Clinical trial NCT02720536
Conditions: Chronic Iron Overload
Keywords: adult pediatric, anemia. Myelodysplastic Syndrome Thalassemia Film coated tablet ICL670 MDS Chelation Deferasirox Iron overload
Sponsor: Novartis Pharmaceuticals
Start date: 2016-08-16; Completion date: 2019-07-23
Enrollment: 53 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Extend evaluation of deferasirox film-coated tablet (FCT) formulation

Detailed description:
Collection of additional safety and efficacy data with deferasirox film-coated tablet (FCT) in patients who had completed study CICL670F2201

* Provide patients who completed 24 weeks of treatment in the core study, CICL670F2201, the possibility to have additional treatment with the deferasirox FCT.
* Collect additional longer term data on the safety and the tolerability of the deferasirox FCT.
* Collect efficacy data on the deferasirox FCT in reduction or maintenance of iron burden as measured by serum ferritin level.

Arms: arm 1: Treatment will be administered daily for up to 24 months. For each patient the daily dose is calculated based on the patient's actual body weight.
Interventions: intervention 1: Deferasirox
Intervention descriptions: intervention 1: Deferasirox FCT will be provided as 90 mg, 180 mg and 360 mg film-coated tablets for oral use.

Protocol documents:
Prot_001.pdf: 
Clinical Development
ICL670, deferasirox
Oncology Clinical Trial Protocol CICL670AIC04 / NCT02720536
Open-label, multicenter, single arm, phase III study to 
collect additional safety and efficacy data with deferasirox 
film-coated tablets in patients completing study 
CICL670F2201
Authors
Document type
Amended Protocol Version
EUDRACT number
2016-000186-23
Version number
01 (Clean)
Development phase
III
Document status
Final
Release date
25-Oct-2017
Property of Novartis
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


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Amended Protocol Version 01 (Clean)
Protocol No. CICL670AIC04
Table of contents
Table of contents .................................................................................................................2
List of figures ......................................................................................................................5
List of tables ........................................................................................................................6
List of abbreviations............................................................................................................7
Glossary of terms.................................................................................................................9
Protocol summary:.............................................................................................................10
Amendment 1 (25-Oct-2017) ...................................................................................................13
1
Background........................................................................................................................18
1.1
Overview of disease pathogenesis, epidemiology and current treatment..............18
1.2
Introduction to investigational treatment...............................................................20
1.2.1
Overview of deferasirox film-coated tablet ..........................................20
2
Rationale............................................................................................................................21
2.1
Study rationale and purpose...................................................................................21
2.2
Rationale for the study design ...............................................................................22
2.3
Rationale for dose and regimen selection..............................................................22
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 ......................................................................................................................24
4.1
Description of study design ...................................................................................24
4.2
Timing of interim analyses and design adaptations...............................................26
4.3
Definition of end of study......................................................................................26
4.4
Early study termination..........................................................................................26
5
Population..........................................................................................................................26
5.1
Patient population..................................................................................................26
5.2
Inclusion criteria ....................................................................................................26
5.3
Exclusion criteria...................................................................................................27
6
Treatment...........................................................................................................................29
6.1
Study treatment......................................................................................................29
6.1.1
Dosing regimen .....................................................................................29
6.1.2
Ancillary treatments..............................................................................30
6.1.3
Rescue medication ................................................................................30
6.1.4
Guidelines for continuation of treatment ..............................................30
6.1.5
Treatment duration................................................................................30


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6.2
Dose escalation guidelines.....................................................................................30
6.3
Dose modifications ................................................................................................31
6.3.1
Dose modification and dose delay ........................................................31
6.3.2
Follow-up for toxicities.........................................................................34
6.4
Concomitant medications ......................................................................................34
6.4.1
Permitted concomitant therapy .............................................................34
6.4.2
Permitted concomitant therapy requiring caution and/or action...........34
6.4.3
Prohibited concomitant therapy ............................................................35
6.4.4
Use of Bisphosphonates (or other concomitant agents)........................35
6.5
Patient numbering, treatment assignment or randomization .................................35
6.5.1
Patient numbering .................................................................................35
6.5.2
Treatment assignment or randomization...............................................35
6.5.3
Treatment blinding................................................................................36
6.6
Study drug preparation and dispensation...............................................................36
6.6.1
Study treatment packaging and labeling ...............................................36
6.6.2
Drug supply and storage........................................................................36
6.6.3
Study drug compliance and accountability ...........................................36
6.6.4
Disposal and destruction .......................................................................37
7
Visit schedule and assessments .........................................................................................37
7.1
Study flow and visit schedule................................................................................37
7.1.1
Screening...............................................................................................41
7.1.2
Run-in period ........................................................................................42
7.1.3
Treatment period ...................................................................................42
7.1.4
Discontinuation of study treatment .......................................................42
7.1.5
Withdrawal of consent ..........................................................................43
7.1.6
Follow-up for safety evaluations...........................................................43
7.1.7
Lost to follow-up...................................................................................44
7.2
Assessment types...................................................................................................44
7.2.1
Efficacy assessments.............................................................................44
7.2.2
Safety and tolerability assessments.......................................................44
7.2.3
Pharmacokinetics ..................................................................................48
7.2.4
Biomarkers ............................................................................................48
7.2.5
Resource utilization...............................................................................48
7.2.6
Patient reported outcomes.....................................................................48
8
Safety monitoring and reporting........................................................................................48
8.1
Adverse events.......................................................................................................48


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8.1.1
Definitions and reporting ......................................................................48
8.1.2
Laboratory test abnormalities................................................................49
8.1.3
Adverse events of special interest.........................................................49
8.2
Serious adverse events...........................................................................................50
8.2.1
Definitions.............................................................................................50
8.2.2
Reporting...............................................................................................50
8.3
Emergency unblinding of treatment assignment ...................................................51
8.4
Pregnancies............................................................................................................51
8.5
Warnings and precautions......................................................................................51
8.6
Data Monitoring Committee..................................................................................51
8.7
Steering Committee ...............................................................................................51
9
Data collection and management.......................................................................................52
9.1
Data confidentiality ...............................................................................................52
9.2
Site monitoring ......................................................................................................52
9.3
Data collection.......................................................................................................53
9.4
Database management and quality control............................................................53
10 Statistical methods and data analysis ................................................................................53
10.1
Analysis sets ..........................................................................................................54
10.1.1
Full Analysis Set ...................................................................................54
10.1.2
Safety set ...............................................................................................54
10.1.3
Other analysis sets.................................................................................54
10.2
Patient demographics/other baseline characteristics .............................................54
10.3
Treatments (study treatment, concomitant therapies, compliance) .......................54
10.4
Primary objective...................................................................................................55
10.4.1
Variable.................................................................................................55
10.4.2
Statistical hypothesis, model, and method of analysis..........................56
10.4.3
Handling of missing values/censoring/discontinuations.......................56
10.4.4
Supportive and Sensitivity analyses......................................................56
10.5
Secondary objectives .............................................................................................56
10.5.1
Secondary efficacy objective ................................................................56
10.5.2
Other Safety objectives .........................................................................56
10.5.3
Resource utilization...............................................................................59
10.5.4
Patient-reported outcomes.....................................................................59
10.6
Exploratory objectives...........................................................................................59
10.7
Interim analysis......................................................................................................59
10.8
Sample size calculation..........................................................................................59


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10.9
Power for analysis of key secondary variables......................................................59
11 Ethical considerations and administrative procedures ......................................................59
11.1
Regulatory and ethical compliance........................................................................59
11.2
Responsibilities of the investigator and IRB/IEC/REB.........................................59
11.3
Informed consent procedures.................................................................................60
11.4
Discontinuation of the study..................................................................................60
11.5
Publication of study protocol and results...............................................................60
11.6
Study documentation, record keeping and retention of documents.......................61
11.7
Confidentiality of study documents and patient records .......................................62
11.8
Audits and inspections...........................................................................................62
11.9
Financial disclosures..............................................................................................62
12 Protocol adherence ............................................................................................................62
12.1
Amendments to the protocol..................................................................................62
13 References (available upon request)..................................................................................63
14 Appendices ........................................................................................................................65
14.1
Dosing tables (Deferasirox FCT)...........................................................................65
14.2
Equivalent dose guidance ......................................................................................70
14.3
Examples of light meal ..........................................................................................71
List of figures
Figure 4-1
Study design..........................................................................................25


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List of tables
Table 3-1
Objectives and related endpoints ..........................................................24
Table 6-1
Dose and treatment schedule for FCT formulation...............................30
Table 7-1
Visit evaluation schedule ......................................................................38
Table 7-2
Local clinical laboratory parameters collection plan ............................45
Table 10-1
Definition of notable/extended ranges for laboratory tests...................57
Table 10-2
Definition of notable ranges for vital signs and weight ........................58
Table 14-1
Deferasirox FCT dosing table for 3.5 mg/kg/day .................................65
Table 14-2
Deferasirox FCT dosing table for 7 mg/kg/day ....................................65
Table 14-3
Deferasirox FCT dosing table for 10.5 mg/kg/day ...............................66
Table 14-4
Deferasirox FCT dosing table for 14 mg/kg/day ..................................66
Table 14-5
Deferasirox FCT dosing table for 17.5 mg/kg/day ...............................67
Table 14-6
Deferasirox FCT dosing table for 21 mg/kg/day ..................................67
Table 14-7
Deferasirox FCT dosing table for 24.5 mg/kg/day ...............................68
Table 14-8
Deferasirox FCT dosing table for 28 mg/kg/day ..................................69
Table 14-9
Patients switching from DT to FCT formulation ..................................70
Table 14-10
Examples of light meal..........................................................................71


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List of abbreviations
AE
Adverse Event
AML
Acute Myeloid Leukemia
ALT/SGPT
Alanine aminotransferase/serum glutamic pyruvic transaminase/SGPT
AST/SGOT
Aspartate aminotransferase/serum glutamic oxaloacetic transaminase/SGOT
AUC
Area under the concentration time curve
AUClast
The AUC from time zero to the last measurable concentration sampling time (tlast) 
(mass × time × volume-1) after single dose
AUCinf
The AUC from time zero to infinity
Cmax
The maximum (peak) observed plasma, blood, serum, or other body fluid drug 
concentration after single dose administration (mass × volume-1)
CMO&PS
Chief Medical Office and Patient Safety
CRO
Contract research organization
DFO
Deferoxamine mesylate
DT
Dispersible tablet
eCRF
Electronic case report/record form
ECG
Electrocardiogram
EOT
End of treatment
FCT
Film-coated tablet
FAS
Full analysis set
GCP
Good Clinical Practice
IB
Investigator’s Brochure
ICH
International conference on harmonization
ICMJE
International Committee of Medical Journal Editors
ICT
Iron chelation therapy
IEC
Independent Ethics Committee
IPSS-R
Revised International Prognostic Scoring System
IRB
Institutional Review Board
LIC
Liver iron concentration
LPLV
Last patient last visit
MDS
Myelodysplastic syndrome
MedDRA
Medical dictionary for regulatory activities terminology
NCCN
National Comprehensive Cancer Network
NSAIDs
Non-steroidal anti-inflammatory drugs
PHI
Protected health information
PRBC
Packed red blood cells
PRO
Patient reported outcome
QoL
Quality of life
RBC
Red blood cells
REB
Research Ethics Board
SAE
Serious adverse event
SUSARs
Suspected Unexpected Serious Adverse Reactions
UGT
Uridine 5'-diphospho-glucuronosyltransferase


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ULN
Upper limit of normal range


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Glossary of terms
Assessment
A procedure used to generate data required by the study.
Dose level
The dose of drug given to the patient (total daily or weekly etc.).
Enrollment
Point/time of patient entry into the study; the point at which informed 
consent must be obtained (i.e. prior to starting any of the procedures 
described in the protocol).
Investigational drug
The study treatment whose properties are being tested in the study; 
this definition is consistent with US CFR 21 Section 312.3 and is 
synonymous with “investigational new drug.”
Investigational treatment
Drug whose properties are being tested in the study as well as their 
associated placebo and active treatment controls (when applicable). 
This also includes approved drugs used outside of their 
indication/approved dosage, or that are tested in a fixed combination. 
Investigational treatment generally does not include other study 
treatments administered as concomitant background therapy required 
or allowed by the protocol when used in within approved 
indication/dosage.
Other study treatment
Any drug administered to the patient as part of the required study 
procedures that were not included in the investigational treatment.
Patient number
A unique identifying number assigned to each patient who enrolls in 
the study.
Period
A subdivision of the study timeline; divides stages into smaller 
functional segments such as Screening, Baseline, Titration, Washout, 
etc.
Premature patient withdrawal
Point/time when the patient exits from the study prior to the planned 
completion of all study treatment administration and/or assessments; 
at this time all study treatment administration is discontinued and no 
further assessments are planned
Stage related to study 
timeline
A major subdivision of the study timeline; begins and ends with major 
study milestones such as enrollment, randomization, completion of 
treatment, etc.
Stop study participation
Point/time at which the patient came in for a final evaluation visit or 
when study treatment was discontinued whichever is later.
Study treatment
Includes any drug or combination of drugs in any study arm 
administered to the patient (subject) as part of the required study 
procedures, including placebo and active drug run-ins.
In specific examples, it is important to judge investigational treatment 
component relationship relative to a study treatment combination; 
study treatment in this case refers to the investigational and non-
investigational treatments in combination.
Study treatment 
discontinuation
Point/time when patient permanently stops taking study treatment for 
any reason; may or may not also be the point/time of premature 
patient withdrawal.
Supportive treatment
Refers to any treatment required by the exposure to a study treatment, 
e.g. premedication of vitamin supplementation and corticosteroid for 
pemetrexed disodium.
Variable
Identifier used in the data analysis; derived directly or indirectly from 
data collected using specified assessments at specified time points


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Protocol summary: 
Title
Open-label, multicenter, single arm, phase III study to collect additional 
safety and efficacy data with deferasirox film-coated tablets in patients 
completing study CICL670F2201
Brief title
Extended evaluation of deferasirox film-coated tablet (FCT) formulation
Sponsor and Clinical 
Phase
Novartis
Phase III
Investigation type
Drug
Study type
Interventional
Purpose and rationale
The purpose of the present study is to:

Assess the safety of the deferasirox FCT formulation in patients with 
transfusion-dependent thalassemia or myelodysplastic syndrome 
(MDS) (very low, low or intermediate risk).

Assess the efficacy of the deferasirox FCT in reduction or 
maintenance of iron burden as measured by serum ferritin level.
Primary Objective 
The primary objective is to evaluate the overall safety of deferasirox FCT 
formulation in patients with transfusion-dependent thalassemia or MDS at 
very low, low or intermediate risk.
Secondary Objective
The secondary objective is:

To evaluate efficacy of deferasirox FCT on serum ferritin levels 
(decrease or maintenance, according to the individual therapeutic 
goal).
Study design
This is a an open-label, multicenter, single arm, phase III study aimed at 
collecting additional data on safety and tolerability as well as data on 
efficacy of the deferasirox FCT formulation in patients with thalassemia or 
MDS (very low, low or intermediate risk) when treated for more than 
24 weeks on study CICL670F2201.
The study treatment duration will be for a maximum of 24 months.
Population
The study population will consist of patients aged 10 years or older, male 
or female with transfusion-dependent thalassemia or MDS at very low, low 
or intermediate risk recruited at Region Europe participating sites that 
have completed the 24-week treatment under study CICL670F2201. 
Patients who have withdrawn prematurely from that study will not be 
enrolled.
Inclusion criteria
Patients eligible for inclusion in this study have to meet all of the following 
criteria:

Have completed 24-weeks of study treatment as described in protocol 
CICL670F2201.

Are deemed to be tolerating deferasirox treatment by the investigator.

Provided written informed consent/assent before any study-specific 
procedures are performed. For pediatric patients, consent will be 
obtained from parent(s) or legal patient’s representative. Investigators 
will also obtain assent of patients according to local, regional or 
national guidelines.


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
Are deemed to be tolerating deferasirox treatment by the investigator if 
continuing directly from study CICL670F2201.
For reference, the inclusion criteria in the study CICL670F2201 were 
stated as follows:
1.
Written informed consent/assent before any study-specific procedures. 
For pediatric patients, consent will be obtained from parent(s) or legal 
patient’s representative. Investigators will also obtain assent of 
patients according to local, regional or national guidelines.
2.
Male and female patients aged ≥10 years
3.
Patients with transfusion-dependent thalassemia and iron overload, 
requiring deferasirox DT at doses of ≥30 mg/kg/day as per the 
investigator’s decision,
OR 
Patients with very low, low or intermediate (int) risk myelodysplastic 
syndrome (MDS) and iron overload, requiring deferasirox DT at doses 
of ≥20 mg/kg/day as per the investigator’s decision.

The very low, low or intermediate (int) risk MDS should be 
determined by the Revised International Prognostic Scoring System 
(IPSS-R) and IPSS-R must be confirmed by a bone marrow 
examination within 6 months prior to study entry and must be 
hematologically stable with a patient’s life expectancy of at least 
1 year.
4.
History of transfusion of at least 20 packed red blood cells (PRBC)
units and anticipated to be transfused with at least 8 units of PRBCs 
annually during the studySerum ferritin > 1000 ng/mL, measured at 
Screening Visit 1 and Screening Visit 2 (the mean value will be used 
for eligibility criteria).
Exclusion criteria
The exclusion criteria will follow those described for CICL670F2201, which 
were as follows:
1.
Creatinine clearance below the contraindication limit in the locally 
approved prescribing information. Creatinine clearance will be 
estimated from serum creatinine at Screening Visit 1 and Screening 
Visit 2 and the mean value will be used for eligibility criteria.
2.
Serum creatinine > 1.5 × upper limit of normal range (ULN) at 
Screening measured at Screening Visit 1 and Screening Visit 2 (the 
mean value will be used for eligibility criteria).
3.
Alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase 
(SGPT) > 5 × ULN, unless liver iron concentration (LIC) confirmed 
as > 10 mg Fe/dw within 6 months prior to Screening Visit 1.
4.
Significant proteinuria as indicated by a urinary protein/creatinine 
ratio > 0.5 mg/mg in a non-first void urine sample at Screening Visit 1 
or Screening Visit 2.
5.
Patients with significant impaired gastrointestinal function or 
gastrointestinal disease that may significantly alter the absorption of 
oral deferasirox (e.g. ulcerative diseases, uncontrolled nausea, 
vomiting, diarrhea, malabsorption syndrome, or small bowel 
resection).
6.
Clinical or laboratory evidence of active Hepatitis B or Hepatitis C 
(Hepatitis B surface Antigen (HBsAg) in the absence of Hepatitis B 
surface antibody (HBsAb) or HCV antibody positive with HCV RNA 
positive).


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7.
Patients with psychiatric or addictive disorders which prevent them 
from giving their informed consent or undergoing any of the treatment 
options or patients unwilling or unable to comply with the protocol.
Investigational and 
reference therapy
Deferasirox FCT will be provided as 90 mg, 180 mg and 360 mg dose 
strengths for once daily oral use. No reference therapy is included in this 
study.
Efficacy assessments
Serum ferritin level
Safety assessments
Safety will be monitored by assessing the following parameters:

Hematology, blood chemistry (including renal and hepatic parameters) 
and urinalysis.

Adverse events (AEs) and in particular specific gastrointestinal events.

Vital signs.

Physical examinations.

Ocular examinations.Auditory examinations.
Other assessments
Not applicable
Data analysis
Data from all centers participating in this study will be pooled for analyses.
Standard descriptive analyses will include:

Frequencies and percentages for categorical data;

n, mean, standard deviation, minimum, median, 25th and 75th
percentiles and maximum for continuous data.
Detailed statistical analysis methods will be defined in statistical analysis 
plan documentation.
Key words
New formulation, deferasirox, film-coated tablet, chelation, iron overload, 
safety, long-term


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Amendment 1 (25-Oct-2017)
Amendment rationale 
This protocol amendment is substantial and it is issued for the following reasons:

The description related to study treatment duration in Protocol Summary, Section 4.1
(Description of study design), Section 6.1.5 (Treatment duration), and Section 7.1.3
(Treatment period) has been amended to clarify that there is no obligation for a subject to 
be withdrawn from the study upon local commercial availability of the FCT.

As this study has its own CTA and EUDRACT numbers and is not, as such, an extension 
study, the references to “Core and Extension” study were removed throughout the protocol. 
However, enrolment is only open to patients who had completed CICL670F2201 study.

In alignment with the Exjade prescribing information, deferasirox is contraindicated in 
patients with estimated creatinine clearance less than 60 mL/min (Section 6.3.1.2),
immediate discontinuation of patient if severe cutaneous adverse reaction occurs 
(Section 6.3.1.5) and guidance on treating patients who develop moderate hepatic 
impairment (Child-Pugh Class B) (Section 6.3.1.6) during the trial is provided.

In addition guidance was added regarding the concomitant administration of deferasirox 
with CYP1A2 substrate theophylline (Section 6.4.2), cholestyramine (Section 6.4.3) and 
drugs that have ulcerogenic potential (Section 6.4.4) in alignment with the Exjade 
prescribing information.

To correct discrepancies on the description of the visit intervals between Table 7-1 (Visit 
evaluation schedule) and protocol text in Section 4.1 (Description of study design), 
Section 6.3.1.3 (Changes in serum ferritin), Section 7.1.3 (Treatment period), and 
Section 7.2.1 (Efficacy assessments).

To clarify the following aspects in Section 6.1.1 (Dosing regimen):

Regarding patient’s recruitment.

Starting dose calculation for patients who completed CICL670F2201 study and 
switched to commercially available deferasirox dispersible tablet or other iron 
chelation therapy.

Timing of drug administration in accordance with the Investigator’s brochure
version 18.1.

Clarification on drug supply disposal and destruction in Section 6.6.4.

To correct the description for local clinical laboratory parameters collection plan 
(Hematology) described in Table 7-2 (Local clinical laboratory parameters collection 
plan).

To remove reference related to collection of pregnancy outcomes for the pregnant partners 
of male patients in Section 8.4 (Pregnancies) in accordance with Novartis’s pregnancy 
guidance working group.

To clarify the demographic and other baseline data to be summarized descriptively in 
Section 10.2 in line with actual eCRF design. Specifically regarding:

Ethnicity


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
ECG

Audiometric test

Ocular exam

To correct the description for duration of treatment exposure, actual and planned daily 
dose in Section 10.3 (Treatments).

Clarification on the descriptive statistical analyses of the primary objective in 
Section 10.4.2 (Statistical hypothesis, model, and method of analysis). Objectives were 
unchanged.

To update description for supportive sensitivity analyses in Section 10.4.4.

To add description for secondary efficacy objective analyses in Section 10.5.1.

To update description for adverse events analyses in Section 10.5.2.1.
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions.

Protocol summary (Study design): Corrected to “The study treatment duration of treatment 
will be for a maximum of 24 months”.

Section 1.2.1.1 (Clinical experience with deferasirox) and Section 2.6 (Risks and 
benefits): Updated “to align with the Exjade prescribing information”.

Section 4.1: Corrected to 

Following enrollment (Visit 3/Day 1) patients will return to the site at 2 week 
intervals until Visit 5 (Month 1). Thereafter, scheduled visits will be monthly.

The planned duration of treatment in this study is for a maximum of 24 months.

In Figure 4-1 references to “Core and Extension” study were removed and undated to 
reflect changes based on the amendment rationale.

Section 6.1.1: Amended to 

“Having completed the 24 weeks of CICL670F2201 study, patients recruited at 
Region Europe participating sites will be invited to participate in this study to continue 
FCT or switch from DT to the FCT formulation”.

“Patients who completed CICL670F2201 study and had switched to commercially 
available DT or other ICT will have to undergo a 5-day washout period and will then 
be assigned FCT at a starting dose equivalent to their last deferasirox dose in 
CICL670F2201 study”.

“Patients will swallow the required number of deferasirox FCT every day either on an 
empty stomach or with a light meal. 

Removed reference related to “However, all patients should take their deferasirox 
FCT dose before 12:00 PM (noon)”.

Section 6.1.5: Corrected to“The duration of treatment in the current study is for a 
maximum of 24 months”.

Section 6.3.1.2: Added “Caution based on creatinine clearance”.


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
Section 6.3.1.3: Corrected to “Following enrollment (Visit 3/Day 1) serum ferritin will be 
monitored at 2 week intervals until Visit 5 (Month 1). Thereafter, scheduled assessments 
will be monthly”.

Section 6.3.1.5: added “Guidance regarding treatment discontinuation if severe cutaneous 
adverse reaction occurs”.

