crushed deferasirox FCT is outlined below in Table 6-2. 


Novartis 
Amended Protocol Version No. 01 (Clean) 
Confidential 
Page 30
6 Protocol No. 
 
 
Table 6-2 
Equivalent dose of deferasirox FCT 
 
ICT Dose Prior to Enrollment 
Starting Dose 
Deferoxamine (mg/kg/day) 
Deferasirox DT (mg/kg/day) 
Deferasirox FCT (mg/kg/day) 
10 
5 
3.5 
20 
10 
7 
30 
15 
10.5 
40 
20 
14 
50 
25 
17.5 
Dose equivalence between deferiprone and deferasirox has not been established in clinical 
studies. For patients pre-treated with deferiprone, the starting dose of deferasirox FCT should 
be 14mg/kg/day. 
Safety assessment will be performed weekly after treatment initiation and thereafter monthly 
during the study. Monthly serum ferritin values and trends will be used to adapt the treatment 
of the patients together with safety data. 
Patients will continue therapy for 24 weeks. 
 
6.1.1 
Dosing regimen 
The recommendations for deferasirox FCT daily dose for pediatric patients’ age ≥ 2 to <6 years 
with transfusional iron overload are the same as for adult patients, i.e. based on the weight of 
the patient. Changes in weight of pediatric patients over time must be taken into account when 
calculating the dose. 
In children with transfusional iron overload aged between 2 and 5 years, exposure is lower than 
in adults. This age group may, therefore, require higher doses than are necessary in adults. 
However, the initial dose should be the same as in adults, with close monitoring by the 
investigator, followed by individual titration. 
 
Table 6-3 
Dose and treatment schedule 
Pharmaceutical form 
Study 
treatments 
Crushed 
Deferasirox 
FCT 
and route of 
administration 
Dose 
Film-coated tablets p.o 
Minimum dose 3.5 mg/kg/day 
Targeted starting dose 14 mg/kg/day 
Maximum dose 28 mg/kg/day 
Dosage is ascertained by patient weight. 
Please refer to dose weight Table 6-1 for 
the recommended dose in mg/ kg/day 
Frequency and/or 
Regimen 
Once daily; all doses 
must be crushed 
prior to 
administration 
 
Deferasirox FCT is for oral use. The full daily dose of one or more film-coated tablets must be 
crushed in the home environment and administered by sprinkling the full dose on to soft food 
(e.g., yogurt or apple sauce [pureed apple]). The dose must be immediately and completely 
consumed, and not stored for future use. The study medication should be taken once daily, 
preferably at the same time each day. 
Subjects who have been established on other chelation therapy will perform a 5 day wash-out 
from the former medication details are provided in Section 7.1.2. 


Novartis 
Amended Protocol Version No. 01 (Clean) 
Confidential 
Page 31
6 Protocol No. 
 
 
The patient’s daily dose will be rounded to the nearest whole tablet according to the available 
strengths of deferasirox FCT tablets (90 mg, 180 mg, and 360 mg). The appropriate daily  dose 
will be calculated by the investigator based on the patient’s actual body weight see Table 6-1. 
The investigator and/or designee will instruct the caregiver and patient to crush the study drug 
and then take the full daily dose of one or more  film-coated  as  prescribed.  Examples  among 
others of an adequate method of crushing of the FCT may be between two pieces of wax paper 
with a rolling pin or with a commercially available pill crusher. All doses planned and 
prescribed to the patient, and all dose changes including reasons for change during the study 
must be recorded in the case report form (CRF). 
During regular study visits, the investigator or pharmacist will give to the patient the appropriate 
number of deferasirox tablets based on the patient’s calculated dose. The number of tablets of 
each strength of deferasirox dispensed will be recorded in the study site’s Study Drug Log. 
Patients will be obliged to return all unused study medication at their next visit. Study 
medication returned by the patients will be counted and unused study medication will be 
recorded by the investigator/pharmacist/designee involved in the study. 
Drug accountability will be noted by the field monitor during site visits and at the completion 
of the trial. 
 
6.1.2 
Ancillary treatments 
Not Applicable 
 
6.1.3 
Rescue medication 
Not Applicable 
 
6.1.4 
Guidelines for continuation of treatment 
For patients who are unable to tolerate the protocol-specified dosing schedule, dose reductions 
are permitted at the discretion of the investigator in order to keep the patient on study drug. 
These changes must be recorded on the dosage administration record electronic (e)CRF. 
The majority of dose reductions, modifications, interruptions are covered in Section 6.3 and 
with further details in Table 6-4. For all cases where a dose adjustment is considered necessary, 
but is not covered in the following sections, the investigator will send a written request to 
Novartis. The request must justify the dose change and provide all supportive clinical and 
laboratory information for complete evaluation by Novartis. Any dose adjustment for reasons 
not included in this section needs to be authorized by Novartis. A written reply will be promptly 
sent back to the investigator by Novartis. 
 
6.1.5 
Treatment duration 
The planned duration of treatment is 24 weeks. Patients may be discontinued from treatment 
with the study drug earlier due to unacceptable toxicity or at the discretion of the investigator 
or the patient. Premature patient withdrawal refers to the point/time when the patient exits from 
the study prior to planned completion of all study treatment administration and/or 


Novartis 
Amended Protocol Version No. 01 (Clean) 
Confidential 
Page 32
6 Protocol No. 
 
 
assessments. At this time, all study treatment is discontinued and after the 30-day safety follow-
up (as possible), no further assessments are planned. 
Patients may continue or resume prescribed iron chelation therapy as per investigator discretion. 
 
6.2 
Dose escalation guidelines 
ICL670F2429 not being an early development study, dose escalation guidelines do not apply; 
for information on dosing regimen, please refer to section 6.1 of the protocol. 
 
6.2.1 
Starting dose rationale 
Not applicable 
 
6.2.2 
Provisional dose levels 
Not Applicable 
 
6.2.2.1 
Implementation of dose escalation decisions 
Not Applicable 
 
6.2.2.2 
Intra-Patient dose escalation 
Not Applicable 
 
6.2.3 
Definitions of dose limiting toxicities (DLTs) 
Not Applicable 
 
6.3 
Dose modifications 
6.3.1 
Dose modification and dose delay 
For patients who do not tolerate the protocol-specified dosing schedule, dose interruptions 
and/or reductions are either recommended or mandated in order to allow patients to continue 
the study treatment. 
These dose modifications are summarized in Table 6-4. Deviations to mandatory dose 
interruptions and/or reductions are not allowed. Permanent treatment discontinuation is 
mandatory for specific events indicated as such in Table 6-4 or listed in Section 7.1.5. 
These dose changes must be recorded on the Dosage Administration Record CRF. 
 
6.3.1.1 
Change in patient’s weight 
The dose of study medication is to be adapted as per locally approved prescribing information 
during the study if the change (increase or decrease) in body weight exceeds 10% of the body 
weight compared to baseline or the last dose adjustment due to change in patient’s body weight. 


Novartis 
Amended Protocol Version No. 01 (Clean) 
Confidential 
Page 33
6 Protocol No. 
 
 
6.3.1.2 
Elevations in serum creatinine 
Serum creatinine must be monitored during the study as stated in visit schedule, refer to Table 
7-1. 
For pediatric patients the following dose adjustment guidance applies: 
• At single increase in serum creatinine (SCr) >ULN and increased by ≥ 33% from baseline, 
maintain DFX dose level and repeat the assessment at next visit as clinically indicated. 
• If serum creatinine (SCr) >ULN and increased by ≥ 33% from baseline on 2 consecutives 
visits, deferasirox dose reduction by 7 mg/kg/day for the FCT is required. 
• If after dose reduction, resolution of serum creatinine occurs (<33%) and within normal 
limits, dose can be re-escalated to 100% of the last dose. 
If increase in serum creatinine recurs 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 may be re- 
escalated to 100% of the last dose depending on the clinical judgement of the investigator. 
If after an initial dose reduction, a progressive increase in serum creatinine beyond the ULN is 
observed, or SCr increase recurs, repeat at adequate dose, a treatment interruption is 
recommended. 
After a treatment interruption, if serum creatinine falls below the age-appropriate ULN on two 
consecutive visits, it is recommended to resume therapy at 50% of the last dose, and after 1 
month, if the serum creatinine increase does not recur, study medication can be returned to 
100% of the last dose (including body weight adjustment if required) depending on the clinical 
judgement of the investigator. 
 
6.3.1.3 
Changes in creatinine clearance 
Pediatric patient who met the eligibility criteria and who experience a renal function decrease 
< LLN (CrCl < 9 0 ml/min) at 2 consecutive visits and the decrease cannot be attributed to other 
causes, DFX must be dose reduced by 7 mg/kg/day. 
If after dose reduction the renal function increases > LLN (CrCl > 90 ml/min), dose may be re- 
escalated to the last daily dose prior dose reduction depending on the clinical judgement of the 
investigator. 
If after dose reduction the renal function remains < LLN (CrCl < 90 ml/min), treatment must 
be interrupted. Treatment may be reinitiated depending on the clinical judgement of the 
investigator. 
If creatinine clearance falls below 60ml/min study treatment must be discontinued. 
 
6.3.1.4 
Changes in serum ferritin 
Serum ferritin must be monitored as stated in visit evaluation schedule, see Table 7-1. 
For iron chelation naïve subjects study entry dose adjustments are allowed after 4 weeks on 
study based on serum ferritin and investigator’s judgement. For iron-chelation pre-treated 


Novartis 
Amended Protocol Version No. 01 (Clean) 
Confidential 
Page 34
6 Protocol No. 
 
 
subjects, the dose of deferasirox should be adjusted if necessary every 3 months based on the 
trends in serum ferritin and investigator’s judgement. 
Dose adjustments should be  made  in  steps  of  3.5  or  7  mg/kg/day and  are  to  be tailored to 
the individual patient’s response and therapy goals (maintenance or reduction of iron burden). In 
patients not adequately controlled with deferasirox, doses of up to 28 mg/kg/day may be 
considered. Deferasirox dose above 28 mg/kg/day is not allowed. 
In patients whose SF level has reached the target (usually between 500 and 1000 ng/mL), dose 
reductions in steps of 3.5  or 7  mg/kg/day are recommended  to  maintain  SF levels within the 
target range. If SF falls below 500 ng/mL, an interruption of study treatment is recommended 
until SF rises above 500 ng/mL. 
 
6.3.1.5 
Changes in urine protein/creatinine ratio 
Proteinuria must be monitored as stated in visit evaluation schedule see Table 7-1. 
For patients who develop proteinuria or a worsening of pre-existing proteinuria (assessed by a 
dipstick) at any visit, microscopic urine assessment should be performed. 
In case of a single increase of the UPCR by quantitative urinalysis measurement, the assessment 
should be repeated at the next visit. Deferasirox dose reduction by 50% is recommended if the 
UPCR increases to >0.5 (mg/mg) in two consecutive non first void urine samples (a minimum 
of 48 hours apart), if all other causes of proteinuria have been excluded. 
Deferasirox must be temporarily interrupted if the UPCR ratio increases to >1.0 (mg/mg) in two 
consecutive non first void urine samples (a minimum of 48 hours apart). 
After resolution (<0.5mg/mg), dose can be resumed again at 100%. 
If increase in UPCR > 0.5mg/mg recurs again within 2 months, study drug needs to be reduced 
to 50% of the last dose. After 2 months, if increase in UPCR does not recur, study medication 
can be returned to 100% of the last dose. 
If increase recurs in UPCR (> 1.0 (mg/mg) recurs in one single non-first void urine samples: 
Interrupt study treatment. 
After resolution (≤ 0.5mg/mg), dose can be resumed again at 50% of the last dose after 1 month, 
if increase in UPCR does not recur for another month, study medication can be returned to 
100% of the last dose. 
Should proteinuria persist, study treatment may be discontinued if the investigator believes it is 
in the best interest of the patient. Novartis may be contacted by the investigator to discuss dosing 
options if the investigator so desires. 
Dose adjustment will be based on laboratory results. 
 
6.3.1.6 
Skin disorders 
 
6.3.1.6.1 Stevens - Johnson syndrome and other severe skin reactions 
Severe skin reactions, including Stevens-Johnson syndrome have been reported during 
deferasirox therapy. If Stevens-Johnson syndrome is suspected, study treatment must be 


Novartis 
Amended Protocol Version No. 01 (Clean) 
Confidential 
Page 35
6 Protocol No. 
 
 
immediately discontinued and not reintroduced. The risk of other severe skin reactions (toxic 
epidermal necrolysis [TEN], drug-reaction with eosinophilia and systemic symptoms [DRESS]) 
cannot be excluded. If Stevens Johnson syndrome or any other severe skin reaction is suspected, 
deferasirox must be discontinued immediately and not reintroduced. Further management is at 
the discretion of the investigator. 
 
6.3.1.6.2 Skin Rash (other than e.g. SJS, TEN, DRESS) 
For skin rash of mild/moderate severity (defined as those causing minimal symptoms which 
require no or minimal supportive treatment), deferasirox 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 deferasirox will be 
interrupted. After the rash resolves, resume deferasirox at 50% of the subject’s last dose, If the 
rash does not recur, increase dose back to 100% of the subject’s dose after 2 weeks. 
For a severe rash (distressing symptoms requiring discontinuation and/or systemic steroids), 
discontinue treatment until resolution of rash. Once the rash has resolved, resume at 50% of 
subject’s dose. If necessary, a brief course of oral steroids may be given concurrently with 
resumption of deferasirox. If the rash does not recur, increase by steps of 3.5 mg/kg day 
deferasirox FCT every 2 weeks until the subject’s last dose is achieved. 
Rare cases of erythema multiforme (EM) have been reported during deferasirox treatment. 
Cases if suspected EM must be reported and DFX dose adjusted in accordance with the above 
recommendations for severe rash. 
If rash recurs, study drug may be discontinued if the investigator believes that is in the best 
interest of the patient. 
 
6.3.1.7 
Increased liver enzyme levels 
If there is a persistent and progressive increase in serum transaminase levels (ALT/AST) that 
cannot be attributed to other causes, deferasirox must be interrupted. Once the cause of the liver 
function test abnormalities has been identified, or after a return to normal levels, cautious re-
initiation of deferasirox treatment at a lower dose followed by gradual dose escalation may be 
considered. In cases of a second rise in serum transaminase levels, the investigator should 
contact Novartis. Refer to table 6.4 for further modification, interruption guidance. 
 
6.3.1.8 
Hepatic Impairment 
In subjects with moderate hepatic impairment (Child-Pugh Class B), put the study medication 
on hold and monitor the patient for total bilirubin, serum albumin, prothrombin time, 
International Normalized Ratio (INR), ascites and hepatic encephalopathy. If liver disease 
prognosis improves, study medication may be reintroduced at 7 mg/kg/day for FCT or 50% of 
previous dose, whichever is less. 
While monitoring continues, the dose may be increased by 3.5 mg/kg/day for FCT every 2 
weeks to a maximum of 50% of the patient’s previous dose if the investigator determines that 
dose increase is in the best interest of the patient. 


Novartis 
Amended Protocol Version No. 01 (Clean) 
Confidential 
Page 36
6 Protocol No. 
 
 
In subjects who develop severe hepatic impairment (Child-Pugh Class C) during the study, 
deferasirox must be discontinued. 
 
6.3.1.9 Dose modification criteria for auditory (decreased hearing) and ocular 
(lens opacities) disturbances 
Auditory (decreased hearing) and ocular (lens opacities) disturbances have been reported with 
deferasirox treatment. Auditory testing will be performed at screening visit 1 before the start of 
deferasirox treatment and at end of treatment and is permitted through the remainder of the 
study at the discretion of the Investigator based on subject’s reporting of symptoms. Ocular 
testing will be performed at screening before the start of deferasirox treatment and at end of 
treatment and is permitted through the remainder of the study at the discretion of the Investigator 
based on the subject’s reporting of symptoms. If auditory or ocular disturbances are noted, dose 
reduction or interruption may be considered and a repeated testing performed as per 
investigator’s judgement. 
 
6.3.1.10 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 must 
be discontinued. Deferasirox must not be reintroduced in patients who have experienced 
previous hypersensitivity reactions on deferasirox due to the risk of anaphylactic shock. 
 
6.3.1.11 Dose modification criteria for cytopenias 
There have been reports (both post-marketing 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 
cytopenias. Reintroduction of therapy with deferasirox may be considered once the cause of 
cytopenia has been identified. 
 
6.3.1.12 Gastrointestinal disturbances 
Some basic recommendations, based on practical experience, can be made to guide 
investigators in managing subjects who experience diarrhea. 
At the first sign of diarrhea, consider anti-diarrhea medication such as loperamide. 
Remind the subject to discontinue any laxative preparations or stool softeners. 
Eat small, frequent meals. Determine if the subject is lactose intolerant. Note that deferasirox 
FCT does not contain lactose. Remind the subject to drink an adequate amount of clear liquid 
per day. 
Patients with GI symptoms (including abdominal pain, nausea, vomiting, and diarrhea) and/or 
patients who are unable to tolerate once a day study drug dosing, the following treatment 
management steps are recommended in the order specified below: 


Novartis 
Amended Protocol Version No. 01 (Clean) 
Confidential 
Page 37
6 Protocol No. 
 
 
• Change the timing of study drug administration from morning to evening, and in addition, 
try using an anti-diarrheal agent for 2 days in case of diarrhea 
• If symptoms still continue, try administering the daily dose as a split dose twice daily. 
Once symptoms resolve, twice daily dosing should be switched back to once daily. 
Do not split dose if only prescribing one tablet per day. 
• Should the GI issues persist, study drug may be discontinued if the investigator believes it 
is in the best interest of the patient. 
 
Table 6-4 
Criteria for dose reduction / interruption and re-initiation of 
deferasirox treatment for adverse drug reactions 
Recommended dose modifications for deferasirox 
Body weight 
Increase/decrease of weight by >10% compared to 
baseline weight or body weight at last dose adjustment 
due to change in patient’s body weight 
 
 
 
 
 
 
Investigations (Renal) 
Serum creatinine and/or creatinine clearance 
Dose of study medication needs to be adapted using 
Deferasirox FCT Weight Dose Table 
 
Dose adjustment needed for Weight changes >10% 
compared to baseline weight or if there is a change in 
patient’s body weight since last dose adjustment. 
 
Smaller variations in body weight (<10%) during study, 
do not require dose adjustments. In this case, baseline 
body weight can be used to calculate correct dose. 
Single increase in serum creatinine ≥33% 
Maintain dose level and repeat the assessment at next 
visit as clinically indicated 
Single serum creatinine increase ≥33% above baseline 
value and >ULN 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patients who met the eligibility criteria and who 
experience a renal function decrease < LLN (CrCl < 
90ml/min) at 2 consecutive visits 
Deferasirox dose reduction by 7 mg/kg/day for the FCT 
is necessary. 
If after dose reduction, resolution of serum creatinine 
occurs (<33%) and within normal limits, dose can be 
re-escalated to 100% of the last dose. 
If increase in serum creatinine recurs 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 may be re-escalated to 
100% of the last dose depending on the clinical 
judgement of the investigator. 
If after an initial dose reduction, a progressive increase 
in serum creatinine beyond the ULN is observed, or 
SCr increases re-occur repeatedly at adequate dose, a 
treatment interruption is recommended. 
After a treatment interruption, if serum creatinine falls 
below the age-appropriate ULN on two consecutive 
visits, it is recommended to resume therapy at 50% of 
the last dose, and after 1 month, if the serum creatinine 
increase does not recur, study medication can be 
returned to 100% of the last dose (including body 
weight adjustment if required) depending on the clinical 
judgement of the investigator. 
If decrease cannot be attributed to other causes, DFX 
must be dose reduced by 7mg/kg/day. 
If after dose reduction the renal function increases > 


Novartis 
Amended Protocol Version No. 01 (Clean) 
Confidential 
Page 38
6 Protocol No. 
 
 


Novartis 
Amended Protocol Version No. 01 (Clean) 
Confidential 
Page 39
6 Protocol No. 
 