Section 6.3.1.6: added “Guidance related to dose modifications for patients with moderate 
hepatic impairment (Child-Pugh B)”.

Section 6.4.2: Added “Guidance related to concomitant use of deferasirox with CYP1A2 
substrate theophylline”.

Section 6.4.3: Added “Guidance related to concomitant use of deferasirox with 
cholestyramine”.

Section 6.4.4: Added “Guidance related to concomitant use of deferasirox with drugs that 
have ulcerogenic potential”.

Section 6.6.4: Updated with “A signed Certificate of Destruction (or equivalent 
documentation as per local procedure) will be required for archiving in the Trial Master 
File”.

Section 7.1.3: Corrected to

“The planned duration of treatment in this study is for a maximum of 24 months”.

“Treatment visits will commence at Visit 3 (Baseline). Patients will return to the site 
at 2 week intervals until Visit 5 (Month 1). Thereafter, scheduled visits will be 
monthly until EOT (Visit 28/Month 24)”.

Section 7.2.1: Corrected to “Serum ferritin testing will be performed at Screening Visit 1 
and 2. Following enrolment (Visit 3/Day 1) serum ferritin will be tested at 2 week 
intervals until Visit 5 (Month 1). Thereafter, scheduled testing will be monthly”.

Table 7-2: Corrected to remove “differential” incorrectly associated with RBC 
morphology as following “Hematocrit, Hemoglobin, Platelets, RBCs, White blood cells 
count with differential (Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils),
RBC Morphology”.

Section 8.4: Removed the sentence regarding the collection of pregnancy outcomes for the 
female partners of male patients and consent to report information regarding these 
pregnancy outcomes.

Section 10.2: Updated to 

“Ethnicity (Hispanic/Latino, Chinese, Indian (Indian subcontinent), Japanese, Other)”.

“Clinically significant abnormality in ECG (Yes, No)”.

“Overall interpretation in audiometric test (Normal, Clinically insignificant 
abnormality, Clinically significant abnormality)”.

“Overall interpretation in ocular exam (Normal, Clinically insignificant abnormality, 
Clinically significant abnormality)”.

Section 10.3: Removed reference related to “duration of exposure (<4 weeks, 4-<12 weeks, 
≥12 weeks” and updated with “duration of exposure (at intervals as described in the 
Statistical Analysis Plan”.


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
Section 10.4.2: Updated to “Frequencies, percentages, and 95% confidence intervals (CIs) 
for overall incidences of any AEs during the on-treatment period”.

Section 10.4.4: Added “Prior chelation therapy (DFX, any other ICT)”.

Section 10.5.1: Added “The Baseline serum ferritin value will be defined as the average of 
the 2 measurements obtained during the Screening period”.

Section 10.5.2.1: Updated with:

An overall summary of type of AEs will be presented by severity.

Specific groupings of AEs of special interest will be considered and the number of 
patients with at least one event in each grouping will be reported.

Incidence of AEs of special interest will be summarized by grouping and preferred 
term.

The following protocol sections were amended to reflect the changes given in the latest 
protocol template version dated 06-Apr-2017.

Section 6.3.1: For patients who do not tolerate the protocol-specified dosing schedule, 
dose interruptions and/or reductions are recommended in order to allow patients to 
continue the study treatment.

Removed “Section 6.3.3 (Anticipated risks and safety concerns of the study drug)”.

Section 7.2.2.7.1: Clinically significant abnormalities present at Screening should be 
reported on the Medical History eCRF page.

Section 8.1.1: Information about any deaths (related to an AE or not) will also be 
collected using an end of treatment form.

Section 8.2.2:

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.

Removed reference related to “the telephone and telefax numbers of the contact 
person in the local DS&E department”.

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.

Novartis DS&E is updated to “Chief Medical Office and Patient Safety”.

Section 8.4: Novartis DS&E is updated to “Chief Medical Office and Patient Safety”.

Section 11.5: Updated “To reflect recent changes in the Novartis Guidelines for the 
Publication of Results from Novartis-sponsored Research”.
IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation.


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The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment.


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1
Background
1.1
Overview of disease pathogenesis, epidemiology and current 
treatment
Chronic iron overload represents a serious complication of potentially lifesaving blood 
transfusions which are the mainstay of therapy in transfusion-dependent anemias. Since 
humans have no mechanism for the active elimination of iron from the body, excess iron 
received via transfusions deposit in various tissues of the body, particularly the liver, heart 
and endocrine organs, leading to end-organ dysfunction and eventually organ failure. Indeed, 
organ failure due to chronic iron overload represents the major cause of death in patients with 
β-thalassemia major who receive blood transfusions regularly without appropriate chelation 
therapy (Cappellini et al 2006).
Overview β-thalassemia
Beta-thalassemias are a group of hereditary blood disorders characterized by anomalies in the 
synthesis of the beta chains of hemoglobin resulting in variable phenotypes ranging from 
severe anemia to clinically asymptomatic individuals.
Beta-thalassemia is prevalent in the Mediterranean basin, the Middle East, Central Asia, India, 
Southern China, and the Far East, as well as countries along the north coast of Africa and in 
South America.
The total annual incidence of symptomatic individuals is estimated at 1 in 1 00 000
throughout the world and 1 in 10 000 people in the European Union. However, accurate data
on carrier rates are lacking for many populations.
Three main phenotypic forms have been described: thalassemia major, thalassemia intermedia 
and thalassemia minor with β-thalassemia major being the most severe form of the disease. 
Individuals with β-thalassemia major usually present within the first 2 years of life with 
severe anemia requiring regular red blood cell (RBC) transfusions. Findings in untreated or 
poorly transfused patients with thalassemia major are growth retardation, pallor, jaundice, 
poor musculature,
hepatosplenomegaly, development
of masses
from
extramedullary 
hematopoiesis, and skeletal changes that result from expansion of the bone marrow. If left 
untreated, 80% of β-thalassemia major patients die within the first 5 years of life due to 
anemia-related conditions. As such, transfusion therapy remains the mainstay of treatment in 
β-thalassemia major patients. Regular transfusion therapy leads to iron overload with 
iron-related complications including endocrine complications, such as growth retardation,
failure of sexual maturation, diabetes mellitus; cardiac complications, such as dilated
myocardiopathy, and liver complications including fibrosis and cirrhosis.
The therapeutic concept of iron chelation has been established with more than 50 years of 
clinical experience with Desferal®, deferoxamine mesylate (DFO). However, poor oral 
bioavailability and short plasma half-life (t1/2) has necessitated its application as slow 
subcutaneous or intravenous infusion. Iron-chelation therapy with DFO is extremely
demanding with many patients experiencing considerable discomfort from administration of
the drug, as well as a significant negative impact on their quality of life (QoL) 


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(Arboretti et al 2001), thus resulting in poor compliance. The lack of compliance with DFO 
administration in patients who have serious blood disorders has necessitated recognition for 
the need of an effective iron chelator which can be given via the more convenient oral route.
Compliance with iron chelation therapy (ICT) mainly influences the frequency and severity of 
iron 
overload-related
complications
(Galanello and Origa 2010) 
with
demonstrated 
improvement in organ dysfunction and survival in patients compliant with therapy 
(Gabutti and Piga 1996).
Transfusions and oral ICT have dramatically improved the QoL for patients with severe
anemias. Previously a rapidly fatal disease in early childhood, β- thalassemia is now a chronic
disease compatible with a prolonged life expectancy. Today, life expectancy varies between
25 and 55 years, depending on patient compliance with medical treatment, particularly iron
chelation (Cappellini 2008).
Overview of myelodysplastic syndromes
The myelodysplastic syndromes (MDS) include a diverse group of acquired disorders of 
hematopoiesis, collectively characterized by bone marrow failure (i.e. inadequate production 
of healthy, mature blood cells) and a tendency for clonal evolution, including progression to 
acute myeloid leukemia (AML) defined by ≥20% blast cells in the marrow.
Although relatively rare, MDS are the most common malignant bone marrow disorders. In the 
general
population,
MDS
occur
in
5 per 1 00 000
people.
However,
among
individuals > 70 years, the incidence increases between 22 and 45 per 1 00 000 and increases
further with age (National Comprehensive Cancer Network ((NCCN) 2011). In most cases, 
the cause of MDS is unknown although some cases have been linked to exposure to 
chemotherapy, radiation, and pesticides.
Managing MDS is complicated by the generally advanced age of the patients, the attendant 
non-hematologic comorbidities, and the older patients’ relative inability to tolerate certain 
intensive forms of therapy (NCCN 2011).
Signs and symptoms of MDS relate to hematopoietic failure, manifesting in anemia, 
thrombocytopenia or leukopenia. The anemia is often severe, leading to regular transfusions 
and reduced QoL.
Treatment goals for patients with lower risk MDS primarily involve managing cytopenias. 
While specific therapies and the use of growth factors may alleviate transfusion requirements 
in some patients, 60-80% of patients do not respond and require ongoing platelet and RBC
transfusions due to impaired hematopoiesis.
In many patients, this leads to chronic RBC transfusion therapy, and the development of 
secondary iron overload. Furthermore, iron overload may already be present in many MDS 
patients even before the start of the transfusion regimen. The intestinal iron intake is 
stimulated due to anemia and/or ineffective erythropoiesis. Liver dysfunction, cirrhosis and 
endocrinopathies have been described in multi-transfused MDS patients (even with a
short-term duration of transfusion), where even mild liver function abnormalities have been 
associated with marked hepatic iron overload and portal fibrosis on biopsy (Schafer et al 1981,
Jaeger et al 1992).


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Iron overload may impact survival in MDS, which is especially relevant for low-risk patients.
A retrospective analysis of 467 MDS patients demonstrated that cardiac failure and liver
cirrhosis constituted 51% and 8% respectively of the non-leukemic causes of death 
(Malcovati et al 2005). Use of DFO in iron-overloaded MDS patients has been reported to 
improve organ dysfunction (Jensen et al 2003, Schafer et al 1985), and even improve 
cytopenias (Jensen et al 1996).
1.2
Introduction to investigational treatment
1.2.1
Overview of deferasirox film-coated tablet
The new deferasirox film-coated tablet (FCT) formulation for oral administration is being 
developed due to the chronic nature of chelation therapy and the importance of patient
compliance. The FCT, which will be used in this study, contains the same active substance of
the iron chelator deferasirox (Exjade® company research code ICL670) but has been
strength-adjusted to achieve comparable exposure to the currently approved dispersible tablet
(DT). The FCT is available in 3 dose strengths (90 mg, 180 mg and 360 mg) and is dosed
based on body weight. The FCTs can be taken with or after a light meal.
1.2.1.1
Clinical experience with deferasirox
The efficacy and safety of deferasirox have been evaluated in a large prospective clinical trials 
program that has generated long-term data in patients with transfusional iron overload from a 
variety of transfusion-dependent anemias. Long-term studies (up to 5 years) in patients aged 
≥2 have demonstrated that deferasirox, administered at doses of 10-40 mg/kg/day effectively 
reduce or maintain total body iron as assessed by serum ferritin or liver iron concentration 
(Cappellini et al 2011). Deferasirox was also shown to prevent or reduce cardiac iron overload 
in patients with thalassemia major as evidenced by changes in T2* cardiac MRI 
(Pennell et al 2010, Pennell et al 2011, Pennell et al 2012, Pennell et al 2014) and to be 
associated with improvement in liver pathology as evidenced by biopsy-assessed Ishak 
fibrosis staging and necro-inflammatory scores (Deugnier et al 2011), as well as improvement 
in hematopoietic parameters in myelodysplastic syndrome (MDS) patients using the 
International Working Group 2006 criteria (Gattermann et al 2012, List et al 2012). 
Improvements in hematopoietic parameters were also seen in patients with Aplastic Anemia 
(Lee et al 2013). Moreover, the data accumulated to date have well characterized the safety 
profile of deferasirox across all age groups and for a wide range of transfusion-dependent 
anemias including β-thalassemia, sickle cell disease, and MDS, indicating that the vast 
majority of adverse events are mild to moderate in severity and manageable with dose 
adjustments or interruptions. In patients with non-transfusion dependent thalassemia and iron 
overload, deferasirox at starting doses of 5 and 10 mg/kg/day with dose escalation up to 
20 mg/kg/day was shown to reduce iron overload as evidenced by significant decreases in 
liver iron concentration and serum ferritin and with an overall safety profile comparable to 
placebo (Taher et al 2012). Continued treatment with up to 2 years resulted in continuous 
decrease in iron overload (Taher et al 2013). A new FCT formulation, containing the same 
deferasirox drug substance as the DT formulation has been developed. As of 31 May 2017, 
the FCT has been approved in several countries worldwide including the US, European Union, 
Canada and Switzerland under the name Jadenu or Exjade. The currently available limited 


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clinical trial data with the new formulation, suggests a safety and efficacy profile that is 
consistent with the known profile of the DT deferasirox formulation. Hence, the continuously 
accumulating and available data to date confirm the favorable benefit-risk profile of 
deferasirox in patients with transfusional iron overload and those with non-transfusion 
dependent thalassemia.
2
Rationale
2.1
Study rationale and purpose
The availability of deferasirox DT (Exjade®) as a once-daily oral chelation treatment provided 
patients with a treatment that was a significant improvement over parenteral DFO therapy. 
This was confirmed in studies that measured satisfaction and QoL of oral vs. parenteral 
chelation (Cappellini et al 2007, Osborne et al 2007). Novartis is currently developing a 
deferasirox FCT with the same active substance as the deferasirox DT but with modified 
excipients.
After strength-adjustment, the new formulation was shown to achieve the same overall 
exposure (AUClast and AUCinf) as the currently approved DT formulation in a single-dose 
healthy volunteer study (ICL670F2102); the peak serum concentrations (Cmax) were 
approximately 30% higher. In addition, a food effect study (ICL670F2103) indicated that the
FCT can be taken with a light meal (the current deferasirox DT has to be taken on an empty
stomach, at least 30 mins before a meal).
Thus, the FCT formulation has the advantage of more favorable pharmacokinetic properties (a 
reduced food effect and a more predictable dose-exposure relationship in clinical practice),
better palatability, and a more convenient mode of administration compared to the currently
available DT formulation. It is intended to be used for all currently approved deferasirox
indications. Thus, the new FCT formulation could represent a significant improvement in 
patient care and support compliance with chelation therapy.

Study CICL670F2201 was a randomized, open-label, multicenter, 2-arm, phase II study 
initiated to: Assess the safety of the DT and the FCT formulations in patients with
transfusion-dependent thalassemia or MDS (very low, low or intermediate risk) treated
over 24 weeks.
The present protocol describes study CICL670AIC04 “Open-label, multicenter, single arm, 
24-month, phase III study to collect additional safety and efficacy data with deferasirox 
film-coated tablets in patients completing study CICL670F2201”, which aims to:

Provide patients enrolled and completing 24 weeks of treatment in study CICL670F2201, 
the possibility to have additional treatment with the deferasirox FCT.

Collect additional longer term data on the safety and the tolerability of the deferasirox
FCT.

Collect efficacy data on the deferasirox FCT in reduction or maintenance of iron burden as 
measured by serum ferritin level.


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2.2
Rationale for the study design
This is an open-label, multicenter, single arm, phase III study that aims to provide additional 
drug exposure following study ICL670F2201, which is a randomized, open-label, multicenter, 
2-arm, phase II study.
Two anemia types, transfusion-dependent thalassemia and MDS (very low, low or
intermediate risk), were chosen for enrollment in study CICL670F2201. As transfusion-
dependent thalassemia patients are more commonly children/adolescents while MDS patients
are mostly adults and elderly, the population selected for CICL670F2201 allowed inclusion of
patients from all deferasirox DT approved age groups. However, not more than 50% of MDS
patients per arm were included in CICL670F2201. Patients assigned to either the deferasirox
DT or deferasirox FCT arm and who completed the study period of 24 weeks are allowed to 
participate in this study. Patients who have withdrawn prematurely from CICL670F2201 will 
not be enrolled. Patients with a lag period between completion of CICL670F2201 and 
enrollment in this study can still be enrolled even if they had to switch to DT or other 
chelation therapy in this period.
The treatment duration of 24 weeks in CICL670F2201 is considered sufficient to assess the
safety, pharmacokinetics (PK) and patient reported outcomes (PRO) of the 2 formulations. 
Previous studies of pediatric and adolescent patients have demonstrated differences in iron 
chelation
medication
compliance
within
this
time
period
(Jordan et al 2012,
Alvarez et al 2009). Long-term safety, tolerability, and efficacy will be assessed as objectives
of this current study.
Overall safety is the primary objective of the current study and will be addressed by 
measuring the frequency and severity of adverse events (AEs) and changes in laboratory
values. Time points for assessing laboratory values have been chosen based on the current
labeling for deferasirox DT (Exjade®) in order to be as close as possible to the daily practice
in administering the study treatment.
Recognizing that it is important to allow patients to continue their therapy under a controlled, 
even if less frequent monitoring plan, this multi-center, open-label study has been designed to
provide additional supply of deferasirox FCT to patients recruited in Region Europe sites in 
study CICL670F2201 through a Novartis ORE-sponsored study, provided the patients have
completed the CICL670F2201 study and are tolerating treatment.
2.3
Rationale for dose and regimen selection
Deferasirox FCT is available in 3 dose strengths (90, 180 and 360 mg). In CICL670F2201, all
ICT naïve patients randomized to the study received a deferasirox DT starting dose of
20 mg/kg/day, or the equivalent FCT starting dose of 14 mg/kg/day. All iron chelation
pre-treated patients received deferasirox DT or an equivalent FCT starting dose corresponding 
to their pre-washout dose. In CICL670F2201, patients on DT formulation were allowed dose
adjustments with ± 5 to 10 mg/kg/day, but no more than 40 mg/kg/day while patients on FCT
formulation were allowed dose adjustments with ± 3.5 to 7 mg/kg/day, but no more than 
28 mg/kg/day.
At the start of this study, the following will occur:


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
Patients continuing directly from the CICL670F2201 study who were originally 
randomized to the deferasirox FCT formulation will continue treatment at the same dose 
they were assigned at the end of the CICL670F2201 study.

Patients continuing directly from the CICL670F2201 study who were originally assigned 
to the deferasirox DT formulation will be switched to the deferasirox FCT formulation and 
will be assigned a deferasirox FCT dose equivalent to the deferasirox DT dose they were 
assigned at the end of CICL670F2201 study (Appendix 14.2).

Patients completing the CICL670F2201 study who had switched to commercially 
available DT or other ICT will have to undergo a 5-day washout period and then use an 
equivalent FCT starting dose corresponding to their pre washout iron chelator dose.
Dose adjustment for better treatment effects based on serum ferritin levels and investigator’s 
judgment, will be allowed if necessary every 3 months, with ± 3.5 to 7 mg/kg/day, but no 
more than 28 mg/kg/day.
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 first worldwide marketing authorization for deferasirox was received on 02-Nov-2005 
(International Birth Date) in United States (US). Deferasirox is approved in over 100 
countries worldwide for the treatment of transfusional hemosiderosis in patients 2 years of age 
and older.
Deferasirox is available as a DT containing 125, 250, or 500 mg of drug substance under 
Exjade® brand name. In certain countries, deferasirox is available as DT containing 100 or 
400 mg and as FCT containing 90, 180 or 360 mg of drug substance. In addition, granules 
corresponding to an amount equivalent to 90, 180, 360 mg and 400 mg of drug substance have 
also been developed. As of 31-May-2017, the FCT has been approved in several countries 
worldwide including the US, European Union, Canada and Switzerland under the name 
Jadenu or Exjade. Granules have been approved in the US and Japan, and received CHMP 
Opinion in European Union.
Approximately, 8 121 subjects have received deferasirox in clinical trials as of 31-Oct-2016. 
The cumulative patient exposure since the International Birth Date of the product is estimated 
to be approximately 335 128 patient-treatment years. Although reports of hypersensitivity, 
pancreatitis, toxic epidermal necrolysis and rare fatal outcomes of renal events are currently 
being incorporated into the core data sheet and prescribing information. The benefit-risk 
profile for deferasirox remains positive for the treatment of iron overload and justifies 
unaltered continuation of the development program.
The risk to subjects in this trial may be minimized by compliance with the eligibility criteria 
and study procedures, close clinical monitoring, specific dose modification (for patients who 


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do not tolerate the protocol-specified dosing schedule) and stopping rules (refer Section 6 for 
details).
3
Objectives and endpoints
Objectives and related endpoints are described in Table 3-1 below.
Table 3-1
Objectives and related endpoints
Objective
Endpoint
Analysis
Primary
Refer to Section 10.4
To evaluate the overall safety of 
deferasirox FCT formulation in 
patients with transfusion-dependent 
thalassemia or MDS at very low, low 
or intermediate risk
Overall safety, as measured by 
frequency and severity of AEs and 
changes in laboratory values of 
interest i.e. serum creatinine and 
creatinine clearance
Secondary
Refer to Section 10.5.1
To evaluate efficacy of deferasirox 
FCT on serum ferritin levels
(decrease or maintenance, 
according to the individual 
therapeutic goal).
Absolute and relative change of 
serum ferritin level over time
Abbreviations: FCT=film-coated tablet; MDS=myelodysplastic syndrome
4
Study design
4.1
Description of study design
This is an open-label, multicenter, single arm, 24-month, phase III study aimed at collecting
additional data on safety and tolerability as well as data on efficacy of the FCT formulation in
patients with transfusion-dependent thalassemia or MDS (very low, low or intermediate risk)
when treated for more than 24 weeks in CICL670F2201. It is a pre-requisite for the patient to
provide written consent for participation in this study. This must be in place prior to
performing any study-related procedures or assessments, including those described at the
Screening Visits (Table 7-1).
Patients from Region Europe participating sites in study CICL670F2201 who have completed 
the 24-week treatment period with ongoing tolerance to deferasirox (in the Investigator’s 
opinion) and fulfilling all other eligibility criteria (Section 5) will be given the opportunity to
continue study treatment and follow-up assessments in this study. This will include patients 
from Region Europe who completed 24-weeks of treatment with either deferasirox FCT or 
deferasirox DT in CICL670F2201; and patients with a lag period between completion of 
CICL670F2201 and start of this study i.e. those patients who completed CICL670F2201 and 
have already switched to commercially available deferasirox DT or another ICT.
In CICL670F2201, iron-chelation naïve patients were assigned either deferasirox DT 
20 mg/kg once daily or deferasirox FCT 14 mg/kg once daily. All iron chelation pre-treated 


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patients were assigned a deferasirox DT or an equivalent FCT starting dose corresponding to
their pre-washout dose. At the start of this study, the following will occur:

Patients continuing directly from CICL670F2201 who were originally randomized to the 
deferasirox FCT formulation will continue treatment at the same dose they were assigned 
at the end of CICL670F2201.

Patients continuing directly from CICL670F2201 who were originally assigned to the 
deferasirox DT formulation will be switched to the deferasirox FCT formulation and will 
be assigned a deferasirox FCT dose equivalent to the deferasirox DT dose they were 
assigned at the end of CICL670F2201 (Appendix 14.2).

Patients completing CICL670F2201 who had switched to commercially available DT or 
other ICT will have to undergo a 5-day washout period and then use an equivalent FCT 
starting dose corresponding to their pre washout iron chelator dose.
Study treatment should be administered by the patient once per day. Following enrollment 
(Visit 3/Day 1) patients will return to the site at 2 week intervals until Visit 5 (Month 1). 
Thereafter, scheduled visits will be monthly (please refer Table 7-1 for study visit evaluation 
schedule). Patients may return to the study center more frequently at the physician’s discretion 
as clinically indicated or as per standard of care. Serious adverse events (SAEs) will be 
reported to the Novartis safety database within 24 hours of investigator or treating physician’s 
knowledge of the event from the time the patient has signed informed consent until at least 30 
days after the patient stopped study treatment. All other assessments are performed as per 
standard of care at the site and will not be captured in the eCRF.
Patients who discontinue study treatment before completing the study should be scheduled for 
a visit within 7 days after the last dose, at which time all of the assessments listed for the end
of treatment (EOT) visit (i.e. Month 24). The planned duration of treatment in this study is for 
a maximum of 24 months.
Figure 4-1
Study design


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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 and accuracy verification 
of the last data point (Visit 28) required for statistical analysis.
Refer to Section 7.1 for details.
4.4
Early study termination
The study can be terminated at any time for any reason by Novartis. Should this be necessary, 
the patient should be seen as soon as possible and the same assessments should be performed 
as described in Section 7 for a prematurely withdrawn patient. The investigator may be 
informed of additional procedures to be followed in order to ensure that adequate 
consideration is given to the protection of the patient’s interests. The investigator will be 
responsible for informing IRBs and/or IECs of the early termination of the trial.
5
Population
5.1
Patient population
The study population will consist of patients aged 10 years or older, male or female with 
transfusion-dependent thalassemia or MDS at very low, low or intermediate risk recruited at 
all Region Europe participating sites that have completed the 24-week treatment under
protocol CICL670F2201 and who have been randomized to the FCT formulation or to the DT 
formulation. Patients who will have withdrawn prematurely from CICL670F2201 will not be 
enrolled. Patients with a lag period between completion of CICL670F2201 and enrollment in 
this study can still be enrolled even if they had to switch to DT or other chelation therapy in 
this period, following washout.
The investigator or designee must ensure that only patients who meet all the following
inclusion and none of the exclusion criteria are offered treatment in the study.
5.2
Inclusion criteria
Patients eligible for inclusion in this study have to meet all of the following criteria:

Have completed 24-weeks of study treatment as described in protocol CICL670F2201.

Are deemed to be tolerating deferasirox treatment by the investigator.

Provided written informed consent/assent before any study-specific procedures are 
performed. For pediatric patients, consent will be obtained from parent(s) or legal 
patient’s representative. Investigators will also obtain assent of patients according to local, 
regional or national guidelines.

Are deemed to be tolerating deferasirox treatment by the investigator if continuing directly 
from protocol CICL670F2201.
The inclusion criteria in study CICL670F2201 were stated as follows:


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1. Written informed consent/assent before any study-specific procedures. For pediatric 
patients, consent will be obtained from parent(s) or legal patient’s representative. 
Investigators will also obtain assent of patients according to local, regional or national 
guidelines.
2. Male and female patients aged ≥10 years
3. Patients with transfusion-dependent thalassemia and iron overload, requiring deferasirox
DT at doses of ≥30 mg/kg/day as per the investigator’s decision, 
OR
Patients with very low, low or intermediate (int) risk myelodysplastic syndrome (MDS) 
and iron overload, requiring deferasirox DT at doses of ≥20 mg/kg/day as per the 
investigator’s decision.

The very low, low or intermediate (int) risk MDS should be determined by the
Revised International Prognostic Scoring System (IPSS-R) and IPSS-R must be 
confirmed by a bone marrow examination within 6 months prior to study entry and 
must be hematologically stable with a patient’s life expectancy of at least 1 year.
4. History of transfusion of at least 20 packed red blood cells (PRBC) units and anticipated 
to be transfused with at least 8 units of PRBCs annually during the study
5. Serum ferritin > 1000 ng/mL, measured at Screening Visit 1 and Screening Visit 2 (the
mean value will be used for eligibility criteria).
5.3
Exclusion criteria
Patients eligible for this study must not meet any of the exclusion criteria defined for study 
CICL670F2201, which were as follows:
1. Creatinine clearance below the contraindication limit in the locally approved prescribing 
information. Creatinine clearance will be estimated from serum creatinine at Screening 
Visit 1 and Screening Visit 2 and the mean value will be used for eligibility criteria.
2. Serum creatinine > 1.5 × upper limit of normal range (ULN) at Screening measured at 
Screening Visit 1 and Screening Visit 2 (the mean value will be used for eligibility 
criteria).
3. Alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase 
(SGPT) > 5 × ULN, unless liver iron concentration (LIC) confirmed as > 10 mg Fe/dw 
within 6 months prior to Screening Visit 1.
4. Significant proteinuria as indicated by a urinary protein/creatinine ratio > 0.5 mg/mg in a 
non-first void urine sample at Screening Visit 1 or Screening Visit 2.
5. Patients with significant impaired gastrointestinal function or gastrointestinal disease that 
may significantly alter the absorption of oral deferasirox (e.g. ulcerative diseases, 
uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel 
resection).
6. Clinical or laboratory evidence of active Hepatitis B or Hepatitis C (Hepatitis B surface 
Antigen (HBsAg) in the absence of Hepatitis B surface antibody (HBsAb) or HCV 
antibody positive with HCV RNA positive).


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7. Patients with psychiatric or addictive disorders which prevent them from giving their 
informed consent or undergoing any of the treatment options or patients unwilling or 
unable to comply with the protocol.
8. Patients with a known history of HIV seropositivity (Elisa or Western blot).
9. History of malignancy of any organ system, treated or untreated, within the past 5 years 
whether or not there is evidence of local recurrence or metastases, with the exception of 
localized basal cell carcinoma of the skin.
10. Patients participating in another clinical trial or receiving an investigational drug.
11. History of hypersensitivity to any of the study drug or excipients.
12. Significant medical condition interfering with the ability to partake in this study (e.g. 
systemic uncontrolled hypertension, unstable cardiac disease not controlled by standard 
medical therapy, systemic disease (cardiovascular, renal, hepatic, etc.).
13. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using effective methods of contraception during 
dosing of study treatment. Effective contraception methods include:

Total abstinence (when this is in line with the preferred and usual lifestyle of the 
patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception.

Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy) or tubal ligation at least 6 weeks before taking study treatment. In case 
of oophorectomy alone, only when the reproductive status of the woman has been 
confirmed by follow-up hormone level assessment.

Male partner sterilization (at least 6 months prior to screening). For female patients on 
the study, the vasectomized male partner should be the sole partner for that patient.

Barrier methods of contraception: Condom or Occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/ vaginal suppository.

Placement of an intrauterine device or intrauterine system.
Please note that deferasirox may reduce the efficacy of hormonal contraception thus it 
is recommended to use alternative methods of contraception as described above.
Women are considered post-menopausal and not of child bearing potential if they 
have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical 
profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical 
bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six 
weeks ago. In the case of oophorectomy alone, only when the reproductive status of 
the woman has been confirmed by follow-up hormone level assessment is she 
considered not of child bearing potential.
14. For prohibited medication please refer to Section 6.4.3.
15. Liver disease with severity of Child-Pugh Class B or C.


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6
Treatment
6.1
Study treatment
The sponsor will provide the following open label study medication:

Deferasirox FCT will be provided as 90 mg, 180 mg and 360 mg film-coated tablets for
oral use.
6.1.1
Dosing regimen
Having completed the 24 weeks of CICL670F2201, patients recruited at Region Europe 
participating sites will be invited to participate in this study to continue FCT or switch from 
DT to the FCT formulation. Patients completing CICL670F2201 and switching to 
commercially available DT or other ICT will still be eligible to enroll in this study after a 
5-day washout period during the Screening period.
All patients randomized in the DT arm in CICL670F2201 and well-managed on treatment 
with deferasirox DT will use an equivalent FCT dose. Patient switching from DT will use an 
equivalent FCT dose at the start of this study corresponding to their DT dose at the end of 
CICL670F2201 (see Appendix 14.2). A patient who is receiving an adjusted dose at the time 
of completing CICL670F2201 will commence this study receiving that adjusted dose until a 
time when the investigator deems it necessary to adjust the dose. Patients who completed 
CICL670F2201 and had switched to commercially available DT or other ICT will have to 
undergo a 5-day washout period and will then be assigned FCT at a starting dose equivalent to 
their last deferasirox dose on CICL670F2201.
Dose adjustment for better treatment effects will be allowed every 3 months based on serum
ferritin levels and the investigator’s judgment. The dose adjustments will be performed in
steps of 3.5 to 7 mg/kg/day for deferasirox FCT.
For each patient the daily dose is calculated by the physician based on the patient’s actual 
body weight, and then rounded up or down to the nearest whole tablet according to the 
available
strengths
of
deferasirox
FCT
tablets
(90 mg,
180 mg and 360 mg, see
Appendix 14.1). All doses planned and prescribed to the patient and all dose changes 
including reasons for change during the study must be recorded in the eCRF.
During the regular study visits, the investigator or pharmacist will dispense to the patient 
and/or legal patient representative, an appropriate number of deferasirox tablets depending on
the patients calculated FCT dose. The number of tablets of each strength dispensed will be 
recorded in the Study Drug dosing Log. Each time the FCT deferasirox drug is dispensed to 
the patient and/or legal patient representative, the investigator will provide detailed 
instructions on how to prepare and administer the dose. Patients or legal patient representative
will be instructed to take the assigned amount of study drug and will be obliged to return all
unused study medication every month. Study medication returned by the patient will be 
counted and unused study medication will be recorded by the investigator/pharmacist
involved in the study. Drug accountability will be noted by the field monitor during site visits
and at the completion of the trial.


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Medication labels will comply with the legal requirements of the countries where the study is 
implemented and be printed in the local language. They will supply no information about the 
patient. Only the patient identifier will be entered on the medication label by the investigator 
or pharmacist before the corresponding medication is handed out to the patient. The storage 
conditions for study drug will be described on the medication label.
Patients will swallow the required number of deferasirox FCT once per day either on an 
empty stomach or with a light meal (see Appendix 14.3 for examples on light meals).
It is recommended that the doses be timed such that they occur at almost the same time each 
day. For example, if the patient took the study medication at 10:00 AM on first day of 
treatment, the subsequent dose would also be taken at approximately 10:00 AM on the next 
day, and so on.
Deferasirox FCT dose adjustments based on safety are allowed at any time point in the study
and will be in increments of 3.5-7 mg/kg/day. Throughout the study, the maximum dose of
deferasirox FCT will be 28 mg/kg/day.
Table 6-1
Dose and treatment schedule for FCT formulation
Study 
treatments
Pharmaceutical form 
and route of
administration
Starting Dose
Dose adjustment
Max dose
Frequency 
and/or Regimen
Deferasirox
Film-coated tablets,
per oral
Described in 
Section 6.1.1
(see 
Appendix 14.2
for guidance)
± 3.5 - 7 mg/kg/day 28 mg/kg/day
Once daily
6.1.2
Ancillary treatments 
Not applicable.
6.1.3
Rescue medication 
Not applicable.
6.1.4
Guidelines for continuation of treatment 
Guidelines for continuation of treatment are described in Section 6.3 Dose modifications.
6.1.5
Treatment duration
The duration of study treatment in the current study is for a maximum of 24 months.
6.2
Dose escalation guidelines 
Not applicable.


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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 recommended in order to allow patients to continue the study treatment.
These dose changes must be recorded on the Dosage Administration Record eCRF.
6.3.1.1
Change in patient weight
The dose of study medication will be adapted using dosing table (provided in Appendix 14.1)
during the study, if the change (increase or decrease) in body weight exceeds 10% of the body 
weight compared to the Visit 3 or the last dose adjustment due to change in patient body
weight.
6.3.1.2
Elevations in serum creatinine
Serum creatinine should be monitored during the study as stated in the visit evaluation 
schedule in Table 7-1.
In case of a single increase in serum creatinine, the assessment will be repeated at the next 
visit, or as clinically indicated.
A deferasirox dose reduction of 7 mg/kg/day for the FCT should be performed if there is a 
rise in serum creatinine of 33% above Baseline value (average of Visit 1 and 2) resulting in a
serum creatinine above the ULN on 2 consecutive visits (a minimum of 7 days apart).
If after a dose reduction, a progressive increase in serum creatinine beyond the ULN is 
observed, a treatment interruption is recommended.
After a treatment interruption, if serum creatinine falls below the age appropriate ULN on
2 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).
Use of deferasirox is contraindicated in patients with estimated creatinine clearance less than 
60 mL/min.
6.3.1.3
Changes in serum ferritin
Following enrollment (Visit 3/Day 1) serum ferritin will be monitored at 2 week intervals 
until Visit 5 (Month 1). Thereafter, scheduled assessments will be monthly. The dose of 
deferasirox FCT should be adjusted if necessary every 3 months based on the trends in serum 
ferritin and the investigator’s judgment.
Dose adjustments should be made in steps of 3.5 or 7 mg/kg/day for deferasirox FCT and are 
to be tailored to the individual patient’s response and therapeutic goals (reduction or 
maintenance 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. Doses above 28 mg/kg/day
for deferasirox FCT are not allowed.


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In patients whose serum ferritin level has reached the target (usually between 500 and
1000 ng/mL), dose reductions in steps of 3.5 or 7 mg/kg/day for deferasirox FCT should be 
considered to maintain serum ferritin levels within the target range. If serum ferritin falls 
below 500 ng/mL, an interruption of study treatment should be considered until serum ferritin 
rises above 500 ng/mL.
6.3.1.4
Changes in urine protein/creatinine ratio
Proteinuria should be monitored during the study as stated in the visit evaluation schedule in
Table 7-1.
For patients who develop proteinuria or a worsening of pre-existing proteinuria (assessed by a 
dipstick) at any visit, urine samples should be collected and assessed by the local laboratory.
In case of a single increase of the urinary protein/creatinine ratio the assessment should be 
repeated at the next visit.
Deferasirox dose reduction by 50% should be performed if the urinary protein/creatinine ratio 
increases to > 0.5 (mg/mg) in 2 consecutive second-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 urinary protein/creatinine ratio increases 
to > 1.0 (mg/mg) in 2 consecutive second-void urine samples (a minimum of 48 hours apart).
Should proteinuria persist, study treatment may be discontinued if the investigator believes it 
is in the best interest of the patient. Novartis may be contacted by the investigator to discuss 
dosing options if the investigator so desires.
Dose adjustment will be based on local laboratory results.
6.3.1.5
Skin rash
For skin rash of mild/moderate severity (defined as those causing minimal symptoms, which 
require no supportive treatment or minimal supportive treatment), study drug should be
continued without dose adjustment. The skin rash may resolve spontaneously without further
intervention.
If the rash persists for > 1 week or becomes more severe, treatment with study drug will be 
interrupted. After the rash resolves, the study drug should be resumed at 50% of the patient’s
last dose and if the rash does not recur, the dose should be increased back to 100% of the 
patient’s dose after 2 weeks.
For a severe rash (distressing symptoms requiring discontinuation and/or systemic steroids), 
treatment should be discontinued until resolution of rash. Once the rash has resolved,
treatment should be resumed at 50% of the 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,
treatment should be increased by steps of 3.5 mg/kg/day for deferasirox FCT every 2 weeks
until the patient’s last dose is achieved.
If the rash recurs, study treatment may be discontinued if the investigator believes that it is in 
the best interest of the patient. Novartis may be contacted by the investigator to discuss dosing 
options if the investigator so desires.


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Other skin disorders
Severe cutaneous adverse reactions, including Stevens-Johnson syndrome, toxic epidermal 
necrolysis and drug reaction with eosinophilia and systemic symptoms have been reported 
during Exjade therapy. If any severe cutaneous adverse reactions is suspected, study treatment 
must be immediately discontinued and not be reintroduced.
6.3.1.6
Increased liver enzyme levels
If there is a persistent and progressive increase in serum transaminase levels (ALT/SGPT; 
aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT) that 
cannot be attributed to other causes, deferasirox should be interrupted. Once the cause of the 
liver function test abnormalities has been identified or after a return to normal levels, cautious 
re-initiation of deferasirox treatment at a lower dose followed by gradual dose escalation may 
be considered. In cases of a second rise in serum transaminase levels, the investigator should
contact Novartis.
Although uncommon (0.3%), elevations of transaminases greater than 10 times the upper limit 
of the normal range, suggestive of hepatitis, have been observed in clinical trials.
Hepatic Impairment
EXJADE is not recommended in patients with severe hepatic impairment (Child-Pugh 
Class C). In patients with moderate hepatic impairment (Child-Pugh Class B), the dose should 
be considerably reduced followed by progressive increase up to a limit of 50%, and EXJADE 
must be used with caution in such patients.
6.3.1.7
Dose modification criteria for auditory and ocular disturbances
Auditory (decreased hearing) and ocular (lens opacities) disturbances have been reported with 
deferasirox treatment. Auditory and ophthalmic testing including fundoscopy is recommended
before the start of deferasirox treatment and at regular intervals thereafter (every 12 months). 
If disturbances are noted, dose reduction or interruption may be considered and a repeated
testing performed as per investigator’s judgement.
6.3.1.8
Dose modification criteria for hypersensitivity reactions
Cases of serious hypersensitivity reactions (such as anaphylaxis and angioedema) have been 
reported in patients receiving deferasirox, with the onset of the reaction occurring in the 
majority of cases within the first month of treatment. If reactions are severe, deferasirox 
should be discontinued and appropriate medical intervention instituted.
6.3.1.9
Dose modification criteria for cytopenias
There have been post-marketing reports (both spontaneous and from clinical trials) of 
cytopenias in patients treated with deferasirox. Most of these patients had pre-existing 
hematological disorders that are frequently associated with bone marrow failure. The 
relationship of these episodes to treatment with deferasirox is uncertain. In line with the 
standard clinical management of such hematological disorders, blood counts should be 
monitored regularly. Dose interruption of treatment with deferasirox should be considered in 


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patients who develop unexplained cytopenia. Reintroduction of therapy with deferasirox may 
be considered as per investigator decision, once the cause of the cytopenia has been identified.
6.3.1.10 Gastrointestinal disturbances
Some basic recommendations, based on practical experience, can be made to guide physicians 
in managing patients who experience diarrhea:

At the first sign of diarrhea, consider anti-diarrheal medication such as loperamide.

Remind patient to discontinue any laxative preparations or stool softeners they may be
taking. 

Advise the patient to eat small but frequent meals.

Determine if the patient is lactose intolerant.
Note: the deferasirox FCT does not contain lactose.

Advise the patient to drink 8 to 10 glasses of clear liquid per day.
If the gastrointestinal issues (including diarrhea, constipation, nausea, vomiting and 
abdominal pain) still persist, then 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
Follow-up for toxicities
Patients whose treatment is interrupted or permanently discontinued due to an AE or
abnormal laboratory value must be followed at least once a week for 4 weeks, and 
subsequently at 4 week intervals, until resolution or stabilization of the event, whichever 
comes first.
6.4
Concomitant medications
6.4.1
Permitted concomitant therapy
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, herbal/natural medications and blood
transfusions) administered during the study must be listed on the Concomitant Medications
eCRF.
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 adverse consequences.
Use of the following treatments as part of the routine clinical care for the patients is allowed:

Patients are also to continue blood transfusions during the study protocol according to the
regimen that they had been receiving prior to enrollment that could allow maintaining a
hemoglobin level of ≥9 g/dL.


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Caution must be exercised in patients who are taking study drug in combination with the 
following drugs:

Deferasirox, as a weak CYP3A4 inducer, may potentially decrease serum levels of 
substances metabolised through CYP3A4 (e.g. cyclosporin, simvastatin, hormonal 
contraceptive agents).

Deferasirox is a moderate inhibitor of CYP2C8 and therefore it may increase serum 
concentrations of substances metabolised through CYP2C8 (e.g. repaglinide, paclitaxel).

Deferasirox increased the exposure of the concomitantly administered CYP1A2 substrate 
theophylline. Therefore, when deferasirox and theophylline are used concomitantly, 
monitoring of theophylline concentration and theophylline dose reduction should be 
considered. An interaction between deferasirox and other CYP1A2 substrates may be 
possible.
6.4.3
Prohibited concomitant therapy
Prohibited concomitant therapy includes:

Aluminium containing antacid therapies.

Concomitant use of deferasirox with potent UDP-glucuronosyltransferase (UGT) inducers
(e.g. rifampicin, phenytoin, phenobarbital, ritonavir) or cholestyramine.

Any ICT other than the study drug.

Any investigational drug other than study medication.
6.4.4
Use of Bisphosphonates (or other concomitant agents) 
Caution must be exercised while administering deferasirox concomitantly with drugs that 
have known ulcerogenic potential, such as oral bisphosphonates, NSAIDs, or corticosteroids, 
and in patients receiving anticoagulants (due to increase in the risk of gastrointestinal 
irritation and bleeding).
6.5
Patient numbering, treatment assignment or randomization
6.5.1
Patient numbering
Each patient in this study retains the same Patient Number that was attributed to him/her in
CICL670F2201 study. This number consists of the Center Number (Center No.) (as assigned
by Novartis to the investigative site) with a sequential patient number suffixed to it, so that
each patient is numbered uniquely across the entire database.
If the patient fails to start treatment for any reason, the reason will be entered into the 
Screening Disposition page.
6.5.2
Treatment assignment or randomization
No randomization of patients will occur in this open-label study. All patients will be assigned 
to deferasirox FCT in this study; a washout period of 5-days will be performed for any 
patients who completed CICL670F2201 and switched to alternate commercial therapy.


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All patients who fulfill all inclusion/exclusion criteria will be given the opportunity to enter 
the current study and receive the FCT formulation. Patients who were on the FCT formulation 
in CICL670F2201 will continue deferasirox FCT while patients on DT will be switched to 
FCT upon entry into the current study. Patients who completed CICL670F2201 but had 
switched to commercially available DT or other iron chelation will still be enrolled in the 
current study and receive FCT after a washout period.
6.5.3
Treatment blinding
Not applicable, this is an open-label study.
6.6
Study drug preparation and dispensation
The investigator or responsible site personnel must instruct the patient or caregiver to take the 
study drugs as per protocol. Study drug(s) will be dispensed to the patient by authorized site 
personnel only. All dosages prescribed to the patient and all dose changes during the study 
must be recorded on the Dosage Administration Record eCRF.
6.6.1
Study treatment packaging and labeling
Site personnel will add the patient number on the medication label. Immediately before 
dispensing the package to the patient, site personnel will detach the outer part of the label 
from the packaging and affix it to the source document (Drug Label Form) for that patient’s 
unique patient number.
The film-coated tablets are packaged in high-density polyethylene bottles with an induction 
seal and child-resistant closure.
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. Upon receipt, the study treatment should be stored 
according to the instructions specified on the drug labels.
6.6.3
Study drug compliance and accountability
6.6.3.1
Study drug compliance
Not applicable.
6.6.3.2
Study drug accountability
Information on study drug will be collected on the Dose Administration Record eCRF and
will include the planned dose (mg/kg/day), actual total daily dose (mg) taken, reason for the
dose change, start date and end date.
The investigator or designee must maintain an accurate record of the shipment and dispensing 
of study treatment in a drug accountability log. Drug accountability will be noted by the field 
monitor during site visits and at the completion of the study. Patients will be asked to return 


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all unused study treatment and packaging on a regular basis, at the end of the study or at the 
time of study treatment discontinuation.
At study close-out, and, as appropriate during the course of the study, the investigator will 
return all used and unused study treatment, packaging, drug labels, and a copy of the 
completed drug accountability log to the Novartis monitor or to the Novartis address provided 
in the investigator folder at each site.
6.6.3.3
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. A signed Certificate of Destruction (or equivalent documentation 
as per local procedure) will be required for archiving in the Trial Master File (TMF).
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.
Patients should be seen for all visits to perform the scheduled assessments on the designated 
day, or as close to is as possible, i.e., not exceeding ± 7 days. In this clinical trial, a week is
7 calendar days. Visits should be planned respective to Visit 3, rather than in relation to the
previous visits.
All data obtained from these assessments must be supported in each patient’s source 
documentation. No eCRF will be used as a source document. The table indicates which data 
are entered into the database (D) or remain in source documents only (S) (column category).