 
 
Recommended dose modifications for deferasirox 
 
 
 
 
 
 
 
 
Investigations (Hepatic) 
Isolated direct (conjugated) Bilirubin elevation 
 
LLN (CrCl >90ml/min), dose may be re-escalated to the 
last daily dose prior dose reduction depending on the 
clinical judgement of the investigator. 
If after dose reduction the renal function remains <LLN 
(CrCl <90ml/min), treatment must be interrupted. 
Treatment may be reinitiated depending on the clinical 
judgement of the investigator. 
If creatinine clearance falls below 60ml/min study 
treatment must be discontinued. 
> ULN – 1.5 x ULN 
Maintain dose level 
> 1.5 - 3.0 x ULN 
Omit dose with weekly monitoring of LFTs, or more 
frequently if clinically indicated, until resolved to ≤ 1.5 x 
ULN. 
If resolved in ≤ 14 days, then maintain dose level 
If resolved in > 14 days, then dose reduction of 3.5 or 7 
mg/kg/day for deferasirox FCT. 
> 3.0 - 10.0 x ULN 
Omit dose with weekly monitoring of LFTs, or more 
frequently if clinically indicated, until resolved to ≤ 1.5 x 
ULN. 
If resolved in ≤ 14 days, then dose reduction of 3.5 or 7 
mg/kg/day for deferasirox FCT 
If resolved in > 14 days, then discontinue patient from 
study drug treatment. The patient needs to be 
monitored weekly (including LFTs), or more frequently 
if clinically indicated until TBIL have resolved to 
baseline or stabilization. Please refer to section 6.3.3 
for additional details on follow-up. 
> 10.0 x ULN* 
Discontinue patient from study drug treatment 
The patient needs to be monitored weekly (including 
LFTs), or more frequently if clinically indicated, until 
TBIL have resolved to baseline or stabilization. Please 
refer to section 6.3.3 for additional details on follow-up. 
 
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) 
 
 
 
 
 
> 5.0 - 10.0 x ULN 
(For patients with baseline value > 3.0 -5.0 x ULN) 
> 5.0 - 10.0 x ULN 
(For patients with baseline value ≤ 3.0 x ULN) 
 
 
 
 
 
> 10.0 - 20.0 x ULN 
(For patients with baseline value > 3.0 -5.0 x ULN) 


Novartis 
Amended Protocol Version No. 01 (Clean) 
Confidential 
Page 40
6 Protocol No. 
 
Maintain dose level. 
Repeat LFTs 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 
LFTs weekly, or more frequently if clinically 
indicated, until resolved to ≤ 3.0 x ULN. Please 
refer to section 6.3.3 for additional details on 
follow-up. 
Maintain dose level. 
 
Omit dose. 
Repeat LFTs as soon as possible, preferably 
within 48- 72 hours from awareness of the 
abnormal results; monitor LFTs 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 
3.5 or 7 mg/kg/day for deferasirox FCT. 
Omit dose. 
Repeat LFTs as soon as possible, preferably 
within 48- 


Novartis 
Amended Protocol Version No. 01 (Clean) 
Confidential 
Page 41
6 Protocol No. 
 
 
 
Recommended dose modifications for deferasirox 
 
 
 
 
> 20.0 x ULN 
(For patients with baseline value > 3.0 -5.0 x ULN) 
 
 
 
 
Combined elevations of AST or ALT and total bilirubin 
For patients with normal baseline ALT or AST or total 
bilirubin value: 
 
AST or ALT >3.0xULN combined with total 
bilirubin >2.0 x ULN without evidence of cholestasis 
OR 
[AST or ALT>2x baseline AND > 3.0 xULN] OR [AST or 
ALT > 8.0 xULN], whichever is lower, combined with 
[total bilirubin >2x baseline AND >2.0 xULN 
 
 
Hepatic impairment 
 
72 hours from awareness of the abnormal results; 
monitor LFTs weekly, or more frequently if clinically 
indicated, until resolved to ≤ baseline. Then dose 
reduction of 3.5 or 7 mg/kg/day for deferasirox FCT. 
Discontinue patient from study drug treatment 
Repeat LFTs as soon as possible, preferably within 48- 
72 hours from awareness of the abnormal results; 
monitor LFTs weekly, or more frequently if clinically 
indicated, until resolved to baseline or stabilization. 
Please refer to section 6.3.3 for additional details on 
follow-up of toxicities. 
 
Interrupt study treatment. 
Permanently discontinue patient from study drug 
treatment if no other plausible explanation can be found 
for the combined increase. 
 
Repeat as soon as possible, preferably within 48 hours 
from awareness of the abnormal results, then with 
weekly monitoring of LFTs, or more frequently if 
clinically indicated, until AST, ALT, or bilirubin have 
resolved to baseline or stabilization. 
 
Please refer to section 6.3.3 for additional details on 
follow-up of toxicities. 
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 7 mg/kg/day for FCT 
or 50% of previous dose, whichever is less. While 
monitoring continues, dose may be increased by 3.5 
mg/kg/day for FCT 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 
Other recommended dose modifications 
Changes in Serum Ferritin 
Study medication must be discontinued. 
500 – 1000 ng/mL 
The dose of deferasirox FCT should be adjusted as 
necessary every 3 months based on the trends in 
serum ferritin and investigator’s judgement. 
ICT naïve  patients  can  adapt  dose  after  4  weeks 
on  study. Dose adjustments for deferasirox FCT 3.5 
mg or 7 mg/kg/day 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 FCT 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 28 mg for deferasirox FCT 


Novartis 
Amended Protocol Version No. 01 (Clean) 
Confidential 
Page 42
6 Protocol No. 
 
are not allowed. 
Dose reductions in steps of 3.5 or 7 mg/kg/day for 


Novartis 
Amended Protocol Version No. 01 (Clean) 
Confidential 
Page 43
6 Protocol No. 
 
 
 
Recommended dose modifications for deferasirox  
deferasirox FCT are 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 
> 0.5 (mg/mg) in two consecutive non- first void urine 
samples (a minimum of 48h apart), if all other causes of 
proteinuria have been excluded. 
 
 
 
 
 
 
 
 
 
 
 
> 1.0 (mg/mg) in one single non-first void urine 
samples. 
 
 
 
 
 
 
 
 
 
Severe skin reactions 
Severe skin reactions, including Stevens-Johnson 
syndrome (SJS), Toxic epidermal necrolysis (TEN), 
DRESS 
 
Skin Rash (other than SJS, TEN, DRESS) 
For skin rash of mild/moderate severity (defined as 
those causing minimal symptoms which require no or 
minimal supportive treatment) 
 
 
 
 
 
 
Severe rash (distressing symptoms requiring 
discontinuation and/or systemic steroids) 
 
For patients who develop proteinuria or a worsening of 
pre-existing proteinuria at any visit, urine samples 
should be collected and assessed by the laboratory.  
In case of a single increase of the urinary 
protein/creatinine ratio the assessment should be 
repeated at the next visit. 
Deferasirox FCT 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. 
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. 
Should proteinuria persist, study treatment may be 
discontinued if the investigator believes it is in the best 
interest of the patient. Novartis may be contacted by 
the investigator to discuss dosing options if the 
investigator so desires. 
Dose adjustment will be based on laboratory results. 
 
Must be reported if occurs during Exjade therapy. 
If SJS ,TEN, DRESS is suspected, study treatment 
must be immediately discontinued and not be 
reintroduced 
 
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. 
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 3.5 
mg/kg/day for deferasirox FCT 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 
 


Novartis 
Amended Protocol Version No. 01 (Clean) 
Confidential 
Page 44
6 Protocol No. 
 
 
 
Recommended dose modifications for deferasirox  
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 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 judgment. 
 
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. 
 
Dose modification criteria for cytopenias 
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 deferasirox due to the risk of anaphylactic shock 
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. 
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. Monitor 
fluid intake and adapt as necessary according to body 
weight. 
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. 
 
 
6.3.2 
Dose adjustments for QTcF prolongation 
Not applicable 


Novartis 
Amended Protocol Version No. 01 (Clean) 
Confidential 
Page 45
6 Protocol No. 
 
 
6.3.3 
Follow-up for toxicities 
Patients whose treatment is interrupted or permanently discontinued due to an adverse event or 
abnormal laboratory value must be followed for at least 30 days. All unresolved toxicities 
should be followed by the investigator until CTCAE Grade ≤1, return to baseline, stabilization 
or the subject is lost to follow-up. 
 
6.3.3.1 
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: 
• For patients with normal ALT and AST and 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], 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 whether the relative pattern of ALT and/or ALP elevation is due to 
cholestatic (R ≤ 2), hepatocellular (R ≥ 5), or mixed (R >2 and < 5) 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. Data and test results must be entered in the hepatotoxicity 
follow up test procedures eCRFs available in the clinical database. 
1. Laboratory tests should include ALT, AST, albumin, creatine kinase, total bilirubin, direct 
and indirect bilirubin, GGT, prothrombin time (PT)/INR and alkaline phosphatase. 
2. 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. 
3. Further testing for acute hepatitis A, B, C or E infection and liver imaging (e.g. biliary 
tract) may be warranted. 
4. Obtain PK sample, as close as possible to last dose of study drug, if PK analysis is 
performed in the study. 
5. 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. 


Novartis 
Amended Protocol Version No. 01 (Clean) 
Confidential 
Page 46
6 Protocol No. 
 
 
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. 
 
6.3.4 
Anticipated risks and safety concerns of the study drug 
Appropriate eligibility criteria, as well as specific dose modification and stopping rules are 
included in this protocol. Recommended guidelines for prophylactic or supportive treatment for 
expected toxicities, including management of study-drug induced AEs i.e., gastrointestinal, skin 
toxicity and diarrhea are provided in Table 6-4. Refer to preclinical toxicity and or clinical data 
found in the Investigator’s Brochure. 
 
6.4 
Concomitant medications 
The patient must be told to notify the investigational site about any new medications he/she 
takes after the start of the study drug. All medications (other than study drug) and significant 
non-drug therapies (including physical therapy and herbal/natural medications) administered 
during the study must be listed on the Concomitant Medications or the Procedures and 
Significant Non-Drug Therapies CRF. Blood transfusions must be entered on the Blood 
Component Transfusion CRF 
 
6.4.1 
Blood transfusion 
History of blood transfusions within the period of 3 months prior to Screening visit 1 must be 
recorded on Blood Component Transfusion CRF page. Additionally, record of blood 
transfusion during the study must collected (see Table 7-1) and entered on the Blood 
Component Transfusion CRF page. 
 
6.4.2 
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 any adverse consequences. 
Aluminum containing antacid therapies should be avoided because they may bind to 
deferasirox. 
The concomitant use of deferasirox with potent UGT inducers (e.g. rifampicin, phenytoin, 
phenobarbital, ritonavir) may result in a decrease in deferasirox efficacy. 
Concomitant use of any iron chelation therapy other than the study drug, investigational 
agents or bile acid sequestrants is not allowed. 
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 non-steroidal anti-inflammatory drugs, corticosteroids, or oral 
bisphosphonates, and use of deferasirox in patients receiving anticoagulants my increase 
the risk of gastrointestinal irritation 


Novartis 
Amended Protocol Version No. 01 (Clean) 
Confidential 
Page 47
6 Protocol No. 
 
 
• Deferasirox, as a weak CYP3A4 inducer, may potential increase serum levels of 
substances metabolized through CYP3A4 (e.g. cyclosporine, simvastatin, hormonal 
contraceptive agents) 
• Deferasirox is a moderate inhibitor of CYP2C8 and therefore, may increase serum 
concentrations of substances metabolized through CYP2C8 (e.g. repaglinide, pa 
paclitaxel) 
 
6.4.3 
Prohibited concomitant therapy 
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 
• Any iron chelation therapy other than study drug 
• Any investigational drug other than the study medication 
6.4.4 
Use of Bisphosphonates (or other concomitant agents) 
Not applicable 
 
6.4.4.1 
Proposed language for other concomitant medications 
Not applicable 
 
6.5 
Patient numbering, treatment assignment or randomization 
6.5.1 
Patient numbering 
Each patient is identified in the study by a Subject Number (Subject 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 Subject 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 subject is numbered uniquely across the entire database. 
Upon signing the informed consent form, the patient is assigned to the next sequential Subject 
No. available to the investigator through the Oracle Clinical RDC interface. 
 
6.5.2 
Treatment assignment or randomization 
This is a single-arm, non-randomized, interventional, open- label, global multi-center study. 
 
6.5.3 
Treatment blinding 
This is an open-label study and therefore, patients, investigators, study site staff and study field 
monitors are not blinded to study treatment. 
 
6.6 
Study drug preparation and dispensation 
The investigator or responsible site personnel will contact the IRT system to register the patient 
by providing the required information into the IRT system. All drug dispensation will be 
registered in IRT. Countries with commercially available deferasirox will register only the 
quantity dispensed as there are no unique kit numbers on commercial drugs. 


Novartis 
Amended Protocol Version No. 01 (Clean) 
Confidential 
Page 48
6 Protocol No. 
 
 
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 CRF. Crushing deferasirox FCT is 
mandatory for this trial. Do not split dose if only prescribing one tablet per day. Caregiver will 
receive instructions from the site study personnel on study drug preparation. 
 
Table 6-5 
Preparation and dispensing 
Study Treatments 
Dispensing 
Preparation 
Crushed 
Deferasirox FCT 
Tablets, including instructions for 
crushing and administration, are 
dispensed by study personnel on an 
outpatient basis. 
Patients will be provided with 
adequate supply of study treatment 
for self-administration at home until 
at least their next scheduled study 
visit. 
All doses of deferasirox FCT must 
be crushed in the home 
environment. Crushing the 
deferasirox FCT is mandatory. 
One example of a crushing method 
is to place the film-coated tablets 
between two pieces of wax paper 
and roll over the wax paper with a 
rolling pin until the tablets become a 
fine powder, then funnel the wax 
paper crushed FCT powder 
contents into a bowl and mix with a 
soft food. 
 
 
6.6.1 
Study treatment packaging and labeling 
 
6.6.1.1 
Countries where Deferasirox FCT is not commercially available 
The study drug will be supplied centrally by Novartis to countries where Deferasirox FCT is 
not commercially available. 
Study medication labels will be in the local language and will comply with the legal 
requirements of the respective country and will include storage conditions and a unique 
medication number. 
. Responsible site personnel will identify the study treatment dosage(s) to dispense to the patient. 
Site personnel will add the patient number on the label. Immediately before dispensing the 
package to the patient, site personnel will record study drug dosage amounts and quantity 
dispensed in the source document (Drug Label Form) for that patient. If the label has 2-parts 
(base plus tear-off label), immediately before dispensing the package to the patient, site 
personnel will detach the outer part of the label from the package and affix it to the patient’s 
source document. 
 
6.6.1.2 
Countries where Deferasirox FCT is commercially available 
Countries where Deferasirox FCT is commercially available will use commercially available 
Deferasirox FCT as study drug and will follow their local process for using commercial product 
for clinical trials. 


Novartis 
Amended Protocol Version No. 01 (Clean) 
Confidential 
Page 49
6 Protocol No. 
 
 
Table 6-6 
Packaging and labeling 
Study treatments 
Packaging 
Labeling (and dosing frequency) 
Deferasirox FCT 
Local Commercial (for countries 
where Deferasirox FCT is marketed) 
Labeled as Deferasirox FCT 
ICL670 
Non-commercial (for countries 
where Deferasirox FCT is not 
marketed) 
Labeled as ICL670 
 
6.6.2 
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. 
Sites in countries where Deferasirox FCT is not commercially available will be supplied 
centrally with study drug (ICL670) by Novartis. Upon receipt, the investigator or designee will 
confirm study drug receipt in IRT and store study drug according to the instructions specified 
on the drug labels and in the Investigator’s Brochure. 
The sites in the countries where Deferasirox FCT is commercially available will use 
commercially available Deferasirox FCT (as study drug) supplied by the local Novartis affiliate. 
Upon receipt, the investigator or designee will store study drug according to the instructions 
specified on the drug label. 
 
Table 6-7 
Supply and storage of study treatments 
Study treatments 
Supply 
Storage 
Deferasirox FCT 
Locally supplied by Novartis for 
countries where Deferasirox FCT is 
marketed 
ICL760 
Centrally supplied by Novartis 
(labeled medication) for countries 
where Deferasirox FCT is not 
marketed. 
Refer to study treatment label 
 
 
Refer to study treatment label 
 
 
6.6.3 
Study drug compliance and accountability 
 
6.6.3.1 
Study drug compliance 
Compliance will be assessed by the investigator and/or study site personnel at each patient visit 
and information provided by the patient and/or caregiver will be captured in the Drug 
Accountability Form. This information must be captured in the source document at each patient 
visit 
 
6.6.3.2 
Study drug accountability 
The investigator or designee must maintain an accurate record of the shipment and dispensing 
of study treatment in a drug accountability log. All drug dispensation will be registered in IRT. 
Drug accountability will be noted by the field monitor during site visits and at the completion 
of the study. Patients will be asked to return all unused study treatment and packaging on a 
regular basis, at the end of the study or at the time of study treatment discontinuation. 


Novartis 
Amended Protocol Version No. 01 (Clean) 
Confidential 
Page 50
6 Protocol No. 
 
 
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. 
 
6.6.3.3 
Handling of other study treatment 
Not applicable. 
 
6.6.4 
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 and indicates with an “X”, the visits when they are 
performed. All data obtained from these assessments must be supported in the patient’s source 
documentation. All data obtained from these assessments and noted with an “S” in the category 
column must be supported in the patient’s source documentation. The “D” in the category 
column must be supported in Novartis eCRF database. 
No CRF will be used as a source document. 


Novartis 
Amended Protocol Version No. 01 (Clean) 
Confidential 
Page 48
8 Protocol No. 
 
 
 
Table 7-1 
Visit evaluation schedule 
 
Category 
Protocol 
Section 
Screening Visit 1 
Day -14 to -8 
Screening Visit 2 
Day -7 to -1 
(Newly Initiated 
DFX patients
Baseline 
End of 
study 
treatment 
(EoT) 
Week 24 
± 7 days 
30 day 
safety 
follow-up 
Visit Name 
SV1 
SV2* 
Week 1 
Day 1 
Week 2 
± 3 days 
Week 3 
± 3 days 
Week 4 
± 3 days 
Week 8 
± 7 days 
Week 12 
± 7 days 
Week 16 
± 7 days 
Week 20 
± 7 days 
Obtain Informed Consent 
D 
11.3 
X 
IRT(IWRS) 
S 
7.1.2.1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Patient History 
Demography 
D 
7.1.2.3 
X 
Inclusion/exclusion 
criteria 
D 
5.2, 5.3 
X 
X 
Medical History 
D 
7.1.2.3 
X 
Transfusion Therapy1 
D 
6.4 
X 
Continuous – up to 30 days after last dose 
Prior and Concomitant 
Medications/Prior 
Chelation 
D 
6.4 
X 
Continuous – up to 30 days after last dose 
Surgical and Medical 
Procedures 
D 
6.4 
X 
Continuous – up to 30 days after last dose 
Physical Examination 
Physical Examination 
S 
7.2.2.1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
D 
7.2.2.3 
X 
X 
Weight 
D 
7.2.2.3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
D 
7.2.2.2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


Novartis 
Amended Protocol Version No. 01 (Clean) 
Confidential 
Page 49
8 Protocol No. 
 
 
Category 
Protocol 
Section 
Screening Visit 1 
Day -14 to -8 
Screening Visit 2 
Day -7 to -1 
(Newly Initiated 
DFX patients
Baseline 
End of 
study 
treatment 
(EoT) 
Week 24 
± 7 days 
30 day 
safety 
follow-up 
Visit Name 
SV1 
SV2* 
Week 1 
Day 1 
Week 2 
± 3 days 
Week 3 
± 3 days 
Week 4 
± 3 days 
Week 8 
± 7 days 
Week 12 
± 7 days 
Week 16 
± 7 days 
Week 20 
± 7 days 
Laboratory Assessments 
Hematology 
D 
7.2.2.5.1 
X 
X 
X 
X 
X 
X 
X 
X 
Chemistry 
D 
7.2.2.5.2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis (Dipstick) 
D 
7.2.2.5.3 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis (Urinary 
protein/creatinine ratio) 
D 
7.2.2.5.3 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis (Microscopic) 
D 
7.2.2.5.3 
As clinically indicated 
Hepatitis markers 
D 
7.1.2.3 
X 
As clinically indicated 
Cardiac Assessments 
ECG 
D 
7.2.2.10. 
1 
X 
As clinically indicated 
Safety 
Adverse events 
D 
8.1 
X 
Continuous – up to 30 days after last dose 
Hepatotoxicity Follow-up 
testing procedures 
D 
6.3.3.1 
As clinically indicated 
Ocular assessments2 
D 
7.2.2.6 
X 
As clinically indicated 
X 
Auditory assessments2 
D 
7.2.2.7 
X 
As clinically indicated 
X 
Observer Reported 
Outcomes 


Novartis 
Amended Protocol Version No. 01 (Clean) 
Confidential 
Page 50
8 Protocol No. 
 
 
Category 
Protocol 
Section 
Screening Visit 1 
Day -14 to -8 
Screening Visit 2 
Day -7 to -1 
(Newly Initiated 
DFX patients
Baseline 
End of 
study 
treatment 
(EoT) 
Week 24 
± 7 days 
30 day 
safety 
follow-up 
Visit Name 
SV1 
SV2* 
Week 1 
Day 1 
Week 2 
± 3 days 
Week 3 
± 3 days 
Week 4 
± 3 days 
Week 8 
± 7 days 
Week 12 
± 7 days 
Week 16 
± 7 days 
Week 20 
± 7 days 
mSICT 
D 
7.2.8 
X3 
X 
X 
X 
Palatability questionnaire 
D 
7.2.8 
X3 
X 
X 
X 
GI symptom 
questionnaire 
D 
7.2.8 
X3 
X 
X 
X 
X 
X 
X 
X 
X 
Study drug dispensation 
D 
6.3.1 
X 
X 
X 
X 
X 
X 
End of phase disposition 
D 
X 
X 
X 
Safety follow-up 
D 
4.1 
X 
* SV2 is applicable only to patients who are chelation naïve or are currently treated with chelation therapy other than deferasirox. Patients on prior deferasirox will NOT be subject to SV2 
1 History of prior transfusion up to 3 months prior to Screening visit 1 (SV1) must be collected at SV1. Additionally, record of transfusion during the study must be collected. 
2 The choice of method for ocular and auditory assessments will be at the discretion of the investigators. Best efforts should be made to perform these assessments in all subjects, although 
feasibility in very young children will be at the discretion of the investigator. 
3 Chelation naïve patients and patients treated with chelation therapy other than deferasirox who stopped chelation treatment more than 7 days prior to Screening visit 1 (SV1) will not 
complete questionnaires at SV1. 


Novartis 
Amended Protocol Version No. 01 (Clean) 
Confidential 
Page 51
1 Protocol No. 
 
 
 
7.1.1 
Molecular pre-screening 
Not applicable 
 
7.1.2 
Screening 
Prior to commencement of the screening examination, the patient and their caregiver(s) must 
have given full informed consent and have completed the study Informed Consent Form.  Once 
this has been signed and dated by the patient’s legal guardian then the investigator can take the 
patients through the study inclusion and exclusion criteria to make sure the patient is fully 
eligible to participate. The investigator or responsible site personnel will register Screening visit 
1 in IRT. 
The full list of assessments to be performed during the screening period (Day -14 to Day 1) is 
detailed in Table 7-1. Two Screening visits at least 7 days apart are needed to perform key safety 
parameters prior to the first dose administration in patients who are chelation naïve or are 
currently treated with a chelation therapy other than deferasirox. 
For patients that are chelation naïve or currently treated with other chelators, the investigator or 
responsible site personnel will register Screening visit 2 in IRT. Patients on prior deferasirox will 
be subject to only screening visit 1 and baseline visit can be scheduled after eligibility is 
established. 
Re-screening for patients who screen-failed is permissible on a case by case basis. Please 
contact Novartis for guidance to get information on how to process screen failures. Re-screening 
visits will be registered in IRT. 
 
7.1.2.1 
Eligibility screening 
Patient eligibility will be checked after screening procedures have been completed. . 
 
7.1.2.2 
Information to be collected on screening failures 
Patients or their caregivers who sign an informed consent but fail to start treatment for any 
reason will be considered a screen failure. The reason for not being started on treatment will be 
entered on the Site Screening Log. Data for screen failure patients will be collected on the 
following eCRFs: 
• Demography 
• Informed consent 
• Inclusion/exclusion 
• Screening phase disposition 
• Adverse events (only if SAE occurred) 
• Death (if applicable) 
• Withdrawal of consent (if applicable) 


Novartis 
Amended Protocol Version No. 01 (Clean) 
Confidential 
Page 52
1 Protocol No. 
 
 
7.1.2.3 
Patient demographics and other baseline characteristics 
At screening visit 1 data will be collected on patient characteristics including demographics 
(age, sex, ethnicity, etc.), medical history (including current medical conditions and history of 
disease), transfusion history, physical examination, laboratory assessments, and vital signs. 
To determine eligibility to be enrolled in the study, patients will also undergo assessments as 
per the inclusion and exclusion criteria which include hematology and chemistry evaluations, 
hepatitis viral history evaluation, serum ferritin, serum creatinine, creatinine clearance, liver 
function enzymes (ALT/AST), direct/total bilirubin, ALP, a known history of HIV positive test 
result (ELISA or Western blot) which is documented in the source documents, history of active 
Hepatitis B and/or C, UPCR, and urinalysis. Patients will also undergo a standard 
ophthalmologic evaluation, audiometry, and ECG. 
 
7.1.3 
Run-in period 
Any current iron chelation therapy except deferasirox will be discontinued to undergo a 5-day 
washout period prior to commencing the 24-week treatment period with crushed deferasirox 
FCT. 
A second screening visit will occur for chelation naïve and patients treated with iron chelation 
therapy other than deferasirox as detailed in Table 7-1. 
 
7.1.4 
Treatment period 
Having completed the screening period, patients will be enrolled and eligibility registered in 
IRT. The patient will then begin therapy with crushed deferasirox FCT as per study protocol. 
The treatment duration is 24 weeks. Study treatment is defined as crushed deferasirox FCT 
applied according to study protocol. Study-mandated evaluations and safety assessments will 
be performed every week for the first month and monthly thereafter in alignment with the visit 
schedule, see Table 7-1. 
 
7.1.5 
Discontinuation of study treatment 
Patients or their caregivers may voluntarily discontinue from the study for any reason at any 
time. If a patient decides to discontinue from the study, the investigator should make a 
reas onabl e 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 may discontinue deferasirox FCT for a given patient if, he/she believes that 
continuation would be detrimental to the patient’s well-being. 
Patients who discontinue d e f e r a s i r o x  F C T  should NOT be considered withdrawn from 
the study. They should return for the assessments indicated in Section 7.2.1. If they fail to return 
for these assessments for unknown reasons, every effort (e.g. telephone, email, letter) should be 
made to contact them as specified in Section 7.1.8. 
Study treatment may be discontinued under the following circumstances: 


Novartis 
Amended Protocol Version No. 01 (Clean) 
Confidential 
Page 53
1 Protocol No. 
 
 
• Adverse Event 
• Death 
• Lack of Efficacy 
• Withdrawal of informed Consent 
• Protocol Deviation 
• Study terminated by sponsor 
• Technical Problem 
• Lost to follow-up 
• Physicians decision 
• Subject/guardian decision 
Patients who discontinue deferasirox FCT should undergo an end of treatment visit within 7 
days followed by a 30 day safety follow-up. 
The Investigator or responsible site personnel must contact the IRT to register the patient’s 
discontinuation. 
 
7.1.5.1 
Replacement policy 
Patients who discontinue or are withdrawn will not be replaced on study. 
 
7.1.6 
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 prior to withdrawal of consent in order to guarantee the validity of the 
study. 
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. 
 
7.1.7 
Follow up for safety evaluations 
All patients must have safety evaluations for 30 days after the last dose of study treatment. Data 
collected should be added to the Adverse Events, Prior and Concomitant Medications, and 
Surgical and Medical procedures eCRFs. All unresolved adverse events should be followed by 
the investigator until the events are resolved, or the subject is lost to follow-up. 


Novartis 
Amended Protocol Version No. 01 (Clean) 
Confidential 
Page 54
1 Protocol No. 
 
 
7.1.8 
Lost to follow-up 
For patients whose status is unclear because they fail to appear for study visits without stating 
an intention to withdraw consent, the investigator should show "due diligence" by contacting 
the patient, family or family physician as agreed in the informed consent and by documenting 
in the source documents steps taken to contact the patient, e.g. dates of telephone calls, 
registered letters, etc. A patient should not be considered lost to follow-up until due diligence 
has been completed. Patients lost to follow up should be recorded as such on the appropriate 
Disposition CRF. 
 
7.1.9 
Unscheduled visits 
Unscheduled safety assessments may be performed as clinically indicated at the discretion of 
the investigator at any time during the study. 
 
7.2 
Assessment types 
7.2.1 
Efficacy assessments 
The efficacy variable will be the change in serum ferritin from baseline to end of treatment. 
Serum ferritin will be performed at screening visit 1 to assess the eligibility of the patient. Serum 
ferritin will be assessed at week 1 /day 1 and monthly during the treatment period. Additional 
assessment of serum ferritin assessments may be performed more frequently if needed in 
accordance with the clinical judgment of the investigator. 
 
7.2.2 
Safety and tolerability assessments 
Safety will be monitored by assessing frequency and severity of adverse events as well as 
physical examination, vital signs, hematology, blood chemistry, urinalysis, ECG, ocular, and 
auditory assessments and laboratory parameters as detailed in Table 7-1. Additional details can 
be found in Section 7.5.1.7. 
For details on AE collection and reporting, refer to Section 8. 
 
7.2.2.1 
Physical examination 
A complete physical examination will be performed at screening visit 1 and each visit as 
detailed in Table 7-1. 
A complete physical examination will include the examination of general appearance, skin, 
neck (including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, 
and extremities, vascular and neurological. If indicated based on medical history and/or 
symptoms, rectal, external genitalia, and pelvic exams will be performed. 
Information about the physical examination must be present in the source documents 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 CRF. Significant new findings that begin or worsen 
after informed consent must be recorded on the Adverse Event page of the patient’s CRF. 


Novartis 
Amended Protocol Version No. 01 (Clean) 
Confidential 
Page 55
1 Protocol No. 
 
 
7.2.2.2 
Vital signs 
Vital signs include blood pressure (supine position preferred when ECG is collected), pulse 
measurement, and body temperature will be measured at screening visit 1, screening visit 2 and 
at all visits including end of treatment as detailed in Table 7-1. 
 
7.2.2.3 
Height and weight 
Standing height will be assessed at screening visit 1 and end of treatment. Weight will be 
assessed at screening visits 1 and 2, week 1/day 1, monthly visits, week 4 through week 20 and 
end of treatment as detailed in Table 7-1. 
Height in centimeters (cm) and body weight (to the nearest 0.1 kilogram [kg] in indoor clothing, 
but without shoes) will be measured. 
 
7.2.2.4 
Performance status 
Not applicable 
 
7.2.2.5 
Laboratory evaluations 
Clinical laboratory parameters will be assessed as detailed in Table 7-2. 
 
Table 7-2 
Local Clinical laboratory parameters collection plan 
 
Test Category 
Test Name 
Hematology 
Hematocrit, Hemoglobin, MCH, MCHC, MCV, Platelets, Red blood cells, White blood 
cells, Differential (Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils) 
Chemistry 
Alkaline phosphatase, ALT , AST, Creatinine, Creatinine clearance, Direct Bilirubin, 
Total Bilirubin, Blood Urea Nitrogen (BUN) or Urea, Uric acid, Total protein, 
Bicarbonate, Albumin, Chloride, Glucose, Inorganic phosphate, Potassium, Sodium, 
Calcium and Magnesium. 
Urinalysis 
Microscopic Panel (Red Blood Cells, White Blood Cells, Casts, Bacterial casts 
Macroscopic Panel (Dipstick): Color, Bilirubin, WBCs, Blood, Glucose, Ketones, Nitrite, 
pH, Protein, Specific Gravity, Urobilinogen 
Urinalysis: Urine protein/creatinine ratio 
Hepatitis markers 
HBsAg, Anti-HCV, Anti-HBs, HCV RNA-PCR quantitative (screening visit 1) 
Analysis of all laboratory specimens including urinary dipstick analysis will be performed by a 
local laboratory. 
 
7.2.2.5.1 Hematology 
Complete blood cell count with differential samples will be collected at screening visit 1, week 
1 and monthly at weeks 4 through 24 as detailed in Table 7-1. 
Parameters to be measured will include: Hemoglobin, Hematocrit, Red Blood Cell Count, Mean 
Corpuscular Volume, Mean Corpuscular Hemoglobin, Mean Corpuscular Hemoglobin 
Concentration, White Blood Cell Count, White Blood Cell Differential, and Platelet Count 
 
7.2.2.5.2 Clinical chemistry 
Clinical chemistry samples will be collected at screening visit 1 and screening visit 2 and at 
visits as detailed in Table 7-1. 


Novartis 
Amended Protocol Version No. 01 (Clean) 
Confidential 
Page 56
1 Protocol No. 
 
 
The parameters to be measured at screening visits and at specific timepoints in the study are as 
follows: 
Screening Visit 1 -All patients: 
Parameters to be measured include serum creatinine, creatinine clearance, blood urea nitrogen 
or urea, total bilirubin, direct bilirubin, ALT, AST, alkaline phosphatase, uric acid, total protein, 
bicarbonate, albumin, chloride, glucose, inorganic phosphate, potassium, sodium, calcium, 
magnesium and serum ferritin. 
Screening Visit 2 - (Only patients who are chelation naïve or treated with iron chelation 
other than deferasirox): 
Parameters to be measured include serum creatinine, creatinine clearance and serum ferritin. 
Study Visit Baseline (Week 1) – All patients: 
Parameters to be measured include serum creatinine, creatinine clearance, blood urea nitrogen 
or urea, total bilirubin, direct bilirubin, ALT, AST, alkaline phosphatase uric acid, total protein, 
bicarbonate, albumin, chloride, glucose, inorganic phosphate, potassium, sodium, calcium, 
magnesium and serum ferritin. 
Study Visit Week 2 – All patients: 
Parameters to be measured include serum creatinine and creatinine clearance 
Study Visit Week 3 – All patients: 
Parameters to be measured include serum creatinine, creatinine clearance, total bilirubin, direct 
bilirubin, ALT, AST, uric acid, total protein, bicarbonate, albumin, chloride, glucose, inorganic 
phosphate, potassium, sodium, calcium, magnesium and alkaline phosphatase. 
Study Visit Weeks 4, 8, 12, 16, 20 and end of treatment – All patients: 
Parameters to be measured include serum creatinine, creatinine clearance, blood urea nitrogen 
or urea, total bilirubin, direct bilirubin, ALT, AST, alkaline phosphatase, uric acid, total protein, 
bicarbonate, albumin, chloride, glucose, inorganic phosphate, potassium, sodium, calcium, 
magnesium and serum ferritin. 
Renal parameters are monitored weekly to establish a reliable pretreatment baseline and hepatic 
parameters are monitored biweekly for safety at the initiation of treatment. 
For calculated CrCl from local labs where the enzymatic method is used to determine creatinine 
clearance the modified Schwartz formula will be used for analysis. This estimate will be 
provided each time serum creatinine is collected. 
For calculated CrCl from local labs where Jaffe method is used we will use the Schwartz 
formula. This estimate will be provided each time serum creatinine is collected. 
All clinical chemistry samples will be sent to local laboratories. 
 
7.2.2.5.3 Urinalysis 
Urinalysis samples will be collected at screening visit 1, week 1/day 1, and at monthly visits 
from week 4 through end of treatment as detailed in Table 7-1. A midstream second voided 


Novartis 
Amended Protocol Version No. 01 (Clean) 
Confidential 
Page 57
1 Protocol No. 
 
 
morning sample will be obtained. Dipstick measurements for specific gravity, pH, blood, white 
blood cells, glucose, protein, bilirubin, color, nitrite, urobilinogen and ketones will be assessed 
at the local site. Microscopic analysis will be performed only in case of a positive dipstick result 
for protein. Dipsticks will be supplied by a local laboratory. Any significant findings on dipstick 
will be followed up with a microscopic evaluation where WBC and RBC sediments will also 
be measured. If ketones are positive, measurement of hemoglobin A1C  and/or fasting pre-
prandial glucose may be performed by the local laboratory at the request of the Investigator. 
At screening visit 1 and in addition to the dipstick measurement, a urine sample (at least 15 mL) 
will be collected and sent to a local laboratory for urinary protein/creatinine ratio to assess the 
eligibility of the patient. In addition, urine samples for urinary protein/creatinine ratios will be 
collected at week 1/day 1 and at monthly visits, weeks 4 through end of treatment. First morning 
void samples must not be used for this analysis. Significant protein is indicated by a urinary 
protein/creatinine ratio >0.5 mg/mg. 
For patients who develop proteinuria or worsening of pre-existing proteinuria (assessed by 
dipstick) at any visit, microscopic analysis must performed by the local laboratory. 
All urinalysis samples will be sent to a local laboratory. 
 
7.2.2.6 
Ocular assessments 
Ocular assessments will be performed at screening visit 1 and at end of treatment according to 
the local (institution’s) clinical practice. The choice of method for ocular assessments will be at 
the discretion of the investigators. Best efforts should be made to perform these assessments in 
all subjects, although feasibility in very young children will be at the discretion of the 
investigator. Additional ocular assessment is permitted at the discretion of the Investigator 
based on patient reporting of symptoms. 
 
7.2.2.7 
Auditory assessments 
Auditory assessments will be performed at screening visit 1 and at end of treatment according 
to local (institution’s) clinical practice. The choice of method for auditory assessments will be 
at the discretion of the investigators. Best efforts should be made to perform these assessments 
in all subjects, although feasibility in very young children will be at the discretion of the 
investigator. Additional auditory assessment is permitted at the discretion of the Investigator 
based on patient reporting of symptoms. 
 
7.2.2.8 
Pregnancy and assessments of fertility 
Not applicable 
 
7.2.2.9 
Radiological examinations 
Not applicable 
 
7.2.2.10 Cardiac assessments 
Not applicable 


Novartis 
Amended Protocol Version No. 01 (Clean) 
Confidential 
Page 58
1 Protocol No. 
 
 
7.2.2.10.1 
Electrocardiogram (ECG) 
A standard 12 lead ECG will be performed at screening visit 1. 
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 initials (where 
regulations permit), patient number, date, and kept in the source documents at the study site. 
Clinically significant abnormalities present at screening should be reported on the Medical 
History CRF 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 CRF page. 
Additional, unscheduled, safety ECGs may be repeated at the discretion of the investigator at 
any time during the study as clinically indicated. Local cardiologist ECG assessment may also 
be performed at any time during the study at the discretion of the investigator. 
 
7.2.2.10.2 Cardiac imaging - MRA (magnetic resonance angiography), MUGA (multiple 
gated acquisition) scan or echocardiogram 
Not applicable 
 
7.2.2.10.3 Cardiac enzymes 
Not applicable 
7.2.2.11 Tolerability 
Patients and/or their caregivers will complete an electronic palatability questionnaire as detailed 
in Table 7-1 and provided in the Appendix 14.1. 
 
7.2.3 
Limitations of the study 
Novartis will carefully ensure that the PASS will not interfere/modify the local medical 
practices. The sites will be selected based on their transfusional hemosiderosis treatment 
experience and patients will be enrolled even if they already started chelation for this indication. 
Novartis will interact with local networks to ensure targeting the best representation as possible. 
Therefore, no limitation of potential selection bias is expected in this trial. 
The limitations of the research may be a small sample size. 
 
7.2.4 
Pharmacokinetics 
Not applicable 
 
7.2.4.1 
Analytical method 
Not applicable 
 
7.2.5 
Biomarkers 
Not applicable 


Novartis 
Amended Protocol Version No. 01 (Clean) 
Confidential 
Page 59
1 Protocol No. 
 
 
7.2.5.1 
Additional biomarker assessments 
Not applicable 
 
7.2.5.1.1 
Optional additional exploratory biomarker assessments using remaining biomarker 
samples 
Not applicable 
 
7.2.6 
Other assessments 
No additional tests will be performed on patients entered into this study. 
 
7.2.7 
Resource utilization 
Not applicable 
 
7.2.8 
Patient reported outcomes 
As detailed in Table 7-1 and provided in Appendix 14.1. patients or their caregivers will 
complete a series of ObsRO questionnaires at the study site (during study visits) as follows: 
• palatability and mSCIT of crushed FCT, at SV1 and at the following visits: week 4, week 
12 and at end of treatment 
• gastrointestinal symptoms of crushed FCT at SV1 and at the following visits: week 2, 
week3, week4 , week 8, week 12, week 16, week 20 and at end of treatment 
Note: Chelation naïve patients and patients treated with chelation therapy who stopped 
treatment more than 7 days prior to Screening visit 1 will not complete questionnaires at 
screening. 
 