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Table 7-1
Visit evaluation schedule
Category
Protocol section
Screening 
(2 visits > 1week
apart)1
Treatment Period
End of
Treatment
Safety
Follow-
up
Visit no.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
to 
27
282
Study month
-2W
D1
W2
M1
M2
M3
M4
M5
M6
M7
M8
M9
M10
M11
M12 
M13 
to 
M23
M24 or 
Within 7 
days of 
last dose
30 
days
after
last 
dose
Informed consent
(D)
7.1.1
X
Inclusion/ exclusion criteria
(D)
7.1.1.1
X
X
History of disease
(D)
7.1.1.3
X
Demography
(D)
7.1.1.3
X
Relevant medical 
history/current medical 
conditions
(D)
7.1.1.3
X
Prior chelation therapy
(D)
7.1.1.3
X
Transfusion/RBC History
(D)
7.1.1.3
X
Transfusions received
(D)
7.1.3
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical exam
(S)
7.2.2.1
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Weight3
(D)
7.2.2.3
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Height
(D)
7.2.2.3
X
Vital signs
(D)
7.2.2.2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Ocular exam4
(D)
7.2.2.4
X
X
X
Audiometry4
(D)
7.2.2.4
X
X
X
ECG
(D)
7.2.2.7.1
X
X
X
Chest X-ray (if clinically 
indicated)5
(D)
7.2.2.6
X


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Protocol No. CICL670AIC04
Category
Protocol section
Screening 
(2 visits > 1week
apart)1
Treatment Period
End of
Treatment
Safety
Follow-
up
Visit no.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
to 
27
282
Study month
-2W
D1
W2
M1
M2
M3
M4
M5
M6
M7
M8
M9
M10
M11
M12 
M13 
to 
M23
M24 or 
Within 7 
days of 
last dose
30 
days
after
last 
dose
Prior and Concomitant
medications
(D)
6.4
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse events
(D)
7.2.2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory assessments6-
Blood
Hematology
(D)
7.2.2.5.1
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Biochemistry
(D)
7.2.2.5.2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum ferritin
(D)
7.2.1
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum creatinine7
(D)
7.2.2.5.2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Creatinine clearance
(D)
7.2.2.5.2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hepatitis testing
(D)
7.2.2.5.5
X
Serum pregnancy test
(D)
7.2.2.5.4
X
Laboratory assessments-
Urine
Urine dipstick
(D)
7.2.2.5.3
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Microscopic urine8
(D)
7.2.2.5.3
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Proteinuria9 (urine protein/ 
creatinine ratio)
(D)
7.2.2.5.3
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine pregnancy test10
(D)
7.2.2.5.4
X
X
Study drug administration11
(D)
Daily intake of study drug for up to 24 months
Dispensed/returned FCT 
(D)
6.1.1
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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Protocol No. CICL670AIC04
Category
Protocol section
Screening 
(2 visits > 1week
apart)1
Treatment Period
End of
Treatment
Safety
Follow-
up
Visit no.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
to 
27
282
Study month
-2W
D1
W2
M1
M2
M3
M4
M5
M6
M7
M8
M9
M10
M11
M12 
M13 
to 
M23
M24 or 
Within 7 
days of 
last dose
30 
days
after
last 
dose
count
Abbreviations: ECG=electrocardiogram ; D=database; RBC=red blood cells ; S=source documents
Note: Treatment and follow-up visits are scheduled relative to Visit 3 (Baseline visit).
1Includes 5-day washout period for patients not continuing directly from CICL670F2201.
2End of Treatment visit will be undertaken for all patients completing the 24 months study, or discontinuing earlier for any reason.
3The dose of study medication will be adapted using Dosing Table (provided in Appendix 14.1) during the study if the change (increase or decrease) in 
body weight exceeds 10% of the body weight compared to the Visit 3 or the last dose adjustment due to change in patient’s body weight.
4Not required if already performed within last 6 months and may be done additionally at discretion of investigator.
5An X-ray evaluation performed in the last 3 months before Screening Visit is acceptable.
6Refer to Table 7-2 for local laboratory parameters collection plan.
7Serum creatinine is assessed at Visit 1 and Visit 2 and their mean will be used to determine eligibility.
8Microscopic urine assessment is only required if positive urine dipstick (see Section 7.2.2.5.3).
9First morning void samples of urine must not be used (see Section 7.2.2.5.3).
10 A pregnancy test can also be carried out for all women of childbearing potential if deemed necessary by the investigator (serum pregnancy test only at 
Screening Visit 1 and urine pregnancy test during Visit 3 and EOT (Visit 28), or at additional time points as per local country requirements.
11Study drug will be administered as described in Section 6.


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7.1.1
Screening
Prior to commencement of the screening examination, the patient must have given full 
informed consent and have completed the study Informed Consent form. Once this has been 
signed and dated by the patient or the legal patient representative, then the investigator can 
take the patient through the study inclusion and exclusion criteria to make sure that the patient 
is fully eligible to participate.
Two Screening Visits are needed to perform key safety parameters prior to first dose 
administration as specified in the label.
Ocular and audiometry examinations must be performed at Screening, should a patient have 
evidence at the Screening Visit that the examination(s) were performed 6 months prior to 
Screening then the examination(s) do not need to be repeated. The examination(s) can be 
performed at any time at the investigators discretion if symptomatically/clinically indicated. 
Serum creatinine will be measured at Screening Visit 1 and Screening Visit 2 and the mean 
value will be used for eligibility criteria.
Proteinuria (Urine protein /creatinine ratio) will be measured at Screening Visit 1 and 
Screening Visit 2 for eligibility criteria.
Pregnancy test will be required for child bearing potential females only.
The full list of assessments to be performed during the Screening period (including the 5-day 
washout period for patients who completed CICL670F2201 study and switched to 
commercially available DT or other chelation therapy) is detailed in Table 7-1.
Re-screening is permissible on a case by case basis. Please contact Novartis for guidance and 
see Section 7.1.1.2 to get information on how to process screen failures.
7.1.1.1
Eligibility screening
After registering for Screening, patient eligibility will be checked once all screening 
procedures are completed.
7.1.1.2
Information to be collected on screening failures
Patients 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 Screening Log. The demographic information and Screening log pages in the eCRF must 
also be completed for Screen Failure patients. No other data will be entered into the clinical 
database for patients who are screen failures, unless the patient experienced a SAE during the 
Screening Phase (see Section 8 for SAE reporting details).
7.1.1.3
Patient demographics and other baseline characteristics
Data will be collected on patient characteristics including demographic information (age, sex, 
ethnicity, etc.) and other background or relevant medical history/current medical condition, 
transfusion history, disease history, prior chelation history, MDS classification using the 
revised International Prognostic Scoring System (IPSS-R), serum pregnancy test, vital signs at 
Visits 1 and/or 2.


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To determine eligibility to be enrolled into the study, patients will also undergo assessments 
as per the inclusion and exclusion criteria which include hematology and biochemistry 
evaluations, hepatitis viral evaluation, serum creatinine and creatinine clearance, a known 
history of HIV positive test result (ELISA or Western blot) which is documented in the source 
documents, active Hepatitis B and/or C, serum pregnancy test and urinalysis.
Other assessments include chest X-ray (if clinically indicated), ocular examination, 
audiometry and electrocardiogram (ECG).
7.1.2
Run-in period 
A washout period of 5 days is allowed for patients who completed CICL670F2201 and 
switched to commercially available DT or other iron chelation therapy. For details, refer 
Table 7-1.
7.1.3
Treatment period
The duration of study treatment in the current study is for a maximum of 24 months.
Treatment visits will commence at Visit 3 (Baseline). Patients will return to the site at 2 week 
intervals until Visit 5 (Month 1). Thereafter, scheduled visits will be monthly until EOT 
(Visit 28/Month 24).
Having completed the 24 weeks of CICL670F2201, patients recruited at Region Europe 
participating sites will be invited to continue FCT or switch from DT to the FCT formulation. 
Patients who completed CICL670F2201 but had switched to commercially available DT or 
other iron chelation will still be enrolled in the current study and receive FCT after a washout 
period.
All patients randomized in the DT arm in CICL670F2201 and well-managed on treatment 
with deferasirox DT will use an equivalent FCT dose. Patient switching from DT will use an 
equivalent FCT dose at the start of this study corresponding to their DT dose at the end of 
CICL670F2201 (see Appendix 14.2). A patient who is receiving an adjusted dose at the time 
of completing CICL670F2201 will commence this study receiving that adjusted dose until a 
time when it is deemed necessary to adjust the dose by the Investigator. Patients completing 
CICL670F2201 that had switched to commercially available DT or other ICT will have to 
undergo a 5-day washout period and then use an equivalent FCT starting dose corresponding 
to their pre-washout iron chelator dose.
Daily dose is calculated by the physician based on the patient’s actual body weight.
For details on study design and dose adjustments, see Section 4 and Section 6.3. For details of 
assessments, see Table 7-1.
7.1.4
Discontinuation of study treatment
Patients may voluntarily discontinue from the study treatment for any reason at any time. If
a patient decides to discontinue from the study treatment, the investigator should make a  
r e a s o n a b l 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 eCRF


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pages. They may be considered withdrawn if they state an intention to withdraw, fail to return
for visits, or become lost to follow-up for any other reason.
The investigator should discontinue study treatment for a given patient if, he/she believes that
continuation would be detrimental to the patient’s well-being.
Study treatment must be discontinued under the following circumstances:

Pregnancy

Unwillingness to comply with procedures as outlined in the study protocol, including 
unwillingness to comply with the prescribed study treatment

Discovery of patient ineligibility

Intake of prohibited medications

AE(s)

Abnormal laboratory value(s)

Unsatisfactory therapeutic effect

Protocol violation

Subject withdrew consent

Lost to follow-up

Administrative problems

Death
Patients who prematurely discontinue study treatment should undergo an EOT visit (Month 24) 
within 7 days from last dose, at which time all of the assessments listed for EOT visit will be 
performed.
7.1.5
Withdrawal of consent
Patients may voluntarily withdraw consent to participate in the study for any reason at any 
time. Withdrawal of consent occurs only when a patient does not want to participate in the 
study any longer, and does not want any further visits or assessments, and does not want any 
further study related contact.
Novartis will continue to retain and use all research results that have already been collected 
for the study evaluation. All biological samples that have already been collected may be 
retained and analyzed at a later date (or as required by local regulations).
If a patient withdraws consent, the investigator should make a reasonable effort (e.g. telephone,
e-mail, letter) to understand the primary reason for this decision and record this information.
Study treatment must be discontinued and no further assessments conducted.
Further attempts to contact the patient are not allowed unless safety findings require 
communication or follow up.
7.1.6
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 AE eCRF and the Concomitant Medications eCRF.


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7.1.7
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 the 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 eCRF.
7.2
Assessment types
7.2.1
Efficacy assessments
Serum ferritin testing will be performed at Screening Visit 1 and 2. Following enrollment 
(Visit 3/Day 1) serum ferritin will be tested at 2 week intervals until Visit 5 (Month 1). 
Thereafter, scheduled testing will be monthly (refer Table 7-1). The Baseline serum ferritin
value will be defined as the average of the 2 measurements obtained during the Screening
period.
7.2.2
Safety and tolerability assessments
Safety will be monitored by assessing physical examination, vital signs and laboratory 
evaluations as well as collecting AEs at every visit. For details on AE collection and reporting
refer to Section 8.
7.2.2.1
Physical examination
A physical examination will be performed at every visit. The physical examination at Visit 3 
will serve as the Baseline physical examination for the entire study. The examination will
entail an examination of general appearance, skin, neck (including thyroid), eyes, ears, nose,
throat, lungs, heart, abdomen, back, lymph nodes, extremities and nervous system.
Information about the physical examination must be present in the source documentation at 
the study site.
Significant findings that were present prior to the signing of informed consent must be
included in the Medical History page on the eCRF. Significant new findings that begin or
worsen after informed consent must be recorded on the AE page of the eCRF.
7.2.2.2
Vital signs
Vital signs include blood pressure and pulse measurements and will be measured at all study 
visits. After the patient has been sitting for five minutes, with back supported and both feet 
placed on the floor, systolic and diastolic blood pressure will be measured 3 times using an
automated validated device, e.g. OMRON, with an appropriately sized cuff. The repeat sitting
measurements will be made at 1 - 2 minute intervals and the mean of the 3 measurements will
be used. In case the cuff sizes available are not large enough for the patient’s arm 
circumference, a sphygmomanometer with an appropriately sized cuff may be used.


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7.2.2.3
Height and weight
Height will be measured at Screening.
Body weight (in indoor clothing, but without shoes) will be measured at Screening and at 
subsequent time points as specified in Table 7-1.
7.2.2.4
Auditory and ocular examination
Patients will undergo auditory and ocular examinations at Screening Visit 1 and at 
unscheduled visits (if needed) as described in the Table 7-1.
The auditory examination includes the following assessments:

Comprehensive audiometry threshold examination

Speech recognition
The ophthalmologic examination includes the following assessments:

Visual acuity test

Tonometry

Slit lamp exam of anterior segment

Slit lamp exam of the lens

Fundoscopic and retinal examination
Information about the audiometry and ocular examinations must be present in the source 
documentation at study site. Significant findings of the audiometry and ocular examinations 
that meet the definition of an AE must be recorded in the AE summary page of the eCRF.
7.2.2.5
Laboratory evaluations
A local laboratory will be used for analysis of all specimens collected (Table 7-2).
Table 7-2
Local clinical laboratory parameters collection plan
Test Category
Test Name
Hematology
Hematocrit, Hemoglobin, Platelets, RBCs, White blood cells count with
differential (Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils), RBC 
Morphology
Biochemistry
Alkaline phosphatase, ALT/SGPT, AST/SGOT, Bicarbonate, Calcium, Chloride,
Creatinine, inorganic phosphorus, potassium; sodium, total bilirubin, direct and 
indirect bilirubin*, BUN or CRP, serum ferritin
Urinalysis
Microscopic Panel** (RBCs, White Blood Cells, Casts, Crystals, Bacteria,
Epithelial cells)
Macroscopic Panel (Dipstick) ( Bilirubin, Blood, Glucose, Ketones, Leukocytes 
esterase, Nitrite, pH, Protein, Specific Gravity, Urobilinogen)
Additional tests
Creatinine clearance, urine protein/creatinine ratio, serum pregnancy test, urine 
pregnancy test, hepatitis tests
RBCs = Red blood cells; WBCs = White blood cells; ALT/SGPT = alanine aminotransferase/serum 
glutamic pyruvic transaminase; AST/SGOT = Aspartate aminotransferase/serum glutamic oxaloacetic
transaminase; BUN = Blood Urea Nitrogen; CRP = C-reactive protein.
*Direct and indirect bilirubin assessment is only required if total bilirubin is > 1.5 ULN


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Test Category
Test Name
**Microscopic urine assessment is only required if positive urine dipstick
7.2.2.5.1 Hematology
Hematology samples will be collected at every visit as described in the visit evaluation 
schedule in Table 7-1.
Safety laboratory parameters monitored during the study will include hematocrit, hemoglobin,
platelets, RBCs, white blood cells count with differential, RBC Morphology with differential 
(basophils, eosinophils, lymphocytes, monocytes, neutrophils).
7.2.2.5.2 Clinical chemistry
Clinical chemistry samples will be collected at every visit, as described in the visit evaluation 
schedule in Table 7-1.
Parameters to be measured will include: alkaline phosphatase, ALT/SGPT, AST/SGOT, 
bicarbonate, calcium, chloride, serum creatinine, inorganic phosphorus, potassium, sodium, 
total bilirubin (direct and indirect bilirubin only required if total bilirubin is >1.5 ULN), blood 
urea nitrogen (BUN) or urea, C-reactive protein (CRP). Also, serum ferritin level will be 
estimated from the blood serum (Section 7.2.1).
In accordance with the deferasirox label, serum creatinine, creatinine clearance, alkaline 
phosphatase, ALT/SGPT, AST/SGOT, direct bilirubin, indirect bilirubin, total bilirubin would 
have been assessed in duplicate before the initiation of therapy in the CICL670AIC04 study to 
establish a reliable pretreatment Baseline.
Creatinine clearance will be estimated using the Cockcroft-Gault equation or Schwartz 
formula for pediatric patients. This estimate will be provided each time serum creatinine is 
collected.
7.2.2.5.3 Urinalysis
Urinalysis samples will be collected at every visit (Table 7-1). A midstream, second voided 
morning urine sample will be obtained. Bilirubin, blood, glucose, ketones, leukocytes esterase, 
nitrite, pH, protein, specific gravity, urobilinogen will be assessed. Microscopic analysis will 
be performed only in case of positive dipstick.
In addition, urine samples for urinary protein/creatinine ratios will be collected at every visit
(Table 7-1). First morning void samples must not be used for this analysis.
For patients who develop proteinuria or a worsening of pre-existing proteinuria (assessed by a 
dipstick) at any visit, please refer to Section 6.3.1.4.
7.2.2.5.4 Pregnancy and assessments of fertility
All female patients capable of becoming pregnant will have a pregnancy test (serum β- human 
chorionic gonadotropin) at Screening Visit 1. A urine pregnancy text will be performed at
Visit 3 and at EOT (Visit 28/Month 24). The results of the test must be available prior to 


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initiating treatment with any study medication. Positive pregnancy tests will exclude a patient 
from participating in this trial.
Any pregnancy during the study must be recorded on a Clinical Trial Pregnancy Form and
reported by the investigator to the local Novartis Clinical Safety & Epidemiology Department
(see Section 8.4 for reporting a pregnancy/pregnancy related SAE) and deferasirox must be 
discontinued. Pregnancy follow-up must be recorded on the same form and must include an
assessment of the possible relationship to the Novartis study drug of any pregnancy outcome.
Any SAE experienced during pregnancy must be reported on the SAE Report Form.
7.2.2.5.5 Hepatitis test
Hepatitis test consists of the following items: Hepatitis B Surface Antibody (Anti-HBs), 
Hepatitis C Antibody (Anti-HCV), Hepatitis B surface Antigen (HBsAg), Qualitative 
w/confirmation, HCV PCR (Quantitative). Hepatitis test will be conducted at Screening 
Visit 1 to assess patient eligibility. A positive text will exclude patient from the study.
7.2.2.6
Radiological examinations
Chest X-ray will be performed at Screening Visit 1 (if clinically indicated). If any chest X-ray 
has been performed 3 months prior to study entry the last available result will be used.
7.2.2.7
Cardiac assessments
7.2.2.7.1 Electrocardiogram (ECG)
A standard 12 lead ECG will be performed

at Screening Visit 1

at Visit 16 and

at Visit 28 (EOT)
Interpretation of the tracing must be made by a qualified physician and documented on the
ECG eCRF page. Each ECG tracing should be labeled with the study number, patient 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 eCRF page. Clinically significant findings must be discussed with Novartis 
prior to enrolling the patient in the study. New or worsened clinically significant findings
occurring after informed consent must be recorded on the AE eCRF page.
7.2.2.7.2 Cardiac imaging - MUGA (multiple gated acquisition) scan or 
echocardiogram
Not applicable.
7.2.2.7.3 Cardiac enzymes
Not applicable.


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7.2.2.8
Tolerability
Not applicable.
7.2.3
Pharmacokinetics
Not applicable.
7.2.4
Biomarkers
Not applicable.
Other assessments
Not applicable.
7.2.5
Resource utilization
Not applicable.
7.2.6
Patient reported outcomes
Not applicable.
8
Safety monitoring and reporting
8.1
Adverse events
8.1.1
Definitions and reporting
An AE is defined as the appearance of (or worsening of any pre-existing) undesirable sign(s),
symptom(s), or medical condition(s) that occur after signed informed consent has been
obtained from the patient/legal patient representative.
Abnormal laboratory values or test results occurring after informed consent constitute AEs
only if they induce clinical signs or symptoms, are considered clinically significant, require
therapy (e.g., hematologic abnormality that requires transfusion or hematological stem cell
support), or require changes in study medication(s).
Except for screening failures, AEs that begin or worsen after informed consent should be 
recorded in the AE eCRF. Conditions that were already present at the time of informed 
consent should be recorded in the Relevant Medical History/Current Medical Conditions
eCRF page. Adverse event monitoring should be continued for at least 30 days following the
last dose of study treatment. Adverse events (including laboratory abnormalities that
constitute AEs) should be described using a diagnosis whenever possible, rather than
individual underlying signs and symptoms. When a clear diagnosis cannot be identified, each 
sign or symptom should be reported as a separate AE.
Severity of AEs will be assessed as mild, moderate, or severe. Information about any deaths
(related to an AE or not) will also be collected using an EOT form.


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The occurrence of AEs should be sought by non-directive questioning of the patient during
the screening process after signing informed consent and at each visit during the current study. 
Adverse events also may be detected when they are volunteered by the patient during the
screening process or between visits, or through physical examination, laboratory test, or other
assessments. As far as possible, each AE should be evaluated to determine:
1. The severity grade (mild, moderate, or severe).
2. Its duration (Start and end dates or Ongoing at End of Study).
3. Its relationship to the study treatment (Reasonable possibility that AE is related: No, Yes).
4. Action taken with respect to study 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 SAE is defined as in Section 8.2.1.
All AE’s should be treated appropriately. If a concomitant medication or non-drug therapy is 
given, this action should be recorded on the AE eCRF.
Once an AE 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.
8.1.2
Laboratory test abnormalities
8.1.2.1
Definitions and reporting
Laboratory abnormalities that constitute an AE 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 AE eCRF. Whenever possible, a diagnosis,
rather than a symptom should be provided (e.g. anemia instead of low hemoglobin). 
Laboratory abnormalities that meet the criteria for AEs 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 AE, 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 AE, should not be reported as
AEs. 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 laboratory abnormality may be required by the protocol in which case the laboratory
abnormality would still, by definition, be an AE and must be reported as such.
8.1.3
Adverse events of special interest 
Adverse events of special interest 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. 


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Adverse events of special interest are defined on the basis of an ongoing review of the safety 
data. Adverse events of special interest are discussed in detail in the IB.
8.2
Serious adverse events
8.2.1
Definitions
Serious adverse event (SAE) is defined as one of the following:

Is fatal or life-threatening

Results in persistent or significant disability/incapacity

Constitutes a congenital anomaly/birth defect

Is medically significant, i.e., defined as an event that jeopardizes the patient or may 
require medical or surgical intervention to prevent one of the outcomes listed above

Requires inpatient hospitalization or prolongation of existing hospitalization,

Note that hospitalizations for the following reasons should not be reported as serious 
adverse events:

Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition

Elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent

Social reasons and respite care in the absence of any deterioration in the patient’s 
general condition

Note that treatment on an emergency outpatient basis that does not result in hospital 
admission and involves an event not fulfilling any of the definitions of a SAE given above 
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 SAEs experienced after this 30 days period should only be reported to Novartis if the 
investigator suspects a causal relationship to the study treatment. Recurrent episodes, 
complications, or progression of the initial SAE must be reported as follow-up to the original 
episode within 24 hours of the investigator receiving the follow-up information. An SAE 
occurring at a different time interval or otherwise considered completely unrelated to a 
previously reported one should be reported separately as a new event.
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 
thorough report. The investigator must assess and record the relationship of each SAE to each 
specific study treatment (if there is more than one study treatment), complete the SAE Report 
Form in English, and 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.


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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 and whether
the patient continued or withdrew from study participation.
If the SAE is not previously documented in the IB or Package Insert (new occurrence) and is
thought to be related to the Novartis study 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, to inform all investigators involved in any study with the same
drug that this SAE has been reported. Suspected Unexpected Serious Adverse Reactions
(SUSARs) will be collected and reported to the competent authorities and relevant ethics
committees in accordance with Directive 2001/20/EC or as per national regulatory 
requirements in participating countries.
8.3
Emergency unblinding of treatment assignment
Not applicable, this is an open-label study.
8.4
Pregnancies
To ensure patient safety, each pregnancy occurring while the patient is on study treatment 
must be reported to Novartis within 24 hours of learning of its occurrence and deferasirox 
must be discontinued. The pregnancy should be followed up to determine outcome, including
spontaneous or voluntary termination, details of the birth, and the presence or absence of any 
birth defects, congenital abnormalities, or maternal and/or newborn complications.
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the
investigator to the oncology Novartis Chief Medical Office and Patient Safety (CMO&PS). 
Pregnancy follow-up should be recorded on the same form and should include an assessment 
of the possible relationship to the study treatment any pregnancy outcome. Any SAE 
experienced during pregnancy must be reported on the SAE Report Form.
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 IB.
Additional safety information collected between IB updates will be communicated in the form
of Investigator Notifications. This information will be included in the patient informed
consent and should be discussed with the patient during the study as needed.
8.6
Data Monitoring Committee 
Not applicable.
8.7
Steering Committee 
Not applicable.


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9
Data collection and management
9.1
Data confidentiality
Information about study subjects will be kept confidential and managed under the applicable 
laws and regulations. Those regulations require a signed subject authorization informing the 
subject of the following:

What protected health information (PHI) will be collected from subjects in this study

Who will have access to that information and why

Who will use or disclose that information

The rights of a research subject to revoke their authorization for use of their PHI.
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization. For subjects that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect follow-up safety information (e.g. has the 
subject experienced any new or worsened AEs) at the end of their scheduled study period.
The data collection system for this study uses built-in security features to encrypt all data for 
transmission in both directions, preventing unauthorized access to confidential participant 
information. Access to the system will be controlled by a sequence of individually assigned 
user identification codes and passwords, made available only to authorized personnel who 
have completed prerequisite training.
9.2
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, Novartis 
personnel (or designated CRO) will review the protocol and eCRFs with the investigators and 
their staff. During the study, the field monitor will visit the site regularly to check the 
completeness of patient records, the accuracy of entries on the eCRFs, the adherence to the 
protocol to Good Clinical Practice, the progress of enrollment, and to ensure that study 
treatment is being stored, dispensed, and accounted for according to specifications. Key study 
personnel must be available to assist the field monitor during these visits.
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information recorded on eCRFs must be traceable to source documents in the 
patient's file. The investigator must also keep the original signed informed consent form (a 
signed copy is given to the patient).
The investigator must give the monitor access to all relevant source documents to confirm 
their consistency with the eCRF entries. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria 
and documentation of SAEs. Additional checks of the consistency of the source data with the 
eCRFs are performed according to the study-specific monitoring plan.