8 
Safety monitoring and reporting 
8.1 
Adverse events 
8.1.1 
Definitions and reporting 
An adverse event is defined as the appearance of (or worsening of any pre-existing) undesirable 
sign(s), symptom(s), or medical condition(s) that occur after patient’s signed informed consent 
has been obtained. 
Abnormal laboratory values or test results occurring after informed consent constitute adverse 
events only if they induce clinical signs or symptoms, are considered clinically significant, 
require therapy (e.g., hematologic abnormality that requires transfusion or hematological stem 
cell support), or require changes in study medication(s). 
Adverse events that begin or worsen after informed consent should be recorded in the Adverse 
Events CRF. Conditions that were already present at the time of informed consent should be 
recorded in the Medical History page of the patient’s CRF. Adverse event monitoring should 
be continued for at least 30 days following the last dose of study treatment. Adverse events 
(including lab abnormalities that constitute AEs) should be described using a diagnosis 


Novartis 
Amended Protocol Version No. 01 (Clean) 
Confidential 
Page 60
1 Protocol No. 
 
 
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. 
Adverse events will be assessed according to severity: mild, moderate or severe. Information 
about any deaths (related to an Adverse Event or not) will also be collected through a Death 
form. 
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: 
1. Severity (Mild, moderate or severe) 
2. Its duration (Start and end dates) 
3. Its relationship to the study treatment (Reasonable possibility that AE is related: No, Yes) 
4. Action taken with respect to study or investigational treatment (none, dose adjusted, 
temporarily interrupted, permanently discontinued, unknown, not applicable) 
5. Whether medication or therapy was given (no concomitant medication/non-drug therapy, 
concomitant medication/non-drug therapy) 
6. Whether it is serious, where a serious adverse event (SAE) is defined as in Section 8.2.1 
and which seriousness criteria have been met 
7. Outcome (not recovered/not resolved, recovered/resolved, recovering/resolving, 
recovered/resolved with sequalae, fatal, unknown). 
If the event worsens the event should be reported a second time in the CRF noting the start date 
when the event worsens in toxicity. For moderate and severe events, if improvement to a lower 
grade is determined a new entry for this event should be reported in the CRF noting the start 
date when the event improved. 
All adverse events should be treated appropriately. If a concomitant medication or non-drug 
therapy is given, this action should be recorded on the Adverse Event CRF. 
Once an adverse event is detected, it should be followed until its resolution or until it is judged 
to be permanent, and assessment should be made at each visit (or more frequently, if necessary) 
of any changes in severity, the suspected relationship to the study treatment, the interventions 
required to treat it, and the outcome. Follow up will continue up to 30 days after study drug 
discontinuation. 
 
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 CRF. Whenever 
possible, a diagnosis, rather than a symptom should be provided (e.g. anemia instead of low 


Novartis 
Amended Protocol Version No. 01 (Clean) 
Confidential 
Page 61
1 Protocol No. 
 
 
hemoglobin). Laboratory abnormalities that meet the criteria for Adverse Events should be 
followed until they have returned to normal or an adequate explanation of the abnormality is 
found. When an abnormal laboratory or test result corresponds to a sign/symptom of an already 
reported adverse event, it is not necessary to separately record the lab/test result as an additional 
event. 
Laboratory abnormalities, that do not meet the definition of an adverse event, should not be 
reported as adverse events. A severe event does not automatically indicate a SAE unless it meets 
the definition of serious as defined below and/or as per investigator’s discretion. A dose hold 
or medication for the lab abnormality may be required by the protocol in which case the lab 
abnormality would still, by definition, be an adverse event and must be reported as such. 
 
8.1.3 
Adverse events of special interest 
Adverse events of special interest (AESI) are defined as events (serious or non-serious) which 
are ones of scientific and medical concern specific to the sponsor’s product or program, for 
which ongoing monitoring and rapid communication by the investigator to the sponsor may be 
appropriate. Such events may require further investigation in order to characterize and 
understand them. 
Adverse events of special interest are defined on the basis of an ongoing review of the safety 
data. AESIs are discussed in detail in the Investigator Brochure. 
Selected AEs, especially related to disturbances of the gastrointestinal tract, will be collected 
and assessed for severity: esophagitis, stomatitis, mouth ulceration, gastric ulcers, hemorrhage, 
abdominal pain, diarrhea, nausea, and vomiting. 
 
8.2 
Serious adverse events 
8.2.1 
Definitions 
Serious adverse event (SAE) is defined as one of the following: 
• Is fatal or life-threatening 
• Results in persistent or significant disability/incapacity 
• Constitutes a congenital anomaly/birth defect 
• Is medically significant, i.e., defined as an event that jeopardizes the patient or may 
require medical or surgical intervention to prevent one of the outcomes listed above 
• Requires inpatient hospitalization or prolongation of existing hospitalization, 
• Note that hospitalizations for the following reasons should not be reported as serious 
adverse events: 
• Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 
• Elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent 
• Social reasons and respite care in the absence of any deterioration in the patient’s 
general condition 


Novartis 
Amended Protocol Version No. 01 (Clean) 
Confidential 
Page 62
1 Protocol No. 
 
 
• Note that treatment on an emergency outpatient basis that does not result in hospital 
admission and involves an event not fulfilling any of the definitions of a SAE given above 
is not a serious adverse event. 
 
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 additional information for the SAE including complications, progression of the initial SAE, 
and recurrent episodes must be reported as follow-up to the original episode within 24 hours of 
the investigator receiving the follow-up information. An SAE occurring at a different time 
interval or otherwise considered completely unrelated to a previously reported one should be 
reported separately as a new event. 
Any SAEs experienced after the 30 day safety evaluation follow-up period should only be 
reported to Novartis if the investigator suspects a causal relationship to the study treatment. 
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 
thorough report. The investigator must assess and record the relationship of each SAE to each 
specific study treatment (if there is more than one study treatment), complete the SAE Report 
Form in English, and submit the completed form within 24 hours to Novartis. Detailed 
instructions regarding the SAE submission process and requirements for signatures are to be 
found in the investigator folder provided to each site. 
Follow-up information is submitted in the same way as the original SAE Report. Each re- 
occurrence, complication, or progression of the original event should be reported as a follow- 
up to that event regardless of when it occurs. The follow-up information should describe 
whether the event has resolved or continues, if and how it was treated, whether the blind was 
broken or not, and whether the patient continued or withdrew from study participation. 
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the Novartis study treatment, an oncology Novartis 
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 
 
8.4 
Pregnancies 
Not applicable 


Novartis 
Amended Protocol Version No. 01 (Clean) 
Confidential 
Page 63
1 Protocol No. 
 
 
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 
 
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. 
Prior to entering key sensitive personally identifiable information (Subject Initials and exact 
Date of Birth), the system will prompt site to verify that this data is allowed to be collected. If 
the site indicates that country rules or ethics committee standards do not permit collection of 
these items, the system will not solicit Subject Initials. Exact date of birth will be solicited to 
establish that the subject satisfies protocol age requirements and to enable appropriate age- 
related normal ranges to be used in assessing laboratory test results. 


Novartis 
Amended Protocol Version No. 01 (Clean) 
Confidential 
Page 64
1 Protocol No. 
 
 
9.2 
Site monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, Novartis 
personnel (or designated CRO) will review the protocol and CRFs with the investigators and 
their staff. During the study, the field monitor will visit the site regularly to check the 
completeness of patient records, the accuracy of entries on the CRFs, the adherence to the 
protocol to Good Clinical Practice, the progress of enrollment, and to ensure that study 
treatment is being stored, dispensed, and accounted for according to specifications. Key study 
personnel must be available to assist the field monitor during these visits. 
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, audiology and ocular exams, and the results 
of any other tests or assessments. All information recorded on CRFs must be traceable to source 
documents in the patient's file. The investigator must also keep the original signed informed 
consent form (a signed copy is given to the patient). 
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the CRF entries. Novartis monitoring standards require full verification for the 
presence of informed consent, adherence to the inclusion/exclusion criteria and documentation 
of SAEs. Additional checks of the consistency of the source data with the CRFs are performed 
according to the study-specific monitoring plan. 
 
9.3 
Data collection 
For sites using Electronic Data Capture (EDC), the designated investigator staff will enter the 
data required by the protocol into the Electronic Case Report Forms (eCRF). The eCRFs have 
been built using fully validated secure web-enabled software that conforms to 21 CFR Part 11 
requirements, Investigator site staff will not be given access to the EDC system until they have 
been trained. Automatic validation programs check for data discrepancies in the eCRFs and, 
allow modification or verification of the entered data by the investigator staff. 
The Principal Investigator is responsible for assuring that the data entered into eCRF is complete, 
accurate, and that entry and updates are performed in a timely manner. 
 
9.4 
Database management and quality control 
For sites using eCRFs, Novartis personnel (or designated CRO) will review the data entered by 
investigational staff for completeness and accuracy. Electronic data queries stating the nature 
of the problem and requesting clarification will be created for discrepancies and missing values 
and sent to the investigational site via the EDC system. Designated investigator site staff are 
required to respond promptly to queries and to make any necessary changes to the data. 
Concomitant treatments 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 and adverse events will be coded using the Medical dictionary for 
regulatory activities (MedDRA) terminology. 
For EDC studies, after database lock, the investigator will receive a CD-ROM of the patient 
data for archiving at the investigational site. 


Novartis 
Amended Protocol Version No. 01 (Clean) 
Confidential 
Page 65
1 Protocol No. 
 
 
All IRT assigned kits (study drug) will be tracked using an Interactive Response Technology 
system. The system will be supplied by a vendor, who will also manage the database. 
 
10 
Statistical methods and data analysis 
The study employs a prospective, multi-center trial design to monitor and assess the safety 
profile of the crushed deferasirox FCT in pediatric patients age ≥2 to <6 years with transfusional 
hemosiderosis over 24 weeks. The study will enroll at least 40 patients worldwide. 
The data will be analyzed by Novartis and/or a designated Clinical Research Organization 
(CRO). 
Continuous variables will be summarized by number of patients, mean, standard deviation, 
minimum, median, and maximum. For selected parameters, 25th and 75th percentiles will also 
be presented. 
Categorical variables will be summarized by frequencies and percentages. 
In addition to the statistical methods outlined below, further details and any additional 
exploratory analyses that may be performed will be described in the Statistical Analysis Plan 
(SAP). 
 
10.1 
Analysis sets 
10.1.1 
Full Analysis Set 
The Full Analysis Set (FAS) comprises all patients who received at least one dose of deferasirox 
FCT during the study. 
 
10.1.2 
Safety set 
The Safety Set includes all patients who received at least one dose of deferasirox FCT during 
the study. 
The Safety Set and the FAS will be the same for this single arm phase IV study. 
 
10.1.3 
Per-Protocol set 
Not applicable 
 
10.1.4 
Dose-determining analysis set 
Not applicable 
 
10.1.5 
Pharmacokinetic analysis set 
Not applicable 
 
10.1.6 
Other analysis sets 
Not applicable 


Novartis 
Amended Protocol Version No. 01 (Clean) 
Confidential 
Page 66
1 Protocol No. 
 
 
10.1.6.1 Efficacy/evaluable set 
Not applicable 
 
10.2 
Patient demographics/other baseline characteristics 
Demographic and other baseline data including disease characteristics will be listed and 
summarized descriptively using the FAS. The baseline visit will be the study visit in which 
dosing of deferasirox FCT is initiated. 
Categorical data will be presented as frequencies and percentages. For continuous data mean, 
standard deviation, minimum, median, and maximum will be presented. 
Relevant medical histories and current medical history at baseline will be summarized by 
system organ class and preferred term. 
 
10.3 
Treatments (study treatment, concomitant therapies, 
compliance) 
Descriptive statistics (n, mean, standard deviation, minimum, median, and maximum) will be 
used to summarize continuous variables (e.g., laboratory assessments), and frequency counts 
and percentages will be provided for categorical variables. 
The duration of exposure to deferasirox FCT as well as the dose intensity (computed as the ratio 
of actual cumulative dose received and actual duration of exposure) will be summarized by 
means of descriptive statistics. 
The number of patients with dose adjustments (reductions, interruption, or permanent 
discontinuation) and the reasons will be summarized and all dosing data will be listed. 
Concomitant medications and significant non-drug therapies prior to and after the start of study 
treatment will be listed and summarized according to the Anatomical Therapeutic Chemical 
(ATC) classification system. 
 
10.4 
Primary objective 
The primary objective of the study is to assess the safety of crushed deferasirox FCT with 
respect to selected gastrointestinal (GI) disorders. Details regarding the analysis of AEs are 
described in Section 10.5.3.2. 
 
10.4.1 
Variable 
The primary endpoint is the number and percentage of patients with selected gastrointestinal 
disorders (esophagitis, stomatitis, mouth ulceration, gastric ulcers, hemorrhage, abdominal pain, 
diarrhea, nausea, and vomiting) up to 24 weeks including 30 days safety follow-up. 
 
10.4.2 
Statistical hypothesis, model, and method of analysis 
Proportion of patients with selected GI disorders will be provided together with the 95% 
confidence interval using the Clopper-Pearson exact method for this proportion. 


Novartis 
Amended Protocol Version No. 01 (Clean) 
Confidential 
Page 67
1 Protocol No. 
 
 
10.4.3 
Handling of missing values/censoring/discontinuations 
Not applicable 
 
10.4.4 
Supportive and Sensitivity analyses 
Not applicable 
 
10.5 
Secondary objectives 
Evaluate AEs suspected to be related to the crushed deferasirox FCT: 
• 
 Number and percentage of patients who experienced AEs suspected to be related to the 
study drug up to 24 weeks including 30 day safety follow-up overall and by SOC. 
To assess the overall safety of crushed deferasirox FCT: 
• Number and percentage of patients with any AEs, SAEs, and AEs leading to 
discontinuation together with their severity up to 24 weeks including 30 days safety 
follow-up will be provided. Details regarding the analysis of AEs are described in Section 
10.5.3.2. 
• Absolute change from baseline over time as box plots for serum creatinine, creatinine 
clearance, UPCR, total bilirubin, ALP, ALT, AST will be provided. Furthermore, shift 
tables using low/normal/high classification will be provided. Details regarding lab 
abnormalities are described in Section 10.5.3.3. 
• Other safety data (e.g., ECGs, vital signs, ocular, auditory examinations) will be 
descriptively summarized. 
To assess the efficacy of deferasirox FCT treatment: 
• Absolute change from baseline over time in SF values up to 24 weeks of treatment will be 
provided 
To evaluate patient treatment satisfaction, palatability and GI symptoms with ObsROs 
• Please refer to Section 10.5.7. 
10.5.1 
Key secondary objective(s) 
Not applicable 
 
10.5.2 
Other secondary efficacy objectives 
Not applicable 
 
10.5.3 
Safety objectives 
 
10.5.3.1 Analysis set and grouping for the analyses 
For all safety analyses, the safety set will 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 


Novartis 
Amended Protocol Version No. 01 (Clean) 
Confidential 
Page 68
1 Protocol No. 
 
 
2. On-treatment period: from day of first dose of study medication to 30 days after last dose 
of study medication 
3. Post-treatment period: starting at day 30+1 after last dose of study medication. 
All 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. 
 
10.5.3.2 Adverse events (AEs) 
Summary tables for adverse events (AEs) will include only AEs that started or worsened during 
the on-treatment period, the treatment-emergent AEs. 
The 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. 
Serious adverse events and non-serious adverse events and adverse events of special interest 
(AESI: including esophagitis, stomatitis, mouth ulceration, gastric ulcers, hemorrhage, 
abdominal pain, diarrhea, nausea and vomiting) during the on-treatment period will be tabulated. 
The number and frequency of overall AEs and gastrointestinal AEs will be summarized for naïve 
(no ICT prior to enrollment) and non-naïve patients. 
All deaths (on-treatment and post-treatment) will be summarized. 
All AEs, deaths and serious adverse events (including those from the pre and post-treatment 
periods) will be listed and those collected during the pre-treatment and post-treatment period 
will be flagged. 
 
10.5.3.3 Laboratory abnormalities 
All laboratory values will be converted into SI units and the severity grade calculated using the 
low/normal/high classifications based on laboratory normal ranges and for selected parameters 
by notable/extended ranges. 
The following summaries will be generated separately for chemistry, urinalysis assessments: 
• Shift tables using normal/notable/extended ranges to compare baseline to the worst on- 
treatment value (where applicable) 
• Listing of all laboratory data with values flagged to show the corresponding 
normal/notable/extended ranges 
For selected lab assessments such as hematology parameters, observed values (and changes 
from baseline) will be summarized by descriptive statistics (n, mean, standard deviation, 
minimum, lower quartile, median, upper quartile, and maximum). 
Creatinine clearance will be estimated using the (modified) Schwartz formula and the change 
from baseline will be provided. 
 
10.5.3.4 Other safety data 
Data on ECG, vital signs, height, weight, ocular and auditory findings will be listed, 
summarized and flagged as appropriate. Any significant findings after the start of the study will 
be documented as AEs and reported as such. 


Novartis 
Amended Protocol Version No. 01 (Clean) 
Confidential 
Page 69
1 Protocol No. 
 
 
Summary statistics of the number of transfusions, average amount RBC (in mL/kg/day) 
transfused per patient, as well as the average iron intake (in mg/kg/day) will be provided. 
 
10.5.3.5 Supportive analyses for secondary objectives 
Not applicable 
 
10.5.3.6 Tolerability 
Tolerability of crushed deferasirox FCT will be assessed by AEs, SAEs, AEs leading to 
discontinuation and observer reported outcomes. 
 
10.5.4 
Pharmacokinetics 
Not applicable 
 
10.5.4.1 Data handling principles 
Not applicable 
 
10.5.5 
Biomarkers 
Not applicable 
 
10.5.5.1 Outline of the data analysis 
Not applicable 
 
10.5.5.2 Data handling principles 
Not applicable 
 
10.5.5.3 Data analysis principles 
Not applicable 
 
10.5.6 
Resource utilization 
Not applicable 
 
10.5.7 
Patient-reported outcomes 
The questionnaires for patients aged ≥ 2 years and <6 years have been designed as observations 
made by caregivers such as the parent or legal guardian. 
Three questionnaires were developed to evaluate crushed deferasirox FCT: the modified 
Satisfaction with Iron Chelation therapy (mSICT), a palatability questionnaire, and a GI 
symptom questionnaire. All questions will be translated into the patient/caregiver’s native 
language. 
All patients or caregivers will complete the ObsRO questions via electronic questionnaires at 
the site and the site study personnel will review and ensure all relevant observations with parent 
or legal guardian are recorded before submission. 


Novartis 
Amended Protocol Version No. 01 (Clean) 
Confidential 
Page 70
1 Protocol No. 
 
 
The mSICT and palatability questionnaire will be completed at screening visit 1 (chelation pre- 
treated patients), week 4, week 12, and end of treatment. The screening  visit  1  mSICT and 
palatability questionnaire responses will be considered as baseline. No mSICT and palatability 
questionnaire will be evaluated at the screening visit for chelation naïve patients and for patients 
who completed a course of chelation therapy more than 7 days prior to screening visit. 
The GI symptoms questionnaire will be completed at screening visit 1 and at the following 
visits: week 2, week3, week4 , week 8, week 12, week 16, week 20 and at end of treatment. 
The screening visit 1 GI symptom questionnaire responses will be considered as baseline. No 
GI symptoms questionnaire will be evaluated at the screening visit for chelation naïve patients 
and for patients who completed a course of chelation therapy more than 7 days prior to screening 
visit 
For the mSICT and palatability questionnaires, 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 each domain score at screening visit 1, week 4, week 12, and end of treatment 
visits, as well as their absolute changes at week 4, week 12, and end of treatment from screening 
visit 1 for chelation pre-treated patients. 
For the chelation naïve patients, only descriptive statistics by visit will be provided. The 
standard descriptive analyses include: n, mean, standard deviation, minimum, median, and 
maximum. The 95% confidence intervals for the absolute mean changes in all domains at week 
4 and week 12 and end of treatment from screening visit 1 will be presented for pre-treated 
chelation patients only. 
GI symptoms will be summarized over time by descriptive statistics for all visits and for all 
patients (i.e. either chelation naïve or pre-treated with chelation therapy). Descriptive statistics 
and the 95% confidence intervals for the absolute mean changes by visit will be provided for 
chelation pre-treated patients. The standard descriptive analyses include: n, mean, standard 
deviation, minimum, median, and maximum. Details about scoring and analyses will be 
included in the Statistical Analysis Plan. 
 
10.6 
Exploratory objectives 
Not applicable 
 
10.7 
Interim analysis 
No formal interim analysis is planned for this study. 
 
10.7.1 
Progression free survival (PFS) 
Not applicable 
 
10.7.2 
Key secondary endpoint: Overall survival (OS) 
Not applicable 


Novartis 
Amended Protocol Version No. 01 (Clean) 
Confidential 
Page 71
1 Protocol No. 
 
 
10.8 
Sample size calculation 
This study is designed to enroll a minimum of 40 patients. Statistical computations were 
performed (see table below) to evaluate probabilities to observe at least one patient with an AE 
given 40 patients and different scenarios of AE incidence rates (Hanely and Lippman- Hand 
1983). This table shows a reasonable chance to observe AE events occurring with an incidence 
of 3% or higher together with the 95% Clopper-Pearson confidence interval (CI) for the 
incidence rate. 
 
Table 10-1 
Clopper-Pearson 95% CI for different incidence of AEs and the 
corresponding probability to observe at least one AE 
 
Incidence of AE 
Clopper-Pearson 95% CI for the 
incidence rate 
Probability that at least one patient out of 
40 experiences that AE 
3% 
(0.00, 0.14) 
0.70 
4% 
(0.00, 0.15) 
0.80 
5% 
(0.01, 0.17) 
0.87 
6% 
(0.01, 0.18) 
0.92 
7% 
(0.01, 0.20) 
0.95 
10% 
(0.03, 0.24) 
0.99 
15% 
(0.06, 0.30) 
1.00 
20% 
(0.09, 0.36) 
1.00 
25% 
(0.13, 0.41) 
1.00 
30% 
(0.17, 0.47) 
1.00 
 
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 


Novartis 
Amended Protocol Version No. 01 (Clean) 
Confidential 
Page 72
1 Protocol No. 
 
 
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 CRFs. 
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. 
Additional consent form 
Additional assent consent form will be provided in accordance with local regulations in each 
applicable country. 
 
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 is committed to following high ethical standards for reporting study results for its 
innovative medicine, including the timely communication and publication of clinical trial 
results, whatever their outcome. Novartis assures that the key design elements of this protocol 
will be posted on the publicly accessible database, e.g. www.clinicaltrials.gov before study start. 
In addition, results of interventional clinical trials in adult patients are posted on 
www.novartisclinicaltrials.com, a publicly accessible database of clinical study results within  1 
year of study completion (i.e., LPLV), those for interventional clinical trials involving pediatric 
patients within 6 months of study completion. 
Novartis follows the ICMJE authorship guidelines (www.icmje.org) and other specific 
guidelines of the journal or congress to which the publication will be submitted 
Authors will not receive remuneration for their writing of a publication, either directly from 
Novartis or through the professional medical writing agency. Author(s) may be requested to 
present poster or oral presentation at scientific congress; however, there will be no honorarium 
provided for such presentations. 
As part of its commitment to full transparency in publications, Novartis supports the full 
disclosure of all funding sources for the study and publications, as well as any actual and 
potential conflicts of interest of financial and non-financial nature by all authors, including 
medical writing/editorial support, if applicable. 
For the Novartis Guidelines for the Publication of Results from Novartis-sponsored Research, 
please refer to www.novartis.com. 


Novartis 
Amended Protocol Version No. 01 (Clean) 
Confidential 
Page 73
1 Protocol No. 
 
 
11.6 
Study documentation, record keeping and retention of 
documents 
Each participating site will maintain appropriate medical and research records for this trial, in 
compliance with Section 4.9 of the ICH E6 GCP, and regulatory and institutional requirements 
for the protection of confidentiality of subjects. As part of participating in a Novartis-sponsored 
study, each site will permit authorized representatives of the sponsor(s) and regulatory agencies 
to examine (and when required by applicable law, to copy) clinical records for the purposes of 
quality assurance reviews, audits and evaluation of the study safety and progress. 
Source data are all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Examples 
of these original documents and data records include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, subjects’ diaries or evaluation 
checklists, pharmacy dispensing records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate and complete, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, and subject files and records kept 
at the pharmacy, at the laboratories, and medico-technical departments involved in the clinical 
trial. 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site Principal Investigator. The study case report form (CRF) is the primary data collection 
instrument for the study. The investigator should ensure the accuracy, completeness, legibility, 
and timeliness of the data reported in the CRFs and all other required reports. Data reported on 
the CRF, that are derived from source documents, should be consistent with the source 
documents or the discrepancies should be explained. All data requested on the CRF must be 
recorded. Any missing data must be explained. Any change or correction to a paper CRF should 
be dated, initialed, and explained (if necessary) and should not obscure the original entry. For 
electronic CRFs an audit trail will be maintained by the system. The investigator should retain 
records of the changes and corrections to paper CRFs. 
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 forms and patient enrollment 
log must be kept strictly confidential to enable patient identification at the site. 


Novartis 
Amended Protocol Version No. 01 (Clean) 
Confidential 
Page 74
1 Protocol No. 
 
 
11.8 
Audits and inspections 
Source data/documents must be available to inspections by Novartis or designee or Health 
Authorities. 
 
11.9 
Financial disclosures 
Financial disclosures should be provided by study personnel who are directly involved in the 
treatment or evaluation of patients at the site - prior to study start. 
 
12 
Protocol adherence 
Investigators ascertain they will apply due diligence to avoid protocol deviations. Under no 
circumstances should the investigator contact Novartis or its agents, if any, monitoring the study 
to request approval of a protocol deviation, as no authorized deviations are permitted. If the 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC/REB it cannot be implemented. All significant protocol 
deviations will be recorded and reported in the CSR. 
 
12.1 
Amendments to the protocol 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, Health Authorities where required, and the IRB/IEC/REB. Only 
amendments that are required for patient safety may be implemented prior to IRB/IEC/REB 
approval. Notwithstanding the need for approval of formal protocol amendments, the 
investigator is expected to take any immediate action required for the safety of any patient 
included in this study, even if this action represents a deviation from the protocol. In such cases, 
Novartis should be notified of this action and the IRB/IEC at the study site should be informed 
according to local regulations (e.g. UK requires the notification of urgent safety measures within 
3 days) but not later than 10 working days. 


Novartis 
Amended Protocol Version No. 01 (Clean) 
Confidential 
Page 75
1 Protocol No. 
 
 
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(10):1187-1193. 
[Cappellini MD, Bejaoui M, Agaoglu L, et al (2011)] Iron chelation with deferasirox in adult 
and pediatric patients with thalassemia major: efficacy and safety during 5 years’ follow-up. 
Blood. 118(4):884-893. 
[Cappellini MD, Cohen A, Piga A et al (2006)] A Phase III study of deferasirox (ICL670), a 
once-daily oral iron chelator, in patients with β-thalassemia. Blood; 107(9):3455-62. 
[Gabutti V, Piga A (1996)] Results of long-term iron-chelating therapy. Acta Haematol; 
95(1):26-26. 
[Howie SRC (2011)] Blood sample volumes in child health research: review of safe limits. 
Bull World Health Organ; 89:46-53. 
ash.confex.com/ash/2016/webprogram/Paper90642.html 
[Kushner J, Porter J, Olivieri N (2001)] Secondary iron overload. Hematology Am Soc 
Hematol Educ Program: 47-61. 
[Nick HP, Acklin P, Lattman R (2003)] Development of tridentate iron chelators from 
desferrithiocin to ICL670. Curr Med Chem; 10(12):1065-1076 
[Pennell DJ, Porter JB, Cappellini MD (2010)] Efficacy of deferasirox in reducing and 
preventing cardiac iron overload in beta-thalassemia. Blood; 115(12):2364-71. 
[Piga A, Galanello R, Forni GL et al (2006)] Randomized phase II trial of deferasirox 
(Exjade, ICL670), a once-daily, orally-administered iron chelator, in comparison to 
deferoxamine in thalassemia patients with transfusional iron overload. Haematologica; 
91(9):873-80. 
[Porter J, Galanello R, Saglio G et al (2008)] Relative response of patients with 
myelodysplastic syndromes and other transfusion-dependent anaemias to deferasirox 
(ICL670): a 1-yr prospective study. Eur J Haematol; 80(2):168-76. 
[Standard-of-Care Clinical Practice Guideline] Available at: thalassemia.com/treatment- 
guidelines-1.aspx#gsc.tab=0 Accessed 23-Jun-2016. 
[Taher AT, Musallam, KM, El-Beshlawy A, et al. (2010)] Age-related complications in 
treatment-naïve patients with thalassemia intermedia. Br. J Haematol.2010;150(4):486-489. 
[Vichinsky E, Onyekwere O, Porter J et al (2007)]. A randomized comparison of deferasirox 
versus deferoxamine for the treatment of transfusional iron overload in sickle cell disease. 
British Journal of Haematology; 136(3):501-508. 
[Vichinsky E (2008)] Oral iron chelators and the treatment of iron overload in pediatric 
patients with chronic anemia. Pediatrics; 121(6):1253-1256. 


Novartis 
Amended Protocol Version No. 01 (Clean) 
Confidential 
Page 76
1 Protocol No. 
 
 
14 
Appendices 
14.1 
mSICT (Modified Satisfaction with Iron Chelation Therapy) - 
crushed FCT 
Directions 
The following questions are about the medicine your child takes for iron overload (too much 
iron in the body) in the past week (past 7 days). Please read each one and answer by yourself. 
There are no right or wrong answers. All of your answers will remain confidential. Choose only 
one answer. 
Items 
1. Over the past week, how often did your child’s medicine for iron overload limit his/her 
usual activities? 
□ Always 
□ Most of the time 
□ Sometimes 
□ Rarely 
□ Never 
 
2. Over the past week, how often was your child upset about the side effects of his/her 
medicine for iron overload? 
□ Always 
□ Most of the time 
□ Sometimes 
□ Rarely 
□ Never 
 
3. Over the past week, how often did your child take his/her medicine for iron overload? 
□ Always 
□ Most of the time 
□ Sometimes 
□ Rarely 
□ Never 


Novartis 
Amended Protocol Version No. 01 (Clean) 
Confidential 
Page 77
1 Protocol No. 
 
 
4. Over the past week, how often did your child express that he/she wanted to stop taking 
medicine for iron overload? 
□ Always 
□ Most of the time 
□ Sometimes 
□ Rarely 
□ Never 
 
5. Over the past week, how often did your child follow the doctor’s instructions for taking 
his/her medicine for iron overload? 
□ Always 
□ Most of the time 
□ Sometimes 
□ Rarely 
□ Never 
 
6. What are the reasons expressed by your child for not always taking his/her medicine for 
iron overload as instructed by the doctor? (Choose all that apply) 
□ Taste 
□ Aftertaste (taste left in your child’s mouth after swallowing his/her medicine) 
□ Inconvenience (for child) 
□ Prepared the medicine incorrectly (took the whole tablet without crushing) 
□ Trouble of crushing the tablet 
□ Other   
 
 
7. Over the past week, how easy or hard did your child tell you it was to take his/her 
medicine for iron overload? 
□ Very easy 
□ Easy 
□ Neither easy nor hard 
□ Hard 
□ Very hard 
 
8. Over the past week, how bothered did your child express that he/she was by the amount of 
time he/she had to wait to eat food after taking medicine for iron overload? 
□ Very bothered 
□ Quite bothered 
□ Moderately bothered 
□ A little bothered 


Novartis 
Amended Protocol Version No. 01 (Clean) 
Confidential 
Page 78
1 Protocol No. 
 
 
□ Not bothered at all 
 
9. Please choose the face that best describes how happy or unhappy your child appeared with 
his/her medicine for iron overload over the past week. 
10. Which type of medicine did your child say he/she liked best? 
□ Tablet to dissolve in liquid 
□ Tablet (taken once a day) 
□ Tablet (taken 3 times a day) 
□ Tablet crushed 
□ Sprinkle powder on food 
□ Injection 
□ I don’t know 
 
11. What are the reasons that your child preferred the “crushed medicine” for iron overload? 
(Choose all that apply) 
□ Taste 
□ Aftertaste (taste left in the child’s mouth after he/she swallows) 
□ Convenience (it’s not a problem to take the medicine – administration) 
□ Number of pills 
□ No/Less side effects 
□ Can correctly prepare the medicine 
□ Easier to remember to take the medicine 
□ Number of times he/she has to take the medicine 
□ No/Less pain on the injection site 
□ Gain personal time with their family and friends 
□ Other   
 
 
 
Directions 
The following questions are about YOUR experiences with the medicine your child takes for 
iron overload in the past week (past 7 days). Please read each one and answer by yourself. 


Novartis 
Amended Protocol Version No. 01 (Clean) 
Confidential 
Page 79
1 Protocol No. 
 
 
There are no right or wrong answers. All of your answers will remain confidential. Choose 
only one answer. 
12. Over the past week, how often did you feel worried that your child was not swallowing 
enough of his/her medicine for iron overload? 
□ Always 
□ Most of the time 
□ Sometimes 
□ Rarely 
□ Never 
 
13. Over the past week, how often did you give your child his/her medicine for iron overload? 
□ Always 
□ Most of the time 
□ Sometimes 
□ Rarely 
□ Never 
 
14. Over the past week, how often did you think to stop giving your child his/her medicine for 
iron overload? 
□ Always 
□ Most of the time 
□ Sometimes 
□ Rarely 
□ Never 
 
15. Over the past week, how often did you follow the doctor’s instructions for giving your 
child his/her medicine for iron overload? 
□ Always 
□ Most of the time 
□ Sometimes 
□ Rarely 
□ Never 
 
16. Based on doctor’s instructions, how easy or hard was it for you to crush the tablet for iron 
overload? 
□ Very easy 
□ Easy 
□ Neither easy nor hard 
□ Hard 


Novartis 
Amended Protocol Version No. 01 (Clean) 
Confidential 
Page 80
1 Protocol No. 
 
 
□ Very hard 
 
17. What are the reasons that you did not always give your child his/her medicine for iron 
overload as instructed by the doctor? (Choose all that apply) 
□ Child refused to take 
□ Forgot to give the medicine 
□ Inconvenient for you or your child 
□ Side effects (for child) 
□ Did not prepare the medicine according to the doctor’s instructions 
□ Did not give the full amount of the prepared medicine 
□ Other   
 
 
18. Over the past week, how easy or hard was it for you to give your child his/her medicine 
for iron overload? 
□ Very easy 
□ Easy 
□ Neither easy nor hard 
□ Hard 
□ Very hard 
 
19. Over the past week, how bothered were you by the amount of time it took to prepare your 
child’s medicine for iron overload? 
□ Very bothered 
□ Quite bothered 
□ Moderately bothered 
□ A little bothered 
□ Not bothered at all 
 
20. Please rank order the following medicines based on what your children most prefers to 
what he/she least prefers. 
Medicine 
Rank (1= most prefer and 6= least prefer) 
Tablet to dissolve in liquid 
Tablet (taken once a day) 
Tablet (taken 3 times a day) 
Tablet crushed 
Sprinkle powder on food 
Injection 


Novartis 
Amended Protocol Version No. 01 (Clean) 
Confidential 
Page 81
1 Protocol No. 
 
 
14.2 
Palatability (taste and ability to consume medicine) 
Questionnaire 
Directions 
The following questions are about the medicine your child takes for iron overload (too much 
iron in the body). Please read each one and answer by yourself. There is no right or wrong 
answer. All of your answers will remain confidential. 
Please answer each question about the medicine your child took for iron overload in the past 
week: 
Items 
1. Please choose the face that best describes your child’s reaction to the taste of the medicine 
for iron overload immediately after putting it in his/her mouth in the past week. 
 
2. Please choose the face that best describes your child’s reaction to the aftertaste of the 
medicine after swallowing his/her medicine for iron overload in the past week. 
 
3. Using the answers listed below, which answer best, describes what happened after your 
child took his/her medicine for iron overload in the past week? 
□ Swallowed and retained ALL of the medicine 
□ Spat out SOME of the medicine 
□ Spat out ALL of the medicine and swallowed none of it 
□ Vomited within 30 minutes after swallowing the medicine 
 
4. How would you describe the amount of liquid that your child took with his/her medicine 
for iron overload in the past week? 


Novartis 
Amended Protocol Version No. 01 (Clean) 
Confidential 
Page 82
1 Protocol No. 
 
 
□ Not enough liquid 
□ Just enough liquid 
□ Too much liquid 
 
14.3 
GI Symptom Questionnaire 
Directions 
Please read each symptom carefully. Indicate how often your child had each symptom over 
the past week. 
Please answer all of the following questions about your child’s GI symptoms after taking 
his/her medication for iron overload. 
Items 
1. Pain in his/her belly 
□ Always 
□ Most of the time 
□ Sometimes 
□ Rarely 
□ Never 
 
2. Nausea (feeling like he/she might throw up) 
□ Always 
□ Most of the time 
□ Sometimes 
□ Rarely 
□ Never 
 
3. Vomiting (throwing up) 
□ Always 
□ Most of the time 
□ Sometimes 
□ Rarely 
□ Never 
 
4. Constipation 
□ Always 
□ Most of the time 
□ Sometimes 
□ Rarely 
□ Never 


Novartis 
Amended Protocol Version No. 01 (Clean) 
Confidential 
Page 83
1 Protocol No. 
 
 
 
5. Diarrhea 
□ Always 
□ Most of the time 
□ Sometimes 
□ Rarely 
□ Never 
 
6. How many bowel movements did your child have in the past week? 
□ 0 (none) 
□ 1 
□ 2 
□ 3 
□ 4 
□ 5-10 
□ 11 or more 


Novartis 
Amended Protocol Version No. 01 (Clean) 
Confidential 
Page 84
1 Protocol No. 
 
 
14.4 
Deferasirox FCT Weight Dose Table 
Body weight ranges per dosing group (kg) 
# of Tablets to dispense 
3.5 
7 
10.5 
14 
17.5 
21 
24.5 
28 
mg/kg/day mg/kg/day mg/kg/day mg/kg/day mg/kg/day mg/kg/day mg/kg/day mg/kg/day [kg] 
[kg] 
[kg] 
[kg] 
[kg] 
[kg] 
[kg] 
[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 
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 
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 


Novartis 
Amended Protocol Version No. 01 (Clean) 
Confidential 
Page 85
1 Protocol No. 
 
 
enroll male or female children, ≥ 2 and < 6 years. For patients with a low body weight (e.g. 
below 19 kg in the 5 mg/kg/day dosing group) the dosing requirements given will not allow for 
the use of the smallest strength available. In such cases a written request will be sent to Novartis, 
to advise on the individual patient enrolment / dose adjustments options. 
 
14.5 
Examples of light meals with soft foods 
Table 14-1 Examples of light meals with soft foods 
 
Example 1 
Amount 
kcal 
g total fats 
Wheat Bread or Toast 
2 slices 
138 
2 
jams, preserves, all 
1 Tablespoon 
109 
0 
flavors 
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) 
124 
1 
pita 
Hummus or deli 
1 Tablespoon hummus or 
27 
1 
chicken/turkey 
2 oz. meat 
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 
14 
0 
celery 
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 
1 cup 
70 
2 
soup, canned 
Baked potato, peel not 
1 medium (2.25-3” 
121 
0 
eaten 
across) 
Skim milk 
1 cup 
83 
0 
banana 
Medium (7-7 7/8” long) 
105 
0 
Total: 
379 
2 


Novartis 
Amended Protocol Version No. 01 (Clean) 
Confidential 
Page 86
1 Protocol No. 
 