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9.3
Data collection
For studies using Electronic Data Capture (EDC), the designated investigator staff will enter 
the data required by the protocol into the eCRF. The eCRFs have been built using fully
validated secure web-enabled software that conforms to 21 CFR Part 11 requirements,
Investigator site staff will not be given access to the EDC system until they have been trained.
Automatic validation programs check for data discrepancies in the eCRFs and, allow
modification or verification of the entered data by the investigator staff.
The Principal Investigator is responsible for assuring that the data entered into eCRF is 
complete, accurate, and that entry and updates are performed in a timely manner.
9.4
Database management and quality control
For studies using eCRFs, Novartis personnel (or designated CRO) will review the data entered 
by investigational staff for completeness and accuracy. Electronic data queries stating the 
nature of the problem and requesting clarification will be created for discrepancies and 
missing values and sent to the investigational site via the EDC system. Designated 
investigator site staff are required to respond promptly to queries and to make any necessary 
changes to the data.
Concomitant treatments and prior medications entered into the database will be coded using 
the WHO Drug Reference List, which employs the Anatomical Therapeutic Chemical 
classification system. Medical history/current medical conditions and adverse events will be 
coded using the Medical dictionary for regulatory activities (MedDRA) terminology.
At the conclusion of the study, the occurrence of any protocol violations will be determined. 
After this action has been completed and the data has been verified to be complete and 
accurate, the database will be declared locked. Authorization is required prior to making any
database changes to locked data, by joint written agreement between the Head of
Biostatistics, PLSS and Data Management and the Global Head of Clinical Development.
For EDC studies, after database lock, the investigator will receive a CD-ROM or paper copies 
of the patient data for archiving at the investigational site.
10
Statistical methods and data analysis
Data from all centers participating in this study will be pooled for analyses.
Standard descriptive analyses will include:

Frequencies and percentages for categorical data;

n, mean, standard deviation, minimum, median, 25th and 75th percentiles and maximum 
for continuous data.
Additional information for analysis methods will be available in statistical analysis plan
documentation


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10.1
Analysis sets
10.1.1
Full Analysis Set
The Full Analysis Set (FAS) comprises of all patients enrolled in this study.
10.1.2
Safety set
The Safety Set includes all enrolled patients who received at least one dose of study treatment 
(deferasirox FCT) and had at least one safety assessment on or after Visit 3 (Day 1).
An entry on the AE eCRF page of “no AE” constitutes as a safety assessment.
The safety analyses will be performed on the safety set and the efficacy (serum ferritin) on the 
on the FAS.
10.1.3
Other analysis sets 
Not applicable.
10.2
Patient demographics/other baseline characteristics
Demographic and other baseline data will be summarized descriptively by formulation and 
overall for the FAS.
Demographic data included age, age group (< 18 years, 18-< 50 years, 50-< 65 years, 
≥65 years),
gender,
race,
and
ethnicity (Hispanic/Latino, Chinese, Indian (Indian 
subcontinent), Japanese, Other). Other background data included weight, weight group (< 20
kg, 20-< 35 kg, 35-< 55 kg, 55-< 75 kg, ≥75 kg), height, main underlying disease, history of
splenectomy (Yes/No), history of chelation therapy (Yes/No), prior deferasirox (Yes/No), 
type of last chelation therapy prior to the study, Hepatitis B and C status, medical history by
MedDRA primary SOC and preferred term, clinically significant abnormality in ECG (Yes, 
No), overall interpretation in audiometric test (Normal, Clinically insignificant abnormality, 
Clinically significant abnormality), overall interpretation in ocular exam (Normal, Clinically 
insignificant abnormality, Clinically significant abnormality), baseline creatinine, baseline
creatinine group (≤ULN, > ULN), baseline creatinine clearance, baseline creatinine clearance
group (< 60, 60-< 90, 90-< 160, ≥160 mL/min), baseline ALT/SGPT, baseline ALT/SGPT 
group (≤ULN, > ULN-5 × ULN, > 5×ULN), baseline AST/SGOT, baseline AST/SGOT 
group (≤ULN, > ULN-5 × ULN, > 5 × ULN), urine protein/creatinine ratio (≤0.2 
mg/mg, > 0.2-≤1 mg/mg, > 1 mg/mg).
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, 25th and 75th percentiles, minimum, and maximum will be 
presented.
10.3
Treatments (study treatment, concomitant therapies, compliance)
The following variables will be summarized with descriptive measures for the Safety Set: 
duration of exposure (at intervals as described in the Statistical Analysis Plan); average
planned (mg/kg/day) and average actual daily dose (mg/day); cumulative planned (mg/kg)
and total actual dose (mg); percentage of planned dose taken; frequency of interruptions, 


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decreases and increases in planned dose overall and by reason for change as recorded in the 
eCRF.
The total patient-years while on treatment, calculated as the sum of (overall drug
exposure)/365.25 will be provided.
The duration of exposure is defined as the number of weeks between the start and end of 
study medication. The end of study medication day is the last day with a non-zero actual dose 
of study medication as recorded on the drug administration pages.
The average daily dose (planned or actual) is calculated as the mean dose over all days
between first and last dose, including interim days with zero dose (interruptions). The 
cumulative dose is calculated as the sum over the daily doses of all days between first and last 
dose. The current weight is used when calculating the actual daily dose.
The percentage of planned dose taken is derived as 100 × cumulative actual dose
(mg)/cumulative planned dose (mg/kg).
Prior and concomitant medications and significant non-drug therapies will be summarized 
using frequency tables according to WHO Anatomical Therapeutic and Chemical class and
WHO generic term. Prior medications are defined as drugs taken prior to the first dose of
study medication. Concomitant medications are medications taken between the first and last
day with study medication, excluding medications started on the last day of study medication.
Medications which start prior to the first dose of study medication and continue thereafter are
counted in both summaries.
10.4
Primary objective
The primary objective of this study is to evaluate the overall safety of the deferasirox FCT 
formulation, as measured by frequency and severity of AEs and changes in laboratory 
parameters, in patients with transfusion-dependent thalassemia or MDS at very low, low or
intermediate risk.
10.4.1
Variable
The primary objective of this study is safety. The safety set will be used for the analysis of 
safety parameters.
The overall observation period in this study will be divided into 3 mutually exclusive
segments:
1. Pre-treatment period: from day of patient’s informed consent to the day before first dose of
study medication
2. On-treatment period i.e. from day of first dose of study medication to 30 days after last
dose of study medication
3. Follow-up period i.e. starting at day 31 after last dose of study medication
Any AEs during on-treatment period and changes from Baseline over time during on-
treatment period for serum creatinine, creatinine clearance, ALT/SGPT, AST/SGOT, RBC,
platelets and white blood cell will be analyzed.


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10.4.2
Statistical hypothesis, model, and method of analysis
Descriptive statistical analyses will be performed to summarize the primary endpoints and 
include:

Frequencies, percentages, and 95% confidence intervals (CIs) for overall incidences of 
any AEs during the on-treatment period.

Number (n), mean, standard deviation, minimum, lower quartile, median, upper quartile
and maximum time to AE.

Number (n), mean, standard deviation, minimum, lower quartile, median, upper quartile 
and maximum for laboratory values for selected laboratory parameters at Baseline, and 
after Months 6 and 12.

Mean ± SE plots for laboratory values for selected laboratory parameters at Baseline, and 
after Months 6 and 12.
For all analysis purposes Baseline refers to the Day 1 (Visit 3) of the current study.
10.4.3
Handling of missing values/censoring/discontinuations
No missing data will be imputed.
10.4.4
Supportive and Sensitivity analyses
Overall AEs and selected laboratory parameters (serum creatinine and creatinine clearance)
of the primary objective will be analyzed for the following subgroups: Main underlying
diseases (MDS and Beta-thalassemia), age groups (10-< 18, 18-< 65 and ≥65 years), actual
average daily dose categories (< 7 mg/kg/day, 7-21 mg/kg/day, and ≥21 mg/kg/day) and prior 
chelation therapy (DFX, any other ICT).
10.5
Secondary objectives
10.5.1
Secondary efficacy objective
To evaluate efficacy of deferasirox FCT on serum ferritin levels (decrease or 
maintenance, according to the individual therapeutic goal)
Serum ferritin level will be summarized at Baseline and at Months 6 and 12 and change from
Baseline for the FAS.
The Baseline serum ferritin value will be defined as the average of the 2 measurements 
obtained during the Screening period.
The absolute and relative change with 95% CI from Baseline at Months 6 and 12 will be
calculated.
10.5.2
Other Safety objectives
All safety analyses described below will be based on the safety set.


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10.5.2.1 Adverse events (AEs)
Summary tables for AEs have to include only AEs that started or worsened during the on-
treatment period, the treatment-emergent AEs. However, all safety data (including those from
the pre and post-treatment periods) will be listed and those collected during the pre-treatment
and post-treatment period are to be flagged.
The incidence of treatment-emergent AEs (new or worsening from Baseline) will be 
summarized by system organ class and or preferred term, severity, type of AE, relation to
study treatment and AEs requiring dose adjustment or interruption. Exposure-adjusted AE
incidence defined as the number of patients with new or worsened AEs during period/[total
number of days patient was on treatment summed for all patients/365.25 days] will be
presented.
An overall summary of type of AEs (e.g. serious, leading to study drug discontinuation, 
requiring dose adjustment or/and interruption) will be presented by severity.
Specific groupings of AEs 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 AEs for 
which there is a specific clinical interest in connection with Deferasirox treatment or adverse 
events which are similar in nature (although not identical). Note that certain AEs may be 
reported within multiple groupings/AEs of special interest.
AEs of special interest are defined by MedDRA terms. Definition for retrieval and 
maintenance is done in separate document in the Novartis Documentum management system 
at the path “CREDI Projects/I/ICL670A/Integrated Medical Safety”. The latest document has 
to be used.
Incidence of AEs of special interest will be summarized by grouping and preferred term.
10.5.2.2 Laboratory abnormalities
All laboratory values will be converted into SI units and the severity grade calculated using 
the low/normal/high classifications based on laboratory normal ranges, and for selected 
parameters by notable/extended ranges (see Table 10-1 below).
The following summaries will be generated separately for hematology, biochemistry and 
urinary laboratory tests:

shift tables using normal/notable/extended ranges to compare Baseline to the worst
on-treatment value

listing of all laboratory data with values flagged to show the corresponding 
normal/notable/extended ranges
Laboratory values (and changes from Baseline) will be summarized by descriptive statistics (n,
mean, standard deviation, minimum, lower quartile, median, upper quartile and maximum) by 
scheduled visits.
Table 10-1
Definition of notable/extended ranges for laboratory tests
Laboratory test
Criteria for notable ranges


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Laboratory test
Criteria for notable ranges
Platelet count
< 100 × 109/L (extended range < 50 × 109/L)
Absolute neutrophils
< 1.5 × 109/L (extended range < 0.5 × 109/L)
Serum creatinine
> 33% increase from Baseline and > ULN at 2 consecutive 
measurements at least 7 days apart
Creatinine clearance
< 60 mL/min at 2 consecutive measurements at least 7 days apart
(extended range < 40 mL/min at 2 consecutive measurements at
least 7 days apart)
Urinary protein/urinary creatinine 
ratio
> 1.0 (mg/mg) at 2 consecutive measurements at least 7 days 
apart
ALT/SGPT and AST/ SGOT
> 5 × ULN and 2 × Baseline (extended range > 10 × ULN and
> 2 × Baseline value)
ULN = Upper limit of normal range; ALT/SGPT = alanine aminotransferase/ serum glutamic pyruvic 
transaminase; AST/SGOT = Aspartate aminotransferase/serum glutamic oxaloacetic transaminase
Creatinine clearance will be estimated using the Cockcroft-Gault equation and the Schwartz 
formula (for pediatric population) and will be displayed using relative change from baseline 
by categories.
10.5.2.3 Other safety data
Electrocardiogram
ECG will be performed at Baseline and after 12 months. Abnormalities will be reported
together with an overall interpretation of the findings. Any abnormalities at Baseline will be
summarized. The investigator will flag all abnormalities which are new or worsened since 
Baseline. All new or worsened abnormalities will be recorded on the AE eCRF page. All
findings of patients with new or worsened clinically significant abnormalities will be listed.
Vital signs
Vital signs and body weight measured more than 30 days after discontinuation of study
medication will be excluded from the analysis.
The absolute change from Baseline weight will be summarized by scheduled visit with n, 
mean, SD, minimum, median, and maximum values.
The criteria for notably abnormal vital signs and weight are displayed in Table 10-2.
Table 10-2
Definition of notable ranges for vital signs and weight
Parameter
Criteria for notable ranges
Systolic blood pressure
≥180 mmHg/≤90 mmHg with increase/decrease from Baseline of
≥20 mmHg
Diastolic blood pressure
≥105 mmHg/≤50 mmHg with increase/decrease from Baseline of
≥15 mmHg
Pulse rate
≥120 bpm/≤50 bpm with increase/decrease from Baseline of ≥15 bpm
Weight
≥7% increase or decrease from Baseline weight


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10.5.2.4 Supportive analyses for secondary objectives 
Not applicable.
10.5.2.5 Tolerability
Not applicable.
10.5.3
Resource utilization 
Not applicable.
10.5.4
Patient-reported outcomes 
Not applicable.
10.6
Exploratory objectives 
Not applicable.
10.7
Interim analysis
Not applicable.
10.8
Sample size calculation
No formal sample size has been calculated. All patients enrolled into the CICL670F2201 
study who have completed 24 months treatment will be offered participation in this current 
protocol and those consenting to participate will contribute to the pool of data.
According to enrolment of CICL670F2201 in Region Europe, a maximum of 90 patients 
should be eligible for enrollment in this study.
10.9
Power for analysis of key secondary variables
Not applicable.
11
Ethical considerations and administrative procedures
11.1
Regulatory and ethical compliance
This clinical study was designed, shall be implemented and reported in accordance with the 
ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC and US Code of Federal Regulations 
Title 21), and with the ethical principles laid down in the Declaration of Helsinki.
11.2
Responsibilities of the investigator and IRB/IEC/REB
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly constituted Institutional Review Board/Independent Ethics Committee/Research 
Ethics Board (IRB/IEC/REB) before study start. Prior to study start, the investigator is 
required to sign a protocol signature page confirming his/her agreement to conduct the study 


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in accordance with these documents and all of the instructions and procedures found in this 
protocol and to give access to all relevant data and records to Novartis monitors, auditors, 
Novartis
Clinical Quality Assurance
representatives,
designated
agents
of
Novartis, 
IRBs/IECs/REBs and regulatory authorities as required.
11.3
Informed consent procedures
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC/REB-approved informed consent or, if incapable of 
doing so, after such consent has been provided by a legally acceptable representative of the 
patient. In cases where the patient’s representative gives consent, the patient should be 
informed about the study to the extent possible given his/her understanding. If the patient is 
capable of doing so, he/she should indicate assent by personally signing and dating the written 
informed consent document or a separate assent form.
Informed consent must be obtained before conducting any study-specific procedures (i.e. all 
of the procedures described in the protocol). The process of obtaining informed consent 
should be documented in the patient source documents. The date when a subject’s Informed 
Consent was actually obtained will be captured in their 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.
Women of child bearing potential should be informed that taking the study medication may 
involve unknown risks to the fetus if pregnancy were to occur during the study and agree that 
in order to participate in the study they must adhere to the contraception requirement for the 
duration of the study. If there is any question that the patient will not reliably comply, they 
should not be entered in the study.
Additional consent form 
Not applicable.
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


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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.
11.6
Study documentation, record keeping and retention of 
documents
Each participating site will maintain appropriate medical and research records for this trial, in 
compliance with Section 4.9 of the ICH E6 GCP, and regulatory and institutional 
requirements for the protection of confidentiality of subjects. As part of participating in a 
Novartis-sponsored study, each site will permit authorized representatives of the sponsor(s) 
and regulatory agencies to examine (and when required by applicable law, to copy) clinical 
records for the purposes of quality assurance reviews, audits and evaluation of the study 
safety and progress.
Source data are all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. 
Examples of these original documents and data records include, but are not limited to, hospital 
records, clinical and office charts, laboratory notes, memoranda, subjects’ diaries or 
evaluation checklists, pharmacy
dispensing records, recorded data from
automated 
instruments, copies or transcriptions certified after verification as being accurate and complete, 
microfiches, photographic negatives, microfilm or magnetic media, x-rays, and subject files 
and records kept at the pharmacy, at the laboratories, and medico-technical departments 
involved in the clinical trial.
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site Principal Investigator. The study case report form (eCRF) is the primary data 
collection instrument for the study. The investigator should ensure the accuracy, completeness, 
legibility, and timeliness of the data reported in the eCRFs and all other required reports. Data 
reported on the eCRF, that are derived from source documents, should be consistent with the 
source documents or the discrepancies should be explained. All data requested on the eCRF 
must be recorded. Any missing data must be explained. For electronic CRFs an audit trail will 
be maintained by the system.


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The investigator/institution should maintain the trial documents as specified in Essential 
Documents for the Conduct of a Clinical Trial (ICH E6 Section 8) and as required by 
applicable regulations and/or guidelines. The investigator/institution should take measures to 
prevent accidental or premature destruction of these documents.
Essential documents (written and electronic) should be retained for a period of not less than 
fifteen (15) years from the completion of the Clinical Trial unless Sponsor provides written 
permission to dispose of them or, requires their retention for an additional period of time 
because of applicable laws, regulations and/or guidelines.
11.7
Confidentiality of study documents and patient records
The investigator must ensure anonymity of the patients; patients must not be identified by 
names in any documents submitted to Novartis. Signed informed consent forms and patient 
enrollment log must be kept strictly confidential to enable patient identification at the site.
11.8
Audits and inspections
Source data/documents must be available to inspections by Novartis or designee or Health
Authorities.
11.9
Financial disclosures
Financial disclosures should be provided by study personnel who are directly involved in the 
treatment or evaluation of patients at the site - prior to study start.
12
Protocol adherence
Investigators ascertain they will apply due diligence to avoid protocol deviations. Under no 
circumstances should the investigator contact Novartis or its agents, if any, monitoring the 
study to request approval of a protocol deviation, as no authorized deviations are permitted. If 
the investigator feels a protocol deviation would improve the conduct of the study this must 
be considered a protocol amendment, and unless such an amendment is agreed upon by 
Novartis and approved by the IRB/IEC/REB it cannot be implemented. All significant 
protocol deviations will be recorded and reported in the CSR.
12.1
Amendments to the protocol
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, Health Authorities where required, and the IRB/IEC/REB. 
Only amendments that are required for patient safety may be implemented prior to 
IRB/IEC/REB approval. Notwithstanding the need for approval of formal protocol 
amendments, the investigator is expected to take any immediate action required for the safety 
of any patient included in this study, even if this action represents a deviation from the 
protocol. In such cases, Novartis should be notified of this action and the IRB/IEC at the study 
site should be informed according to local regulations (e.g. UK requires the notification of 
urgent safety measures within 3 days) but not later than 10 working days.


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Protocol No. CICL670AIC04
13
References (available upon request)
Alvarez O, Rodriguez-Cortes H, Robinson N, et al (2009) Adherence to deferasirox in 
children and adolescents with sickle cell disease during 1-year of therapy. J Pediatr Hematol 
Oncol; 31:739-44.
Arboretti R, Tognoni G, Alberti D, et al (2001) Pharmacosurveillance and quality of care of 
thalassaemic patients. A large scale epidemiological survey. Eur J Clin Pharmacol; 56:915-22.
Cappellini MD, Cohen A, Piga A, et al (2006) A Phase III study of deferasirox (ICL670), a 
once-daily oral iron chelator, in patients with β-thalassemia. Blood; 107:3455-62.
Cappellini MD, Bejaoui M, Agaoglu L, et al (2007) Prospective evaluation of patient-reported
outcomes during treatment with deferasirox or deferoxamine for iron overload in patients with
beta-thalassemia. Clin Therap; 29:909-17.
Cappellini MD (2008) Long-term efficacy and safety of deferasirox. Blood Rev; 22:S35-41.
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: 884-93.
Deugnier Y, Turlin B, Ropert M, et al (2011) Improvement in liver pathology of patients with 
beta-thalassemia treated with deferasirox for at least 3 years. Gastroenterology; 141:1202-11.
Galanello R and Origa R (2010) Beta-thalassemia. Orphanet J Rare Dis; 5:11.
Gabutti V and Piga A (1996) Results of Long-Term Iron-Chelating Therapy. Acta Haematol;
95:26-36.
Gattermann N, Finelli C, Della Porta M, et al (2012) Hematologic responses to deferasirox 
therapy in transfusion-dependent patients with myelodysplastic syndromes. Haematologica; 
97:1364-71.
Jaeger M, Aul C, Sohngen D, et al (1992). Iron overload in polytransfused patients with MDS:
Use of L1 for oral iron chelation. Drugs of Today; 28:143-7.
Jensen PD, Heickendorff L, Pedersen B, et al (1996). The effect of iron chelation on 
haemopoiesis in MDS patients with transfusional iron overload. Br J Haematol; 94:288-99.
Jensen PD, Jensen FT, Christensen T, et al (2003) Relationship between hepatocellular injury
and transfusional iron overload prior to and during iron chelation with desferrioxamine: a 
study in adult patients with acquired anemias. Blood; 101:91-6.
Jordan LB, Vekeman F, Sengupta A, et al (2012) Persistence and compliance of deferoxamine
versus deferasirox in Medicaid patients with sickle-cell disease. J Clin Pharm Ther; 37:173-81.
Lee JW, Yoon SS, Shen ZX, et al (2013) Hemotologic responses in patients with aplastic 
anemia treated with deferasirox: a post hoc analysis from the EPIC study. Haematologica. 98: 
1045-8.
List AF, Baer MR, Steensma DP, et al (2012) Deferasirox reduces serum ferritin and labile 
plasma iron in RBC transfusion-dependent patients with myelodysplastic syndrome. J Clin 
Oncol. 30(17): 2134-9.


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Protocol No. CICL670AIC04
Malcovati L, Della Porta MG, Pascutto C, et al (2005) Prognostic factors and life expectancy
in myelodysplastic syndromes classified according to WHO Criteria: a basis for clinical
decision making. J Clin Oncol; 23:7594-603.
[National Comprehensive Cancer Network] NCCN Clinical Practice Guidelines in Oncology 
Myelodysplastic Syndromes. Version 2.2011. Available at: 
http://www.nccn.org/professionals/physician_gls/pdf/mds.pdf Accessed August 9, 2011.
Osborne RH, De Abreu Lourenço R, Dalton A, et al (2007) Quality of life related to oral 
versus subcutaneous iron chelation: a time trade-off study. Value Health; 10:451-6.
Pennell DJ, Porter JB, Cappellini MD, et al (2010) Efficacy of deferasirox in reducing and 
preventing cardiac iron overload in beta-thalassemia. Blood; 115:2364-71.
Pennell DJ, Porter JB, Cappellini MD, et al (2011) Continued improvement in myocardial 
T2* over 2 years of deferasirox therapy in beta-thalassemia major patients with cardiac iron 
overload. Haematologica; 96: 48-54.
Pennell DJ, Porter JB, Cappellini MD, et al (2012) Deferasirox for up to 3 years lead to 
continued improvement of myocardial T2* in patients with beta-thalassemia major. 
Haematologica; 97: 842-8.
Pennell DJ, Porter JB, Piga A, et al (2014) 1-year randomized controlled trial of deferasirox 
vs deferoxamine for myocardial iron removal in b-thalassemia major (CORDELIA). Blood; 
123:1447-54.
Schafer AI, Cheron RG, Dluhy R, et al (1981) Clinical consequences of acquired transfusional 
iron overload in adults. N Engl J Med; 304:319-24.
Schafer AI, Rabinowe S, Le Boff MS, et al (1985) Long-term efficacy of deferoxamine iron 
chelation therapy in adults with acquired transfusional iron overload. Arch Intern Med; 
145:1217-21.
Taher AT, Porter JB, Viprakasit V, et al (2012) Deferasirox reduces iron overload 
significantly in nontransfusion-dependent thalassemia: 1-year results from a prospective, 
randomized, docuble-blind, placebo-controlled study. Blood; 120:970-7.
Taher AT, Porter JB, Viprakasit V, et al (2013) Deferasirox effectively reduces iron overload 
in non-transfusion-dependent thalassemia (NTDT) patients: 1-year extension results from the 
THALASSA study. Ann Hematol; 92:1485-93.


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Protocol No. CICL670AIC04
14
Appendices
14.1
Dosing tables (Deferasirox FCT)
To guide the investigator and/or pharmacist on the number of deferasirox FCT tablets of a 
given strength to prescribe to a given patient, taking into account the patient’s body weight 
and protocol specified dosing scheme described above, a table is provided below. Where the
calculated dose cannot be constituted by the available tablet strengths, the closest dose is
applied. An example illustrating this approach is provided here below:
For a patient whose body weight is 46 kg, and whose planned deferasirox FCT dose is
14 mg/kg/day, the calculated deferasirox FCT daily dose would be 644 mg. So taking into 
account the available strengths of 90, 180 and 360 mg deferasirox FCT tablets, the patient 
should receive the closest daily dose of 630 mg which can be easily constituted by taking
1 × 90 mg + 1 × 180 mg + 1 × 360 mg deferasirox FCT tablets = 3 tablets.
The dosing tables below have been constructed with cut-offs for lower and upper body 
weights being 20 and 147 kg respectively depending on the dose administered. This is taking 
into account that CICL670F2201 study enrolled male or female patients ≥10 years.
Table 14-1
Deferasirox FCT dosing table for 3.5 mg/kg/day
Pt Weight in kg
Closest Dose (mg)
90 mg
180 mg
360 mg
20 - 38
90
1
39 - 64
180
1
65 - 89
270
1
1
90 - 115
360
1
116 - 141
450
1
1
Table 14-2
Deferasirox FCT dosing table for 7 mg/kg/day
Pt Weight in kg
Closest Dose (mg)
90 mg
180 mg
360 mg
20 - 32
180
1
33 - 44
270
1
1
45 - 57
360
1
58 - 70
450
1
1
71 - 83
540
1
1
84 - 96
630
1
1
1
97 - 109
720
2
110 - 122
810
1
2
123 - 134
900
1
2
135 - 147
990
1
1
2


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Protocol No. CICL670AIC04
Table 14-3
Deferasirox FCT dosing table for 10.5 mg/kg/day
Pt Weight in kg
Closest Dose (mg)
90 mg
180 mg
360 mg
20 - 21
180
1
22 - 29
270
1
1
30 - 38
360
1
39 - 46
450
1
1
47 - 55
540
1
1
56 - 64
630
1
1
1
65 - 72
720
2
73 - 81
810
1
2
82 - 89
900
1
2
90 - 98
990
1
1
2
99 - 106
1080
3
107 - 115
1170
1
3
116 - 124
1260
1
3
125 - 132
1350
1
1
3
133 - 141
1440
4
Table 14-4
Deferasirox FCT dosing table for 14 mg/kg/day
Pt Weight in kg
Closest Dose (mg)
90 mg
180 mg
360 mg
20 - 22
270
1
1
23 - 28
360
1
29 - 35
450
1
1
36 - 41
540
1
1
42 - 47
630
1
1
1
48 - 54
720
2
55 - 60
810
1
2
61 - 67
900
1
2
68 - 73
990
1
1
2
74 - 80
1080
3
81 - 86
1170
1
3
87 - 92
1260
1
3
93 - 99
1350
1
1
3
100 - 105
1440
4
106 - 112
1530
1
4
113 - 118
1620
1
4
119 - 125
1710
1
1
4
126 - 131
1800
5
132 - 137
1890
1
5
138 - 144
1980
1
5


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Amended Protocol Version 01 (Clean)
Protocol No. CICL670AIC04
Table 14-5
Deferasirox FCT dosing table for 17.5 mg/kg/day
Pt Weight in kg
Closest Dose (mg)
90 mg
180 mg
360 mg
20 - 23
360
1
24 - 28
450
1
1
29 - 33
540
1
1
34 - 38
630
1
1
1
39 - 43
720
2
44 - 48
810
1
2
49 - 53
900
1
2
54 - 59
990
1
1
2
60 - 64
1080
3
65 - 69
1170
1
3
70 - 74
1260
1
3
75 - 79
1350
1
1
3
80 - 84
1440
4
85 - 89
1530
1
4
90 - 95
1620
1
4
96 - 100
1710
1
1
4
101 - 105
1800
5
106 - 110
1890
1
5
111 - 115
1980
1
5
116 - 120
2070
1
1
5
121 - 125
2160
6
126 - 131
2250
1
6
132 - 136
2340
1
6
137 - 141
2430
1
1
6
Table 14-6
Deferasirox FCT dosing table for 21 mg/kg/day
Pt Weight in kg
Closest Dose (mg)
90 mg
180 mg
360 mg
20 - 23
450
1
1
24 - 27
540
1
1
28 - 31
630
1
1
1
32 - 36
720
2
37 - 40
810
1
2
41 - 44
900
1
2
45 - 48
990
1
1
2
49 - 53
1080
3
54 - 57
1170
1
3
58 - 61
1260
1
3
62 - 66
1350
1
1
3


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Amended Protocol Version 01 (Clean)
Protocol No. CICL670AIC04
Pt Weight in kg
Closest Dose (mg)
90 mg
180 mg
360 mg
67 - 70
1440
4
71 - 74
1530
1
4
75 - 78
1620
1
4
79 - 83
1710
1
1
4
84 - 87
1800
5
88 - 91
1890
1
5
92 - 96
1980
1
5
97 - 100
2070
1
1
5
101 - 104
2160
6
105 - 108
2250
1
6
109 - 113
2340
1
6
114 - 117
2430
1
1
6
118 - 121
2520
7
122 - 126
2610
1
7
127 - 130
2700
1
7
131 - 134
2790
1
1
7
135 - 138
2880
8
139 - 143
2970
1
8
Table 14-7
Deferasirox FCT dosing table for 24.5 mg/kg/day
Pt Weight in kg
Closest Dose (mg)
90 mg
180 mg
360 mg
20 - 23
540
1
1
24 - 27
630
1
1
1
28 - 30
720
2
31 - 34
810
1
2
35 - 38
900
1
2
39 - 41
990
1
1
2
42 - 45
1080
3
46 - 49
1170
1
3
50 - 52
1260
1
3
53 - 56
1350
1
1
3
57 - 60
1440
4
61 - 63
1530
1
4
65 - 67
1620
1
4
68 - 71
1710
1
1
4
72 - 74
1800
5
75 - 78
1890
1
5
79 - 82
1980
1
5
83 - 85
2070
1
1
5


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Amended Protocol Version 01 (Clean)
Protocol No. CICL670AIC04
Pt Weight in kg
Closest Dose (mg)
90 mg
180 mg
360 mg
86 - 89
2160
6
90 - 93
2250
1
6
94 - 97
2340
1
6
98 - 100
2430
1
1
6
101 - 104
2520
7
105 - 108
2610
1
7
109 - 111
2700
1
7
112 - 115
2790
1
1
7
116 - 119
2880
8
120 - 122
2970
1
8
123 - 126
3060
1
8
127 - 130
3150
1
1
8
131 - 133
3240
9
134 - 137
3330
1
9
138 - 141
3420
1
9
Table 14-8
Deferasirox FCT dosing table for 28 mg/kg/day
Pt Weight in kg
Closest Dose (mg)
90 mg
180 mg
360 mg
21 - 24
630
1
1
1
25 - 27
720
2
28 - 30
810
1
2
31 - 33
900
1
2
34 - 36
990
1
1
2
37 - 40
1080
3
41 - 43
1170
1
3
44 - 46
1260
1
3
47 - 49
1350
1
1
3
50 - 52
1440
4
53 - 56
1530
1
4
57 - 59
1620
1
4
60 - 62
1710
1
1
4
63 - 65
1800
5
66 - 69
1890
1
5
70 - 72
1980
1
5
73 - 75
2070
1
1
5
76 - 78
2160
6
79 - 81
2250
1
6
82 - 85
2340
1
6


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Amended Protocol Version 01 (Clean)
Protocol No. CICL670AIC04
Pt Weight in kg
Closest Dose (mg)
90 mg
180 mg
360 mg
86 - 88
2430
1
1
6
89 - 91
2520
7
92 - 94
2610
1
7
95 - 97
2700
1
7
98 - 101
2790
1
1
7
102 - 104
2880
8
105 - 107
2970
1
8
108 - 110
3060
1
8
111 - 114
3150
1
1
8
115 - 117
3240
9
118 - 120
3330
1
9
121 - 123
3420
1
9
124 - 126
3510
1
1
9
127 - 130
3600
10
131 - 133
3690
1
10
134 - 136
3780
1
10
137 - 139
3870
1
1
10
140 - 142
3960
11
14.2
Equivalent dose guidance
All patients randomized in the DT arm in CICL670F2201 study and well-managed on 
treatment with deferasirox DT will use an equivalent FCT dose (refer Table 14-9 for 
guidance).
All patients randomized in the FCT arm in CICL670F2201 study and well-managed on 
treatment with deferasirox FCT will use the same starting FCT dose.
Table 14-9
Patients switching from DT to FCT formulation
Previous dose
Equivalent dose to be used
Deferasirox DT (mg/kg/day)
Deferasiorx FCT (mg/kg/day)
5
3.5
10
7
15
10.5
20
14
25
17.5
30
21
35
24.5
40
28


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Protocol No. CICL670AIC04
14.3
Examples of light meal
Table 14-10
Examples of light meal
amount
K cal
g total fats
Example 1
Wheat Bread or Toast
2 slices
138
2
jams, preserves, all 
flavors
1 Tablespoon
109
0
banana
medium (7-7 7/8" long)
105
0
orange juice
1 cup
114
0
skim milk
1 cup
83
0
Total
549
2
Example 2
Pita Bread
1 medium (5.25" across) pita
124
1
hummus or deli 
chicken/turkey
1 Tablespoon humuus or 2 oz 
meat
27
1
apple
medium (2.75" across)
72
0
salsa, red, cooked
6 Table spoons
26
0
carrots & celery sticks
4 carrot sticks (3" long) and 
small 5" stalk of celery
14
0
Total
263-295
2
Example 3
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
vegetable chicken noodle 
soup, canned
1 cup
70
2
baked potato, peel not 
eaten
1 medium (2.25-3" across)
121
0
skim milk
1 cup
83
0
banana
medium (7-7 7/8" long)
105
0
Total
379
2
Example 5
egg whites, cooked, no 
fat added
2 large egg whites
32
0
salsa, red, cooked
6 Tablespoons
26
0
Wheat Bread or Toast
2 slices
138
2


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Amended Protocol Version 01 (Clean)
Protocol No. CICL670AIC04
amount
K cal
g total fats
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
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

SAP_000.pdf: 
Clinical Development
ICL670/deferasirox
CICL670AIC04 / NCT02720536
Open-label, multicenter, single arm, phase III study to 
collect additional safety and efficacy data with deferasirox 
film-coated tablets in patients completing study 
CICL670F2201
Statistical Analysis Plan (SAP) Amendment 1
TEMPLATE VERSION AND DATE: Final 2.0 25-Apr-2016, Effective 03-May-2016
Author:
PLS Trial Statistician, 
Document type:
SAP Documentation
Document status:
Final
Release date:
26-Aug-19
Number of pages:
34
Property of Novartis
For business use only
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


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SAP Amendment 1
CICL670AIC04
Document History – Changes compared to previous final version of SAP
Date
Time 
point
Reason for update
Outcome for update
Section and 
title impacted 
(Current)
24AUG2018
Prior 
to DB 
lock
Creation of final 
version
N/A - First version
NA
26AUG2019
Prior 
to DB 
lock
Working 
hyperlinks
Update hyperlinks
All
Insufficient patient 
numbers for main 
underlying disease 
subgroup analysis
Removed main 
underlying disease 
as a subgroup of 
interest
Section 2.2.1 
Subgroup of 
interest
Insufficient patient 
numbers for age 
subgroup analysis
Removed age as a 
subgroup of interest
Section 2.2.1 
Subgroup of 
interest
Align baseline 
creatinine 
clearance 
categories with 
shift table 
categories
Updated the baseline 
categories for 
creatinine clearance
Section 2.4.2 
Background 
and 
demographic 
characteristics
Current unit does 
not accurately 
present the data
Updated time since 
last blood 
transfusion to be in 
days rather than 
years
Section 2.4.2 
Background 
and 
demographic 
characteristics
Insufficient patient 
numbers for age 
subgroup analysis
Removed the 
summary of the 
relative consumed 
tablet count by age 
group
Section 2.5.1 
Study 
treatment/ 
compliance
Inconsistency in 
definition of 
concomitant 
medication in SAP 
vs TFL shells
Clarified definition 
of concomitant 
medication
Section 2.5.2 
Prior and 
concomitant 
therapies


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SAP Amendment 1
CICL670AIC04
Date
Time 
point
Reason for update
Outcome for update
Section and 
title impacted 
(Current)
Insufficient patient 
numbers for age 
subgroup analysis
Removed the 
summary of the 
incidence of AEs, 
regardless of study 
drug relationship, by 
age group
Section 2.9.1 
Adverse events 
(AEs)
Insufficient patient 
numbers for age 
subgroup analysis
Removed the 
summary of AESIs 
by age group
Section 2.9.1.1 
Adverse events 
of special 
interest/ 
grouping of 
AEs
Implication of 
more than one 
treatment group in 
a single arm study
Removed the text 
“and treatment 
group”
Section 2.9.3 
Laboratory data
Clarification of 
definition of 
baseline serum 
ferritin
Added text to clarify 
the definition of 
baseline serum 
ferritin
Section 4 
Change from 
protocol 
specified 
analyses


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SAP Amendment 1
CICL670AIC04
Table of contents
Table of contents .................................................................................................................4
List of abbreviations............................................................................................................6
1
Introduction .........................................................................................................................8
1.1
Study design.............................................................................................................8
1.2
Study objectives and endpoints ...............................................................................9
2
Statistical methods.............................................................................................................10
2.1
Data analysis general information .........................................................................10
2.1.1
General definitions................................................................................11
2.2
Analysis sets ..........................................................................................................12
2.2.1
Subgroup of interest ..............................................................................12
2.3
Assessment windows, baseline and post-baseline definitions, missing data 
handling .................................................................................................................12
2.3.1
Definition of baseline date ....................................................................12
2.3.2
Baseline and post-baseline definitions..................................................13
2.3.3
Time windows.......................................................................................13
2.4
Patient disposition, demographics and other baselinecharacteristics ....................15
2.4.1
Patient disposition.................................................................................15
2.4.2
Background and demographic characteristics.......................................16
2.4.3
Medical history......................................................................................18
2.5
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................18
2.5.1
Study treatment/compliance..................................................................18
2.5.2
Prior and concomitant therapies............................................................20
2.5.3
Rescue medication ................................................................................21
2.6
Analysis of the primary objective..........................................................................21
2.6.1
Primary endpoint...................................................................................21
2.6.2
Statistical hypothesis, model, and method of analysis..........................22
2.6.3
Handling of missing values/censoring/discontinuations.......................22
2.6.4
Supportive analyses...............................................................................22
2.7
Analysis of the key secondary objective ...............................................................22
2.8
Analysis of secondary efficacy objective(s)..........................................................22
2.8.1
Secondary endpoints .............................................................................22
2.8.2
Statistical hypothesis, model, and method of analysis..........................22
2.8.3
Handling of missing values/censoring/discontinuations.......................23
2.9
Safety analyses.......................................................................................................23
2.9.1
Adverse events (AEs)............................................................................23


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SAP Amendment 1
CICL670AIC04
2.9.2
Deaths....................................................................................................25
2.9.3
Laboratory data .....................................................................................25
2.9.4
Other safety data ...................................................................................26
2.10
Pharmacokinetic endpoints....................................................................................26
2.11
Pharmacodynamic and PK/Pharmacodynamic analyses .......................................27
2.12
Patient-reported outcomes .....................................................................................27
2.13
Biomarkers.............................................................................................................27
2.14
Other exploratory analyses ....................................................................................27
2.15
Interim analysis......................................................................................................27
3
Sample size calculation .....................................................................................................27
4
Change to protocol specified analyses ..............................................................................27
5
Appendix ...........................................................................................................................28
5.1
Imputation rules.....................................................................................................28
5.1.1
AE date imputation ...............................................................................28
5.1.2
Concomitant medication date imputation .............................................30
5.1.3
Medical history date of diagnosis imputation.......................................32
5.1.4
Other imputations..................................................................................32
5.2
Statistical models...................................................................................................33
5.3
Rule of exclusion criteria of analysis sets..............................................................34
6
References .........................................................................................................................34


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List of abbreviations
AE
Adverse event
ALT/SGPT
Alanine aminotransferase/serum glutamic pyruvic transaminase
AST/SGOT
Aspartate aminotransferase/serum glutamic oxaloacetic transaminase
ATC
Anatomical Therapeutic Classification
BMI
Body mass index
C-G
Cockcroft-Gault
CI
Confidence interval
CL
Confidence level for limits
CrCl
Creatinine Clearance
CSR
Clinical study report
DAR
Dosage Administration Record
DFX
Deferasirox
DRP
Data review plan
DT
Dispersible tablet
eCRF
Electronic Case Report Form
EDC
Electronic data capture
EOT
End of treatment
F
Frequency
FAS
Full Analysis Set
FCT
Film-coated tablet
gMean
Geometric mean
HBsAg
Hepatitis B surface antigen
HBsAb
Hepatitis B surface antibody
HCV
Hepatitis C virus
HLT
High level term
ICT
Iron chelation therapy
IDMS
Isotope dilution mass spectrometry
IPSS-R
Revised International Prognostic Scoring System
MDS
Myelodysplastic syndrome
MedDRA
Medical Dictionary for Drug Regulatory Affairs
n
Number of non-missing observations
NMQ
Novartis MedDRA queries
PD
Protocol deviation
PK
Pharmacokinetics
PLS
Product Lifecycle Services
PRBC
Packed red blood cells
PRO
Patient-reported outcomes
PT
Preferred term
Q1
Lower quartile
Q3
Upper quartile
RBC
Red blood cell
SAE
Serious adverse event


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SAP
Statistical analysis plan
SCr
Serum Creatinine
SD
Standard deviation
SE
Standard error
SI
Standard international
SMQ
Standardized MedDRA queries
SOC
System organ class
SOP
Standard Operating Procedure
TEAE
Treatment emergent adverse event
TFLs
Tables, figures, and listings
ULN
Upper limit of normal range
UPC
Urine protein/creatinine ratio
WBC
White blood cell
WHO
World Health Organization


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1
Introduction
This statistical analysis plan (SAP) describes the statistical analysis planned in Section 10 of 
the study protocol (Clinical Trial Protocol CICL670AIC04 Amended Protocol Version 1, 25
October 2017) along with any additional analyses, specifications, or deviations from the 
protocol planned before unmasking of the data. This may be used as a first draft of Section 9.7 
(Statistical methods planned in the protocol and determination of sample size) and Appendix 
16.1.9 (Documentation of statistical methods) of the Clinical Study Report (CSR).
Determination of sample size is specified in Section 3.
This document is written in the future tense. The SAP text will be reviewed and updated 
(including conversion to past tense) for entry into the CSR after the analysis has taken place.
The data will be analyzed by Novartis Product Lifecycle Services (PLS). Any data analysis 
carried out independently by the investigator should be submitted to Novartis before publication 
or presentation.
1.1
Study design
This is an open-label, multicenter, single arm, phase III study aimed at collecting additional 
data on safety and tolerability as well as data on efficacy of the film-coated tablet (FCT)
formulation in patients with transfusion-dependent thalassemia or myelodysplastic syndrome 
(MDS) (very low, low or intermediate risk) when treated for more than 24 weeks in 
CICL670F2201. 
Patients from Region Europe participating sites in CICL670F2201who have completed the 24
week treatment period with ongoing tolerance to deferasirox (DFX) (in the investigator’s 
opinion) and fulfilling all other eligibility criteria will be given the opportunity to continue study 
treatment and follow-up assessments in this study. This will include patients from Region 
Europe who completed 24 weeks of treatment with either DFX FCT or DFX dispersible tablet 
(DT) in CICL670F2201; and patients with a lag period between completion of CICL670F2201
and start of this study, i.e. those patients who completed CICL670F2201 and have already 
switched to commercially available DFX DT or another iron chelation therapy (ICT). 
In CICL670F2201, iron-chelation naïve patients were assigned either DFX DT 20 mg/kg once 
daily or DFX FCT 14 mg/kg once daily. All iron chelation pre-treated patients were assigned a 
DFX DT or an equivalent FCT starting dose corresponding to their pre-washout dose. At the 
start of this study, the following was planned to occur:

Patients continuing directly from CICL670F2201 who were originally randomized to the 
DFX FCT formulation will continue treatment at the same dose they were assigned at the 
end of CICL670F2201.

Patients continuing directly from CICL670F2201 who were originally assigned to the 
DFX DT formulation will be switched to the DFX FCT formulation and will be assigned a 
DFX FCT dose equivalent to the DFX DT dose they were assigned at the end of 
CICL670F2201.

Patients completing CICL670F2201 who had switched to commercially available DT or 
other ICT will have to undergo a 5-day washout period and then be assigned  an 
equivalent FCT starting dose corresponding to their last DFX dose on CICL670F2201.


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However, no patient for this study continued directly from CICL670F2201.
Study treatment should be administered by the patient once per day, preferably at the same hour. 
Following enrolment (Visit 3/Day 1) patients will return to the site at 2 week intervals until 
Visit 5 (Month 1). Thereafter scheduled visits will be monthly. Patients may return to the study 
center more frequently at the physician’s discretion as clinically indicated or as per standard of 
care. The planned duration of study treatment in this study is for a maximum of 24 months.
According to enrolment of CICL670F2201 in Region Europe, a maximum of 90 patients should 
be eligible for enrollment in this study. However as only three countries (Austria, Greece, and 
Italy) are participating in this study which is less than originally foreseen, it is planned to enroll 
a maximum of 58 patients.
There is no interim analysis planned for this study.
Figure 1-1
Study design
1.2
Study objectives and endpoints
The study objectives and related endpoints are detailed in the following table (Table 1-1).
Table 1-1
Objectives and endpoints
Objective
Endpoint
Primary
To evaluate the overall safety of DFX
FCT 
formulation 
in 
patients 
with 
transfusion-dependent thalassemia or 
MDS at very low, low or intermediate risk
Overall safety, as measured by frequency and severity of 
adverse events (AEs) and changes in laboratory values of 
interest i.e. serum creatinine and creatinine clearance*
Secondary


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Objective
Endpoint
To evaluate efficacy of DFX FCT on 
serum 
ferritin 
levels 
(decrease 
or 
maintenance, according to the individual 
therapeutic goal)
Absolute and relative change of serum ferritin level over time
* Schwartz et al 1987
2
Statistical methods
2.1
Data analysis general information
This study will be conducted under the sponsorship of Novartis.
All analyses will be performed using SAS® statistical software (Version 9.4 or a more recent 
version) unless otherwise noted.
Data will be summarized with respect to demographic and baseline characteristics, primary, and 
secondary assessments, along with safety observations.
Descriptive statistics (the number of non-missing observations [n], mean, median, standard 
deviation [SD], lower quartile [Q1], upper quartile [Q3], minimum, and maximum values) will 
be presented for continuous variables. The following number of decimal places will be used: 
mean, median, Q1, and Q3 values to 1 more decimal place than the raw data; minimum and 
maximum to the same number of decimal places as the raw data and SD to 2 more decimal 
places than the raw data. If required, the geometric mean (gMean) will be derived by calculating 
the mean of the natural log transformed individual values. This value will then be back 
transformed to give the gMean.
For categorical variables, the number and percentage of each category within a variable will be 
calculated for non-missing data. If a count of zero is obtained for categorical data, only the zero 
count will be displayed. If no treatment group satisfies a category, then the category will be 
displayed, unless stated otherwise. A row (category) denoted ‘Missing’ will be included in 
count tabulations if a non-zero count of missing values is present. In addition, the corresponding 
percentage for this row will be displayed.
The safety observation period (days) for treated patients begins at the first administration of 
study treatment within this study (refer to Figure 1-1). It finishes at:

the date of the Month X visit for patients that attend it (for patients who have not 
discontinued study treatment or study prior to the Month X visit)

the latest day in the window for the Month X for patients who have not discontinued 
(study treatment or study) prior to the Month X visit but do not attend that visit

the date of the last visit (including the study discontinuation visit) for patients who have
discontinued study treatment prior to the Month X visit
where Month X is the last scheduled visit in the study.
Safety observation period (days) is defined as:

(date of last administration of study treatment - date of first administration of study 
treatment) + 31 (i.e. 30 days after last administration of study treatment)


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The study day for a baseline or post-baseline scheduled or unscheduled visit is defined as:

Study day = (Date of visit) – (Date of baseline visit) + 1
For visits prior to baseline, the study day is defined as:

Study day = (Date of visit) – (Date of baseline visit)
Date of baseline visit is the date of first administration of study treatment.
Change from baseline and relative change from baseline will only be summarized for patients 
with both baseline and post-baseline data for the relevant visit and will be calculated using the 
following formulae:

Change from baseline = Post-baseline value −baseline value

Relative change from baseline (%) = 100 × ([Post-baseline value −baseline value] ⁄ 
baseline value)
All data will be listed by center and patient number, unless stated otherwise.
2.1.1
General definitions
All analyses will be based on assessments according to the investigator. This study will consist 
of the following epochs (refer to Figure 1-1):

a pre-treatment period

from day of patient’s study informed consent for this study to the day before first 
administration of study treatment within this study

an on-treatment period

from day of first administration of study treatment within this study to 30 days after 
last administration of study treatment

a follow-up period

starting at day 31 after last administration of study treatment within this study to the 
date of the last assessment collected in this study
Study treatment refers to:

DFX FCT (Exjade®)

The investigational open-label treatment will be provided as 90 mg, 180 mg, and 360 
mg DFX FCT for oral use.