 
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 
 
Post-Authorization Safety Study (PASS) 
 
Yes 
No 
 
Is this a PASS study - If yes, follow instructions below 

SAP_001.pdf: 
Clinical Development
ICL670/deferasirox FCT/Exjade®
Study Number: CICL670F2429 / NCT03372083
A single-arm interventional Phase IV, post-authorization 
study evaluating the safety of pediatric patients with 
transfusional hemosiderosis treated with deferasirox 
crushed film coated tablets
Statistical Analysis Plan (SAP)
Author:
 Trial Statistician
Document type:
SAP amendment 2
Document status:
Final
Release date:
December 16, 2019
Number of pages:
36
Property of Novartis
For business use only
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


Novartis
For business use only
Page 2
SAP amendment 2
ICL670F2429
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-
Aug-
2017
Prior to 
FPFV
Creation 
of 
final version
N/A - First version
NA
14 
July 
2018
Amend 1
Visit schedule 
is modified in 
the 
protocol 
amendment 
1 
and thus the 
data 
analyses 
for 
ObsRO 
(mSICT, 
palatability and 
GI 
symptom 
questionnaires
are 
impacted
due to change 
in 
visit 
schedule.

Spelled out how to analyze 
mSICT, palatability and GI 
symptom questionnaire for 
chelation naive and pre-
treated 
chelation 
therapy
patients.
Section 2.13
13-
Dec-
2019
Amend 2

Allowed flagging for post-
treatment data, if any
Section 2.1.2.7

Removed subgroup analysis 
as the patient population is 
too small
Section 2.3

Removed 
“Age 
will 
be 
calculated based on patient’s 
first screening date” as age is 
collected on the CRF page 
directly
Section 2.5

Added 
prior 
medications/therapies to the 
listing and flagged them 
appropriately
Section 2.7

Removed 
proportion 
calculation based on the 
Section 2.8.2


Novartis
For business use only
Page 3
SAP amendment 2
ICL670F2429
Date
Time 
point
Reason for 
update
Outcome for update
Section and title 
impacted 
(Current)
number of patients without 
event who will discontinue 
after the baseline visit prior to 
2 week scheduled visis for 
primary 
endpoint. 
All 
patients will be considered for 
this analysis

Changed 
the 
content 
in 
section 
2.8.3 
to 
Not 
applicable 
to 
align 
with 
protocol
Section 2.8.3

Corrected the equation to 
follow the standard
Section 2.8.4

Removed 
the 
disclosure 
related information as they 
will not be part of CSR
Section 2.11.1

Changed subgroup analysis to 
not applicable to maintain 
consistency with protocol
Section 2.11.2

Added 
clarification 
in 
analysis for ECG values
Section 2.11.7

Updated the notable range for 
vital 
signs 
to 
pediatric 
population requirements
Section 2.11.7.1

Clarified the 2 groups of 
patients 
in 
ObsRO 
as 
“Chelation naïve patients and 
patients treated with chelation 
therapy other than deferasirox 
who 
stopped 
chelation 
treatment more than 7 days 
prior to Screening visit” and 
“patients 
pre-treated 
with 
deferasirox”. Changed the 
box plots to scores instead of 
change from baseline.
Section 2.13


Novartis
For business use only
Page 4
SAP amendment 2
ICL670F2429
Table of contents
1
Introduction .........................................................................................................................9
1.1
Study design.............................................................................................................9
1.2
Study objectives and endpoints ...............................................................................9
2
Statistical methods.............................................................................................................10
2.1
Data analysis general information .........................................................................10
2.1.1
General presentation of descriptive summaries ....................................11
2.1.2
General definitions................................................................................11
2.1.2.1
Investigational drug and study treatment...............................................................11
2.1.2.2
Date of first administration of study treatment......................................................11
2.1.2.3
Date of last administration of study treatment.......................................................11
2.1.2.4
Screening failure....................................................................................................11
2.1.2.5
Study day...............................................................................................................11
2.1.2.6
Baseline .................................................................................................................12
2.1.2.7
On-treatment assessment/event and observation periods ......................................12
2.2
Analysis sets ..........................................................................................................12
2.2.1
Full Analysis Set ...................................................................................12
2.2.2
Safety Analysis Set ...............................................................................13
2.2.3
Per-Protocol set .....................................................................................13
2.2.4
Dose-determining analysis set...............................................................13
2.2.5
Pharmacokinetic analysis set.................................................................13
2.2.6
Other analysis set ..................................................................................13
2.2.7
Efficacy/evaluable set ...........................................................................13
2.3
Subgroup of interest...............................................................................................13
2.4
Protocol deviations ................................................................................................13
2.5
Patient disposition, demographics and other baseline characteristics ...................13
2.6
Treatments (study treatment and compliance).......................................................15
2.6.1
Cumulative dose....................................................................................15
2.6.2
Duration of exposure.............................................................................15
2.6.3
Planned and actual dose intensity .........................................................15
2.6.4
Dose Change .........................................................................................16
2.7
Prior, concomitant and post therapies....................................................................16
2.7.1.1
Prior chelation therapy...........................................................................................17
2.7.1.2
Blood transfusion history.......................................................................................17
2.7.2
Post therapies ........................................................................................17
2.8
Analysis of the primary objective..........................................................................17
2.8.1
Primary endpoint...................................................................................17


Novartis
For business use only
Page 5
SAP amendment 2
ICL670F2429
2.8.2
Statistical hypothesis, model, and method of analysis..........................18
2.8.2.1
Statistical hypothesis test.......................................................................................18
2.8.3
Handling of missing values/censoring/discontinuations.......................18
2.8.4
Supportive analyses...............................................................................18
2.9
Analysis of the key secondary objective ...............................................................18
2.10
Analysis of secondary efficacy objective(s)..........................................................18
2.10.1
Secondary endpoints .............................................................................18
2.10.2
Statistical hypothesis, model, and method of analysis..........................19
2.10.3
Handling of missing values/censoring/discontinuations.......................19
2.11
Safety analyses.......................................................................................................19
2.11.1
Adverse events (AEs)............................................................................20
2.11.1.1
Adverse events of special interest / grouping of AEs............................................21
2.11.2
Subgroup analysis .................................................................................21
2.11.3
Deaths....................................................................................................21
2.11.4
Laboratory data .....................................................................................21
2.11.5
Other safety data ...................................................................................23
2.11.5.1
ECG and cardiac imaging data ..............................................................................23
2.11.5.2
Vital signs..............................................................................................................23
2.11.5.3
Auditory and ocular findings.................................................................................24
2.11.5.4
Hepatic dysfunction...............................................................................................24
2.12
Pharmacokinetic endpoints....................................................................................24
2.13
Observer reported outcomes (ObsRO) ..................................................................24
2.13.1
mSICT...................................................................................................25
2.13.1.1
Adherence..............................................................................................................25
2.13.1.2
Preference..............................................................................................................28
2.13.1.3
Concerns................................................................................................................28
2.13.2
Palatability questionnaire......................................................................29
2.13.3
GI symptom questionnaire....................................................................30
2.14
Biomarkers.............................................................................................................31
2.15
Other exploratory analyses ....................................................................................31
2.16
Interim analysis......................................................................................................31
3
Sample size calculation .....................................................................................................31
4
Change to protocol specified analyses ..............................................................................32
5
Appendix ...........................................................................................................................32
5.1
Imputation rules.....................................................................................................32
5.1.1
Study drug.............................................................................................32
5.1.2
AE date imputation ...............................................................................33


Novartis
For business use only
Page 6
SAP amendment 2
ICL670F2429
5.1.3
Concomitant medication date imputation .............................................34
5.1.3.1
Prior therapies date imputation..............................................................................34
5.1.3.2
Other imputations ..................................................................................................35
5.2
Creatinine clearance recalculation.........................................................................35
5.3
Statistical models...................................................................................................36
5.3.1
Primary analysis....................................................................................36
5.3.2
Key secondary analysis.........................................................................36
6
Reference...........................................................................................................................36


Novartis
For business use only
Page 7
SAP amendment 2
ICL670F2429
List of abbreviations
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALP
Alkaline Phosphatase
ALT
Alanine aminotransferase/serum glutamic pyruvic transaminase/SGPT
AST
Aspartate aminotransferase/serum glutamic oxaloacetic 
transaminase/SGOT
ATC
Anatomical Therapeutic Chemical
BMI
Body Mass Index
CI
Confidence Interval
CrCl
Creatinine Clearance
CRF
Case report/record form
CTC
Common terminology criteria
CTCAE
Common Terminology Criteria for Adverse Events
CSR
Clinical study report
DAR
Dose administration record
DFX
Deferasirox
DRL
Drug reference listing
ECG
Electrocardiogram
eCRF
Electronic case report/record form
FAS
Full Analysis Set
FCT
Film coated tablet
GCP
Good Clinical Practice
GI
Gastrointestinal
ICL670
Deferasirox/Exjade®
ICT
Iron Chelation Therapy
MedDRA
Medical Dictionary for Regulatory Activities
mSICT
Modified Satisfaction with Iron Chelation Therapy
ObsROs
Observer-reported Outcomes
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SCr
Serum Creatinine
SD
Standard deviation
SOC
System organ class
TBIL
Total Bilirubin
TLF
Tables, Listings and Figures


Novartis
For business use only
Page 8
SAP amendment 2
ICL670F2429
UPCR
Urine protein and creatinine ratio
SSD
Study Specification Document
WHO
World health organization


Novartis
For business use only
Page 9
SAP amendment 2
ICL670F2429
1
Introduction
The purpose of this Statistical Analysis Plan (SAP) is to describe the implementation of the 
statistical analysis specified in the protocol. Final Clinical Study Report (CSR) will be written 
based on this SAP. Current SAP is written following finalized protocol version 01 (Amended 
protocol), disease area standards and deferasirox (film coated tablet (FCT)) project specific 
standard TFLs. All decisions regarding final analysis, as defined in the SAP document, have 
been made prior to database lock of the study data.
1.1
Study design
This is an interventional, prospective, single arm, open label, global multi-center, non-
randomized study to monitor and assess the safety profile of the crushed deferasirox FCT in 
pediatric patient’s age between ≥2 to < 6 years with transfusional hemosiderosis over 24 weeks. 
The purpose of this study is to address a European Health Authorities (CHMP/PRAC) post-
marketing requirement. CHMP/PRAC have requested Novartis for an additional post-
authorization safety study to characterize the pediatric safety profile and to provide safety data 
on selected AEs (esophagitis, stomatitis, mouth ulceration, gastric ulcers, hemorrhage, 
abdominal pain, diarrhea, nausea, and vomiting).   
This study will enroll at least 40 patients worldwide. 
The study will include a screening period (from Day 0-14) with two visits at least 7 days apart 
to assess eligibility of patients that are chelation naïve or on a prior iron chelator treatment other 
than deferasirox (DFX). Only one screening visit (screening visit 1) will occur for prior DFX 
treated patients to determine eligibility. Any patients treated with prior chelation therapy except 
deferasirox will be discontinued to undergo a 5-day washout period before initiation of 24-
week treatment period with crushed deferasirox FCT. 
Safety assessments will be performed weekly after treatment initiation for the first 4 weeks and 
thereafter monthly during the study. Monthly serum ferritin values and trends will be used to 
adapt the treatment of the patients together with safety data. Patients will continue therapy for 
up to 24 weeks.
There is no interim analysis planned for this study.
1.2
Study objectives and endpoints
The study objectives and endpoints are described in the following table:  
Table 1-1 Study objectives and endpoints 
Objective
Primary
Endpoint


Novartis
For business use only
Page 10
SAP amendment 2
ICL670F2429
To assess the safety of crushed 
deferasirox FCT with respect to 
selected gastrointestinal (GI) 
disorders in pediatric patients 
aged ≥2 to < 6 years with 
transfusional iron overload up to 
24 weeks including 30 days 
safety follow up
Number and percentage of patients with selected 
gastrointestinal disorders (esophagitis, stomatitis, 
mouth ulceration, gastric ulcers, hemorrhage, 
abdominal pain, diarrhea, nausea, and vomiting) up 
to 24 weeks including 30 days safety follow-up
Secondary
Evaluate AEs suspected to be 
related 
to 
the 
crushed 
deferasirox FCT
Number and percentage of patients who experienced 
AEs suspected to be related to study treatment up to 
24 weeks including a 30 day follow up overall and by 
SOC.
To assess the overall safety of 
crushed FCT of deferasirox
Overall safety up to 24 weeks including 30 days 
safety follow-up as measured by frequency and 
severity of adverse events, serious adverse events 
(SAEs) and AEs leading to discontinuation and 
absolute change from baseline over time (shift tables 
will also be provided) for serum creatinine, creatinine 
clearance, UPCR, total bilirubin, ALP, ALT, AST). 
Other safety data (e.g., ECGs, vital signs, ocular, 
auditory examinations) will also be summarized.
To 
assess 
the 
efficacy 
of 
deferasirox FCT treatment
Change from baseline over time in SF up to 24 weeks 
of treatment 
To evaluate patient treatment 
satisfaction, palatability, and GI 
symptoms with Observer-
reported Outcomes (ObsROs)
Domain scores with ObsROs (Modified Satisfaction 
with Iron Chelation Therapy [mSICT], palatability, 
and GI symptom) questionnaires
2
Statistical methods
This section contains information that will be used to draft CSR Section 9.7 on statistical 
analysis.
2.1
Data analysis general information
Data will be analyzed by Novartis Oncology Biostatistics and Statistical programming 
personnel according to the data analysis described in Section 10 of the ICL670F2429 protocol, 
which will be available in Appendix 16.1.1 of the Clinical Study Report (CSR). Important 
information is given in the following sections and details are provided. For the final analysis, 
SAS version 9.4 or later (upon availability) will be used. As specified in the protocol, the study 
will continue until last patient received last dose plus 30-days follow-up. This date will be 
considered as the cut-off date. 


Novartis
For business use only
Page 11
SAP amendment 2
ICL670F2429
Data from all patients who signed the main study informed consent for study participation in 
centers that participate in this study will be used in the analysis; due to expected small size of
enrollment at individual centers, no center effect will be assessed. Each analysis will use all 
data in the database up to the analysis cutoff date, determined prior to database lock.
All available data from all patients up to the cutoff date will be reported. 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).
2.1.1
General presentation of descriptive summaries
Qualitative data (e.g., gender, race, etc.) will be summarized by frequency count and 
percentages. Percentages will be calculated using the number of patients in the relevant 
population   as the denominator.
Quantitative data (e.g., age, body weight, etc.) will be summarized by appropriate descriptive 
statistics (i.e. mean, standard deviation, median, minimum, and maximum). For selected 
parameters 25th and 75th percentiles will also be presented in box plots.
2.1.2
General definitions
2.1.2.1
Investigational drug and study treatment 
Investigational drug will refer to the crushed Deferasirox FCT only. In this document, the term 
investigational drug will be referred as study treatment and will be used throughout this 
document.
2.1.2.2
Date of first administration of study treatment
The date of first administration of study treatment will be derived as the first date when a 
nonzero dose of study treatment is administered as per the Dosage Administration CRF. For the 
sake of simplicity, the date of first administration of study treatment will also be referred as 
start of study treatment.
2.1.2.3
Date of last administration of study treatment
The date of last administration of study treatment is defined as the last date when a nonzero 
dose of study treatment was administered as per Dose Administration (e)CRF. 
2.1.2.4
Screening failure
Screening failures are patients who have been enrolled and failed screening criteria in a study. 
These patients will never receive investigational drug.
2.1.2.5
Study day
The study day for safety assessments (e.g. adverse event onset, laboratory abnormality 
occurrence, vital sign measurement, dose interruption etc.) and for efficacy assessment (e.g. 


Novartis
For business use only
Page 12
SAP amendment 2
ICL670F2429
serum ferritin) and Observer-reported Outcomes will be calculated as the difference between
the date of the event (onset date of an event, assessment date etc.) and the start of study treatment
plus 1. The first day of study treatment is therefore study day 1 if event will start after start date 
of study treatment.
Study day=date of event – start date of study treatment+1
For any assessment or events such as baseline disease characteristics or medical history (e.g., 
time since diagnosis of disease) that is supposed to occur prior to treatment start date, study
day will be negative and will be calculated as:
Study Day = Event date –treatment start date.
The study day will be displayed in the data listings.
2.1.2.6
Baseline
For the safety and the efficacy evaluations, the last available assessment on or before the date 
of start of study treatment will be defined as baseline. If patients have no value as defined above, 
the baseline result will be missing.
2.1.2.7
On-treatment assessment/event and observation periods
The overall observation period will be divided into three mutually exclusive segments: 
1. pre-treatment period: from day of subject’s first informed consent to the day before first 
administration of study treatment
2. on-treatment period: from date of first administration of study treatment to 30 days after 
date of last actual administration of any study treatment (including start and stop date)
3. post-treatment period: starting at day 30+1 after last administration of study treatment.
All safety data (including those from the pre-treatment period) will be listed and those collected 
during the pre-treatment period are to be flagged. If any safety data from the post-treatment 
period is collected, it will be flagged.
2.2
Analysis sets
The following analysis sets are defined in the study protocol.
2.2.1
Full Analysis Set 
The Full Analysis Set (FAS) comprises all patients who received at least one dose of deferasirox 
FCT during the study.


Novartis
For business use only
Page 13
SAP amendment 2
ICL670F2429
2.2.2
Safety Analysis Set
The Safety Set includes all patients who received at least one dose of deferasirox FCT during 
the study. Note that the Safety Set and the FAS will be the same for this single arm phase IV 
study.
2.2.3
Per-Protocol set
Not applicable
2.2.4
Dose-determining analysis set
Not applicable
2.2.5
Pharmacokinetic analysis set
Not applicable
2.2.6
Other analysis set
Not applicable
2.2.7
Efficacy/evaluable set
Not applicable
2.3
Subgroup of interest
Not Applicable
2.4
Protocol deviations
Frequency counts and percentages of patients with any CSR reportable protocol deviation 
(selection criteria not met, patient not withdrawn as per protocol, treatment deviation, prohibited 
concomitant medication, and other (Good Clinical Practice (GCP) deviation) will be tabulated 
by the deviation type category using FAS. 
The full list of protocol deviations is documented in the Study Specification Document (SSD)
Module 3. All protocol deviations will be listed. 
2.5
Patient disposition, demographics and other baseline 
characteristics
Screen failures recorded in the end of screening phase disposition will comprise patients who 
have been enrolled i.e. signed the main ICF and were screened but were not treated. The 
screening failure disposition table will include:

Number (%) of screen-failed patients

Reasons for screening failure


Novartis
For business use only
Page 14
SAP amendment 2
ICL670F2429
The percentage for the screening phase disposition will be calculated based on the number of 
patients whose consents are obtained. All screen failure patients with reasons for screen failure 
will be listed.
Patient disposition will be summarized using the FAS. The disposition table will include:

Number (%) of treated

Number (%) discontinued before 24-week schedule visit

Number (%) of patients who completed the end of treatment

Primary reason for study treatment phase discontinuation (based on the ‘End of 
Treatment Phase’ page)
All demographic data and baseline disease characteristics will be summarized and listed 
based on the FAS. Categorical data (e.g. gender, age, race, and ethnicity) will be summarized 
by frequency counts and percentages; the number and percentage of patients with missing data 
will be provided. Continuous data (e.g. age, weight, height) will be summarized by descriptive 
statistics (n, mean, median, standard deviation, minimum and maximum).
Medical history
Medical history and ongoing conditions will be summarized and listed. The summaries will be 
presented by primary system organ class (SOC) and preferred term (PT). Medical history and 
current medical conditions will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) terminology. The MedDRA version used for reporting will be specified in the CSR 
and as a footnote in the applicable tables/listings. History of surgical and other medical 
procedures and any prior hepatic findings at baseline will be listed using FAS.
Other baseline characteristics
Clinically significant abnormality in ECG (yes or no) along with ECG parameters (heart rate, 
PR, QT, QTCF and QRS), overall interpretation in audiometric test (normal or clinically 
significant or insignificant abnormality as per CRF), and interpretation in ocular exam (normal 
or clinically significant or insignificant abnormality) at baseline will be summarized and listed 
using FAS.
The following variables will be summarized as a continuous and categorical data using FAS,
except for urine protein/creatinine ratio which will be presented as categorical data as shown 
below:

Creatinine will be categorized as: ≤ULN, >ULN - ≤1.5*ULN, >1.5*ULN

Recalculated Creatinine Clearance (CrCl) will be categorized as: <90 and ≥90 mL/min

ALT and AST will be categorized as: ≤ULN, >ULN-≤2.5*ULN, >2.5*ULN

Urine protein/creatinine ratio: ≤0.5, >0.5 

Serum ferritin will be categorized as: ≥1000 to 2500, ≥2500 to 5000, >5000 ng/ mL


Novartis
For business use only
Page 15
SAP amendment 2
ICL670F2429
2.6
Treatments (study treatment and compliance)
2.6.1
Cumulative dose 
The planned daily dose of a subject is collected on the CRF page as dose prescribed in 
mg/kg/day and the actual daily dose is calculated by dividing the total daily dose collected on 
the CRF page in mg by the current weight (kg) corresponding to that visit and based on the start 
and end dates. The current weight is equal to the weight on the same visit when dose was 
administered or the last available weight before the dosing visit if the same visit weight is 
missing. Cumulative dose (mg/kg) is defined as the sum over the daily doses of all days between 
first and last dose. For patients who did not take any drug, the cumulative dose is by definition 
equal to zero. 
Cumulative dose = sum of (daily dose at a visit * (end date of dose –start date of dose +1))
The planned cumulative dose (mg/kg) for a study treatment component refers to the total 
planned dose as per the protocol up to the last date of investigational drug administration. The 
actual cumulative dose (mg/kg) refers to the total actual dose administered, over the duration 
for which the subject is on the study treatment as documented in the Dose Administration eCRF.
2.6.2
Duration of exposure
Duration of exposure to study treatment is considered by taking into account the duration of 
exposure to the investigational drug: 
Duration of exposure (weeks) = [(last date of exposure to study treatment) – (date of first
                                                   administration of study treatment) + 1]/7,
The last date of exposure to study treatment is the date when the last study drug will be 
administered (see section 2.1.2.3). 
Summary of duration of exposure of study treatment in weeks will include categorical 
summaries and descriptive summaries (i.e. n, mean, standard deviation, median, max and min)
in weeks. The time interval will be categorized as: <4 weeks, 4 to <12 weeks, 12-<20 weeks
20-<=24 weeks, >24 weeks. Frequency counts and percentages will be presented for the number 
of patients in each time interval using the Safety Set.
2.6.3
Planned and actual dose intensity
Planned dose intensity (PDI) and actual dose intensity (DI) for subjects with non-zero duration 
of exposure are defined as follows: 
PDI (mg/kg/day) = [planned cumulative dose during the time of
exposure (mg/kg)]/Duration of exposure (days)


Novartis
For business use only
Page 16
SAP amendment 2
ICL670F2429
DI (mg/kg/day) = [actual cumulative dose during the time of exposure
(mg/kg)]/Duration of exposure (days)
Relative dose intensity (RDI) is defined as follows:
RDI (%) = (DI (mg/kg/day) / PDI (mg/kg/day)) *100
Planned dose intensity, actual dose intensity and relative dose intensity (<70%, 70%-90%
and >90%) will be summarized by means of descriptive statistics using Safety Set. 
2.6.4
Dose Change
‘Dose interrupted’, and ‘Dose change’ fields from the Dosage Administration CRF pages will 
be used to determine the dose reductions, dose interruptions. The corresponding fields ‘Reason 
for dose changed/dose interrupted’ will be used to summarize the reasons. Dose interruption 
and dose reduction are defined as follows:

Interruption is defined as any period of zero actual daily dose prior to treatment end 
date.