Treatment visits will occur at Visit 3 (Day 1), then every 2 weeks until Visit 5 (Month 
1). Thereafter visits will be monthly until end of treatment (EOT) (Visit 28/Month 24).

The planned duration of study treatment in this study is for a maximum 24 months.
The date of first administration of study treatment within this study will be derived as the first 
date when a non-zero actual dose of study drug was administered as recorded on the Dosage 
Administration Record (DAR) Electronic Case Report Form (eCRF). The date of first 
administration of study drug within this study will also be referred to as ‘start of study treatment’.
The date of last administration of study treatment is defined as the last date when a non-zero 
actual dose of study drug was administered as recorded on the DAR eCRF. This date will also 
be referred to as ‘last date of study treatment’.


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2.2
Analysis sets
The Full Analysis Set (FAS) comprises of all patients enrolled in this study.
The Safety Set includes all enrolled patients who received at least one dose of study treatment 
(DFX FCT) and had at least one safety assessment on or after Visit 3 (Day 1). An entry on the 
AE eCRF page of ‘no AE’ constitutes a safety assessment.
The safety analyses will be performed on the Safety Set and the efficacy (serum ferritin) on the 
FAS.
The number of patients within each of the analysis sets used in this study will be summarised. 
Frequency counts and percentages of patients in the FAS will be tabulated by protocol deviation 
(PD) type. The results will be grouped using the broad categories defined in the current Standard 
Operating Procedure (SOP) which are:

Patient did not satisfy entry criteria

Patient received the wrong treatment or incorrect dose

Patient developed study/treatment withdrawal criteria during the study, but was not
withdrawn

Patient took an excluded concomitant medication

Others
All PDs will be listed by center and patient number for the FAS.
Note: There is no per protocol set in this study. Therefore no PD will lead to exclusion from 
any of the analysis sets (defined earlier within this section). 
2.2.1
Subgroup of interest
The subgroups of interest for this study are:

actual average daily dose (< 7, 7 to < 21, ≥21 mg/kg/day)
Note: The actual total daily dose is collected on the DAR eCRF in mg, day is implied as it 
is a daily dose (mg/day). This dose will then be adjusted for the current weight (kg). The 
current weight is the weight prior or on the date of the start of each dosage record. If there 
are multiple weight assessments taken on the same day, then the mean value of these records 
will be used for the current weight.

prior chelation therapy (DFX, any other ICT)
2.3
Assessment windows, baseline and post-baseline definitions, 
missing data handling
2.3.1
Definition of baseline date
Baseline date is referred to as Day 1 of the study. It is defined as the date of first administration 
of study treatment in this study on Day 1 for treated patients.


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2.3.2
Baseline and post-baseline definitions
The baseline value for efficacy and safety variables is the last available, non-missing, 
(scheduled or unscheduled) value collected prior to first administration of study treatment on 
Day 1 of this study (or the first date when a non-zero actual dose of study drug was 
administered), unless otherwise stated. 
Some baseline assessments may be recorded on the day of the baseline visit (Visit 3/Day 1). 
However the time of each of these assessments may not be recorded in the eCRF. In this case, 
only the assessments which, according to the protocol, should have been conducted pre-dose 
on Day 1 will be assumed to have been done prior to administration of study treatment on Day 
1 when deriving baseline values recorded on the day of the baseline visit (Visit 3/Day 1).
All data collected after baseline (see Section 2.3.1 for definition of baseline date) are defined 
as post-baseline.
2.3.3
Time windows
2.3.3.1
Study drug exposure
Study drug will be dispensed at Visit 3 (Day 1), then every 2 weeks until Visit 5 (Month 1) and 
monthly thereafter. Dose adjustments based on safety are allowed at any time point during the 
study.
An appropriate number of DFX FCT tablets, depending on the patient’s calculated dose, will 
be dispensed to the patient. Information on study drug strength will be collected on the DAR 
eCRF and includes the planned dose (mg/kg/day), actual total daily dose (mg/day) taken, reason 
for the dose change, start date, and end date of each treatment dose.
Table 2-1 shows the defined study periods for drug exposure, where a month is regarded as 4 
weeks.
All assessments within a time period will be used to calculate the drug exposure for the 
corresponding period.
Table 2-1
Study periods for drug exposure
Study period
Study period definition
Study period categories
[Week 1 to Month 1]
Study Day 1 to Study Day 28
<4 weeks
[Month 1 to Month 2]
Study Day 29 to Study Day 56
4 to < 8 weeks
[Month 2 to Month 3]
Study Day 57 to Study Day 84
8 to < 12 weeks
[Month 3 to Month 4]
Study Day 85 to Study Day 112
12 to < 16 weeks
[Month 4 to Month 5]
Study Day 113 to Study Day 140
16 to < 20 weeks
[Month 5 to Month 6]
Study Day 141 to Study Day 168
20 to < 24 weeks
[Month 6 to Month 7]
Study Day 169 to Study Day 196
24 to < 28 weeks
[Month 7 to Month 8]
Study Day 197 to Study Day 224
28 to < 32 weeks
[Month 8 to Month 9]
Study Day 225 to Study Day 252
32 to < 36 weeks
[Month 9 to Month 10]
Study Day 253 to Study Day 280
36 to < 40 weeks
[Month 10 to Month 11]
Study Day 281 to Study Day 308
40 to < 44 weeks
[Month 11 to Month 12]
Study Day 309 to Study Day 336
44 to < 48 weeks


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Study period
Study period definition
Study period categories
[Month 12 to Month 13]
Study Day 337 to Study Day 364
48 to < 52 weeks
[Month 13 to Month 14]
Study Day 365 to Study Day 392
52 to < 56 weeks
[Month 14 to Month 15]
Study Day 393 to Study Day 420
56 to < 60 weeks
[Month 15 to Month 16]
Study Day 421 to Study Day 448
60 to < 64 weeks
[Month 16 to Month 17]
Study Day 449 to Study Day 476
64 to < 68 weeks
[Month 17 to Month 18]
Study Day 477 to Study Day 504
68 to < 72 weeks
[Month 18 to Month 19]
Study Day 505 to Study Day 532
72 to < 76 weeks
[Month 19 to Month 20]
Study Day 533 to Study Day 560
76 to < 80 weeks
[Month 20 to Month 21]
Study Day 561 to Study Day 588
80 to < 84 weeks
[Month 21 to Month 22]
Study Day 589 to Study Day 616
84 to < 88 weeks
[Month 22 to Month 23]
Study Day 617 to Study Day 644
88 to < 92 weeks
[Month 23 to Month 24]
Study Day 645 to Study Day 672
92 to < 96 weeks
[Month 24 to Month 25]
Study Day 673 to Study Day 700
96 to < 100 weeks
[Month 25 to Month 26]
Study Day 701 to Study Day 728
100 to < 104 weeks
[Month 26 to Month 27]
Study Day 729 to Study Day 756
104 to < 108 weeks
[Month 27 to EOT]
Study Day ≥757
≥108 weeks
2.3.3.2
Laboratory data and vital signs
Laboratory data (biochemistry, hematology, and urinary parameters as well as serum creatinine, 
creatinine clearance, and proteinuria) and vital signs will be collected at screening visits, regular 
patient visits, and EOT.
If two or more assessments are performed within a time window then the assessment closest to 
the planned visit will be used in analyses by time window. When two values are equidistant 
from the planned assessment, the later one will be used in analyses. 
Note: For worst post-baseline assessment, all on-treatment values are considered regardless of 
time windows. Table 2-2 shows the defined time windows, where a month is regarded as 4 
weeks.
Table 2-2
Time windows for laboratory and vital signs data
Time window
Planned visit timing
Time window definition
On-treatment
Baseline
On or before Study Day 1*
≤ Study Day 1*
Week 2
Study Day 15
Study Day 2 to Study Day 21
Month 1
Study Day 29
Study Day 22 to Study Day 43
Month 2
Study Day 57
Study Day 44 to Study Day 71
Month 3
Study Day 85
Study Day 72 to Study Day 99
Month 4
Study Day 113
Study Day 100 to Study Day 127
Month 5
Study Day 141
Study Day 128 to Study Day 155
Month 6
Study Day 169
Study Day 156 to Study Day 183
Month 7
Study Day 197
Study Day 184 to Study Day 211
Month 8
Study Day 225
Study Day 212 to Study Day 239
Month 9
Study Day 253
Study Day 240 to Study Day 267


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Time window
Planned visit timing
Time window definition
Month 10
Study Day 281
Study Day 268 to Study Day 295
Month 11
Study Day 309
Study Day 296 to Study Day 323
Month 12
Study Day 337
Study Day 324 to Study Day 351
Month 13
Study Day 365
Study Day 352 to Study Day 379
Month 14
Study Day 393
Study Day 380 to Study Day 407
Month 15
Study Day 421
Study Day 408 to Study Day 435
Month 16
Study Day 449
Study Day 436 to Study Day 463
Month 17
Study Day 477
Study Day 464 to Study Day 491
Month 18
Study Day 505
Study Day 492 to Study Day 519
Month 19
Study Day 533
Study Day 520 to Study Day 547
Month 20
Study Day 561
Study Day 548 to Study Day 575
Month 21
Study Day 589
Study Day 576 to Study Day 603
Month 22
Study Day 617
Study Day 604 to Study Day 631
Month 23
Study Day 645
Study Day 632 to Study Day 659
Month 24
Study Day 673
Study Day 660 to Study Day 687
Month 25
Study Day 701
Study Day 688 to Study Day 715
Month 26
Study Day 729
Study Day 716 to Study Day 743
Month 27
Study Day 757
Study Day 744 to Study Day 771
Month 28
Study Day 785
≥Study Day 772
EOT
EOT
N.A.
Note: if no data were collected at 
the EOT visit the last post-baseline 
(extension) available data obtained 
before EOT will be used.
*Study Day 1 = first day of study treatment in this study
2.4
Patient disposition, demographics and other 
baselinecharacteristics
Patient disposition, background and demographic characteristics will be reported for the FAS, 
unless otherwise specified.
No inferential tests for differences in background and demographic characteristics will be 
performed.
2.4.1
Patient disposition
The number of patients screened will be summarized by countryand center. 
The number and percentage (based on the number of patients in the FAS) of patients who 
complete the study will be displayed. The primary reason for premature study discontinuation 
will also be displayed. 
The total number of patients screened and the number of patients screened, but did not start 
treatment will be shown. The primary reason for screening failure will be summarized.
All patient disposition data will be listed by center and patient number for the FAS.


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2.4.2
Background and demographic characteristics
Demographic, background data and key efficacy variables at baseline will be summarized for 
the FAS.
The time since diagnosis of disease will be derived using the following formula:
Time since diagnosis (years) = (Date of informed consent −Date of diagnosis) ⁄ 365.25
Demographics 
Categorical variables

age (< 18, 18 to < 50, 50 to < 65, ≥65 years)

child bearing potential (Able to bear children, Premenarche, Post menopausal, Sterile – of 
child bearing age)

Note: Child bearing potential will only be completed for patients where gender is 
marked as female.

ethnicity (Hispanic/Latino, Chinese, Indian [Indian subcontinent], Japanese, Other)

sex (Male, Female)

predominant race (Caucasian, Black, Asian, Native American, Pacific Islander, Other)

weight (< 20, 20 to < 35, 35 to < 55, 55 to < 75, ≥75 kg)
Continuous variables

age (years)

height (cm)

weight (kg)

body mass index (BMI) (kg/m2)
Disease characteristics
Categorical variables

hepatitis B surface antigen (HBsAg) (Negative, Positive, Indeterminate/Borderline)

hepatitis B surface antibody (HBsAb) (Negative, Positive, Indeterminate/Borderline)

hepatitis C virus (HCV) antibody positive (Negative, Positive, Indeterminate/Borderline, 
Below detectable limit)

HCV RNA positive (Negative, Positive, Indeterminate/Borderline, Below detectable limit)

hepatitis status (Hepatitis B, Hepatitis C, Hepatitis B and C, No Hepatitis)

Hepatitis B is defined as HBsAg in the absence of HBsAb (i.e. HBsAg is positive and 
HBsAb is negative). HBsAg and HBsAb must be measured from the same sample, 
otherwise Hepatitis B status cannot be determined.

Hepatitis C is defined as HCV antibody positive with HCV RNA positive. HCV 
antibody positive and HCV RNA positive must be measured from the same sample, 
otherwise Hepatitis C status cannot be determined.


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
Note: If there is no confirmatory assessment of HCV RNA measured from the 
same sample as HCV antibody, then the status of Hepatitis C will be regarded as 
Unknown/Undetermined.

hematologically stable since last bone marrow examination (Yes, No)

history of ICT (Yes, No)

history of splenectomy (Yes, No)

Note: Patients with history of splenectomy are defined as those patients with a 
splenectomy recorded before Visit 3 (Day 1) (started before first administration of 
study treatment) in Relevant medical history/Current medical conditions eCRF
(Preferred term [PT]: Splenectomy).

main underlying disease (MDS with very low risk as per the Revised International 
Prognostic Scoring System [IPSS-R], MDS with low risk as per the IPSS-R, MDS with 
intermediate risk as per the IPSS- R, Thalassemia)

formulation of the ICT received during CICL670F2201 (DFX DT, DFX FCT)

type of last ICT prior to the study (Deferoxamine, Deferiprone, Combination therapy of 
Deferoxamine and Deferiprone, DFX, Combination therapy of Deferoxamine and DFX, 
Combination therapy of DFX and Deferiprone, Other)
Continuous variables

time since diagnosis (years)

time since last bone marrow examination (years)

time since last blood transfusion (days)

total number of blood transfusions received since last 12 months
Hepatitis data (HBsAg, HBsAb, HCV antibody positive, HCV RNA positive, Hepatitis status) 
will also be summarized by visit (see Table 2-2 for time windows definition). Hepatitis status 
was planned to be determined at Visit 3 (Day 1) however there is an option if some information 
was not collected then this can be collected at a later time-point. 
Baseline abnormalities in ECG, audiometric test, and ocular exam
Categorical variables

clinically significant abnormality in ECG (Yes, No)

overall interpretation in audiometric test (Normal, Clinically insignificant abnormality, 
Clinically significant abnormality)

overall interpretation in ocular exam (Normal, Clinically insignificant abnormality, 
Clinically significant abnormality)
Baseline laboratory values
Categorical variables

Alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase (SGPT) (≤Upper 
limit of normal range (ULN), > ULN to 5×ULN, > 5×ULN)


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
Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT) (≤
ULN, > ULN to 5×ULN, > 5×ULN)

Serum creatinine (≤ULN, > ULN)

Creatinine clearance (< 40, 40 to < 60, ≥60 mL/min)

Urine protein/creatinine ratio (UPC) (≤0.2, > 0.2 to ≤1.0, > 1.0 mg/mg)
Continuous variables

ALT/SGPT (U/L)

AST/SGOT (U/L)

Serum creatinine (umol/L)

Creatinine clearance (mL/min)

UPC (mg/mg)
All demographic and baseline data will be listed by center and patient number for the FAS.
2.4.3
Medical history
Relevant medical history and current medical conditions will be tabulated by system organ class 
(SOC) and PT of the Medical Dictionary for Regulatory Activities (MedDRA) dictionary 
(version 19.1 or a more recent version) for the FAS. The SOCs will be presented in alphabetical 
order. PTs will be sorted by decreasing proportion and alphabetical order.
Furthermore, medical history data will be listed by center and patient number for the FAS.
2.5
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance)
Unless otherwise stated, all analyses will be based on patients in the Safety Set.
2.5.1
Study treatment/compliance
Study treatment
Definitions of duration of exposure, total patient-years exposure, average daily dose, 
cumulative total dose as well as percentage of planned dose taken are defined in the following 
table (Table 2-3).
Table 2-3
Study drug exposure
Term
Definition
Overall drug exposure (days)
[(date of last administration of study treatment) − (date of first 
administration of study treatment) + 1]
Drug exposure on dose X (days)
[(date of last administration of study treatment on dose X) − 
(date of first administration of study treatment on dose X) + 
1]
Average dose (planned [mg/kg/day] or 
actual [mg/kg/day]
Mean dose over all days between first and last dose,
including interruptions: sum of all (X dose × corresponding
drug exposure on dose X)  ⁄ overall drug exposure


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Term
Definition
Final dose (planned [mg/kg/day] or 
actual [mg/kg/day])
Last non-zero dose record
Cumulative dose (planned [mg/kg] or 
actual [mg/day])
Sum of daily doses over all days between first administration 
of study treatment and last administration of study treatment
Total patient-years (years)
Overall duration of exposure (days)  ⁄ 365.25
Percentage of planned dose taken (%)
100 × (Cumulative actual dose [mg/kg]  ⁄ Cumulative planned 
dose [mg/kg])
Note:
(1) The actual dose will be adjusted for the current weight (kg). The current weight is the weight prior 
or on the date of the start of each dosage record. If there are multiple weight assessments taken on 
the same day, then the mean value of these records will be used for the current weight.
(2) Cumulative dose is the sum of daily doses hence day is not part of the unit.
Descriptive statistics for the number of days a patient was on study treatment will be provided 
for the Safety Set.  The table will also provide the total patient-years that all patients were on 
treatment. The frequency and percentage of patients belonging to each categorical range of 
exposure weeks will be provided (see Table 2-1 for definition of study period categories). 
In addition, summary statistics (frequency and percentage of patients for categorial varaibles; 
descriptive statistics for continuous variables) of dosage will be provided for:
Categorical variables

average planned dose (< 10.5, 10.5 to < 17.5, 17.5 to < 24.5, ≥24.5 mg/kg/day)

average actual dose (< 10.5, 10.5 to < 17.5, 17.5 to < 24.5, ≥24.5 mg/kg/day)

final planned dose (< 10.5, 10.5 to < 17.5, 17.5 to < 24.5, ≥24.5 mg/kg/day)

final actual dose (< 10.5, 10.5 to < 17.5, 17.5 to < 24.5, ≥24.5 mg/kg/day)
Continuous variables

average planned dose (mg/kg/day) 

average actual dose (mg/kg/day)

final planned dose (mg/kg/day)

final actual dose (mg/kg/day)

cumulative planned dose (mg/kg) 

cumulative actual dose (mg/kg)

percentage of planned dose taken (%)

duration of actual dose (days)

The duration of actual dose refers to the number of days in the study where actual 
dose is non-zero.

relative duration of actual dose (%)

The relative duration of actual dose is defined as the ratio of duration of actual dose 
(days) to overall drug exposure (days).
Futhermore, the frequency and percentage of patients with dose decreases, increases in planned 
dose, or dose interruptions, the corresponding reasons, and average length of dose interruptions 
will be summarized. A shift table to compare final planned dose to final actual dose will also 


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be provided. A planned dose reduction is when a planned dose is lower than the previous 
planned dose, a planned zero dose is included as a dose reduction record. A planned dose 
increase is when a planned dose is higher than the previous planned dose. Patients with more 
than one reason for planned dose change are counted once per reason in each category 
(reduction or increase). A dose interruption is when an actual dose is recorded as zero.
Average actual daily dose will be also graphically presented using a box plot over time (see 
Table 2-1 for study period definition).
Study treatment data will be listed by center and patient number for the Safety Set.
Study compliance
The patient compliance with DFX FCT will be evaluated using the count of DFX FCT by the 
relative consumed tablet count (%). The relative consumed tablet count is defined as the ratio 
of total count consumed to total count prescribed, where

Total count consumed is derived from cumulative dispensed and returned counts:
The total count consumed is calculated as the sum of counts dispensed minus the sum of 
counts returned.

Total count prescribed is cumulative prescribed count:
The prescribed count corresponds to the count prescribed by the investigator for the period 
that the patient should have taken the study treatment during this period. For each strength 
(90 mg, 180 mg, and 360 mg tablets), the prescribed count for a period is calculated from 
the daily prescribed count at the beginning of this period multiplied by the duration (days) 
of this period. The daily prescribed count is the sum of counts prescribed per strength. The 
duration of a period will be calculated using the following formula:
(end date of the period) - (start date of the period) + 1
The subsequent period duration calculation will exclude the start day (i.e., a day will be not 
be counted in subsequent periods). The total count prescribed is the sum of counts 
prescribed over all periods.
If a patient does not return the study drug, the compliance will not be calculated.
Descriptive statistics including 95% confidence interval (CI) for the mean relative consumed 
tablet count will be provided.
In addition, the persistence of DFX FCT will be summarised at Month 3, Month 6, Month 9, 
and Month 12. Persistence is defined as the continuous use of DFX FCT without a gap of ≥ 30 
or ≥ 60 days over a fixed time interval of interest. A gap will be calculated as the time between 
two consecutive dates of study drug administration when study drug was administered (i.e. 
actual dose is non-zero) within the fixed time interval of interest.
Furthermore, a listing will be provided including dispensed/returned and prescribed counts as 
well as the relative consumed tablet count by center and patient number for the Safety Set.
2.5.2
Prior and concomitant therapies
The number and percentage of patients taking prior and concomitant therapies will be 
summarized for the Safety Set.


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Summaries will be presented separately for prior and/or concomitant medications. Concomitant 
therapies will include medications and significant non-drug therapies taken between the first 
and last day with study medication + 30 days, excluding medications that start on the last day 
of study medication. Prior therapies will include medications or significant non-drug therapies 
starting and ending prior to the start of study treatment in this study. Medications starting prior 
to the start of study treatment in this study and continuing after the start of study treatment will 
be counted in both summaries.
Prior or concomitant medication will be identified based on recorded or imputed start dates of 
medication taken in this study. The rules for imputing incomplete start dates are described in 
Section 5.1.2.
Medications will be identified by Anatomical Therapeutic Chemical (ATC) class and PT 
according to the World Health Organization (WHO) Drug Reference List dictionary (201603 
or a more recent version). Tables will show the overall frequency and percentage of patients 
receiving at least one dose of the therapy.
A listing of prior and concomitant therapies will be provided by center and patient number for 
the Safety Set.
2.5.3
Rescue medication
Rescue medication is not planned in this study.
2.6
Analysis of the primary objective
The primary objective of this study is to evaluate the overall safety of the DFX FCT formulation, 
as measured by frequency and severity of AEs and changes in laboratory parameters, in patients 
with transfusion-dependent thalassemia or MDS at very low, low or intermediate risk.
2.6.1
Primary endpoint
The primary variables are:

treatment emergent AEs (TEAEs) 

An AE is defined as treatment emergent if its onset date is on or after (≥) the first 
administration of study treatment within this study or events present prior to start of 
study treatment but increased in severity on or after (≥) the first administration of 
study treatment within this study but not later than 30 days after the last study 
treatment in this study (i.e. during the safety observation period, see Section 2.1 for 
definition).

changes from baseline at Months 6 and 12 for the following laboratory assessments: 

serum creatinine

creatinine clearance

ALT/SGPT

AST/SGOT

red blood cell (RBC)

platelets


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
white blood cell (WBC)
2.6.2
Statistical hypothesis, model, and method of analysis
No hypotheses will be tested. All analyses will be descriptive in nature.
The incidence of any TEAEs overall and by severity will be summarized using frequency counts, 
percentages of patients, and 95% CIs for percentages obtained using Clopper-Pearson method.
Laboratory data will be summarized using descriptive statistics including 95% CI of the mean 
for raw values and absolute change from baseline at each visit (see Table 2-2 for time windows 
definition). Furthermore, mean and standard error (SE) values will be plotted over time (see 
Table 2-2 for time windows definition) for each of the laboratory parameters of interest (serum 
creatinine, creatinine clearance, ALT/SGPT, AST/SGOT, RBC, platelets, WBC total).
The analysis of the primary variables will be performed on the Safety Set.
2.6.3
Handling of missing values/censoring/discontinuations
No missing values will be imputed however missing partial AE dates will be imputed following 
the rules outlined in Section 5.1.1.
2.6.4
Supportive analyses
Overall AEs and selected laboratory parameters (serum creatinine and creatinine clearance) of 
the primary objective will be analyzed separately by the subgroups of interest outlined in 
Section 2.2.1.
2.7
Analysis of the key secondary objective
There is no key secondary objective for this study.
2.8
Analysis of secondary efficacy objective(s)
The secondary objective of this study is to evaluate the efficacy of DFX FCT on serum ferritin 
levels (decrease or maintenance, according to the individual therapeutic goal).
2.8.1
Secondary endpoints
The secondary variables are:

serum ferritin level at baseline, Month 6 (Visit 10), and Month 12 (Visit 16)

change from baseline in serum ferritin at Month 6 (Visit 10) and Month 12 (Visit 16)
It should be noted that the maximum serum ferritin provided by certain laboratories is 4500 
ng/mL with values above 4500 ng/mL represented as “>4500”. If there is an occurrence of 
“>4500”, the site will record this value in the electronic data capture (EDC) system as 4500 
ng/mL. For derivations and table summaries, the value of 4501 will be used; for listings this 
value will be shown as “>4500”.
2.8.2
Statistical hypothesis, model, and method of analysis
No hypotheses will be tested. All analyses will be descriptive in nature.