Reduction is a subset of the dose changes, defined as a decrease from the previous 
planned non-zero dose, even if this decrease has been directly preceded by an
interruption. Patient has dose decrease or reduction at visit if the dose assignment at the 
visit will be nonzero and lower than the last available one before the visit and daily dose 
is nonzero at the visit. For example, in the sequence 14 mg/kg/day – 0 mg/kg/day – 7 
mg/kg/day, the 7mg/kg/day dose will be counted as a reduction and in the sequence 
14mg/kg/day – 7 mg/kg/day – 3.5 mg/kg/day, 3.5 mg/kg/day will be counted as two 
reductions.
The number and percentage of patients with dose interruption and/or dose reduction along with 
reasons for dose interruption/reduction will be summarized using the safety set. Dose increase
will not be included in these summaries.
Listings of all doses of the study treatment along with dose reduction and dose interruption 
reasons will be produced using the Safety set.
2.7
Prior, concomitant and post therapies
Medications will be classified as prior or concomitant based on the following rules and will be
coded using the WHO Drug Reference Listing (WHO DRL) dictionary that employs the WHO 
Anatomical Therapeutic Chemical (WHO ATC) classification system. Summaries will include:

Prior medications will be defined to be drugs taken prior to the first dose of study 
medication.


Novartis
For business use only
Page 17
SAP amendment 2
ICL670F2429

Concomitant medications will be medications taken during the on-treatment period. 
Medications which started prior to the first dose of study medication and continued 
thereafter will be counted in both summaries.
Concomitant medications and significant non-drug therapies prior to and after the start of study 
treatment will be listed and summarized according to the Anatomical Therapeutic Chemical 
(ATC) classification system using Safety set. Prior medication/therapies that started before the 
first dose of study treatment, or those starting after 30 days from the last day of study medication
will be flagged in the listing.
2.7.1.1
Prior chelation therapy
History of iron chelation therapy is collected in prior or concomitant medication CRF page. By 
the drug name, the prior chelation therapy will be identified.
Prior chelation therapy will be summarized by lowest ATC class and preferred term. Summaries 
will include time from last treatment to start of study treatment. Duration of iron chelation prior 
to start of study treatment will be categorized into time intervals (< 1, 1-<3, 3- <6 and >=6 
months of cumulative therapy). Duration of prior chelation therapy will be calculated based on 
start and the end date of the therapy, i.e. duration (days) = end date – start date+1. Frequency 
counts and percentages will be presented for the number of patients in each interval. 
Prior chelation therapy and chelation naïve patients will be listed using FAS.
2.7.1.2
Blood transfusion history
The number of patients with prior blood transfusions within the period of 3 months prior to 
Screening visit 1, and the average amount of RBC (in mL/kg/day) will be summarized using 
descriptive statistics and listed using the FAS.
2.7.2
Post therapies
The study will end after last dose of study treatment plus 30 days follow-up.  Post therapies, if 
any will be flagged in the listings. 
2.8
Analysis of the primary objective
The primary objective of the study is to assess the safety of crushed deferasirox FCT with 
respect to selected gastrointestinal (GI) disorders. 
2.8.1
Primary endpoint
The primary endpoint is the proportion of patients with selected gastrointestinal disorders 
(esophagitis, stomatitis, mouth ulceration, gastric ulcers, hemorrhage, abdominal pain, diarrhea, 


Novartis
For business use only
Page 18
SAP amendment 2
ICL670F2429
nausea, and vomiting) up to 24 weeks including 30 days safety follow-up. Selected 
gastrointestinal disorders will be captured from AE page of eCRFs and PT term will be used.
Corresponding PT terms will be oesophagitis, Barrett’s esophagitis, stomatitis, mouth ulceration, 
gastric ulcer, gastrointestinal haemorrhage, abdominal pain, diarrhoea, nausea and vomiting. If 
patients discontinue earlier than 24-week visit, the patients will be followed 30 days after 
discontinuation of study treatment. 
2.8.2
Statistical hypothesis, model, and method of analysis
Proportion of patients with selected GI disorders will be provided together with the
corresponding 95% confidence interval using the Clopper-Pearson exact method for this 
proportion (see section 5.3.1).
2.8.2.1
Statistical hypothesis test 
No hypothesis will be tested for this primary endpoint.
2.8.3
Handling of missing values/censoring/discontinuations
Not applicable
2.8.4
Supportive analyses
Exposure-adjusted adverse event incidence will be presented by the severity and preferred 
term for the primary analysis. It is defined as:
Number of patients with new or worsened AEs on selected gastrointestinal disorder
during on −treatment period
Patient −Year exposure/365.25
Patient-year exposure is counted in days up to the first qualifying adverse event (or end of 
time at risk for subjects without adverse event), divided by 365.25.
2.9
Analysis of the key secondary objective
Not applicable
2.10
Analysis of secondary efficacy objective(s)
The secondary efficacy objective for this study is to assess the efficacy of deferasirox FCT 
treatment.
2.10.1
Secondary endpoints
The secondary efficacy endpoint for this study will be the change from baseline over time in 
serum ferritin (SF) up-to 24 weeks of treatment.


Novartis
For business use only
Page 19
SAP amendment 2
ICL670F2429
2.10.2
Statistical hypothesis, model, and method of analysis
A summary table will be provided for the change in SF from baseline for each visit up-to 24 
weeks of treatment using FAS. A listing will also be provided including current SF level, change 
from baseline by visit and by patient. A graphical representation of SF change from baseline by 
box-plot will be provided for each visit using FAS.
For the summary table, all scheduled and unscheduled visits will be considered. If a scheduled 
visit does not occur, then an unscheduled visit will be mapped to a scheduled visit by the below 
rule:

The target date of a scheduled visit will be defined relative to Day 1 as (X-1)*7+1, where 
X is the number of weeks, such as X=1, 2, … For example, the target day for Week 12 
visit will be (12-1)*7+1 = 78 days.

Unscheduled visit then will be mapped to a scheduled visit by:
o
Weeks 2 and 3: -1 day / +1 day
o
Week 4 : -1 day/+7 days
o
Week 8,12,16, 20 and 24 (EOT): -7 days / +7 days
If a scheduled visit already exists, then no unscheduled visit will be mapped against a scheduled 
visit. If no scheduled visits exist, the unscheduled visit which is the closest to the target 
scheduled visit will be considered. If two unscheduled visits are equidistant from the targeted
scheduled visit then prior to the targeted scheduled visit will be consider as scheduled visit.
After mapping unscheduled visit to a scheduled visit, only scheduled visit will be considered 
for the summary level outputs.
2.10.3
Handling of missing values/censoring/discontinuations
Change from baseline will only be calculated for patients with both baseline and post baseline 
values as:
           Change from baseline = post baseline value – baseline value. 
In case of any post-baseline or baseline observation(s) is missing for any patient, the change of 
baseline value will be missing. 
2.11
Safety analyses
As stated in the protocol (Section 10.5), the following secondary safety endpoints will be 
evaluated:
AEs suspected to be related to the crushed deferasirox FCT:

Number and percentage of patients who experienced AEs suspected to be related to the 
study treatment up to 24 weeks including 30 day safety follow-up overall and by SOC, 
PT and severity (see section 2.11.1).
Overall safety of crushed deferasirox FCT:


Novartis
For business use only
Page 20
SAP amendment 2
ICL670F2429

Number and percentage of patients with any AEs, SAEs, and AEs leading to 
discontinuation together with their severity up to 24 weeks including 30 days safety 
follow-up will be provided. Details regarding the analysis of AEs are described in 
section 2.11.1.

Absolute change from baseline over time will be provided graphically by box plots for 
serum creatinine, creatinine clearance, UPCR, total bilirubin, ALP, ALT, AST for each 
visit. Furthermore, shift tables using low/normal/high classification will be provided. 
Details regarding laboratory abnormalities are described in Section 2.11.4. See section 
2.10.2 for the mapping of an unscheduled visit to a scheduled visit and box plots and 
shift tables will be generated for each scheduled visit only after mapping an unscheduled 
visit.
2.11.1
Adverse events (AEs)
All AEs recorded during the study are coded using the latest version of the medical dictionary 
for regulatory activities (MedDRA). Adverse events will not be assessed according to the 
common terminology criteria for AEs (CTCAE); instead, AE severity (mild, moderate, severe) 
will be used to report treatment-emergent AEs starting on or after the date of first study 
medication (including AEs that start within 30 days after the discontinuation of the study 
medication).
Frequency tables for treatment-emergent AEs will be presented. The summary tables will 
include the number of patients, and the percentage of patients experiencing the AE. Multiple 
occurrences of the same event in the same patient will be counted only once in the frequency 
tables. However, all adverse events will be included in the AE listings.
Frequency tables will display at least the MedDRA system organ class or preferred term, AE 
severity (mild, moderate, severe) or both, and relationship to study treatment. The following 
tables will be generated based on the data up-to 24 weeks including 30 days follow-up:

Adverse events, regardless of study treatment relationship

Adverse events, suspected to be study treatment related

Serious adverse events, regardless of study treatment relationship

Serious adverse events, suspected to be study treatment relationship

Adverse events leading to study drug discontinuation, regardless of study treatment
relationship

Adverse events leading to study drug discontinuation, suspected to be study treatment
relationship

Adverse events requiring dose adjustment or interruption, regardless of study 
treatment relationship

Adverse events requiring additional therapy, regardless of study treatment relationship


Novartis
For business use only
Page 21
SAP amendment 2
ICL670F2429

Adverse events which are not serious adverse events, regardless of study treatment
relationship
2.11.1.1 Adverse events of special interest / grouping of AEs
Specific groupings of adverse events of special interest will be considered and the number of 
patients with at least one event in each grouping will be reported. Such groups consist of adverse 
events for which there is a specific clinical interest in connection with deferasirox treatment. 
Note that certain adverse events will be reported within multiple groupings/AESIs. AESIs are 
defined by MedDRA terms. Definition for retrieval (maintenance of terms considered AESI) is 
in case retrieval strategy (eCRS). To select the corresponding records from SAS dataset ECRS 
in Novartis computing environment, use

Compound name = “ICL670”,

Compound indication = “ICL670 Chronic iron overload”

and records without CRS Version End Date, means the latest version.
All safety topics flagged in the eCRS using the core safety flag will be considered for the 
analysis.
AESI will be summarized regardless of study drug relationship, by grouping, preferred term. 
Gastrointestinal AEs will also be summarized as a part of AESI.
2.11.2
Subgroup analysis
Not Applicable
2.11.3
Deaths
Summaries for on-treatment (treatment +30 days) deaths will be produced by system organ 
class, and preferred term using the Safety set.
All deaths will be listed for the safety set. If any data after end of treatment plus 30 days is 
collected, it will be flagged in the listing.
2.11.4
Laboratory data
All laboratory values will be converted into SI units and the severity grade calculated using the 
low/normal/high classifications based on local laboratory normal ranges and for selected
parameters by notable/extended ranges.
The following summaries will be generated separately for chemistry, hematology and
urinalysis assessments:

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


Novartis
For business use only
Page 22
SAP amendment 2
ICL670F2429
Shift tables will be generated for each hematology and chemistry test, cross-tabulating 
low/normal/high/missing baseline laboratory values against low/normal/high/missing post-
baseline values. In particular, the following shift tables will be produced:

Shift tables using the low/normal/high/(low and high) classification to compare baseline to 
the worst on-treatment value for the hematology parameters: hemoglobin, RBC counts, 
hematocrit and platelets

Shift tables using the low/normal/high/ (low and high) classification to compare baseline to 
the worst on-treatment value for the chemistry parameters: ALT, AST, total bilirubin, direct 
bilirubin, serum creatinine, UPCR and alkaline phosphatase.
For selected lab assessments such as hematology parameters: hemoglobin, RBC counts, 
hematocrit and platelets; chemistry parameters: ALT, AST, total bilirubin, direct bilirubin, 
creatinine clearance, serum creatinine, UPCR and alkaline phosphatase observed values (and 
changes from baseline) will be summarized by descriptive statistics.
The number and percentage of patients with laboratory results (from scheduled and unscheduled 
visits) meeting the criteria for notable values (see table above) will be presented. 
Table 2-1 Criteria for clinically notable and extended laboratory ranges
Parameter
Criteria
Absolute neutrophils
<1.5×109/L (extended range <0.5×109/L)
Platelets
<100×109/L (extended range <50×109/L)
ALT/AST
>5×ULN and >2×baseline value (extended range >10×ULN 
and >2×baseline value)
Alkaline phosphatase
<2×ULN
Serum creatinine
>33% increase from baseline and >ULN at two consecutive 
measurements at least 7 days apart
Creatinine clearance
<60 mL/min at two consecutive measurements at least 7 days 
apart (extended range <40 mL/min)
Urinary total protein/creatinine ratio
>1.0 mg/mg at two consecutive measurements at least 7 days 
apart
Total bilirubin
>2×ULN
Direct bilirubin
>2×ULN
Summaries for the change from baseline will be provided for all parameters. Creatinine 
clearance will be estimated using the (modified) Schwartz formula (additional details in section 
5.2). An unscheduled visit will be mapped to a scheduled visit per section 2.10.2.
Potential Hy’s Law events are defined as patients with concurrent occurrence of AST or ALT > 
3×ULN and TBIL > 2×ULN and ALP < 2×ULN in the same assessment sample during the on-
treatment period. Potential Hy’s law events will be tabulated using Safety set.


Novartis
For business use only
Page 23
SAP amendment 2
ICL670F2429
2.11.5
Other safety data
2.11.5.1 ECG and cardiac imaging data
2.11.5.1.1
Data handling
In case ECG measurements are replicated at any assessment, the average of the ECG parameters 
at that assessment will be used in the analyses.
2.11.5.1.2
Data analysis
12-lead ECGs including PR, QRS, QT, QTcF and HR intervals will be obtained for each subject 
during the study as clinically indicated. ECG data will be read and interpreted centrally.

QT and QTcF
o
New value of > 450 and ≤ 480 ms
o
New value of > 480 and ≤ 500 ms
o
New value of > 500 ms
o
Increase from baseline of > 30 ms to ≤ 60 ms
o
Increase from baseline of > 60 ms

HR
o
Increase from baseline >25% and to a value > 120 bpm
o
Decrease from baseline >25% and to a value < 65 bpm

PR
o
Increase from baseline >25% and  to a value > 160 ms
o
New value > 200 ms

QRS
o
Increase from baseline >25% and  to a value > 80 ms 
o
New values of QRS > 120 ms 
A listing of all ECG assessments will be produced using Safety set, notable values and post-
treatment assessments (if any) will be flagged. 
2.11.5.2 Vital signs
Vital sign assessments will be performed in order to characterize basic body function. The 
following parameters are collected: height (cm), weight (kg), body temperature (°C), supine
systolic and diastolic blood pressure (mmHg) and supine pulse rate (bpm). 
The change from baseline in systolic and diastolic blood pressures, pulse rate, temperature and 
weight will be summarized by scheduled visit with descriptive statistics. An unscheduled visit 
will be mapped to a scheduled visit per section 2.10.2.
A listing will be provided for all vital signs and BMI (Body Mass Index). Notable vital signs 
will be flagged. The criteria for notably abnormal vital signs are displayed in Table 
2-2.


Novartis
For business use only
Page 24
SAP amendment 2
ICL670F2429
Table 2-2
Definition of notable ranges for vital signs 
Vital sign (unit)
Notable high value 
Notable low value
Weight (kg)
increase >= 10% from baseline
decrease  >= 10% from baseline
Systolic blood 
pressure (mmHg)
>=110 and 
increase from baseline of >=20
<=85 and
decrease from baseline of >=20
Diastolic blood 
pressure (mmHg)
>=72 and 
increase from baseline of >=15 
<=50 and 
decrease from baseline of >=15
Pulse rate (bpm)
>=120 and 
increase from baseline of >15
<=50 and 
decrease from baseline of >15
Body 
temperature ( o C)
>= 40
<=35
2.11.5.3 Auditory and ocular findings
Auditory and ocular exams will be performed at screening, EOT and as needed basis. Auditory
data will be listed using the Safety set. The listing will include the date when the tests were
performed, overall interpretation of the test and any clinical significant abnormality findings. 
Ocular data will also be listed using the Safety set. The listing will include the date of 
assessment performed, overall interpretation and any clinical significant abnormality findings.
2.11.5.4 Hepatic dysfunction
Hepatic dysfunction will be captured through imaging, liver event pathology, liver event by 
autoimmune disorder, liver serology and liver function tests from the study eCRFs. Due to less 
number of patients enrolled in the study and considering hepatic cases observed are rare for this 
compound, no summary will be provided; instead, any findings of hepatic dysfunction will be 
listed using Safety set. 
2.12
Pharmacokinetic endpoints
Not applicable.
2.13
Observer reported outcomes (ObsRO)
There are three set of PRO questionnaires designed to evaluate crushed deferasirox FCT: 

Modified Satisfaction with Iron Chelation Therapy (mSICT) questionnaire

Palatability (taste and ability to consume medicine) questionnaire

GI symptom questionnaire
All these questionnaires will be translated in caregivers’ native language and will be answered 
electronically by the caregivers (legal guardian or the parent) at the time of protocol defined 
visits. The site study personnel will review and will ensure that all relevant observations with 
parent/ legal guardian are recorded before electronic submission.


Novartis
For business use only
Page 25
SAP amendment 2
ICL670F2429
2.13.1
mSICT
The mSICT questionnaire will be completed at screening visit 1, week 4, week 12 and EOT. 
The responses from screening visit 1 for mSICT questionnaire will be considered as baseline. 
The modified SICT consists of 20 items that represent 3 domains (see Figure 2-1): 

Adherence

Preference

Concerns 
2.13.1.1 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)
Even the adherence domain is divided into two perspective, all the items will be answered by 
the caregivers due to minors (2-6 years of age) enrolled in this study. First set of questionnaires
will reflect about the child’s devotion of taking the medicine and second set of questionnaires
will reflect caregivers perspective of adherence for study medication. Out of 20 items of mSICT 
questionnaire, child’s perspective domain scores consist of 6 items (Item: 3, 4, 5, 7, 8 and 9) 
while caregiver’s perspective is captured by 6 items (Item: 13, 14, 15, 16, 18 and 19), i.e. overall 
12 items will measure the adherence of the treatment.  
Non-adherence items from the child perspective and caregiver’s perspective domains consist of 
one item each (Item: 6) and (Item: 17) respectively.
Child’s perspective of adherence: 
Item 3 captures about the frequency of medicine intake and item 5 discusses about how often 
child follows the doctor’s instructions. Items 3 and 5 will be measured using a 5-point response 
scale: “Always” =1 (best), “Most of the time” =2, “Sometimes” =3, “Rarely” =4 and “Never” 
=5(worst). 
Item 4 discusses about how often the child express to stop the medication. The scale will be 
used to measure this as “Always” =5 (worst), “Most of the time” =4, “Sometimes” =3, “Rarely” 
=2, and “Never” =1 (best).  
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 (best), “Easy” =2, “Neither easy or hard” =3, “Hard” =4, and “Very hard” =5 (worst).
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 will be “Very bothered” =5
(worst), “Quite Bothered” =4, “Moderately bothered” =3, “A little bothered” =2, and “Not 
bothered at all” =1 (best).


Novartis
For business use only
Page 26
SAP amendment 2
ICL670F2429
Item 9 reports “how happy your child appeared” and is scored on a scale from 1=Very happy 
(best) to 5=Very unhappy (worst). 
Caregiver’s perspective of Adherence:
Item 13 asks the caregivers about how often medicine is given to the child and item 15 asks
about how often caregivers follow doctor’s instruction for giving child his/her medicine. Item
13 and 15 both are measured using a 5-point response scale: “Always” =1 (best), “Most of the 
time” =2, “Sometimes” =3, “Rarely” =4 and “Never” =5 (worst). 
Conversely, item 14 will capture the caregiver perspective about “how often he/she thought of 
stopping the medicine”. Item 14 will be scored as “Always” =5 (worst), “Most of the time” =4, 
“Sometimes” =3, “Rarely” =2, and “Never” =1 (best). 
Item 16 and 18 focus on “how easy/hard was it to crush the medicine” and “How easy/hard was 
it to give your child his/her medicine” respectively and use the same response scale “Very easy” 
=1 (best), “Easy” =2, “Neither easy nor hard” =3, “Hard” =4, and “Very hard” =5 (worst). 
Similarly, item 19 captures “bothered by the amount of time it took to prepare medication” 
and uses the response scale “Very bothered” =5 (worst), “Quite Bothered” =4, “Moderately 
bothered” =3, “A little bothered” =2, and “Not bothered at all” =1 (best). 
Figure 2.1 Proposed Conceptual Models for the Modified Satisfaction with Iron 
Chelation Therapy Questionnaire


Novartis
For business use only
Page 27
SAP amendment 2
ICL670F2429
Adherence Domain Score Calculation 
A separate adherence domain scores 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. Note that Item 6 and 17 will be 
analyzed separately and thus will not be included while calculating caregiver’s perspective for 
adherence, i.e. it will not be included in the summation.
Child’s Perspective and Caregiver’s Perspective Checklist for Non-adherence
Only respondents who, at item 5 (for the child's perspective) and item 15 (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 the “child’s perspective of adherence” 
and “caregiver’s perspective of adherence,” there is an item to capture the reasons for non-
adherence, where the respondent can check all the reasons that apply. 
From the child’s perspective, item 6 (“reason expressed by your child for not always taking the 
medicine as instructed by the doctor”) and item 17 from the caregiver perspective (“reason that 
you did not always give your child his/her medicine as instructed by the doctor”) capture the 
reasons for non-adherence. These response options are treated as a standalone checklist, which 
captures the child’s and caregiver's perspective on the reasons why the child did not always take 
their medication as instructed. See Figure 2.2
     Figure 2.2 Conceptual models for item 6 and item 17 of the modified SICT
     
This item will be used as a standalone item to further understand the overall Adherence domain
and the responses will be presented descriptively using frequency counts.  


Novartis
For business use only
Page 28
SAP amendment 2
ICL670F2429
2.13.1.2 Preference
This domain consists of 3 items (item 10, item 11 and item 20). Item 10 will assess “what type 
of medication did your child like the best”. Item 11 will assess “the reason of preference for 
crushed medicine”. Item 20 will capture the rank of the medicine based on whatever the 
children prefer. These item are to be considered a single items and the responses will be 
presented descriptively using frequency counts.
2.13.1.3 Concerns
Similar to adherence domain, concerns will be captured 2 ways: 
1. based on the child’s perspective (Item 1 and 2) and 
2. also based on the caregiver’s perspective (Item 12)
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 
measured using a 5-point response scale from “Always” =1 (worst), “Most of the time” =2, 
“Sometimes” =3, “Rarely” =4, and “Never” =5 (best); and a sum of scores for a Concerns 
domain for the child's perspective will be created if both items are non-missing. A higher score 
will indicate lesser concerns.
There is only a single item to capture concern in regards to caregiver’s perspective. The item 
12 captures about “how worried whether the child is swallowing enough medication” and is 
scored on a 5-point response scale from “Always” =1 (worst), “Most of the time” =2, 
“Sometimes” =3, “Rarely” =4, and “Never” =5 (best). A higher score on the single item domain 
will indicate lesser caregiver concern.
For the mSICT questionnaire, the score for each domain (adherence and concerns) will be the 
mean of the score of items included in the corresponding domain. Note that for these domains, 
child’s perspective and caregiver’s perspective will be summarized separately. Standard 
descriptive analyses will be performed for each domain (adherence and concerns) score at
screening visit 1 (baseline), week 4, week 12, and end of treatment visits, as well as their 
changes from baseline at week 4, week 12, and end of treatment for pre-treated chelation 
patients where baseline evaluation is available. For the Chelation naïve patients and patients 
treated with chelation therapy other than deferasirox who stopped chelation treatment more than 
7 days prior to Screening visit, only descriptive statistics by visit will be provided. The standard 
descriptive analyses include: n, mean, standard deviation, minimum, median, and maximum. 
The 95% confidence intervals will be presented for the changes in mean from baseline for all 
domains at week 4 and week 12 and EOT for patients pre-treated with deferasirox only.
Box plot will be presented to summarize the scores graphically for each domain at week 4, week 
12 and EOT.


Novartis
For business use only
Page 29
SAP amendment 2
ICL670F2429
All preference items will be analyzed descriptively by visit.
2.13.2
Palatability questionnaire
Like mSICT questionnaire, the palatability questionnaire will be completed at screening visit 1,
week 4, week 12, and EOT. The responses at screening visit 1 for palatability questionnaire will 
be considered as baseline. 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 “Very good” =1 (best), “Good” =2, “Neither good nor bad” =3, 
“Bad” =4, and “Very bad” =5 (worst). 
The aftertaste item will be treated as an independent item (and will not be part of the scoring) 
and will be presented descriptively using frequency counts. 
A summary of items 1, 3 and 4 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
“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
Table 2.2 Scoring Matrix for the Palatability Questionnaire
Score
Q1 – Taste
Q3 – What 
happened
Q4 – 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
Not enough & too much 1
4
5
Bad & Very bad; 2
Swallowed all: 1
Just enough 2
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


Novartis
For business use only
Page 30
SAP amendment 2
ICL670F2429
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
For the palatability questionnaire, standard descriptive analyses based on the derived scores will 
be provided at screening visit 1 (baseline), week 4, week 12, and EOT, as well as their changes 
from baseline at week 4, week 12, and EOT for patients pre-treated with deferasirox. For the 
Chelation naïve patients and patients treated with chelation therapy other than deferasirox who 
stopped chelation treatment more than 7 days prior to Screening visit, only descriptive statistics 
by visit will be provided. The standard descriptive analyses include: n, mean, standard deviation, 
minimum, median, and maximum. The 95% confidence intervals will be presented for the mean 
changes from baseline at week 4 and week 12 and EOT for patients pre-treated with deferasirox. 
Box plot will be presented to summarize the scores graphically at week 4, week 12 and EOT.
2.13.3
GI symptom questionnaire
The GI symptom questionnaire consists of 6 items, 5 of which are scored using a 1-5 rating 
scale with appropriate end anchors to rate the symptom. The items are “Pains in the belly”, 
“Nausea (feeling like throwing up)”, “Vomiting”, “Constipation” and “Diarrhea”. All are 
scored as “Always”=5 (worst), “Most of the time”=4, “Sometimes”=3, “Rarely”=2, “Never”=1 
(best). 
The sixth item assesses bowel movement frequency during the past week, using 7 response 
options 0 = 0 (“None”), 1 = 1, 2 = 2, 3 = 3, 4 = 4, 5 = “5 – 10” and 6 = “11 or more”.
The GI symptoms questionnaire will be completed at all visits starting at screening visit 1 
(excluding screening visit 2) until end of treatment. Response from GI symptom questionnaire 
at screening visit 1 will be considered as baseline.
A GI symptom score will be created as a summary score of all items (5 items), where a lower 
score represents a less severe GI symptom and a higher score represents a more severe GI 
symptom. Item 6 will be excluded from the calculation of the weekly GI Symptom score; it 
will be used as a standalone item and will be presented descriptively using frequency counts.
The weekly average will be calculated when there are at least 4 non-missing daily responses by 
a subject. No additional imputation will be carried out. 
GI symptoms will be summarized over time by descriptive statistics for all visits and for all 
patients (i.e. either Chelation naïve patients and patients treated with chelation therapy other 
than deferasirox who stopped chelation treatment more than 7 days prior to Screening visit or 
patients pre-treated with deferasirox). Descriptive statistics and the 95% confidence intervals 


Novartis
For business use only
Page 31
SAP amendment 2
ICL670F2429
for the absolute mean changes by visit will be provided for patients pre-treated with deferasirox. 
The standard descriptive analyses include: n, mean, standard deviation, minimum, median, and 
maximum. 
GI symptom scores as well as item 6 (bowel movement) will be summarized using descriptive 
statistics with the change from baseline to week 2, week3, week4, week 8, week 12, week 16, 
week 20 and EOT for patients pre-treated with deferasirox.
Box plot will be presented to summarize the scores graphically at week 2, week3, week4, week 
8, week 12, week 16, week 20 and EOT.
2.14
Biomarkers
Not applicable.
2.15
Other exploratory analyses
Not applicable
2.16
Interim analysis
Not applicable
3
Sample size calculation
This study is designed to enroll a minimum of 40 patients. Statistical computations were 
performed (see table below) to evaluate probabilities to observe at least one patient with an AE 
given 40 patients and different scenarios of AE incidence rates (Hanley and Lippman-Hand 
1983). This table shows a reasonable chance to observe AE events occurring with an incidence 
of 3% or higher together with the 95% Clopper-Pearson confidence interval (CI) for the 
incidence rate.
Table 3-1 Clopper-Pearson 95% CI for different incidence of AEs and the
corresponding probability to observe at least one AE
Incidence of AE
Clopper-Pearson 95% CI for 
the incidence rate
Probability that at least one patient out 
of 40 experiences that AE
3%
(0.00, 0.14)
0.70
4%
(0.00, 0.15)
0.80
5%
(0.01, 0.17)
0.87
6%
(0.01, 0.18)
0.92
7%
(0.01, 0.20)
0.95
10%
(0.03, 0.24)
0.99
15%
(0.06, 0.30)
1.00
20%
(0.09, 0.36)
1.00
25%
(0.13, 0.41)
1.00


Novartis
For business use only
Page 32
SAP amendment 2
ICL670F2429
30%
(0.17, 0.47)
1.00
4
Change to protocol specified analyses

According to statistical section 10.5.3.2 in the protocol, the number and frequency of 
overall AEs and gastrointestinal AEs will be summarized for naïve (no ICT prior to 
enrollment) and non-naïve patients. However, this will not be done. Further, only on-
treatment deaths will be summarized instead of all deaths. All deaths will be presented 
in the listings with post-treatment deaths flagged.

According to statistical section 10.5.3.4 in the protocol, Data on ECG, vital signs, height, 
weight, ocular and auditory findings will be listed, summarized and flagged as 
appropriate. However, ECG, auditory and ocular findings are only listed but not 
summarized due to the limited amount of data collected (only unscheduled assessments 
for ECG and mostly EOT visits for ocular and auditory at post baseline).
5
Appendix
This will be used later for drafting CSR Appendix 16.1.9.
5.1
Imputation rules
5.1.1
Study drug
The following rule will be used for the imputation of date of last administration for a given 
study treatment component.
Case 1: The date of last administration is completely missing, and the EOT visit date is 
complete, then this latter date should be used.  
Case 2: Only Year (yyyy) of the dose end date is available and yyyy < the year of EOT date:  
Impute date= Dec31yyyy
Case 3: Only Year (yyyy) of the dose end date is available and yyyy = the year of EOT date: 
Impute date=EOT date
Case 4: Both Year (yyyy) and Month (mm) is available for the date of last administration, and 
yyyy = the year of EOT date and mm < the month of EOT visit:  
Impute date= last day of the Month (mm).
After imputation, compare the imputed date with the start date of that specific record, if the 
imputed date is < start date of that record
Impute date= the start date of that record.


Novartis
For business use only
Page 33
SAP amendment 2
ICL670F2429
Subjects with missing start dates are to be considered missing and no imputation will be made.
If the date of first administration is missing, then the date of last administration should not be 
imputed.
5.1.2
AE date imputation
Date imputation is the creation of a new, complete date from a partial one according to an 
agreed and acceptable algorithm. Missing date for AE will be handled according to STL 
standard.
A partial date is simply an incomplete date e.g., ddOCT2001 the days are missing from this 
DDMMMYYYY date.
Partial adverse event start dates, if left partial, would ultimately mean the following

It would not be possible to place the adverse event in time.

Therefore the treatment/dosage at the time of the event would be unknown. 

Therefore the event could not be reported/summarized appropriately – if at all.
There will be no attempt to impute the following

Missing AE start dates 

AE start dates missing the year

Partial/missing AE end dates
Table 5-1      AE/treatment date abbreviations
Day
Month
Year
Partial AE start date
<not used>
AEM
AEY
Treatment start date (TRTSTD)
<not used>
TRTM
TRTY
The following matrix Table 5-2 describes the possible combinations and their associated 
imputations. In the boxes the upper text indicates the imputation and the lower text the
relationship of the AE start date to the treatment start date (TRTSTD).
Table 5-2     
AE partial date imputation algorithm
AEM Missing
AEM < TRTM
AEM = TRTM
AEM > TRTM
AEY Missing
NC
Uncertain
NC
Uncertain
NC
Uncertain
NC
Uncertain
AEY < 
TRTY
(D)
Before TRTSTD
(C)
Before TRTSTD
(C)
Before TRTSTD
(C)
Before TRTSTD
AEY = 
TRTY
(B)
Uncertain
(C)
Before TRTSTD
(B)
Uncertain
(A)
After TRTSTD


Novartis
For business use only
Page 34
SAP amendment 2
ICL670F2429
AEY > 
TRTY
(E)
After TRTSTD
(A)
After TRTSTD
(A)
After TRTSTD
(A)
After TRTSTD
Table 5-3       AE/treatment date relationship and imputation
Relationship
Before TRTSTD
Indicates AE start date prior to Treatment Start Date 
After TRTSTD
Indicates AE start date after Treatment Start Date
Uncertain
Insufficient to determine the relationship of AE start date to 
Treatment Start Date
Imputation Calculation
NC/Blank 
No convention/imputation
(A)
01MONYYYY
(B)
TRTSTD+1
(C)
15MONYYYY
(D)
01JULYYYY
(E)
01JANYYYY
The following Table 5-4 gives a few examples.
Table 5-4 Example Scenarios
Partial AE start 
date
Treatment start 
date
Relationship
Imputation 
calculation
Imputed date
12mmyyyy
20OCT2001
Uncertain
NC
<blank>
ddmmm2000
20OCT2001
Before
(D)
01JUL2000
ddmmm2002
20OCT2001
After
(E)
01JAN2002
ddmmm2001
20OCT2001
Uncertain
(B)
21OCT2001
ddSEP2001
20OCT2001
Before
(C)
15SEP2001
ddOCT2001
20OCT2001
Uncertain
(B)
21OCT2001
ddNOV2001
20OCT2001
After
(A)
01NOV2001
5.1.3
Concomitant medication date imputation
The imputation of the start date of concomitant medication will follow the same convention 
for AE date. Partial concomitant medication end date will not be imputed.
5.1.3.1
Prior therapies date imputation
Start date:


Novartis
For business use only
Page 35
SAP amendment 2
ICL670F2429
The same rule which is applied to the imputation of AE/concomitant medication start date will 
be used with the exception that for scenario (B) will be replaced to be ‘start date of study drug
-1’.
End date:
Imputed date = min (start date of study drug, last day of the month), if day is
missing; Imputed date = min (start date of study drug, 31DEC), if month and day are
missing.
If the end date is not missing and the imputed start date is after the end date, use the end date
as the imputed start date.
If both the start date and the end date are imputed and if the imputed start date is after the 
imputed end date, use the imputed end date as the imputation for the start date.
5.1.3.2
Other imputations
Incomplete date for death
All dates must be completed with day, month and year.
If the day or month is missing, death will be imputed to the maximum of the last contact date 
(excluding the date of death) and the following:

Missing day:                    15th of the month and year of death

Missing day and month:  July 1st of the year of death  
5.2
Creatinine clearance recalculation
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
eGFR (mL/min/1.73m2)=
186.3× (SCr×0.01131) – 1.154×age– 0.203×E×S where,
E is ethnicity: E=1.212 if patient is black, else E=1 
S is sex: S=0.742 if patient is female, else S=1


Novartis
For business use only
Page 36
SAP amendment 2
ICL670F2429
5.3
Statistical models
5.3.1
Primary analysis
Let X be the number of success observed in the sample and $%&(&, )) is a binomial random 
variable with n trials and probability of success ).
Because of the relationship between the binomial and the beta distribution, the Clopper-Pearson 
interval is sometimes presented as an alternative format that uses the beta distribution as:
$ +,
2 ; ., & −. + 11 < ) < $ +1 −,
2 ; . + 1, & −.1
Where x is the number of success n is the number of trials and $(3, ,, 4) is the p-th quantile 
from the beta distribution with shape parameters ,, 4.  
When x = 0 the interval is 50, 1 −+
7
81
9/:
; and when x = n, it is 5+
7
81
9/:
, 1;
[1]
The beta distribution is, in turn, related to the F-distribution so another formulation of the 
Clopper-Pearson interval can be written using F-quantiles:
>1 +
& −. + 1
.? @,
2 ; 2., 2(& −. + 1)A
B
C9
< ) < >1 +
& −.
(. + 1)? @1 −,
2 ; 2(. + 1), 2(& −.)A
B
C9
[2]
Where x is the number of success, n is the number of trials and ?(D, E9, E8) is the c-th quantile 
from an F-distribution with E9 and E8 degrees of freedom.
Since Clopper-Pearson interval is the exact interval since it is based directly on the binomial 
distribution rather than any normal approximation to binomial distribution. Thus, Clopper-
Pearson distribution will be used in calculating confidence interval.
5.3.2
Key secondary analysis
Not applicable 
6
Reference
Thulin, Måns (2014). "The cost of using exact confidence intervals for a binomial proportion". 
Electronic Journal of Statistics. 8 (1): 817–840. ISSN 1935-7524. doi:10.1214/14-EJS909.
Agresti, Alan; Coull, Brent A. (1998). "Approximate is better than 'exact' for interval estimation 
of binomial proportions". The American Statistician. 52: 119–126. JSTOR 2685469. 
MR 1628435. doi:10.2307/2685469.