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Serum ferritin will be summarized using descriptive statistics of raw values, absolute change 
from baseline, and relative change from baseline at each visit (see Table 2-2 for time windows 
definition). The summaries will include n, mean with respective 95% CI, SD, minimum, Q1, 
median, Q3, and maximum. 
The analysis of the secondary variables will be performed on the FAS.
2.8.3
Handling of missing values/censoring/discontinuations
No missing values will be imputed.
2.9
Safety analyses
The safety evaluations during the study will be summarized for the Safety Set, unless otherwise 
specified. 
No inferential tests for differences in safety analyses will be performed.
2.9.1
Adverse events (AEs)
All AEs occurring before first administration of study treatment in this study will be assigned 
to the pre-treatment period and those occurring after last drug intake + 30 days will be assigned 
to the follow-up period (for listings only). Only TEAEs will be summarized.
AEs will be coded by primary SOC and PT according to the MedDRA dictionary (version 19.1 
or a more recent version). 
The following AE summaries will be presented:

AEs, regardless of study drug relationship

AEs by maximum severity grade (mild, moderate, severe), regardless of study drug 
relationship

AEs, suspected to be related to the study treatment

serious AEs (SAEs), regardless of study drug relationship

AEs leading to study drug discontinuation, regardless of study drug relationship

AEs requiring study drug dose adjustment or interruption, regardless of study drug 
relationship 

AEs requiring additional therapy, regardless of study drug relationship
In addition an overall summary of type of AEs (e.g. serious, leading to study drug 
discontinuation, requiring dose adjustment or/and interruption) will be presented overall and by 
maximum severity grade. An overall summary of AEs will also be presented overall and by 
maximum severity grade using frequency and percentage of patients along with 95% CIs for 
percentages obtained using Clopper-Pearson method.
AEs will be summarized by presenting the frequency and percentage of patients having at least 
one AE, and having at least one AE by primary SOC and/or PT, severity, and relationship to 


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study drug by treatment group. A patient with multiple occurrences of an AE will be counted 
only once in the AE category.
For the legal requirements of clinicaltrials.gov and EudraCT, two required tables on TEAEs 
which are not SAEs with an incidence greater than 5% and on treatment emergent SAEs and 
SAEs suspected to be related to study treatment will be provided by primary SOC and PT.
If for the same patient, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same primary SOC and PT:

a single occurrence will be counted if there is ≤ 1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE

more than one occurrence will be counted if there is > 1 day gap between the end date of 
the preceding AE and the start date of the consecutive AE
For occurrence, the presence of at least one SAE/SAE suspected to be related to study 
treatment/non-SAE has to be checked in a block e.g., among AEs in a ≤ 1 day gap block, if at 
least one SAE is occurring, then one occurrence is calculated for that SAE.
In addition exposure-adjusted AE incidence will be presented by PT. It is defined as:
(	
  	 ℎ	 
 
		  
 ℎ	  −
		 	
)
( 	
    	   
		 	 	
  	 / 365.25 )
Furthermore, all AEs (AEs during the pre-treatment period, TEAEs, AEs during the follow-up
period) will be listed by center and patient number for the FAS. This will also include details 
of the AE (e.g., verbatim given by the investigator as well as the primary SOC and PT), onset 
date, end date, severity, and relationship to study treatment.
2.9.1.1
Adverse events of special interest/grouping of AEs
Specific groupings of AEs of special interest (AESI) will be considered and the number of 
patients with at least one event in each grouping will be reported. Such groups consist of AEs 
for which there is a specific clinical interest in connection with DFX treatment or AEs which 
are similar in nature (although not identical). Note that certain AEs may be reported within 
multiple groupings.
All AESI groupings are defined through the use of PT, High Level Terms (HLT), primary SOC, 
Standardized MedDRA Queries (SMQ), Novartis MedDRA Queries (NMQ) or through a 
combination of these components. The MedDRA terms to be used are defined in an independent 
AESI search table which is located in the document management system in the ‘CREDI 
Projects/I/ICL670A/Integrated Medical Safety’ folder. The latest AESI search table will be 
used.
The AESI search table will be used to map reported AEs to the notable AEs groupings. The list 
of AESIs may be updated during the course of the trial based on accumulating safety data. 
Therefore the CSR will list the AE groupings used and provide a listing of the corresponding 
AESI search table.
AESIs will be summarized regardless of study drug relationship, by grouping and PT. 


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In addition, AESIs during the first 6 and 12 months of treatment during this study will be 
summarized regardless of study drug relationship, by grouping and PT.  
2.9.1.2
Selected gastrointestinal TEAEs
The incidence of any gastrointestional TEAE as well as selected gastrointestional TEAEs will 
be summarized by using frequency and percentage of patients along with 95% CIs for 
percentages obtained using Clopper-Pearson method.
Selected gastrointestional AEs include the following PTs: diarrhoea, constipation, nausea, 
vomiting, and abdominal pain.
2.9.2
Deaths
The number and percentage of deaths resulting from SAEs suspected to be related to study 
treatment and SAEs irrespective of study treatment relationship will be provided by primary 
SOC and PT.
In addition, the primary and contributing reason for death will be listed for all deaths by center 
and patient number. 
2.9.3
Laboratory data
Hematology, serum chemistry, and urinalysis parameters will be presented using standard 
international (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.
Raw values as well as absolute and relative change from baseline values for hematology, 
biochemistry, and urinalysis laboratory parameters will be summarized descriptively by visit
(see Table 2-2 for time windows definition).
The following summaries will be generated separately for hematology, biochemistry, and 
urinary laboratory tests:

shift tables using normal/notable/extended ranges to compare baseline to the worst on-
treatment value

listing of all laboratory data with values flagged to show the corresponding 
normal/notable/extended ranges
All data, including data from unscheduled visits, will be considered when identifying abnormal 
values. 
Shift tables based on normal ranges to compare baseline to the worst post-baseline value will 
be provided by parameter for hematology, biochemistry, and urinary laboratory data.
A similar shift table will be provided based on notable/extended ranges for key safety laboratory
parameters defined in Section 10.5.2.2 (Clinical Trial Protocol CICL670AIC04 Amended 
Protocol Version 1, 25 October 2017).


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2.9.4
Other safety data
2.9.4.1
ECG and cardiac imaging data
All data from ECG will be listed by center and patient number for the FAS. Patients with 
clinically significant abnormal interpretations or abnormal values will be flagged. A listing of 
patients with new or worsened clinically significant ECG abnormality compared to baseline 
will be provided.
2.9.4.2
Vital signs
Vital signs (sitting blood pressure [systolic blood pressure, diastolic blood pressure], weight, 
and BMI) will be summarized for the Safety Set using descriptive statistics, by visit for raw 
values and absolute change from baseline. 
Clinically notable values for certain vital sign measurements are defined in Section 10.5.2.3
(Clinical Trial Protocol CICL670AIC04 Amended Version 1, 25 October 2017). The frequency 
and percentage of patients with clinically notable values values will be presented for the Safety 
Set.
Patient listings of vital signs data will be provided by center and patient number for the FAS. 
Values which are clinically notable will be flagged.
2.9.4.3
Other safety assessments
Serum and urine pregnancy test results (if applicable) will be listed for female patients. All data 
from chest X-ray examination, auditory test, ocular assessment, hepatitis testing, and pregnancy 
test will be listed for the FAS.
Descriptive statistics for blood transfusion data during the treatment phase (on-treatment period) 
will be provided by visit (see Table 2-2 for time windows definition) for the Safety Set:

platelets (amount transfused [mL], hematocrit of blood transfused [%])

packed RBC (PRBC) (amount transfused [mL], hematocrit of blood transfused [%])

whole blood (amount transfused [mL], hematocrit of blood transfused [%])
Summary statistics for the number of transfusions (platelets, PRBC, whole blood) per patient 
will be presented by frequency distribution (number of patients with 1 unit transferred, 
number of patients with 2 units transferred, on up to the maximum number of units transferred 
for any one patient) and visit (see Table 2-2 for time windows definition).
Note: Each blood transfusion will be recorded separately on the Blood transfusion - During 
treatment phase eCRF, therefore the sum of each of the blood tranfusion parameters of 
interest which occur during the time window of interest will be presented.
Data related to blood transfusion during the treatment phase will be listed by center and patient 
number for the FAS.
2.10
Pharmacokinetic endpoints
There are no pharmacokinetic (PK) endpoints in this study.


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2.11
Pharmacodynamic and PK/Pharmacodynamic analyses
There are no pharmacodynamic and PK/pharmacodynamic analyses planned in this study.
2.12
Patient-reported outcomes
There are no patient-reported outcomes (PRO) analyses planned in this study.
2.13
Biomarkers
There are no biomarker analyses planned in this study.
2.14
Other exploratory analyses
There are no other exploratory analyses planned in this study.
2.15
Interim analysis
There are no interim analyses in this study.
3
Sample size calculation
No formal sample size has been calculated. All patients enrolled into CICL670F2201 who have 
completed 24 weeks treatment will be offered participation in this current protocol and those 
consenting to participate will contribute to the pool of data.
According to enrolment of CICL670F2201 in Region Europe, a maximum of 90 patients should 
be eligible for enrollment in this study. However as only three countries (Austria, Greece, and
Italy) are participating in this study which is less than originally foreseen, it is planned to enroll 
a maximum of 58 patients.
4
Change to protocol specified analyses
Due to insufficient patient numbers in the categories for the subgroups: age and main underlying 
disease, it was agreed to remove the planned age and main underlying disease subgroup 
analyses.
Within the protocol, it is stated that the Baseline serum ferritin value will be defined as the 
average of the 2 measurements obtained during the Screening period. It was clarified that this 
statement is in reference to the eligibility criteria and baseline serum ferritin should be derived 
for analysis purposes as outlined in Section 2.3.2.


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5
Appendix
5.1
Imputation rules
5.1.1
AE date imputation
5.1.1.1
AE end date
For the purpose of date imputation, the study treatment follow-up period date is defined as the 
last available visit date, i.e. including unscheduled visits after the end of study visit.
1. If the AE end date month is missing, the imputed end date should be set to the earliest of 
the (study treatment follow-up period date, 31DECYYYY, date of death).
2. If the AE end date day is missing, the imputed end date should be set to the earliest of the 
(study treatment follow-up period date, last day of the month, date of death).
3. If AE year is missing or AE is ongoing, the end date will not be imputed.
If the imputed AE end date is less than the existing AE start date then use AE start date as AE 
end date.
5.1.1.2
AE start date
AEs with completely missing onset dates will be considered to be treatment emergent.  AEs 
with partially missing onset dates will also be included as treatment emergent when the month 
(if it exists) and the year occur on or later than the month and year of first administration of 
study treatment within this study.
Partial AE start dates are imputed with reference to the first administration of study treatment 
(TRTSTD) within this study as outlined in the table below. 
The date value is split into day, month, year sections and referenced in the imputation table as 
outlined below
Day
Month
Year
Partial AE Start Date 
Not used 
MON 
YYYY
Treatment Start Date (TRTSTD) 
Not used 
TRTM
TRTY
The following matrix explains the logic behind the imputation. 
Comparison of 
month section
MON missing
MON<TRTM
MON=TRTM
MON>TRTM
YYYY missing
NC
NC
NC
NC
YYYY<TRTM
(D) =
01JULYYYY
Before Treatment
Start
(C) =
15MONYYYY
Before Treatment
Start
(C) =
15MONYYYY
Before Treatment
Start
(C) =
15MONYYYY
Before Treatment
Start
YYYY=TRTY
(B) =
TRTSTD+1
Uncertain
(C) =
15MONYYYY
Before Treatment
(A)
= TRTSTD+1
Uncertain
(A)
= 01MONYYYY
After Treatment


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Comparison of 
month section
MON missing
MON<TRTM
MON=TRTM
MON>TRTM
Start
Start
YYYY>TRTY
(E) =
01JANYYYY
After Treatment
Start
(A)
= 01MONYYYY
After Treatment
Start
(A)
= 01MONYYYY
After Treatment
Start
(A)
= 01MONYYYY
After Treatment
Start
The following table is the legend to the logic matrix.
Relationship
Before Treatment start
Partial date indicates AE start date prior to Treatment 
Start Date in this study
After Treatment start
Partial date indicates AE start date after Treatment Start 
Date in this study
Uncertain
Partial date insufficient to determine relationship of AE
start date to Treatment Start Date in this study
Imputation calculation
NC/Blank Uncertain
No convention
(A) After Treatment Start or Uncertain 
MAX( 01MONYYYY, TRTSTD+1 )
(B) Uncertain 
TRTSTD+1
(C) Before Treatment Start
15MONYYYY
(D) Before Treatment Start
01JULYYYY
(E) After Treatment Start
01JANYYYY
Before imputing the AE start date, find the AE start reference date.

If the AE end date is complete and the (imputed) AE end date < TRTSTD then AE start 
reference date = min (study informed consent date, earliest visit date).

Else AE start reference date = TRTSTD
To impute AE start date:
1. If the AE start date year value is missing, the date uncertainty is too high to impute a
rational date. Therefore, if the AE year value is missing, the imputed AE start date is set
to NULL.
2. If the AE start date year value is less than the study treatment start date year value, the AE 
started before study treatment. Therefore:
a. If AE month is missing, the imputed AE start date is set to the mid-year point 
(01JULYYYY).
b. Else if AE month is not missing, the imputed AE start date is set to the mid-month point 
(15MONYYYY). 
3. If the AE start date year value is greater than the study treatment start date year value, the 
AE started after study treatment. Therefore:


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a. If the AE month is missing, the imputed AE start date is set to the year start point 
(01JANYYYY).
b. Else if the AE month is not missing, the imputed AE start date is set to the later of 
(month start point (01MONYYYY), AE start reference date + 1 day).
4. If the AE start date year value is equal to the study treatment start date year value:
a. And the AE month is missing the imputed AE start date is set to the AE reference start 
date + 1 day.
b. Else if the AE month is less than the study treatment start month, the imputed AE start 
date is set to the mid-month point (15MONYYYY).
c. Else if the AE month is equal to the study treatment start date month or greater than the 
study treatment start date month, the imputed AE start date is set to the later of (month 
start point (01MONYYYY), AE start reference date + 1 day).
If complete (imputed) AE end date is available and the imputed AE start date is greater than the 
(imputed) AE end date, then imputed AE start date should be set to the (imputed) AE end date.
5.1.2
Concomitant medication date imputation
5.1.2.1
Concomitant medication end date
To impute concomitant end date:
1. If the concomitant end date year value is missing, the date uncertainty is too high to impute 
a rational date. Therefore, if the concomitant end year value is missing or ongoing, the 
imputed concomitant end date is set to NULL.
2. Else, if the concomitant end date month is missing, the imputed end date should be set to 
the earliest of the (study treatment follow-up period date, 31DECYYYY, date of death).
3. If the concomitant end date day is missing, the imputed end date should be set to the earliest 
of the (study treatment follow-up period date, last day of the month, date of death).
If the imputed concomitant end date is less than the existing concomitant start date, use the 
concomitant start date as the imputed concomitant end date.
5.1.2.2
Concomitant medication start date
Concomitant treatments with partial start dates will have the date or dates imputed. Partial 
concomitant treatment start dates are imputed with reference to the first administration of study 
treatment (TRTSTD) within this study in accordance with the rules outlined below.
Day
Month
Year
Partial AE Start Date 
Not used 
MON 
YYYY
Treatment Start Date (TRTSTD) 
Not used 
TRTM
TRTY
The following matrix explains the logic behind the imputation. 
Comparison of 
month section
MON missing
MON<TRTM
MON=TRTM
MON>TRTM
YYYY missing
(C)
Uncertain
(C)
Uncertain
(C)
Uncertain
(C)
Uncertain


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Comparison of 
month section
MON missing
MON<TRTM
MON=TRTM
MON>TRTM
YYYY<TRTM
(D) =
01JULYYYY
Before Treatment
Start
(A) =
15MONYYYY
Before Treatment
Start
(A) =
15MONYYYY
Before Treatment
Start
(A) =
15MONYYYY
Before Treatment
Start
YYYY=TRTY
(C)
Uncertain
(A) =
15MONYYYY
Before Treatment
Start
(C)
Uncertain
(B)
= 01MONYYYY
After Treatment
Start
YYYY>TRTY
(E) =
01JANYYYY
After Treatment
Start
(B)
= 01MONYYYY
After Treatment
Start
(B)
= 01MONYYYY
After Treatment
Start
(B)
= 01MONYYYY
After Treatment
Start
The following table is the legend to the logic matrix.
Relationship
Before Treatment start
Partial date indicates CMD start date prior to Treatment 
Start Date in this study
After Treatment start
Partial date indicates CMD start date after Treatment 
Start Date in this study
Uncertain
Partial date insufficient to determine relationship of  
CMD start date to Treatment Start Date in this study
Imputation calculation
NC/Blank Uncertain
No convention
(A) Before Treatment Start
15MONYYYY
(B) After Treatment Start
MAX( 01MONYYYY, TRTSTD+1 )
(C) Uncertain
IF CMDTYP1C IN (1, 3) THEN TRTSTD-1
ELSE IF CMDTYP1C IN (. 2) THEN TRTSTD+1
(D) Before Treatment Start
01JULYYYY
(E) After Treatment Start
01JANYYYY
To compute concomitant start date:
1. If the concomitant  start date year value is missing, the imputed concomitant start date is set 
to one day prior to study treatment start date.
2. If the concomitant start date year value is less than the study treatment start date year value, 
the concomitant medication started before study treatment. Therefore: 
a. If the concomitant month is missing, the imputed concomitant start date is set to the 
mid-year point (01JULYYYY).


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b. Else if the concomitant month is not missing, the imputed concomitant start date is set 
to the mid-month point (15MONYYYY).
3. If the concomitant start date year value is greater than the study treatment start date year 
value, the concomitant started after study treatment. Therefore: 
a. If the concomitant month is missing, the imputed concomitant start date is set to the year 
start point (01JANYYYY). 
b. Else if the concomitant month is not missing, the imputed concomitant start date is set 
to the month start point (01MONYYYY).
4. If the concomitant start date year value is equal to the study treatment start date year value:
a. And the concomitant month is missing or the concomitant month is equal to the study 
treatment start date month, then the imputed concomitant start date is set to one day 
prior to study treatment start date.
b. Else if the concomitant month is less than the study treatment start date month, the 
imputed concomitant start date is set to the mid-month point (15MONYYYY).
c. Else if the concomitant month is greater than the study treatment start date month, the 
imputed concomitant concomitant start date is set to the month start point 
(01MONYYYY).
If complete (imputed) concomitant end date is available and the imputed concomitant start date 
is greater than the (imputed) concomitant end date, then imputed concomitant start date should 
be set to the (imputed) concomitant end date. 
5.1.3
Medical history date of diagnosis imputation
Completely missing dates and partially missing end dates will not be imputed. Partial dates of 
diagnosis will be compared to the treatment start date.

If DIAG year < study treatment start date year and DIAG month is missing, the imputed 
DIAG date is set to the mid-year point (01JULYYYY)

Else if DIAG month is not missing, the imputed DIAG date is set to the mid-month point 
(15MONYYYY)

If DIAG year = study treatment start date year and (DIAG month is missing OR DIAG 
month is equal to study treatment start month), the imputed DIAG date is set to one day 
before study treatment start date
5.1.4
Other imputations
5.1.4.1
Age
The age of patients with a completely missing date of birth will be set to missing. If a patient’s 
date of birth is partially missing then

If the year is missing then the age will be set to missing

Else if the month is missing then the day will be set to 01 and the month will be set to July

Else if the day is missing then the day will be set to 15.


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If a patient has a partially missing date of birth and an imputed age of 17 years then this will be 
set at 18 years. However, if the imputed age were 16 years then the imputed age will remain at 
16 years.
5.1.4.2
Dose interruptions, dose delays, and dose changes
This section provides additional details to those included in Section 2.5.1.
Dose interruption
A dose interruption will be indicated in the eCRF by a dosing record with an actual total daily 
dose of 0 mg for one or more days. In order not to over count interruptions, dosing records with 
0 mg entered as last dosing record will not be counted as interruptions. Those represent the 
reason for permanent discontinuation and will therefore be presented in the reason for treatment 
discontinuation analysis.
Dose reduction
A reduction is defined as a decrease from the previous non-zero dose. For example, in the 
sequence of planned dose (mg/kg/day) 25-0-15, the 15 mg/kg/day dose will be counted as a 
reduction. The planned zero dose is also counted as a dose reduction record. The reduction will 
be determined using the eCRF ‘planned dose’. If the planned dose is reduced as described above, 
a reduction will be counted.
5.2
Statistical models
Clopper Pearson CI
CL  =  Confidence level for limits in %  (i.e. 95) 
F   =  Frequency (i.e. number of successes)
N   =  Number of patients 
&pl. =  Lower CL              
&pu. =  Upper CL             
%macro exactcl(cl,f,n,pl,pu);
  _P=&F./&N.;     _PCT=100*_P;
  Z=PROBIT(1-(100-&CL.)/200);
  XX2=FINV((100-&CL.)/200,2*&F.,2*(&N.-&F.+1),0);
  XX3=FINV((100+&CL.)/200,2*(&F.+1),2*(&N.-&F.),0);
  IF _P=0   THEN &pl.=0;
            ELSE &pl.=100*&F.*XX2/(&N.-&F.+1+&F.*XX2);
  IF _P=1   THEN &pu.=100;
            ELSE &pu.=100*(&F.+1)*XX3/(&N.-&F.+(&F.+1)*XX3);
%mend exactcl;


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5.3
Rule of exclusion criteria of analysis sets 
Table 5-1
Protocol deviation categories used
PD Category
PD Code
Eligibility
E
Discontinuation of treatment/ study
D
Prohibited Concomitant Medication
M
Study drug (incorrect dose, wrong treatment)
S
Other
O
The full list of PDs are defined in the data review plan (DRP) which is located in the 
document management system in the following folder:

‘CREDI Projects/I/ICL670A/CREDI Studies/ICL670AIC04/Administrative Files (study 
level)/Validation and Planning documents’
Table 5-2
Patient classification
Analysis Set
PD ID that
   
cause patients to be excluded
Non-PD criteria that cause 
patients to be excluded
FAS
I03
Not enrolled
SAF
I03, D05
Not in FAS;
No study drug taken during the study;
Not having at least one post-baseline safety 
assessment on or after Visit 3 (Day 1)
6
References
Cheng WJ et al (2018) Adherence to iron chelation therapy in patients who switched from 
deferasirox dispersible tablets to deferasirox film-coated tablets. Current Medical Research and 
Opinion; DOI: 10.1080/03007995.2018.1470500
Schwartz GJ, Brion LP, Spitzer A (1987) The use of plasma creatinine concentration for 
estimating glomerular filtration rate in infants, children, and adolescents. Pediatr Clin North 
Am; 34(3):571-90.